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TOXICOLOGICAL PROFILE FOR
CHLORINE
U.S. DEPARTMENT OF HEALTH AND HUMAN SERVICES
Public Health Service
Agency for Toxic Substances and Disease Registry
November 2010
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DISCLAIMER
The use of company or product name(s) is for identification only and does not imply endorsement by the
Agency for Toxic Substances and Disease Registry.
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UPDATE STATEMENT
A Toxicological Profile for Chlorine, Draft for Public Comment was released in October 2007. This
edition supersedes any previously released draft or final profile.
Toxicological profiles are revised and republished as necessary. For information regarding the update
status of previously released profiles, contact ATSDR at:
Division of Toxicology and Environmental Medicine/Applied Toxicology Branch
1600 Clifton Road NE
Mailstop F-62
Atlanta, Georgia 30333
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FOREWORD
This toxicological profile is prepared in accordance with guidelines* developed by the Agency for Toxic
Substances and Disease Registry (ATSDR) and the Environmental Protection Agency (EPA). The
original guidelines were published in the Federal Register on April 17, 1987. Each profile will be revised
and republished as necessary.
The ATSDR toxicological profile succinctly characterizes the toxicologic and adverse health effects
information for these toxic substances described therein. Each peer-reviewed profile identifies and
reviews the key literature that describes a substance's toxicologic properties. Other pertinent literature is
also presented, but is described in less detail than the key studies. The profile is not intended to be an
exhaustive document; however, more comprehensive sources of specialty information are referenced.
The focus of the profiles is on health and toxicologic information; therefore, each toxicological profile
begins with a public health statement that describes, in nontechnical language, a substance's relevant
toxicological properties. Following the public health statement is information concerning levels of
significant human exposure and, where known, significant health effects. The adequacy of information to
determine a substance's health effects is described in a health effects summary. Data needs that are of
significance to protection of public health are identified by ATSDR.
Each profile includes the following:
(A) The examination, summary, and interpretation of available toxicologic information and
epidemiologic evaluations on a toxic substance to ascertain the levels of significant human
exposure for the substance and the associated acute, subacute, and chronic health effects;
(B) A determination of whether adequate information on the health effects of each substance
is available or in the process of development to determine levels of exposure that present a
significant risk to human health of acute, subacute, and chronic health effects; and
(C) Where appropriate, identification of toxicologic testing needed to identify the types or
levels of exposure that may present significant risk of adverse health effects in humans.
The principal audiences for the toxicological profiles are health professionals at the Federal, State, and
local levels; interested private sector organizations and groups; and members of the public.
This profile reflects ATSDR’s assessment of all relevant toxicologic testing and information that has been
peer-reviewed. Staffs of the Centers for Disease Control and Prevention and other Federal scientists have
also reviewed the profile. In addition, this profile has been peer-reviewed by a nongovernmental panel
and was made available for public review. Final responsibility for the contents and views expressed in
this toxicological profile resides with ATSDR.
Thomas R. Frieden, M.D., M.P.H.
Administrator
Agency for Toxic Substances and
Disease Registry
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*Legislative Background
The toxicological profiles are developed under the Comprehensive Environmental Response,
Compensation, and Liability Act of 1980, as amended (CERCLA or Superfund). CERCLA section
104(i)(1) directs the Administrator of ATSDR to “…effectuate and implement the health related
authorities” of the statute. This includes the preparation of toxicological profiles for hazardous
substances most commonly found at facilities on the CERCLA National Priorities List and that pose the
most significant potential threat to human health, as determined by ATSDR and the EPA. Section
104(i)(3) of CERCLA, as amended, directs the Administrator of ATSDR to prepare a toxicological profile
for each substance on the list. In addition, ATSDR has the authority to prepare toxicological profiles for
substances not found at sites on the National Priorities List, in an effort to “…establish and maintain
inventory of literature, research, and studies on the health effects of toxic substances” under CERCLA
Section 104(i)(1)(B), to respond to requests for consultation under section 104(i)(4), and as otherwise
necessary to support the site-specific response actions conducted by ATSDR.
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QUICK REFERENCE FOR HEALTH CARE PROVIDERS

Toxicological Profiles are a unique compilation of toxicological information on a given hazardous
substance. Each profile reflects a comprehensive and extensive evaluation, summary, and interpretation
of available toxicologic and epidemiologic information on a substance. Health care providers treating
patients potentially exposed to hazardous substances will find the following information helpful for fast
answers to often-asked questions.
Primary Chapters/Sections of Interest
Chapter 1: Public Health Statement: The Public Health Statement can be a useful tool for educating
patients about possible exposure to a hazardous substance. It explains a substance’s relevant
toxicologic properties in a nontechnical, question-and-answer format, and it includes a review of
the general health effects observed following exposure.
Chapter 2: Relevance to Public Health: The Relevance to Public Health Section evaluates, interprets,
and assesses the significance of toxicity data to human health.
Chapter 3: Health Effects: Specific health effects of a given hazardous compound are reported by type
of health effect (death, systemic, immunologic, reproductive), by route of exposure, and by length
of exposure (acute, intermediate, and chronic). In addition, both human and animal studies are
reported in this section.
NOTE: Not all health effects reported in this section are necessarily observed in the clinical
setting. Please refer to the Public Health Statement to identify general health effects observed
following exposure.
Pediatrics: Four new sections have been added to each Toxicological Profile to address child health
issues:
Section 1.6 How Can (Chemical X) Affect Children?
Section 1.7 How Can Families Reduce the Risk of Exposure to (Chemical X)?
Section 3.7 Children’s Susceptibility
Section 6.6 Exposures of Children
Other Sections of Interest:

Section 3.8 Biomarkers of Exposure and Effect
Section 3.11 Methods for Reducing Toxic Effects
ATSDR Information Center

Phone: 1-800-CDC-INFO (800-232-4636) or 1-888-232-6348 (TTY) Fax: (770) 488-4178
E-mail: cdcinfo@cdc.gov Internet: http://www.atsdr.cdc.gov
The following additional material can be ordered through the ATSDR Information Center:
Case Studies in Environmental Medicine: Taking an Exposure History—The importance of taking an

exposure history and how to conduct one are described, and an example of a thorough exposure
history is provided. Other case studies of interest include Reproductive and Developmental
Hazards; Skin Lesions and Environmental Exposures; Cholinesterase-Inhibiting Pesticide
Toxicity; and numerous chemical-specific case studies.
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Managing Hazardous Materials Incidents is a three-volume set of recommendations for on-scene

(prehospital) and hospital medical management of patients exposed during a hazardous materials
incident. Volumes I and II are planning guides to assist first responders and hospital emergency
department personnel in planning for incidents that involve hazardous materials. Volume III—
Medical Management Guidelines for Acute Chemical Exposures—is a guide for health care
professionals treating patients exposed to hazardous materials.
Fact Sheets (ToxFAQs) provide answers to frequently asked questions about toxic substances.
Other Agencies and Organizations
The National Center for Environmental Health (NCEH) focuses on preventing or controlling disease,
injury, and disability related to the interactions between people and their environment outside the
workplace. Contact: NCEH, Mailstop F-29, 4770 Buford Highway, NE, Atlanta,
GA 30341-3724 • Phone: 770-488-7000 • FAX: 770-488-7015.
The National Institute for Occupational Safety and Health (NIOSH) conducts research on occupational
diseases and injuries, responds to requests for assistance by investigating problems of health and
safety in the workplace, recommends standards to the Occupational Safety and Health
Administration (OSHA) and the Mine Safety and Health Administration (MSHA), and trains
professionals in occupational safety and health. Contact: NIOSH, 200 Independence Avenue,
SW, Washington, DC 20201 • Phone: 800-356-4674 or NIOSH Technical Information Branch,
Robert A. Taft Laboratory, Mailstop C-19, 4676 Columbia Parkway, Cincinnati, OH 45226-1998
• Phone: 800-35-NIOSH.
The National Institute of Environmental Health Sciences (NIEHS) is the principal federal agency for
biomedical research on the effects of chemical, physical, and biologic environmental agents on
human health and well-being. Contact: NIEHS, PO Box 12233, 104 T.W. Alexander Drive,
Research Triangle Park, NC 27709 • Phone: 919-541-3212.
Referrals
The Association of Occupational and Environmental Clinics (AOEC) has developed a network of clinics
in the United States to provide expertise in occupational and environmental issues. Contact:
AOEC, 1010 Vermont Avenue, NW, #513, Washington, DC 20005 • Phone: 202-347-4976
• FAX: 202-347-4950 • e-mail: AOEC@AOEC.ORG • Web Page: http://www.aoec.org/.
The American College of Occupational and Environmental Medicine (ACOEM) is an association of

physicians and other health care providers specializing in the field of occupational and
environmental medicine. Contact: ACOEM, 25 Northwest Point Boulevard, Suite 700, Elk
Grove Village, IL 60007-1030 • Phone: 847-818-1800 • FAX: 847-818-9266.
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CONTRIBUTORS
CHEMICAL MANAGER(S)/AUTHOR(S):
G. Daniel Todd, Ph.D.
Patricia Ruiz, Ph.D.
Larry Cseh, R.S.
Pam Tucker, M.D.
John Doyle, M.P.A.
ATSDR, Division of Toxicology and Environmental Medicine, Atlanta, GA
Fernando T. Llados, Ph.D.
Daniel J. Plewak, B.S.
Mario Citra, Ph.D.
SRC, Inc., North Syracuse, NY
THE PROFILE HAS UNDERGONE THE FOLLOWING ATSDR INTERNAL REVIEWS:
1. Health Effects Review. The Health Effects Review Committee examines the health effects
chapter of each profile for consistency and accuracy in interpreting health effects and classifying
end points.
2. Minimal Risk Level Review. The Minimal Risk Level Workgroup considers issues relevant to
substance-specific Minimal Risk Levels (MRLs), reviews the health effects database of each
profile, and makes recommendations for derivation of MRLs.
3. Data Needs Review. The Applied Toxicology Branch reviews data needs sections to assure
consistency across profiles and adherence to instructions in the Guidance.
4. Green Border Review. Green Border review assures the consistency with ATSDR policy.
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PEER REVIEW
A peer review panel was assembled for chlorine. The panel consisted of the following members:
1. John Balmes, M.D., Professor in Residence, Department of Medicine, University of California,

San Francisco, San Francisco, California;
2. Meryl Karol, Ph.D., Professor Emeritus, Associate Dean for Academic Affairs and Research,
University of Pittsburgh, Pittsburgh, Pennsylvania; and
3. Dennis Shusterman, M.D., MPH, Professor Emeritus, Department of Medicine, University of

California, San Francisco, California.
These experts collectively have knowledge of chlorine's physical and chemical properties, toxicokinetics,
key health end points, mechanisms of action, human and animal exposure, and quantification of risk to
humans. All reviewers were selected in conformity with the conditions for peer review specified in
Section 104(I)(13) of the Comprehensive Environmental Response, Compensation, and Liability Act, as
amended.
Scientists from the Agency for Toxic Substances and Disease Registry (ATSDR) have reviewed the peer
reviewers' comments and determined which comments will be included in the profile. A listing of the
peer reviewers' comments not incorporated in the profile, with a brief explanation of the rationale for their
exclusion, exists as part of the administrative record for this compound.
The citation of the peer review panel should not be understood to imply its approval of the profile's final
content. The responsibility for the content of this profile lies with the ATSDR.
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CHLORINE xiii
CONTENTS
DISCLAIMER ..............................................................................................................................................ii
UPDATE STATEMENT .............................................................................................................................iii
FOREWORD ................................................................................................................................................ v
QUICK REFERENCE FOR HEALTH CARE PROVIDERS....................................................................vii
CONTRIBUTORS.......................................................................................................................................ix
PEER REVIEW ...........................................................................................................................................xi
CONTENTS...............................................................................................................................................xiii
LIST OF FIGURES ..................................................................................................................................xvii
LIST OF TABLES.....................................................................................................................................xix
1. PUBLIC HEALTH STATEMENT.......................................................................................................... 1
1.1 WHAT IS CHLORINE?................................................................................................................. 2
1.2 WHAT HAPPENS TO CHLORINE WHEN IT ENTERS THE ENVIRONMENT? ................... 2
1.3 HOW MIGHT I BE EXPOSED TO CHLORINE?........................................................................ 3
1.4 HOW CAN CHLORINE ENTER AND LEAVE MY BODY?..................................................... 3
1.5 HOW CAN CHLORINE AFFECT MY HEALTH?...................................................................... 4
1.6 HOW CAN CHLORINE AFFECT CHILDREN? ......................................................................... 5
1.7 HOW CAN FAMILIES REDUCE THE RISK OF EXPOSURE TO CHLORINE? ..................... 5
1.8 IS THERE A MEDICAL TEST TO DETERMINE WHETHER I HAVE BEEN EXPOSED
TO CHLORINE?............................................................................................................................ 6
1.9 WHAT RECOMMENDATIONS HAS THE FEDERAL GOVERNMENT MADE TO
PROTECT HUMAN HEALTH? ................................................................................................... 6
1.10 WHERE CAN I GET MORE INFORMATION? .......................................................................... 7
2. RELEVANCE TO PUBLIC HEALTH ................................................................................................... 9
2.1 BACKGROUND AND ENVIRONMENTAL EXPOSURES TO CHLORINE IN THE
UNITED STATES ......................................................................................................................... 9
2.2 SUMMARY OF HEALTH EFFECTS......................................................................................... 10
2.3 MINIMAL RISK LEVELS (MRLs) ............................................................................................ 14
3. HEALTH EFFECTS.............................................................................................................................. 25
3.1 INTRODUCTION........................................................................................................................ 25
3.2 DISCUSSION OF HEALTH EFFECTS BY ROUTE OF EXPOSURE ..................................... 25
3.2.1 Inhalation Exposure .............................................................................................................. 26
3.2.1.1 Death.............................................................................................................................. 26
3.2.1.2 Systemic Effects............................................................................................................. 46
3.2.1.3 Immunological and Lymphoreticular Effects ................................................................ 70
3.2.1.4 Neurological Effects ...................................................................................................... 71
3.2.1.5 Reproductive Effects...................................................................................................... 73
3.2.1.6 Developmental Effects................................................................................................... 73
3.2.1.7 Cancer ............................................................................................................................ 74
3.2.2 Oral Exposure........................................................................................................................ 75
3.2.2.1 Death.............................................................................................................................. 75
3.2.2.2 Systemic Effects............................................................................................................. 76
3.2.2.3 Immunological and Lymphoreticular Effects ................................................................ 96
3.2.2.4 Neurological Effects ...................................................................................................... 97
3.2.2.5 Reproductive Effects...................................................................................................... 97
3.2.2.6 Developmental Effects................................................................................................... 98
3.2.2.7 Cancer ............................................................................................................................ 98
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3.2.3 Dermal Exposure................................................................................................................. 100
3.2.3.1 Death............................................................................................................................ 100
3.2.3.2 Systemic Effects........................................................................................................... 100
3.2.3.3 Immunological and Lymphoreticular Effects .............................................................. 104
3.2.3.4 Neurological Effects .................................................................................................... 104
3.2.3.5 Reproductive Effects.................................................................................................... 104
3.2.3.6 Developmental Effects................................................................................................. 104
3.2.3.7 Cancer .......................................................................................................................... 104
3.3 GENOTOXICITY ...................................................................................................................... 105
3.4 TOXICOKINETICS................................................................................................................... 107
3.4.1 Absorption........................................................................................................................... 107
3.4.1.1 Inhalation Exposure ..................................................................................................... 107
3.4.1.2 Oral Exposure .............................................................................................................. 109
3.4.1.3 Dermal Exposure ......................................................................................................... 109
3.4.2 Distribution ......................................................................................................................... 109
3.4.2.2 Oral Exposure .............................................................................................................. 109
3.4.2.3 Dermal Exposure ......................................................................................................... 110
3.4.3 Metabolism.......................................................................................................................... 110
3.4.4 Elimination and Excretion................................................................................................... 110
3.4.4.2 Oral Exposure .............................................................................................................. 110
3.4.4.3 Dermal Exposure ......................................................................................................... 111
3.4.5 Physiologically Based Pharmacokinetic (PBPK)/Pharmacodynamic (PD) Models ........... 111
3.5 MECHANISMS OF ACTION ................................................................................................... 112
3.5.1 Pharmacokinetic Mechanisms............................................................................................. 112
3.5.2 Mechanisms of Toxicity...................................................................................................... 114
3.5.3 Animal-to-Human Extrapolations ....................................................................................... 115
3.6 TOXICITIES MEDIATED THROUGH THE NEUROENDOCRINE AXIS ........................... 115
3.7 CHILDREN’S SUSCEPTIBILITY............................................................................................ 117
3.8 BIOMARKERS OF EXPOSURE AND EFFECT ..................................................................... 120
3.8.1 Biomarkers Used to Identify or Quantify Exposure to Chlorine......................................... 121
3.8.2 Biomarkers Used to Characterize Effects Caused by Chlorine........................................... 122
3.9 INTERACTIONS WITH OTHER CHEMICALS ..................................................................... 122
3.10 POPULATIONS THAT ARE UNUSUALLY SUSCEPTIBLE ............................................ 122
3.11 METHODS FOR REDUCING TOXIC EFFECTS................................................................ 124
3.11.1 Reducing Peak Absorption Following Exposure............................................................. 124
3.11.2 Reducing Body Burden ................................................................................................... 125
3.11.3 Interfering with the Mechanism of Action for Toxic Effects .......................................... 125
3.12 ADEQUACY OF THE DATABASE..................................................................................... 126
3.12.1 Existing Information on Health Effects of Chlorine........................................................ 126
3.12.2 Identification of Data Needs............................................................................................ 130
3.12.3 Ongoing Studies .............................................................................................................. 139
4. CHEMICAL AND PHYSICAL INFORMATION.............................................................................. 143
4.1 CHEMICAL IDENTITY............................................................................................................ 143
4.2 PHYSICAL AND CHEMICAL PROPERTIES......................................................................... 143
5. PRODUCTION, IMPORT/EXPORT, USE, AND DISPOSAL .......................................................... 151
5.1 PRODUCTION .......................................................................................................................... 151
5.2 IMPORT/EXPORT .................................................................................................................... 152
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5.3 USE ............................................................................................................................................ 152
5.4 DISPOSAL ................................................................................................................................. 158
6. POTENTIAL FOR HUMAN EXPOSURE ......................................................................................... 159
6.1 OVERVIEW............................................................................................................................... 159
6.2 RELEASES TO THE ENVIRONMENT ................................................................................... 160
6.2.1 Air ....................................................................................................................................... 160
6.2.2 Water ................................................................................................................................... 163
6.2.3 Soil ...................................................................................................................................... 164
6.3 ENVIRONMENTAL FATE ...................................................................................................... 164
6.3.1 Transport and Partitioning................................................................................................... 164
6.3.2 Transformation and Degradation ........................................................................................ 165
6.3.2.1 Air ................................................................................................................................ 165
6.3.2.2 Water............................................................................................................................ 166
6.3.2.3 Sediment and Soil ........................................................................................................ 167
6.3.2.4 Other Media ................................................................................................................. 167
6.4 LEVELS MONITORED OR ESTIMATED IN THE ENVIRONMENT .................................. 167
6.4.1 Air ....................................................................................................................................... 168
6.4.2 Water ................................................................................................................................... 168
6.4.3 Sediment and Soil ............................................................................................................... 168
6.4.4 Other Environmental Media................................................................................................ 168
6.5 GENERAL POPULATION AND OCCUPATIONAL EXPOSURE ........................................ 169
6.6 EXPOSURES OF CHILDREN.................................................................................................. 170
6.7 POPULATIONS WITH POTENTIALLY HIGH EXPOSURES .............................................. 170
6.8 ADEQUACY OF THE DATABASE ........................................................................................ 171
6.8.1 Identification of Data Needs ............................................................................................... 172
6.8.2 Ongoing Studies .................................................................................................................. 174
7. ANALYTICAL METHODS................................................................................................................ 177
7.1 BIOLOGICAL MATERIALS.................................................................................................... 177
7.2 ENVIRONMENTAL SAMPLES .............................................................................................. 177
7.3 ADEQUACY OF THE DATABASE ........................................................................................ 179
7.3.1 Identification of Data Needs ............................................................................................... 182
7.3.2 Ongoing Studies .................................................................................................................. 183
8. REGULATIONS, ADVISORIES, AND GUIDELINES..................................................................... 185
9. REFERENCES .................................................................................................................................... 191
10. GLOSSARY ...................................................................................................................................... 213
APPENDICES
A. ATSDR MINIMAL RISK LEVELS AND WORKSHEETS ............................................................. A-1
B. USER’S GUIDE.................................................................................................................................. B-1
C. ACRONYMS, ABBREVIATIONS, AND SYMBOLS...................................................................... C-1
D. INDEX ................................................................................................................................................ D-1
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LIST OF FIGURES
3-1. Levels of Significant Exposure to Chlorine – Inhalation ................................................................... 42
3-2. Levels of Significant Exposure to Hypochlorite Solution – Oral ....................................................... 88
3-3. Conceptual Representation of a Physiologically Based Pharmacokinetic (PBPK) Model for a
Hypothetical Chemical Substance.................................................................................................... 113
3-4. Existing Information on Health Effects of Chlorine Gas ................................................................. 127
3-5. Existing Information on Health Effects of Hypochlorite Solution ................................................... 128
4-1. Speciation of Cl2, HOCl, and OCl- as a Function of pH................................................................... 148
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LIST OF TABLES
3-1. Levels of Significant Exposure to Chlorine – Inhalation ................................................................... 30
3-2. Acute Effects of Chlorine Exposure on the Respiratory Tract of Humans......................................... 47
3-3. Levels of Significant Exposure to Hypochlorite Solution – Oral ....................................................... 77
3-4. Levels of Significant Exposure to Hypochlorous Acid and/or Sodium Hypochlorite
Chlorine - Dermal............................................................................................................................. 101
3-5. Genotoxicity of Sodium Hypochlorite In Vivo................................................................................. 106
3-6. Genotoxicity of Sodium Hypochlorite In Vitro ................................................................................ 108
4-1. Chemical Identity of Chlorine .......................................................................................................... 144
4-2. Commonly Used Terms Related to Chlorinated Water .................................................................... 145
4-3. Physical and Chemical Properties of Chlorine ................................................................................. 146
5-1. Companies that Produce Chlorine in the United States and Annual Capacities for 2006 ................ 153
5-2. Facilities that Produce, Process, or Use Chlorine............................................................................. 155
5-3. U.S. Chlorine Imports and Exports by Year in Metric Tons ............................................................ 157
6-1. Releases to the Environment from Facilities that Produce, Process, or Use Chlorine ..................... 161
6-2. Ongoing Studies Regarding the Potential for Human Exposure to Chlorine ................................... 175
7-1. Analytical Methods for Determining Chlorine in Environmental Samples...................................... 180
8-1. Regulations, Advisories, and Guidelines Applicable to Chlorine and Chlorine Compounds .......... 187
CHLORINE xx

CHLORINE 1
1. PUBLIC HEALTH STATEMENT
This public health statement tells you about chlorine and the effects of exposure to it.
The Environmental Protection Agency (EPA) identifies the most serious hazardous waste sites in the
nation. These sites are then placed on the National Priorities List (NPL) and are targeted for long-term
federal clean-up activities. Chlorine gas is too reactive to be detected in environmental media at
hazardous waste sites. Any chlorine gas released at these sites would be quickly converted to other
substances whose primary source may or may not have been chlorine.
When a substance is released either from a large area, such as an industrial plant, or from a container,
such as a drum or bottle, it enters the environment. Such a release does not always lead to exposure. You
can be exposed to a substance only when you come in contact with it. You may be exposed by breathing,
eating, or drinking the substance, or by skin contact. Since chlorine is highly reactive, you are unlikely to
be exposed directly to it unless there has been a large scale accidental release in the nearby vicinity.
If you are exposed to chlorine, many factors will determine whether you will be harmed. These factors
include the dose (how much), the duration (how long), and how you come in contact with it. You must
also consider any other chemicals you are exposed to and your age, sex, diet, family traits, lifestyle, and
state of health.
The subject of this profile is molecular chlorine (Cl2), which exists as a gas under normal environmental
conditions or as a liquid when stored under pressure. Although molecular chlorine is used in some water
disinfection processes, the resulting solution, commonly referred to as chlorinated water, does not actually
contain molecular chlorine. Therefore, water disinfection and the chemicals present in chlorinated water,
such as hypochlorite, are not the main focus of this document and are only discussed where relevant.
CHLORINE 2
1.1 WHAT IS CHLORINE?
Chlorine is a gas It is very unstable and quickly reacts with many substances to form other
with a very chemicals.
irritating odor
Used in Chlorine is an extremely important industrial chemical that is used in the

manufacturing production of thousands of products.
and water
disinfection It is also used for water disinfection, although the chlorine itself is quickly
transformed into other chemicals at the beginning of the process.
Chlorine gas is A common misconception is that molecular chlorine (Cl2) is present in

not present in chlorinated water. During water chlorination, molecular chlorine gas may be
chlorinated water added to the water at first; however, the chlorine is quickly transformed into
other chemicals, which actually disinfect the water. Hypochlorous acid and
hypochlorite anion are two of these chemicals that disinfect the water.
The terms “free chlorine” and “aqueous chlorine” in drinking water usually
refer to the amount of hypochlorous acid and hypochlorite in the water. It is
important to recognize that these compounds are different from molecular
chlorine.
Bleach is not One of the important products that chlorine is used to make is bleach, and
chlorine people sometimes confuse chlorine with bleach. Bleach contains a
compound called sodium hypochlorite. If you mix acidic chemicals with
bleach, chlorine can be formed and given off as a gas.
For more information on the sources, properties, and uses of chlorine, see Chapters 4 and 5.
1.2 WHAT HAPPENS TO CHLORINE WHEN IT ENTERS THE ENVIRONMENT?
Chlorine is very Chlorine is very unstable, and reacts with a variety of chemicals and water
unstable in the when it is released into the environment.
environment
Rapidly broken
down
• Air Chlorine is broken down by sunlight within a matter of several minutes.
• Water Chlorine dissolves in water and is converted into chloride and hypochlorous
acid.
Chlorine can If chlorine is spilled into water or onto soil or if it is released from a tank into
travel from its the air, the chlorine will evaporate very quickly forming a greenish-yellow
source cloud that can be carried by the wind from the source.
For more information on chlorine in the environment, see Chapter 6.

CHLORINE 3
1.3 HOW MIGHT I BE EXPOSED TO CHLORINE?
Most people are Because chlorine is so reactive, it is not normally detected in the
not expected to environment except for very low levels in the air above seawater.
be exposed to
chlorine
Accidental You may be exposed through breathing, skin contact, and eye contact if an
exposure to accident involving chlorine takes place nearby, such as a liquid chlorine spill,
chlorine a leak from a chlorine tank, or a leak from a facility that produces or uses
chlorine.
You may also be exposed to chlorine if you mix household chemicals such
as toilet cleaner with bleach.
Hypochlorous acid is used to treat swimming pool water. You may be

exposed to chlorine gas through the improper use of swimming pool
chemicals.
Workplace air People who work in places where chlorine is made or used may be exposed
to low levels over a period of time.
People may be exposed to high levels if a large amount of chlorine is

released during an accident.
For more information on human exposure to chlorine, see Chapter 6.
1.4 HOW CAN CHLORINE ENTER AND LEAVE MY BODY?
Chlorine gas Chlorine gas can enter your body through your nose or your mouth.
enters your body
only when you At low concentrations (less than 10 ppm), almost all of the chlorine is
breathe it in. removed from the air in the upper part of the respiratory airways and only a
very small amount may reach your lungs.
If you drink hypochlorite solution, it may react with the acids in your
stomach and possibly form chlorine gas.
Immediately Chlorine gas reacts with the water in the cells located in the surface of the
reacts with other respiratory airways and forms other compounds that produce irritation of the
chemicals airways.
Most of these compounds eventually are transformed into chloride ions,

which are normal components of the body.
For more information on how chlorine enters and leaves the body, see Chapter 3.
CHLORINE 4
1.5 HOW CAN CHLORINE AFFECT MY HEALTH?
This section looks at studies concerning potential health effects in animal and human studies.
The effect of chlorine on human health depends on how much chlorine is present, how you are exposed to
it, and the length of exposure.
Short-term The following effects have been observed in humans briefly exposed to
exposure to chlorine:
chlorine in air • mild nose irritation at 1–3 ppm
• eye irritation at 5 ppm
• throat irritation at 5–15 ppm
• immediate chest pain, vomiting, changes in breathing rate, and
cough at 30 ppm
• lung injury (toxic pneumonitis) and pulmonary edema (fluid in the
lungs) at 40–60 ppm
• death after 30 minute exposure to 430 ppm
• death after a few minute exposure to 1,000 ppm
The concentrations listed above are approximate; the effects will depend
also on exposure duration. In general, people who suffer from respiratory
conditions such as allergies or hay fever, or who are heavy smokers, tend to
experience more severe effects than healthy subjects or nonsmokers.
Long-term No significant harmful health effects were observed in workers exposed for
exposure to years to relatively low concentrations of chlorine (around 1 ppm).
chlorine in air
The tissues inside the nose were principally affected in animals exposed to
chlorine for longer durations.
Short-term Drinking small amounts of hypochlorite solution (less than a cup) can
exposure to produce irritation of the esophagus. Drinking concentrated hypochlorite
hypochlorite solution can produce severe damage to the upper digestive tract and even
solution by death. These effects are most likely caused by the caustic nature of the
ingestion hypochlorite solution and not from exposure to molecular chlorine.
Long-term There is no information on long-term ingestion of hypochlorite solution in

exposure to humans. Animals that drank hypochlorite solution in water for up to 2 years
hypochlorite did not show any significant health effects. The amount of hypochlorite
solution by solution in the water that the animals drank was much smaller than what is
ingestion found in household bleach.
Skin exposure to Spilling hypochlorite solution on the skin can produce irritation. The severity
hypochlorite of the effects depends on the concentration of sodium hypochlorite in the
solution bleach.
Further information on the health effects of chlorine in humans and animals can be found in Chapters 2
and 3.
CHLORINE 5
1.6 HOW CAN CHLORINE AFFECT CHILDREN?
This section discusses potential health effects in humans from exposures during the period from
conception to maturity at 18 years of age.
Children are likely Short-term exposures (minutes) to high concentrations of chlorine affect
to have similar children in the same manner they affect adults (i.e., mucous membrane and
effects as adults, respiratory tract irritation). We do not know what the effects could be in
but may be more children following longer-term (weeks or longer), low-level exposure to
sensitive than chlorine gas, but this type of exposure occurs only in workers and is not
adults relevant to children. We also do not know what the effects could be in
children following longer-term, low-level exposure to hypochlorite solution.
Birth defects We do not know whether exposure to chlorine gas during pregnancy can
result in damage to unborn babies because there are no studies of pregnant
women or pregnant animals exposed to chlorine gas.
One study of rats exposed to hypochlorite solution during pregnancy found

no evidence of birth defects or any other developmental alteration in the
baby rats. The amount of chlorine that the rats consumed was many times
higher than what people are normally exposed to through drinking water.
1.7 HOW CAN FAMILIES REDUCE THE RISK OF EXPOSURE TO CHLORINE?
Do not mix bleach Chlorine gas can be released to the air when bleach is mixed with other
with household cleaning solutions that contain an acid like some toilet cleaners. Mixing
cleaners bleach with ammonia also produces very hazardous gases, such as
chloramines.
Store household Always store household chemicals in their original labeled containers out of
chemicals out of reach of young children to prevent accidental poisonings. Never store
reach of young household chemicals in containers children would find attractive to eat or
children drink from, such as old soda bottles.
Follow Chlorine gas can also be released to the air when chemicals used to
instructions for chlorinate swimming pools are mishandled. If you have a swimming pool at
swimming pool home, read the labels of the chlorination products carefully and do not let
disinfection children play with these products.
CHLORINE 6
1.8 IS THERE A MEDICAL TEST TO DETERMINE WHETHER I HAVE BEEN EXPOSED TO

CHLORINE?
There are no There are no medical tests to determine whether you have been exposed
medical tests specifically to chlorine.
available for
chlorine Chlorine is transformed in the body into chloride ions, which are normal
components of the body. An enormous amount of chlorine has to be
inhaled or ingested in order to detect a significant increase in chloride ions
in the blood. This has occurred in a few cases of ingestion of large amounts
of hypochlorite solution and one of them was a fatal case.
1.9 WHAT RECOMMENDATIONS HAS THE FEDERAL GOVERNMENT MADE TO

PROTECT HUMAN HEALTH?
The federal government develops regulations and recommendations to protect public health. Regulations
can be enforced by law. The EPA, the Occupational Safety and Health Administration (OSHA), and the
Food and Drug Administration (FDA) are some federal agencies that develop regulations for toxic
substances. Recommendations provide valuable guidelines to protect public health, but cannot be
enforced by law. The Agency for Toxic Substances and Disease Registry (ATSDR) and the National
Institute for Occupational Safety and Health (NIOSH) are two federal organizations that develop
recommendations for toxic substances.
Regulations and recommendations can be expressed as “not-to-exceed” levels, that is, levels of a toxic
substance in air, water, soil, or food that do not exceed a critical value that is usually based on levels that
affect animals; they are then adjusted to levels that will help protect humans. Sometimes these not-to-
exceed levels differ among federal organizations because they used different exposure times (an 8-hour
workday or a 24-hour day), different animal studies, or other factors.
Recommendations and regulations are also updated periodically as more information becomes available.
For the most current information, check with the federal agency or organization that provides it.
CHLORINE 7
Some regulations and recommendations for chlorine include the following:
Levels in air set EPA established an environmental air limit of 0.5 ppm. Exposure to higher
by EPA levels could result in discomfort and irritation. Dependent on the
concentration, these effects may be reversible when exposure ends.
Levels in OSHA set a legal limit of 1 ppm chlorine in air as a ceiling limit. At no time
workplace air set should a worker’s exposure exceed this limit.
by OSHA
Levels in drinking EPA established a maximum contaminant level (MCL) and maximum
water set by EPA residual disinfectant level (MRDL) of 4 mg/L for free chlorine in drinking
water.
1.10 WHERE CAN I GET MORE INFORMATION?
If you have any more questions or concerns, please contact your community or state health or
environmental quality department, or contact ATSDR at the address and phone number below.
ATSDR can also tell you the location of occupational and environmental health clinics. These clinics
specialize in recognizing, evaluating, and treating illnesses that result from exposure to hazardous
substances.
Toxicological profiles are also available on-line at www.atsdr.cdc.gov and on CD-ROM. You may
request a copy of the ATSDR ToxProfilesTM CD-ROM by calling the toll-free information and technical
assistance number at 1-800-CDCINFO (1-800-232-4636), by e-mail at cdcinfo@cdc.gov, or by writing
to:
Division of Toxicology and Environmental Medicine
1600 Clifton Road NE
Mailstop F-62
Atlanta, GA 30333
Fax: 1-770-488-4178
CHLORINE 8
Organizations for-profit may request copies of final Toxicological Profiles from the following:
National Technical Information Service (NTIS)

5285 Port Royal Road
Springfield, VA 22161
Phone: 1-800-553-6847 or 1-703-605-6000
Web site: http://www.ntis.gov/
CHLORINE 9
2. RELEVANCE TO PUBLIC HEALTH
2.1 BACKGROUND AND ENVIRONMENTAL EXPOSURES TO CHLORINE IN THE

UNITED STATES
Chlorine is a greenish-yellow gas with a pungent, irritating odor. It is stored and transported as a liquid
under pressure. Chlorine is transported as either a liquid or a gas through pipelines within chemical plants
or over distances of several kilometers. When chlorine is released into the environment, it reacts with
both organic and inorganic substances that it comes into contact with. When chlorine gas is released into
water, such as during water chlorination, it quickly dissolves in the water and then disproportionates
within seconds to form chloride and hypochlorous acid. Chlorine may be released into the environment
from facilities where it is produced or used, or during accidents, such as a chlorine tank rupture or a liquid
chlorine spill. Most of the chlorine released during these types of incidents is expected to volatilize into
the air forming a greenish-yellow chlorine gas cloud. Because chlorine is approximately 2.5 times
heavier than air, the chlorine cloud remains near the ground. This cloud can be carried away from the site
of release by the wind. Chlorine undergoes direct photolysis in the air and its half-life in the troposphere
is on the order of several minutes.
Because it is so reactive, chlorine gas is normally not detected in the environment except at low levels in
seawater aerosols. Therefore, background exposure of the general population to chlorine is not expected
to represent a health concern. Human biomonitoring data are not available for chlorine. Analyzing
human biological tissue and fluids for chlorine is not relevant because >95% of the chlorine that is
inhaled (over a 1–5 ppm range) is removed in the upper respiratory tract and eventually joins the chloride
pool in the body. The amount of chlorine that would need to be inhaled to induce a significant increase in
extracellular chloride in the body is probably a lethal amount.
There are two primary means by which the general population may be exposed to chlorine. Individuals
located near an accidental release of chlorine, either from a manufacturing facility or the transportation of
liquefied chlorine may be exposed to high levels of this gas through inhalation and dermal contact if the
cloud travels in their direction. In addition, people who mix acidic solutions with hypochlorite solutions,
such as bleach or certain types of swimming pool chemicals, may accidentally be exposed to chlorine gas.
Children may be exposed to chlorine through the same routes that affect adults, except for occupational
exposures. Occupational exposure to low levels of chlorine gas in air may occur for individuals who
work at facilities that produce or use chlorine. These individuals may also be exposed to high chlorine
concentrations if an accidental release occurs inside the facility.
CHLORINE 10
Exposure to chlorine through drinking water is expected to be very low. Free chlorine in drinking water
is defined as the sum of dissolved chlorine gas, hypochlorous acid, and hypochlorite anion. As discussed
in Chapters 4 and 6, the level of dissolved chlorine in water is extremely low, except under acidic
conditions; therefore, the term free chlorine in public water systems typically refers to the concentration
of hypochlorous acid and hypochlorite anion. The term total chlorine as it pertains to water sanitation
practices usually refers to the amount of free chlorine plus chloroamines (sometimes called combined
chlorines) produced during the sanitation process. It is important to recognize that these compounds are
different from molecular chlorine even though the terminology is often used interchangeably.
2.2 SUMMARY OF HEALTH EFFECTS
Chlorine Gas. The principal targets of exposure to chlorine gas are the respiratory airways and the eyes.
Exposure can occur only by direct contact of inhaled chlorine gas with the respiratory epithelium or via
direct contact of the eyes with the gas. The skin seems to be a less sensitive target to direct contact with
chlorine gas possibly because it lacks the moisture of mucous membranes. The effects of acute-duration
exposures to high concentrations of chlorine have been known for almost a century, starting with its use
as a chemical weapon at Ypres, Belgium, during World War I. Additional information regarding the
effects of brief high-level exposures to chlorine has been collected from accidental exposures following
leaks during transport of tanks containing liquid chlorine, leaks from storage tanks, domestic accidents
involving bleach solutions, mishandling of chemicals used at swimming pools, and even accidents in high
school science experiments. These and many additional studies, including studies in volunteers exposed
to controlled concentrations of chlorine, indicate that exposures to 1–3 ppm produce mild irritation of the
nose that can be tolerated for about 1 hour; 5 ppm may produce eye irritation; headache and throat
irritation may occur at concentrations of 5–15 ppm; 30 ppm produces immediate chest pain, nausea and
vomiting, dyspnea, and cough; 40–60 ppm produces toxic pneumonitis and pulmonary edema; 430 ppm
usually causes death in 30 minutes, and 1,000 ppm is fatal within a few minutes. In most cases, death is
the result of pulmonary edema. Accidental releases of chlorine have affected adults and children, and a
few reports suggested that children might be more susceptible than adults to the effects of chlorine. This
may be due to the smaller diameter of the airways of children compared to adults.
The effects of exposure to chlorine seem to depend, at least above a certain minimal exposure
concentration, on the duration of exposure and exposure concentration, and the moisture content of the
surface contacted by the gas (i.e., the respiratory epithelium). Exposures to relatively low concentrations
CHLORINE 11
of chlorine (<5 ppm) are not expected to affect deep lung structures since most of the inhaled chlorine
(>95%) is scrubbed in the upper portion of the respiratory tract, whether breathing is through the nose or
through the mouth. With the exception of cough, substernal pain, and respiratory distress, the symptoms
occurring after exposure to moderate concentrations of chlorine generally subside within 24 hours.
Edema, observed following high exposures, is caused by marked alveolar capillary congestion followed
immediately by focal and confluent area of fluid with a high content of fibrinogen. Pulmonary edema
peaks in 12–24 hours and the resulting hypoxia further increases capillary permeability, which creates a
vicious cycle. Initially, the pulmonary fluid is interstitial, but if it overwhelms the capacity of the
lymphatic system to drain it, the alveoli become filled. A further complication is the formation of hyaline
membranes from the alveolar fluid with high-fibrinogen content, which along with developing areas of
atelectasis (collapse), and right to left shunting of blood, explains the poor oxygen diffusion with resultant
hypoxemia and later hypercapnea. Subjects surviving the acute phase of exposure to high concentrations
of chlorine may still be in danger of delayed death due to bronchial pneumonia or pneumonia. The
complications of chlorine inhalation fit the histological condition known as diffuse alveolar damage that
is associated with the clinical condition known as the adult respiratory distress syndrome.
Not all of the signs and symptoms exhibited by subjects exposed to moderate to high concentrations of
chlorine gas are caused directly by chlorine. In general, it is believed that effects such as nausea and
vomiting are reflex in origin, and headache and loss of consciousness are probably due to the hypoxia
caused by pulmonary edema. Leukocytosis is almost always found in subjects admitted to emergency
departments following exposure to high chlorine gas and is most likely a general response to
inflammation. Anxiety and changes in blood pressure and heart rate also are commonly mentioned in
case reports. While cardiovascular alterations can be due in part to a ventilation perfusion mismatch, they
may also represent a general response to the stress and anxiety of having been involved in a chemical
accident and being admitted to a health facility.
Prolonged exposures to relatively low concentrations of chlorine in occupational settings have not given
indications of respiratory or other health problems among the workers, but additional better-controlled
studies are necessary to add confidence to these early findings. Workers occasionally experience brief
episodes of high exposure (“gassing” incidents), in some cases to concentrations high enough to warrant a
visit to the emergency room. In some of these cases and also in some cases of high exposure of the
general population, long-term follow-up has shown persistent respiratory alterations that included airway
obstruction and reactive airway dysfunction syndrome (RADS). RADS is defined as an asthma-like
illness after a single acute exposure to a respiratory irritant in otherwise healthy individuals, characterized
CHLORINE 12
by increased responsiveness to methacholine challenge. There are many factors that can play a role in
whether residual effects will be present, including exposure level and duration of exposure, medical
treatment following exposure, length of the follow-up, underlying respiratory disease, and smoking status.
A series of reports by Kilburn suggested that acute exposure to high concentrations of chlorine produced
long-term neurobehavioral effects (i.e., memory loss, slow reaction time, impaired balance, hearing loss,
visual alterations). No other study of chlorine-exposed subjects has included neurobehavioral testing, but
this could potentially be examined in animal models. It is not known whether exposure to chlorine gas
can affect reproduction or development in humans. Only one early study reported that pregnancy
outcome was not affected among female workers at a chlorine plant. There is also no relevant
information regarding effects of chlorine exposure on the immune system. A few studies of workers in
the chemical industry did not find any evidence that chlorine gas is carcinogenic. The EPA, the
International Agency for Research on Cancer (IARC), and the Department of Health and Human Services
(DHHS) have not classified chlorine gas as to its carcinogenicity.
The respiratory system is also the target of chlorine toxicity in animals. Animals exposed briefly to high
concentrations of chlorine gas have shown respiratory effects similar to those observed in humans, with
the added observations of severe gross and microscopic changes in the respiratory airways. Chlorine, in
relatively low concentrations (1–3 ppm), also induced histological alterations in the respiratory tract,
particularly the upper portion, in intermediate- and chronic-duration inhalation studies in animals. In
these studies, there was no indication that chlorine exposure affects reproductive parameters. No studies
are available that evaluated whether chlorine affects immunocompetence or the development of young
organisms. Chlorine gas was not carcinogenic in rats and mice exposed to up to 2.5 ppm for 2 years.
Hypochlorite Solutions. At very low pH (<2), it is theoretically possible that chlorine gas can be formed;
therefore, exposures to hypochlorite solutions are briefly discussed even though, under normal pH, the
predominant species are expected to be hypochlorous acid and hypochlorite (for a detailed discussion and
definitions of terms related to the chemistry of chlorine in water, please see Chapter 4). The principal
targets of exposure to hypochlorite solutions are the upper gastrointestinal tract and the skin. Exposure to
hypochlorite can occur via accidental or intentional ingestion of chlorine bleach or via direct contact of
the skin with hypochlorite solutions. In most cases, ingestion of small amounts (less than a cup) of
sodium hypochlorite bleach (approximately 5.25% sodium hypochlorite, 52,250 ppm, or 52,250 mg/L)
(ppm in water = mg/L) can produce esophageal irritation without permanent consequences. However,
fatalities due to ingestion of sodium hypochlorite have been reported. In a reported case, an autopsy of a
CHLORINE 13
woman who drank an unknown amount of bleach revealed esophageal and gastric mucosal erosions,
perforations at the gastroesophageal junction, and extensive necrosis of adjacent soft tissue. Aspiration of
hypochlorite bleach into the lungs following ingestion of bleach also has been reported as a cause of
death. The lethal dose of sodium hypochlorite in adults has been reported to be approximately 200 mL of
a solution containing 3–6% chlorine. No significant additional toxicities have been reported in humans
following oral exposure to hypochlorite. Two intermediate-duration studies in which volunteers were
exposed to known amounts of chlorine in water provided no evidence of adverse effects. In one of them,
consumption of water containing 5 mg/L chlorine (approximately 0.036 mg Cl/kg/day) had no significant
effect on hematology, serum chemistry, urinalysis, or additional physiological parameters. Another study
of limited scope showed that consumption of water containing 20 ppm chlorine (approximately 0.4 mg
Cl/kg/day) had no significant effect on serum lipids or serum levels of thyroid hormones. It is not known
whether oral exposure to chlorine can affect the immune and nervous systems, or reproduction or
development in humans. There are no studies of cancer in humans exposed to chlorine itself. Based on
inadequate evidence for carcinogenicity of hypochlorite salts in animals and no data from studies in
humans, a study determined that hypochlorite salts are not classifiable as to their carcinogenicity in
humans.
Direct contact of the skin with household chlorine bleach can cause skin irritation in humans. Although
sodium hypochlorite generally is not considered a contact sensitizer, several cases of allergic contact
dermatitis have been reported. Commercial household bleaches are prepared with sodium hydroxide and
are typically very alkaline; it is this property that may result in the irritant contact dermatitis. The limited
information regarding ocular effects of direct contact of the eye with hypochlorite solutions suggest that
splashes in the eye with house solutions of sodium hypochlorite rarely result in serious consequences.
For the most part, the results of oral and dermal studies of chlorine in animals support the observations in
humans. Studies in which hypochlorite bleach was placed in the esophagus of animals reproduced the
observations following high exposure in humans. Additional intermediate- and chronic-duration studies
that examined hematology and clinical chemistry parameters and conducted gross and microscopic
examination of tissues from rats and mice following exposure to chlorinated water provided little
evidence of chlorine-related toxicity. In the intermediate-duration studies, Sprague-Dawley rats,
F344 rats, and B6C3F1 mice were dosed for 90 days with up to 24.9, 85, and 39.2 mg Cl/kg/day,
respectively. In the chronic-duration studies, rats were exposed for 2 years to up to 14.4 mg Cl/kg/day
and mice to up 24.2 mg Cl/kg/day. Studies in animals have provided no evidence that exposure to
hypochlorite ions adversely affects the immune or nervous system, although an 8-week study in rats
CHLORINE 14
reported alterations in some immune parameters of unknown toxicological significance (reduced delayed-
type hypersensitivity reaction, increased prostaglandin E2 synthesis by macrophages, and reduced
oxidative metabolism by macrophages following stimulation with phorbol myristate acetate). Exposure
of male and female rats to hypochlorite before and during breeding and of the females during gestation
and lactation did not cause reproductive effects in either sex or adverse developmental effects in the
offspring. Cancer bioassays in rats and mice have been negative except for equivocal evidence of
increased incidence of leukemia in female F344 rats in one study’s bioassay. It should be mentioned,
however, that one study considered the overall evidence only weakly supportive of an association
between the occurrence of mononuclear cell leukemia and the consumption of chlorinated water based on
the following: (1) the increase in leukemia was slight and not clearly dose-related, (2) there was no
decrease in tumor latency, and (3) the incidence in concurrent controls was less than in historical controls.
A limited number of studies of in vivo genotoxicity of hypochlorite ion provided negative results.
2.3 MINIMAL RISK LEVELS (MRLs)
Estimates of exposure levels posing minimal risk to humans (MRLs) have been made for chlorine. An
MRL is defined as an estimate of daily human exposure to a substance that is likely to be without an
appreciable risk of adverse effects (noncarcinogenic) over a specified duration of exposure. MRLs are
derived when reliable and sufficient data exist to identify the target organ(s) of effect or the most sensitive
health effect(s) for a specific duration within a given route of exposure. MRLs are based on
noncancerous health effects only and do not consider carcinogenic effects. MRLs can be derived for
acute, intermediate, and chronic duration exposures for inhalation and oral routes. Appropriate
methodology does not exist to develop MRLs for dermal exposure.
Although methods have been established to derive these levels (Barnes and Dourson 1988; EPA 1990a),
uncertainties are associated with these techniques. Furthermore, ATSDR acknowledges additional
uncertainties inherent in the application of the procedures to derive less than lifetime MRLs. As an
example, acute inhalation MRLs may not be protective for health effects that are delayed in development
or are acquired following repeated acute insults, such as hypersensitivity reactions, asthma, or chronic
bronchitis. As these kinds of health effects data become available and methods to assess levels of
significant human exposure improve, these MRLs will be revised.
CHLORINE 15
Inhalation MRLs
• An MRL of 0.06 ppm has been derived for acute-duration inhalation exposure (14 days or less) to
chlorine gas.
The effects of acute-exposure of humans and animals to chlorine have been well characterized (see
Sections 2.2 and 3.2.1.2). Chlorine is a sensory irritant (substance capable of eliciting sensory irritation)
and the most sensitive target for chlorine toxicity in humans and in animals is the respiratory system.
Information that could be used for quantitative risk assessment regarding effects from acute exposure of
humans to chlorine is available from studies of volunteers exposed to chlorine gas for 15 minutes to
8 hours (Anglen 1981; D’Alessandro et al. 1996; Rotman et al. 1983; Schins et al. 2000; Shusterman et al.
1998, 2003b). Some of these studies, as detailed below, also included sensitive individuals. Collectively,
the results of these studies suggest that brief exposures to concentrations of chlorine ≤0.5 ppm do not
cause sensory irritation or significant alterations in pulmonary function tests, but exposure to ≥1 ppm
chlorine can induce transient respiratory and eye irritation and slight alterations in pulmonary function
tests. Evaluations of soldiers gassed during World War I provide information on the effects of acute
exposure to very high concentrations of chlorine and also on potentially persistent effects of acute
exposure (Berghoff 1919; DOA 1933; Meakins and Priestley 1919). Similar information is available in
many reports of accidental exposures to chlorine gas of workers and members of the general population
(i.e., Agabiti et al. 2001; Agency for Toxic Substances and Disease Registry 1998; Bonetto et al. 2006;
CDC 1991, 2005; Chasis et al. 1947; Chester et al. 1977; Hasan et al. 1983; Schönhofer et al. 1996;
Sexton and Pronchik 1998; Weill et al. 1969). In both the war cases and the accidental exposures to
chlorine gas, the concentrations of chlorine were generally not known. These high exposure cases have
provided data on respiratory effects and on additional signs and symptoms of intoxication with chlorine
that are not due to a direct action of chlorine, but that probably represent reflex responses and/or general
responses to inflammation and stress that were caused by products of chlorine’s reaction with bodily
fluids. Some of these responses include nausea, vomiting, headache, anxiety, alterations in blood
pressure, and leukocytosis.
The acute-duration database in animals is extensive, and includes a great number of studies conducted
after the use of chlorine as a chemical weapon during World War I (for review, see DOA [1933] and
Withers and Lees [1985b]). Most of the early studies provide information regarding lethal concentrations
of chlorine as well as descriptions of the pathology of the respiratory tract caused by exposure to
relatively high concentrations of chlorine. Although qualitatively informative, the early data do not meet
current guidelines for use in quantitative risk assessment. More recent studies in animals, mainly rodents,
CHLORINE 16
have confirmed the earlier findings regarding sensory irritation and pathological changes in the
respiratory tract (Barrow and Smith 1975; Buckley et al. 1984; Demnati et al. 1995; Jiang et al. 1983;
Leustik et al. 2008; Tian et al. 2008; Yildirim et al. 2004). In general, morphological alterations in the
nasal mucosa of rats and mice occurred with chlorine concentrations >5 ppm. Specific lowest-observed-
adverse-effect levels (LOAELs) for sensory irritation in rodents are not available. However, in response
to exposure to irritant substances, a reflex mechanism allows rodents to decrease the respiratory rate as a
protective response (Alarie 1973). The concentration of the irritant that induces a 50% decrease in
respiratory rate has been termed RD50 and is commonly used to compare the irritant potencies of
chemicals. This reflex reaction has also been demonstrated in humans, dogs, and cats (Alarie 1973).
Acute-duration inhalation studies provided very little information regarding end points other than those
involving the respiratory system. Body weight loss, which is due to reduced food consumption, was
reported in some studies (Dodd et al. 1980; Jiang et al. 1983).
Evaluation of the acute-duration inhalation database summarized above indicates that sensory irritation
and pulmonary function in humans are the most sensitive end points for exposure to chlorine and will
serve as the basis for derivation of an acute-duration inhalation MRL for chlorine. These findings were
reported in a group of studies that can serve as co-principal studies (Anglen 1981; D’Alessandro et al.
1996; Rotman et al. 1983; Schins et al. 2000; Shusterman et al. 1998, 2003b). A detailed description of
these studies is provided in Appendix A.
Collectively, this group of studies provides evidence of sensory irritation and transient pulmonary
changes occurring in humans exposed to 1 ppm chlorine for up to 8 hours/day. The pulmonary changes
indicated increased airway resistance and reduced air flow. No such changes were reported in volunteers
exposed to 0.5 ppm chlorine (0.4 ppm in the D’Alessandro et al. [1996]) study. The longest exposure
duration was 8 hours (Anglen 1981; Rotman et al. 1983). These studies also included sensitive
individuals: an atopic subject in the study by Rotman et al. (1983), subjects showing methacholine
hyperresponsiveness in the study by D’Alessandro et al. (1996), and subjects exhibiting seasonal allergic
rhinitis (Shusterman et al. 1998). Also of significance is the fact that Rotman et al. (1983) reported that
exposure to 1 ppm for 8 hours induced greater changes in pulmonary function tests than exposure to the
same concentration for 4 hours, suggesting that the response was related to duration in addition to
concentration. Given this information, an acute-duration inhalation MRL for chlorine can be derived by
duration adjustment of the no-observed-adverse-effect level (NOAEL) of 0.5 ppm for continuous
exposure (0.5 ppm x 8 hours/24 hours = 0.167 ppm) (8 hours was the longest period of exposure for
which there is information). Although sensitive individuals were tested in some of these studies, the
CHLORINE 17
number of individuals tested at the region of the NOAEL (0.4–0.5 ppm) was small. Therefore, an
uncertainty factor of 3 is used to account for sensitive populations. The resulting acute-duration
inhalation MRL for chlorine is 0.06 ppm (0.167 ppm/3).
• An MRL of 0.002 ppm has been derived for intermediate-duration inhalation exposure (15–
364 days to chlorine gas.
No human studies were available that could serve as the basis for derivation of an intermediate-duration
inhalation MRL. The animal database for intermediate-duration exposure to chlorine is limited to two
studies. In one study, male and female F344 rats were exposed to 0, 1, 3, or 9 ppm chlorine 6 hours/day,
5 days/week for 6 weeks (Barrow et al. 1979). In the other study, male and female F344 rats were
exposed to 0, 0.5, 1.5, or 5 ppm chlorine 6 hours/day, 5 days/week for 62 days (Kutzman 1983). Aside
from a reduction in final body weight of approximately 11% relative to controls in female rats exposed to
0.5 ppm chlorine (most likely due to reduced food consumption) in the Kutzman (1983) study, the most
sensitive target for chlorine exposure was the respiratory tract. Barrow et al. (1979) described
inflammation of the nasal turbinates in rats exposed to ≥1 ppm chlorine, whereas loss of cilia and
epithelium in the trachea was seen in rats exposed to ≥0.5 ppm in the Kutzman (1983) study. No
NOAELs for respiratory effects were established in either study. Since incidences of animals with
respiratory lesions were presented in the Kutzman (1983) study, but not in the Barrow et al. (1979) study,
the Kutzman (1983) study was selected as the principal study for derivation of an intermediate-duration
inhalation MRL for chlorine (more complete descriptions of the end points evaluated and the reported
results in these studies can be found in Section 3.2 and Appendix A).
There were no significant exposure-related increases in the incidences of animals with histological lesions
in any of the examined tissues with the exception of a loss of cilia in the trachea (Kutzman 1983). The
incidences of slight to moderate loss of tracheal cilia were 1/23, 12/23, 4/23, and 13/23 in the 0, 0.5, 1.5,
and 5 ppm exposure groups, respectively. Although the incidence for this lesion in the mid-exposure
group was not significantly different from the control incidence, a statistically significant (p=0.0055)
Cochran-Armitage trend test for these data can be demonstrated. However, when attempts were made to
apply dose-response models to the data, no adequate fits of EPA Benchmark Dose Software (BMDS)
models to the data were obtained (p-values for chi-square goodness of fit statistics were <0.1). Thus, the
LOAEL of 0.5 ppm was used as the point of departure for deriving an intermediate-duration inhalation
MRL for chlorine, after it was converted to a human equivalent concentration (HEC) using the EPA
cross-species dosimetric methodology (EPA 1994a) for a category 1 gas, as follows:
CHLORINE 18
LOAEL[HEC] = LOAEL[ADJ] x RGDRTB
where:
LOAEL[ADJ] = 0.5 ppm x 6/24 hours x 5/7 days = 0.09 ppm and
RGDRTB = ratio of the regional gas dose in rats to that of humans for the tracheobronchial region
RGDRTB = (VE/SATB)A / (VE/SATB)H
where:
VE = minute volume (0.137 L/minute for rats, 13.8 L/minute for humans [EPA 1994a]) and
SATB = surface area of the tracheobronchial region (22.5 cm2 for rats and 3,200 cm2 for humans
[EPA 1994a])
LOAEL[HEC] = 0.09 ppm x (0.137 L/minute/22.5 cm2) / (13.8 L/minute/3,200 cm2) = 0.14 ppm
Applying an uncertainty factor of 90 (3 for extrapolation from animals to humans with dosimetric
adjustment, 3 for the use of a minimal LOAEL, and 10 for human variability) to the LOAEL[HEC] yields
an intermediate-duration inhalation MRL of 0.002 ppm for chlorine.
• An MRL of 0.00005 ppm has been derived for chronic-duration inhalation exposure (365 days or
more) to chlorine gas.
There is no information regarding chronic-duration exposure of the general population to chlorine

because this type of exposure occurs only in occupational settings. There are few studies of chronically-
exposed workers in which there is some documentation regarding exposure levels and in which there is no
evidence, at least explicitly mentioned in the studies, of the workers having being subjected to acute
episodes of high exposure or “gassing” incidents. One of these studies involved 600 workers from
25 plants producing chlorine subjected to an evaluation of medical and occupational histories, blood and
urine tests, pulmonary function tests, and electrocardiogram (Patil et al. 1970). Exposure data were
available for 332 workers and showed a time-weighted average (TWA) 8-hour mean of 0.15±0.29 ppm
(range, 0.006–1.42 ppm). Evaluation of the 332 workers who had exposure data showed that none of the
end points examined (those subjected to recall or measured) showed a dose-response relationship. The
mean concentration of 0.15 ppm may be considered a NOAEL for the study, but limitations such as
unclear analytical methodology, no clear definition of the case/control populations, and insufficient detail
regarding the method of analysis render the NOAEL questionable. A respiratory health assessment of
392 male pulp mill workers exposed predominantly to a mean 8-hour TWA of 0.18 ppm chlorine (other
possible exposures included, sulfur dioxide, hydrogen sulfide, and methylmercaptan, in addition to
various particulates) found that, relative to a control group, the pulp mill workers complained more
frequently of usual phlegm, wheeze without cold, and chest illness (Enarson et al. 1984). However, the
most significant finding was that a subgroup of nonsmokers (n=4) had a significantly lower fixed
CHLORINE 19
expiratory flow rate at 25–75% vital capacity (FEF25–75%) and forced expiratory volume in
1 second/forced vital capacity (FEV1/FVC) ratio than the control workers. Given the small number of
workers involved and the possibility of exposure to multiple chemicals, the validity of the 0.18 ppm as an
effect level is questionable. An additional issue to consider is that neither one of these studies seemed
adequate to detect possible mild alterations in the nasal cavity, a sensitive target of chlorine exposure in
humans and animals, as described in Sections 2.2 and 3.2.1.2. Due to the limitations mentioned above,
these long-term studies are insufficient for quantitative risk assessment.
There are only two chronic-duration inhalation studies of chlorine in animals. One is a 1-year study in
monkeys (Klonne et al. 1987) and the other is a 2-year bioassay in rats and mice (Wolf et al. 1995). Both
studies tested similar concentrations of chlorine (up to 2.3 ppm in monkeys and 2.5 ppm in rats and mice)
and evaluated multiple end points including respiratory tract histopathology, hematology, and clinical
chemistry. In both studies, the upper respiratory tract was the target for chlorine toxicity. In general,
lesions were less severe in the monkeys than in rats and mice, but extended more distally in the
respiratory tract. In rats and mice, an increased incidence of minimal to moderate alterations occurred
with the lowest exposure concentration tested, 0.4 ppm chlorine. In general, the nasal lesions were site-
specific, but the severity and/or incidence were not always concentration-dependent. Lesions observed
included respiratory and olfactory epithelial degeneration, septal fenestration, mucosal inflammation,
respiratory epithelial hyperplasia, squamous metaplasia, and goblet cell hypertrophy and hyperplasia, and
secretory metaplasia of the transitional epithelium of the lateral meatus. For the most part, monkeys
exhibited only mild concentration-related respiratory epithelial hyperplasia with focal loss of cilia over
the range of concentrations tested (0, 0.1, 0.5, and 2.3 ppm) and showed no evidence of the major nasal
lesions seen in rats and mice. These differences are probably related to species-specific respiratory-tract
airflow characteristics (Ibanes et al. 1996), which in turn, are determined by anatomical differences.
Moreover, rats and mice are obligatory nose breathers with a greater surface-area-to-volume ratio of the
upper respiratory tract than primates. Therefore, exposure of rodents and primates to equal concentrations
for equal amounts of time will likely result in greater pathological changes in the nasal area of the rodent
(Barrow et al. 1979). It appears, therefore, that primates are a better model to evaluate potential
respiratory effects in humans than rodents. For these reasons, the study in monkeys (Klonne et al. 1987)
was selected for deriving a chronic-duration inhalation MRL for chlorine.
In the principal study, male and female Rhesus monkeys (4/sex/exposure level) were exposed to 0, 0.1,
0.5, or 2.3 ppm chlorine 6 hours/day, 5 days/week for 1 year (Klonne et al. 1987). The only treatment-
related histopathological effects consisted of focal epithelial hyperplasia characterized by increased cell
CHLORINE 20
numbers and loss of cilia and goblet cells in the respiratory epithelium of the nose and trachea. The
affected areas of the nasal passages showed hypercellularity with loss of goblet cells and cilia. In some of
these areas, the nuclei showed altered polarity. Lesions were more frequent on the angular margins of the
turbinates and less frequent on the lateral wall or septum adjacent to these margins. In some cases, the
respiratory epithelial hyperplasia was associated with mild suppurative inflammatory response. Lesions
in the trachea resembled those in the nose, but were less severe and involved only a small circumferential
section of the ventral and ventrolateral trachea. The combined incidences of hyperplasia in the nasal
epithelium with loss of goblet cells and cilia, characterized as trace and mild in males and females, were
1/8, 3/8, 6/8, and 8/8 in the control, 0.1, 0.5, and 2.3 ppm exposure groups, respectively. The exposure
concentration of 0.1 ppm is considered a minimal LOAEL for nasal lesions in monkeys.
Incidence data for nasal lesions in male and female monkeys exposed to chlorine gas (Klonne et al. 1987)
were analyzed using the benchmark dose (BMD) approach for MRL derivation (further details of the
modeling are presented in Appendix A) (EPA 2008a). Models in the EPA BMDS (version 1.4.1) (i.e.,
Gamma, Logistic, Log-logistic, Multi-stage, Probit, Log-probit, Quantal linear, and Weibull) were fit to
the nasal lesion data to determine potential points of departure for the MRL. A Quantal linear model
provided the best fit to the data. From this model, the predicted exposure concentration associated with a
10% extra risk (BMC10) for nasal lesions in monkeys was 0.04 ppm; the lower 95% confidence limit on
this concentration (BMCL10) was 0.02 ppm. The monkey BMCL10 served as the point of departure for the
chronic-duration MRL, after it was converted to a HEC (BMCL10[HEC]) using the EPA cross-species
dosimetric methodology (EPA 1994a) for a category 1 gas, as follows:
BMCL10[HEC] = BMCL10[ADJ] x RGDRET
where:
BMCL10[ADJ] = 0.02 ppm x 6/24 hours x 5/7 days = 0.004 ppm and
RGDRET = ratio of the regional gas dose in rats to that of humans for the extrathoracic region
RGDRET = (VE/SAET)A / (VE/SAET)H
where:
VE = minute volume 2.1 m3/day for monkeys, calculated using the allometric equation for
monkeys in EPA (1988) assuming a body weight of 7 kg for Rhesus monkeys with nasal
cavity surface area of 62 cm2 (Gross and Morgan 1991); 20 m3/day for humans (EPA 1994a)
and
SAET = 62 cm2 surface area of the nasal cavity in Rhesus monkeys weighing 7 kg (Gross and
Morgan 1991); 200 cm2 for humans (EPA 1994a)
RGDRET = (2.1 m3/day / 62 cm2) / (20 m3/day / 200 cm2) = 0.34

CHLORINE 21
BMCL10[HEC] = 0.004 ppm x 0.34 = 0.00136 ppm
Applying an uncertainty factor of 30 (3 for extrapolation from animals to humans with dosimetric
adjustment and 10 for human variability) to the BMCL10[HEC] yields a chronic-duration inhalation MRL of
0.00005 ppm for chlorine.
For the purpose of comparison, using the NOAEL/LOAEL approach would yield a chronic-duration
inhalation MRL of 0.00007 ppm for chlorine. This results from duration-adjusting the LOAEL of
0.1 ppm (0.1 ppm x 6/24 x 5/7 = 0.02 ppm) and then multiplying the LOAEL[ADJ] by the RGDRET of
0.34 calculated above (LOAEL[HEC] = 0.02 ppm x 0.34 = 0.007 ppm). Applying an uncertainty factor of
100 (10 for extrapolation from a LOAEL to NOAEL, 3 for animal to human extrapolation using
dosimetric adjustments, and 3 for human variability) to the LOAEL[HEC] of 0.007 ppm would result in a
chronic-duration inhalation MRL of 0.00007 ppm for chlorine, which is very close to the MRL calculated
by benchmark analysis. If the LOAEL is considered a minimal LOAEL, then the composite uncertainty
factor would be 30 and the resulting MRL would be 0.0002 ppm, which is 4 times higher than the MRL
calculated by benchmark analysis.
Oral MRLs
Oral MRLs were not derived for hypochlorite solutions for the following reasons. MRLs are derived
when reliable and sufficient data exist to identify a target organ(s) of effect or the most sensitive health
effect(s) for a specific duration within a given route of exposure. Scientifically, as part of having
sufficient and reliable data, it is important to be able to see the full, or at least a significant range, of the
dose-response curve. In the case of the oral database for hypochlorite solutions, no reliable LOAEL could
be identified at levels of hypochlorite that could reasonably be encountered in the environment. It is a
matter of policy of ATSDR not to derive free-standing MRLs. A summary of the oral database is
presented below.
Earlier acute-duration studies in animals tried to reproduce the lesions to the esophagus and/or stomach
due to ingestion of bleach. In most studies, commercial hypochlorite bleach was administered through a
tube directly into the esophagus and, in some cases, the distal end of the esophagus was artificially
occluded to prolong and control the contact time between the solution and the mucosa (Hook and Lowry
1974; Landau and Saunders 1964; Strange et al. 1951; Yarington 1970). Only three acute modern studies
in animals were available. Cunningham (1980) administered 0, 8, 40, or 200 ppm Cl/kg/day (as sodium
CHLORINE 22
hypochlorite) to Wistar rats (10 females/dose group) by gavage in milk for 14 days and reported that this
treatment had no significant effect on growth or on the weight of the brain, liver, kidney, or heart. No
other end points were evaluated. In a limited scope study, Meier et al. (1985) exposed male B6C3F1 mice
(10/dose group) to 0, 1.6, 4, or 8 mg Cl/kg/day (from sodium hypochlorite or hypochlorous acid) for
5 days and reported that in mice treated with sodium hypochlorite and sacrificed 3 weeks after exposure,
there were significant increases in sperm abnormalities at 1.6, 4, and 8 mg Cl/kg/day (not clearly dose-
related), but no such increases were seen in mice sacrificed 1 or 5 weeks after exposure. In addition, no
increases in sperm abnormalities were seen in mice treated with hypochlorous acid, which the
investigators considered “somewhat surprising since hypochlorite should be converted to hypochlorous
acid in the acid pH of the stomach.” Furukawa et al. (1980) administered sodium hypochlorite in the
water to male and female F344 rats for 14 days and reported weight loss at approximately ≥36 mg
Cl/kg/day accompanied by marked reductions in water consumption. No histological evaluations were
conducted in this study.
Two human studies were located in the available intermediate-duration oral database. A study of limited
scope evaluated serum lipid profile and serum levels of thyroid hormones in volunteers who drank
1.5 L/day of distilled water containing 0 or 20 ppm chlorine (0 or 0.4 mg Cl/kg/day based on a mean body
weight of 71 kg from the study) for 4 weeks (Wones et al. 1993). No significant deviations from
normality were found. In the other study, consumption of water containing 5 mg/L chlorine
(approximately 0.036 mg Cl/kg/day) for 12 weeks by 10 volunteers had no significant effect on
hematology, serum chemistry, urinalysis, and additional physiological parameters (Lubbers et al. 1982).
Since the study did not control for non-experimental ingestion of chlorine by the volunteers, the actual
dose of chlorine cannot be estimated, but is likely to have been higher than 0.036 mg Cl/kg/day.
Few intermediate-duration studies in animals were located that examined a wide range of end points
following exposure to hypochlorite solutions chlorine. These studies showed that the main effect of
exposure to solutions of hypochlorous acid or sodium hypochlorite, particularly at the higher
concentrations levels, is a reduction of water intake that is due to taste aversion. The available
intermediate-duration oral studies evaluated systemic toxicity (body weight, tissue and organ
histopathology, hematology, clinical chemistry) (Abdel-Rahman et al. 1984; Cunningham 1980; Daniel et
al. 1990, 1991; Furukawa et al. 1980) and also provided information, albeit limited, on immunological/
lymphoreticular (organ weight and histopathology and limited immunocompetence) (Daniel et al. 1990,
1991; Exon et al. 1987), neurological (weight and histopathology of the brain and sciatic nerve) (Daniel et
al. 1990, 1991), reproductive (male and female reproductive organ weight and histopathology, fertility,
CHLORINE 23
and sperm parameters) (Carlton et al. 1986; Daniel et al. 1990, 1991), and developmental effects (fetal
viability and fetal weight in a gestation exposure study) (Carlton et al. 1986). None of the available
studies reported effects that could be attributed directly to chlorine or only reported effects that were
considered of unknown toxicological significance. LOAELs were not identified in the intermediate-
duration studies, but in one of these studies, rats exposed to 4.1 mg Cl/kg/day (the highest dose tested) for
8 weeks showed a statistically significant reduction in delayed-type hypersensitivity reaction (DTH) to
bovine serum albumin, increased prostaglandin E2 synthesis by macrophages, and reduced oxidative
metabolism (Exon et al. 1987). The toxicological significance of these findings is unknown.
The highest NOAEL identified in intermediate-duration oral studies is 76 mg Cl/kg/day for reduction in
body weight gain in rats dosed with sodium hypochlorite in the drinking water for 13 weeks (Hasegawa et
al. 1986). Doses of 152 and 305 mg Cl/kg/day were associated with reductions in final body weight of
19 and 47%, respectively, relative to controls. This study, however, has serious limitations including no
reporting of food or water consumption and lack of presentation of data on other end points. Three other
13-week studies are available. Furakawa et al. (1980) administered up to approximately 85 mg Cl/kg/day
(from sodium hypochlorite) to F344 rats for 92 days and reported significant reductions in final body
weight males at 85 and 50 mg Cl/kg/day (19 and 46%, respectively) and in females at 84 mg Cl/kg/day
(30%) relative to controls. This was accompanied by significant reductions of up to 66% in water
consumption. For the most part, clinical chemistry hematology tests were unremarkable. Gross necropsy
showed bladder abnormalities (no further description) among all groups, while microscopic examination
showed endocardial hyperplasia and fibrosis of the myocardium in males and females dosed with 84 mg
Cl/kg/day. Daniel et al. (1990) exposed male and female Sprague-Dawley rats to chlorine in the drinking
water and evaluated a number of end points including organ histopathology, hematology, and clinical
chemistry. Daniel et al. (1991) conducted a similar study in male and female B6C3F1 mice. In neither
study were there significant toxic effects that could be attributed to exposure to chlorine. However, in
both studies, water consumption was significantly decreased, particularly in the high-dose groups. In
high-dose male (16.7 mg/ Cl/kg/day) and female (24.9 mg Cl/kg/day) rats, water consumption was
reduced 36 and 38%, respectively; in high-dose male (34.4 mg Cl/kg/day) and female (39.2 mg
Cl/kg/day) mice, water intake was reduced 30 and 20%, respectively. The decrease in water intake,
which resulted in dehydration and possibly altered electrolyte balance, could explain the reductions in
weight gain and sporadic changes in hematological parameters, clinical chemistry, and organ weights
observed in both rats and mice. In the absence of effects that could be clearly attributed to chlorine
toxicity, the highest doses tested represent the NOAELs for the studies; no LOAELs were defined.
CHLORINE 24
No chronic-duration human study of exposure to hypochlorous acid or sodium hypochlorite was located;
thus, a target for long-term exposure to chlorine in humans has not been identified. Three chronic-
duration studies were available, two in rats (Hasegawa et al. 1986; NTP 1992) and one in mice (NTP
1992). In the NTP (1992) study, the only treatment-related effect was a reduction in water consumption,
particularly at the higher dose levels of chlorine, which, as generally agreed, is due to taste aversion. All
three studies evaluated a comprehensive number of end points including hematology and clinical
chemistry and tissue and organ histopathology. The highest NOAEL was 133 mg Cl/kg/day for female
rats in the Hasegawa et al. (1986) study. However, final body weight in low- and high-dose females at
termination (104 weeks) was 11 and 20% lower, respectively, than in controls. Hasegawa et al. (1986)
stated that in females, the daily water intake was “somewhat lower” (no data provided) than in the other
groups during the first year, but that this trend was not observed during the second year. In addition, the
investigators indicated that in males, water intake was comparable among groups, except during the last
20 weeks of the study, during which time water intake was consistently 10–20% higher in the
experimental groups than in the controls. The latter seems to be inconsistent with findings in other
studies that reported marked reductions in water consumption at lower chlorine concentrations (i.e.,
Daniel et al. 1990, 1991; NTP 1992). In the NTP (1992) studies, F344 rats received doses of up to
14.4 mg Cl/kg/day and B6C3F1 mice up to 24.2 mg Cl/kg/day for up to 2 years. No significant alterations
attributable to chlorine exposure were noticed in either species for a wide range of end points assessed.
CHLORINE 25
3. HEALTH EFFECTS
3.1 INTRODUCTION
The primary purpose of this chapter is to provide public health officials, physicians, toxicologists, and
other interested individuals and groups with an overall perspective on the toxicology of chlorine. It
contains descriptions and evaluations of toxicological studies and epidemiological investigations and
provides conclusions, where possible, on the relevance of toxicity and toxicokinetic data to public health.
A glossary and list of acronyms, abbreviations, and symbols can be found at the end of this profile.
3.2 DISCUSSION OF HEALTH EFFECTS BY ROUTE OF EXPOSURE
To help public health professionals and others address the needs of persons living or working near
hazardous waste sites, the information in this section is organized first by route of exposure (inhalation,
oral, and dermal) and then by health effect (death, systemic, immunological, neurological, reproductive,
developmental, genotoxic, and carcinogenic effects). These data are discussed in terms of three exposure
periods: acute (14 days or less), intermediate (15–364 days), and chronic (365 days or more).
Levels of significant exposure for each route and duration are presented in tables and illustrated in
figures. The points in the figures showing no-observed-adverse-effect levels (NOAELs) or lowest-
observed-adverse-effect levels (LOAELs) reflect the actual doses (levels of exposure) used in the studies.
LOAELs have been classified into "less serious" or "serious" effects. "Serious" effects are those that
evoke failure in a biological system and can lead to morbidity or mortality (e.g., acute respiratory distress
or death). "Less serious" effects are those that are not expected to cause significant dysfunction or death,
or those whose significance to the organism is not entirely clear. ATSDR acknowledges that a
considerable amount of judgment may be required in establishing whether an end point should be
classified as a NOAEL, "less serious" LOAEL, or "serious" LOAEL, and that in some cases, there will be
insufficient data to decide whether the effect is indicative of significant dysfunction. However, the
Agency has established guidelines and policies that are used to classify these end points. ATSDR
believes that there is sufficient merit in this approach to warrant an attempt at distinguishing between
"less serious" and "serious" effects. The distinction between "less serious" effects and "serious" effects is
considered to be important because it helps the users of the profiles to identify levels of exposure at which
major health effects start to appear. LOAELs or NOAELs should also help in determining whether or not
CHLORINE 26
3. HEALTH EFFECTS
the effects vary with dose and/or duration, and place into perspective the possible significance of these
effects to human health.
The significance of the exposure levels shown in the Levels of Significant Exposure (LSE) tables and
figures may differ depending on the user's perspective. Public health officials and others concerned with
appropriate actions to take at hazardous waste sites may want information on levels of exposure
associated with more subtle effects in humans or animals (LOAELs) or exposure levels below which no
adverse effects (NOAELs) have been observed. Estimates of levels posing minimal risk to humans
(Minimal Risk Levels or MRLs) may be of interest to health professionals and citizens alike.
A User's Guide has been provided at the end of this profile (see Appendix B). This guide should aid in
the interpretation of the tables and figures for Levels of Significant Exposure and the MRLs.
This toxicological profile discusses health effects that result from exposure to chlorine gas. However,
ATSDR feels there is a need to inform the public about the role of chlorine in the process of disinfection
of water, namely, the production of hypochlorous acid and hypochlorite ion when chlorine is introduced
in water. As a way to inform the public, ATSDR has decided to include some information regarding the
health effects of hypochlorite solutions in the Profile for chlorine. For chlorine gas, the most important
route of exposure is inhalation. For hypochlorous acid and sodium hypochlorite, the most important
routes of exposure are oral and dermal.
3.2.1 Inhalation Exposure
3.2.1.1 Death
There is extensive information regarding the lethal effects of exposure to high concentrations of chlorine.
Much of the information available is derived from the use of chlorine gas as a chemical weapon at the
battle of Ypres, Belgium, during World War I. Approximately 150 tons of chlorine released from
6,000 cylinders killed, by some accounts, 800 soldiers and incapacitated 2,500–3,000 (Joy 1997). In a
review of the effects of warfare gases, the U.S. Department of Army (DOA 1933) stated that of the total
70,752 casualties from gas poisoning in the American Expeditionary Forces, 1,843 were gassed with
chlorine. A study of 838 of these subjects revealed that 4 deaths were due to later-developing effects of
chlorine gassing. The causes of death were broncho-pneumonia, lobar pneumonia, purulent pleurisy, and
tuberculous meningitis. In an evaluation of the after effects of chlorine gassing in 700 members of the
First Canadian Division, Meakins and Priestley (1919) reported that five deaths had occurred, three
CHLORINE 27
3. HEALTH EFFECTS
apparently due to an acute pneumonic condition. One death occurred 5 months after exposure to chlorine
and, although the exact cause of death was unknown, the symptoms recorded were pain in the left chest,
dyspnea, orthopnea, and pronounced cyanosis. The concentration of chlorine to which the soldiers were
exposed during the gas attacks is unknown.
DOA (1933) summarized the pathology of chlorine exposure leading to death in 24 hours as follows: an
acute inflammation of the trachea and bronchi is followed by congestion and edema of the entire
respiratory tract. The edema and consolidation of the lungs lead to acute dilation followed by passive
congestion of the abdominal viscera. Acute death is the result of the pulmonary edema and respiratory
and cardiovascular failure. Subacute death is generally due to pulmonary infection with resulting
bronchitis and pneumonia (DOA 1933). Postmortem findings include: acute conjunctivitis, congestion of
abdominal organs (especially the liver), increased lung volume, fluid in the pleural cavity, mottled
appearance on lung surface with scattered areas of emphysema, pleural hemorrhage, perivascular edema,
and dilation of blood vessels, frothy fluid filling the trachea and bronchi, red mucous membranes, and
heart enlargement and dilated heart chambers (especially the right side) (DOA 1933).
There are also reports of deaths due to spills of chlorine gas to the environment following railroad
accidents. CDC (2005) reported that in January 2005, a train in South Carolina carrying chlorine tanker
cars collided with another train and an estimated 11,500 gallons of chlorine gas were immediately
released to the air causing the death of nine persons. The primary cause of death of those who died at the
scene was asphyxia (Van Sickle et al. 2009). Reported findings included congested lungs, pulmonary
edema, and tracheal and bronchial erythema. CDC (2005) also reported that a similar accident on
June 2004 in Texas released approximately 90,000 pounds of chlorine gas resulting in two fatalities
among residents near the site. Eight people died as a direct result of lung injury caused by exposure to
chlorine following a freight train accident in Florida in February 1978 (Jones et al. 1986). A train
accident in San Luis Potosí, Mexico, in August 1981 caused the release of an unspecified amount of
chlorine gas, which caused the death of 14 people (Costero and Falcón Escobedo 1983). An 11-month-
old infant died after liquid chlorine spilled as a result of a derailment in La Barre, Louisiana, in January
1961 (Joyner and Durel 1962). The child died hours after exposure and the cause of death presumably
was massive pulmonary edema. Joyner and Durel (1962) indicate that 7 hours after the accident, levels of
400 ppm chlorine were measured in areas 75 yards from the wreck. Citing an unpublished report, Baxter
et al. (1989) stated that the rupture of a chlorine storage vessel in Romania in 1939 caused the death of
68 people.
CHLORINE 28
3. HEALTH EFFECTS
Dixon and Drew (1968) reported the case of a worker at a factory producing chlorine who was exposed to
chlorine gas that leaked from a faulty valve for about 30 minutes and died 3–3.5 hours later; postmortem
examination showed that pulmonary edema was the prime cause of death. Adelson and Kaufman (1971)
reported the death of two healthy adults 25 and 76 hours after being exposed to chlorine gas that leaked
into their home from a nearby water filtration plant while they were sleeping. An autopsy of the earlier
death showed congested and edematous lungs whose cut surfaces released substantial amounts of water
and frothy liquid on pressure, and injected tracheobronchial mucosa. Postmortem examination of the later
death showed a similar picture of the lungs with the additional findings of swollen brain with flattening of
convolutions and subarachnoid hemorrhage. Suzuki et al. (2001) reported the case of a worker who
inhaled concentrated chlorine gas and died from pulmonary thrombosis 6 days after exposure.
Using information on lethal effects of chlorine in animals and humans from the literature, Withers and
Lees (1985a) developed probit equations to derive a revised estimate of the lethal toxicity of chlorine that
considers physical activity, particularly inhalation rate, effectiveness of medical treatment, and the form
of the lethal toxic load function. The LC50 values for a 10-minute exposure with standard level of activity
were estimated at 433, 173, and 364 ppm for the regular, vulnerable, and average population,
respectively. For a 30-minute exposure, the corresponding LC50 values were estimated at 250, 100, and
210 ppm, respectively. Prater (1990) indicates that concentrations of 400 ppm can be lethal to humans in
30 minutes and that immediate death follows inhalation of a concentration of 1,000 ppm. Concentrations
between 1,000 and 1,200 ppm for 30 minutes are lethal to humans according to a review of earlier data
from various American authors by Withers and Lees (1985b).
Even more abundant information exists regarding lethal effects of chlorine in animals. For data regarding
work beginning with World War I, the reader is referred to a review by Withers and Lees (1985b). Work
conducted at the U.S. Army’s Medical Research Laboratory of the Chemical Warfare Service cited by
DOA (1933) indicates that acute exposures to concentrations >870 ppm were usually lethal to dogs,
whereas concentrations below 656 ppm were rarely fatal. Additional studies also in dogs, also
summarized by DOA (1933), indicate that dogs that died within 24 hours of gassing showed severe injury
to the mucous membranes of the upper respiratory tract, congestion, and edema of the entire respiratory
tract including the peribronchial tissues and the sheaths of the large blood vessels. There was also acute
inflammatory reaction of the lungs that developed into pneumonia. In dogs dying 2–5 days after gassing,
the most important feature was the inflammatory process, whereas in dogs dying 5–14 days after gassing
death was due to pulmonary infection. Since the original sources were not available, these studies in dogs
are not listed in Table 3-1.
CHLORINE 29
3. HEALTH EFFECTS
Weedon et al. (1940) conducted lethality studies in unspecified strains of rats and mice. In a group of
eight rats exposed to 1,000 ppm chlorine, the first death occurred in 20 minutes and all were dead in
1.7 hours. The exposure level of 1,000 ppm was the LC50 in 53 minutes, and 250 ppm was the LC50 in
440 minutes. Rats that died immediately after exposure showed slight brain congestion; lungs distended
and hemorrhagic with cut surfaces wet and foamy; distended heart; liver congestion; distended and
hemorrhagic stomach; distended intestines; and congested kidneys. In mice, the first death occurred in
21 minutes, and all eight were dead in 50 minutes. The 1,000 ppm exposure level was a 28-minute LC50,
whereas 250 ppm was a 440-minute LC50. Mice that died immediately after exposure had slight brain
congestion; lungs partly collapsed and hemorrhagic; moderately distended heart; liver congestion;
distended and hemorrhagic stomach; slightly distended intestines, and congested kidneys.
In lethality studies conducted by Zwart and Woutersen (1988), 5,484 ppm was a 5-minute LC50 in Wistar
rats, whereas 447 ppm was a 60-minute LC50; in Swiss-Webster mice, 1,032 ppm was a 10-minute LC50
and 516 ppm was a 30-minute LC50.
In a different study in mice, a 10-minute LC50 of 302 ppm was calculated in intact mice and 131 ppm in
mice that were exposed via a cannula placed in the trachea, suggesting that the nose is an effective
scrubber of chlorine (Alarie 1981). In a study in mechanically-ventilated pigs, exposure to 140 ppm
chlorine for 10 minutes caused the death of four out of five pigs within 6 hours of exposure (Gunnarsson
et al. 1998). Death was caused by cardiovascular failure triggered by a severe mismatching of ventilation
and perfusion. Additional information on lethal concentrations of chlorine in various animal species can
be found in World Health Organization (WHO 1982).
Lethality was also reported in an intermediate-duration study in rats (10/sex/exposure level) exposed to 1,
3, or 9 ppm 6 hours/day, 5 days/week for 6 weeks (Barrow et al. 1979). Three rats from the 9 ppm
exposure level group died before day 30 and had lesions consistent with chlorine exposure (widespread
inflammation of the respiratory tract with hyperplasia and hypertrophy of epithelial cells of the respiratory
bronchioles, alveolar ducts, and alveoli). The specific times of death were not reported.
The LOAEL values for death in each species and duration category are recorded in Table 3-1 and plotted
in Figure 3-1.
Table 3-1 Levels of Significant Exposure to Chlorine - Inhalation
CHLORINE
Exposure/ LOAEL
Duration/
a Frequency Reference
Key to Species NOAEL Less Serious Serious
(Route)
Figure (Strain) System (ppm) (ppm) (ppm) Chemical Form Comments
ACUTE EXPOSURE
Death
1 Rat 1 hr Vernot et al. 1977
293 (1-hour LC50)
(Sprague- 293
Dawley)
31
2 Rat 1 min - 16 hr Weedon et al. 1940

1000 (50% killed in 53
(NS) minutes)
1000
250 (50% killed in 440

minutes)
3. HEALTH EFFECTS
250
27
3 Rat 5-60 min Zwart and Woutersen 1988

688 (30-minute LC50)
(Wistar) 688
1926 (10-minute LC50)

1926

5486

447
23
4 Mouse 10 min Alarie 1981

302 M (10-minute LC50
(Swiss- followed by 3-hour
Webster) observation period)
302
35
5 Mouse 16 hr Weedon et al. 1940

1000 (50% killed in 28
(NS) minutes)
1000
250 (50% killed in 440

minutes)
250
28
30
Table 3-1 Levels of Significant Exposure to Chlorine - Inhalation (continued)
CHLORINE
Exposure/ LOAEL
Duration/
(Route)
6 Mouse 10-30 min Zwart and Woutersen 1988

1032 (10-minute LC50)
(Swiss- 1032
Webster) 516 (30-minute LC50)

516
24
Systemic
7 Human 4-8 hr b
Resp 0.5 1 (itching and burning of
Anglen 1981
nose and throat; altered
0.5
pulmonary function)
34
Ocular 0.5 1 (eye irritation)
3. HEALTH EFFECTS
0.5 1
8 Human 1 hr D'Alessandro et al. 1996

Resp 0.4 1 (transient alterations in
pulmonary function tests)
0.4
9 Human 8 hr b
Resp 0.5 M 1 M (changes in pulmonary
Rotman et al. 1983
function tests; runny
0.5
nose; throat burning)
Ocular 0.5 M 1 M (eye irritation)

0.5 1
10 Human 3d b
Resp 0.5 M Schins et al. 2000 NOAEL is for
6 hr/d 0.5
pulmonary function.
11 Human 15 min b
Resp 0.5 Shusterman et al. 1998 NOAEL is for nasal
0.5
airway resistance and
pulmonary peak flow.
103
31
CHLORINE
Exposure/ LOAEL
Duration/
(Route)
12 Human 15 min Shusterman et al. 2003b

Resp 1 (increased nasal airway
resistance)
1
13 Rat 10 min Barrow and Steinhagen 1982

Resp 25 M (50% decrease in
(Fischer- 344) respiratory rate, RD50)
25
21
14 Rat 2-10 min Demnati et al. 1995 NOAEL and LOAEL

Resp 100 M 200 M (slight perivascular
3. HEALTH EFFECTS
(Sprague- 100
edema in the lung) are for 2-minute

Dawley) exposure and
200
evaluation 72 hours
later.
29
15 Rat 1-10 d Dodd et al. 1980

Resp 12 M (swelling of the nose and
(Fischer- 344) 5 d/wk wheezing)
6 hr/d
12
38
Ocular 12 M (swelling around the

eyes)
12
Bd Wt 12 M (approximately 20%
weight loss)
12
32
CHLORINE
Exposure/ LOAEL
Duration/
(Route)
16 Rat 1-5 d
Resp 9.1 M (erosion and ulceration of Jiang et al. 1983
(Fischer- 344) 6 hr/d olfactory epithelium)
9.1
32
Bd Wt 9.1 M (13% weight loss on day

5)
9.1
17 Rat 30 min Leustik et al. 2008

Resp 184 M (histological and
(Sprague- biochemical evidence of
Dawley) lung injury)
3. HEALTH EFFECTS
184
105
18 Rat 1-12 hr McNulty et al. 1983

Resp 2.5 M 5 M (reduced total sulfydryl
(Fischer- 344) 2.5
content in nasal
respiratory epithelium
after 6-hour exposure)
5
44
19 Rat 15 min Yildirim et al. 2004

Resp 1330 M (pulmonary edema and
(Sprague- hemorrhage)
Dawley)
1330
37
20 Mouse 10 min Barrow et al. 1977

Resp 9.3 M (50% reduction in
(Swiss- respiratory rate, RD50)
Webster)
9.3
20
33
CHLORINE
Exposure/ LOAEL
Duration/
(Route)
21 Mouse 5d Buckley et al. 1984

6 hr/d Resp 9.3 M (exfoliation, erosion,
(Swiss- ulceration, necrosis of
Webster) nasal respiratory
epithelium)
9.3
22
22 Mouse 60 min Gagnaire et al. 1994

Resp 3.5 M (50% reduction in
(Hybrid) respiratory rate, RD50)
3.5
39
3. HEALTH EFFECTS
23 Mouse 1-5 d
6 hr/d Resp 9.1 M (erosion and ulceration of Jiang et al. 1983
(Swiss- the olfactory epithelium)
Webster)
9.1
33
Bd Wt 9.1 M (21% weight loss on day

5)
9.1
24 Mouse 5 min Martin et al. 2003

Resp 100 M (flattening of pulmonary
(Hybrid) epithelium)
100
36
25 Mouse 15 min Morris et al. 2005

Resp 2.3 F (50% decrease in
(C57BL/6N) breathing frequency,
RD50)
2.3
19
26 Mouse 60 min Tian et al. 2008

Resp 221 (biochemical and
(C57BL/6N) histological evidence of
lung injury)
221
104
34
CHLORINE
Exposure/ LOAEL
Duration/
(Route)
27 Rabbit 30 min Barrow and Smith 1975

Resp 50 100 (pulmonary edema
(NS) 50
followed by emphysema)
100
26
INTERMEDIATE EXPOSURE
Death
28 Rat 6 wk
9 (death in 3/10 before day Barrow et al. 1979
(Fischer- 344) 5 d/wk 30 of exposure)
6 hr/d
9
25
Systemic
3. HEALTH EFFECTS
29 Rat 6 wk Barrow et al. 1979
Resp 1 F (inflammation of nasal 9 (erosion of nasal
(Fischer- 344) 5 d/wk turbinates) mucosal epithelium)
6 hr/d
1 9
Gastro 3 9 (focal erosion of gastric

mucosa)
3
Hemato 5 9 (increased hematocrit in

females and segmented
5
neutrophils in males)
9
Hepatic 1 3 (cytoplasmic vacuolation

of hepatocytes)
1
Renal 3 9 (slight to moderate

kidney congestion)
3
Ocular 1 3 (ocular irritation)

1 3
Bd Wt 1 3 F (15% decreased final 9 M (43% decreased final

weight) weight)
1
3 9
35
CHLORINE
Exposure/ LOAEL
Duration/
(Route)
30 Rat 62 d c
Resp 0.5 M (loss of cilia and 5 (severe upper respiratory Kutzman 1983 NOAELs are for organ
(Fischer- 344) 5 d/wk epithelium in the irritation) histopathology.
6 hr/d
trachea)
5
0.5
40
Cardio 5
5
Hepatic 5M
5
Renal 5M
5
Ocular 0.5 1.5 (occasional signs of eye 5 (severe eye irritation)
3. HEALTH EFFECTS
irritation)
0.5 5
1.5
Bd Wt 0.5 F (final weight 11% lower 5 F (weight loss; final weight

than controls) 32% lower than controls)
0.5 5
Immuno/ Lymphoret
31 Rat 62 d Kutzman 1983 NOAEL is for
5
(Fischer- 344) 5 d/wk 5
histopathology of
6 hr/d spleen and
peribronchial lymph
nodes.
41
Neurological
32 Rat 62 d Kutzman 1983 NOAEL is for
5
histopathology of the
6 hr/d brain.
42
Reproductive
33 Rat 62 d Kutzman 1983 NOAEL is for fertility in
5
males and females and
6 hr/d sperm morphology.
43
36
CHLORINE
Exposure/ LOAEL
Duration/
(Route)
CHRONIC EXPOSURE
Systemic
34 Monkey 1 yr d
Resp 0.1 F (minimal nasal epithelial Klonne et al. 1987 NOAELs are for organ
(Rhesus) 5 d/wk histopathology.
6 hr/d hyperplasia)
0.1
Cardio 2.3
2.3
Gastro 2.3
2.3
Hemato 2.3
2.3
Musc/skel 2.3
2.3
Hepatic 2.3
3. HEALTH EFFECTS
2.3
Renal 2.3
2.3
Endocr 2.3
2.3
Dermal 2.3
2.3
Ocular 0.5 2.3 (conjunctival irritation)

0.5 2.3
Bd Wt 2.3
2.3
37
CHLORINE
Exposure/ LOAEL
Duration/
(Route)
35 Rat M: 2 yr, 5 d/wk, Wolf et al. 1995 NOAELs are for gross
Resp 0.4 (alterations of minimal
(Fischer- 344) 6 hr/d severity in nasal and microscopic
F: 2 yr, 3 d/wk, pathology of organs
6 hr/d epithelium)
and tissues.
0.4
11
Cardio 2.5
2.5
Gastro 2.5
2.5
Hemato 2.5
2.5
Musc/skel 2.5
3. HEALTH EFFECTS
2.5
Hepatic 2.5
2.5
Renal 2.5
2.5
Endocr 2.5
2.5
Dermal 2.5
2.5
Ocular 2.5
2.5
Bd Wt 2.5
2.5
38
CHLORINE
Exposure/ LOAEL
Duration/
(Route)
36 Mouse 2 yr Wolf et al. 1995 NOAELs are for gross

5 d/wk Resp 0.4 (minimal to moderate
(B6C3F1) alterations in the nasal and microscopic
6 hr/d pathology of organs
epithelium)
and tissues.
0.4
15
Cardio 2.5
2.5
Gastro 2.5
2.5
Hemato 2.5
2.5
Musc/skel 2.5
3. HEALTH EFFECTS
2.5
Hepatic 2.5
2.5
Renal 2.5
2.5
Endocr 2.5
2.5
Dermal 2.5
2.5
Ocular 2.5
2.5
Bd Wt 2.5
2.5
Immuno/ Lymphoret
37 Monkey 1 yr Klonne et al. 1987 NOAEL is for
5 d/wk 2.3
(Rhesus) 2.3
histopathology of lymph
6 hr/d nodes and spleen.
6
38 Rat M: 2 yr, 5 d/wk, Wolf et al. 1995 NOAEL is for gross and
2.5
(Fischer- 344) 6 hr/d 2.5
microscopic pathology
F: 2 yr, 3 d/wk, of lymphoreticular
6 hr/d tissues.
12
39
CHLORINE
Exposure/ LOAEL
Duration/
(Route)

5 d/wk 2.5
(B6C3F1) 2.5
and microscopic
6 hr/d pathology of
immunoreticular organs
and tissues.
16
Neurological
5 d/wk 2.3
(Rhesus) 2.3
histopathology of
6 hr/d central and peripheral
components of the
nervous system.
3. HEALTH EFFECTS
8
2.5
F: 2 yr, 3 d/wk, of central and
6 hr/d peripheral components
of the nervous system.
13

5 d/wk 2.5
(B6C3F1) 2.5
and microscopic
6 hr/d pathology of the brain,
spinal, and sciatic
nerve.
17
Reproductive
5 d/wk 2.3
(Rhesus) 2.3
histopathology of
6 hr/d reproductive organs
and tissues.
7
40
CHLORINE
Exposure/ LOAEL
Duration/
(Route)
2.5
F: 2 yr, 3 d/wk, of reproductive organs.
6 hr/d
14
a The number corresponds to entries in Figure 3-1.
b Used to derive an acute-duration inhalation minimal risk level (MRL) of 0.06 ppm; the MRL was derived by adjusting the NOAEL of 0.5 ppm for continuous exposure (0.5 ppm x
8/24) and dividing by an uncertainty factor of 3 to account for human variability.
c Used to derive an intermediate-duration MRL of 0.002 ppm; the MRL was derived by dividing the LOAEL[HEC] of 0.14 ppm by an uncertainty factor of 90 (3 for extrapolation from
animals to humans with dosimetric adjustment, 3 for use of a minimal LOAEL, and 10 for human variability).
3. HEALTH EFFECTS
d Used to derive a chronic-duration inhalation MRL of 0.00005 ppm; the MRL was derived by dividing the BMCL10[HEC] of 0.00136 ppm by an uncertainty factor of 30 (3 for
extrapolation from animals to humans with dosimetric adjustment and 10 for human variability).
Bd Wt = body weight; Cardio = cardiovascular; d = day(s); Endocr = endocrine; F = Female; Gastro = gastrointestinal; Hemato = hematological; hr = hour(s); Immuno/Lymphoret =
immunological/lymphoreticular; LC50 = lethal concentration, 50% kill, LOAEL = lowest-observed-adverse-effect level; M = male; min = minute(s); Musc/skel = musculoskeletal;
NOAEL = no-observed-adverse-effect level; NS = not specified; occup = occupational; ppm = parts per million; RD50 = 50% decrease in respiration rate; Resp = respiratory; wk =
week(s); yr = year(s)
41
Figure 3-1 Levels of Significant Exposure to Chlorine - Inhalation

Acute (≤14 days)

CHLORINE
Systemic
ry ht
to eig
ira r W
ath sp ula dy
De Re Oc Bo
ppm
10000
3r
3r
19r
1000 5m 6m 2r
3r
6m 3r
4m 1r
5m 2r 26m 14r 17r

3. HEALTH EFFECTS
100
24m 14r 27h
27h
13r
15r 15r 15r

10 20m 21m 23m 16r 23m 16r
18r
22m
25m 18r

1
7 8 9 12 7 9
7 9 10 11 7 9
8
0.1
0.01
c-Cat -Humans f-Ferret n-Mink Cancer Effect Level-Animals Cancer Effect Level-Humans LD50/LC50
d-Dog k-Monkey j-Pigeon o-Other LOAEL, More Serious-Animals LOAEL, More Serious-Humans Minimal Risk Level
42
r-Rat m-Mouse e-Gerbil LOAEL, Less Serious-Animals LOAEL, Less Serious-Humans for effects
p-Pig h-Rabbit s-Hamster NOAEL - Animals NOAEL - Humans other than
q-Cow a-Sheep g-Guinea Pig Cancer
Figure 3-1 Levels of Significant Exposure to Chlorine - Inhalation (Continued)
Intermediate (15-364 days)

CHLORINE
Systemic

r
lar na
l
al p ho
u ti gic
t
ym al e
ry sc tes igh gic tiv
ato va in tolo c e o/L lo duc
ath spir r dio str
o
ma pati nal ula
r
dyW mu
n
uro p ro
De Re Ca Ga He He Re Oc Bo Im Ne Re
ppm

10
28r 29r 29r 29r 29r 29r
30r 30r 29r 30r 30r 30r 30r 31r 32r 33r
29r 29r 29r 29r 29r
30r

1
29r 29r 29r 29r
3. HEALTH EFFECTS
30r 30r 30r
0.1
0.01
0.001
43
Chronic (≥365 days)

CHLORINE
Systemic
lar al l tal
y u tin ica ele
r as
c es g k
ato v int olo los c
spir rdio s tro m at s cu p ati na
l
Re Ca Ga He Mu He Re
ppm

10

34k 36m 35r 34k 36m 35r 34k 36m 35r 34k 36m 35r 34k 36m 35r 34k 36m 35r
36m 35r
3. HEALTH EFFECTS
0.1 34k
0.01
0.001
0.0001
1E-5
44

CHLORINE
Systemic

r
p ho
t al e
igh ym tiv
rine l e o/L logic duc
r yW n
d oc r ma ula d mu u ro p ro
En De Oc Bo Im Ne Re
ppm

10

34k 36m 35r 34k 36m 35r 34k 36m 35r 34k 36m 35r 37k 39m 38r 40k 42m 41r 43k 44r
34k
3. HEALTH EFFECTS
0.1
0.01
0.001
0.0001
1E-5
45
CHLORINE 46
3. HEALTH EFFECTS
3.2.1.2 Systemic Effects
The highest NOAEL and all reliable LOAEL values from each study for systemic effects in each species
and duration category are recorded in Table 3-1 and plotted in Figure 3-1.
Respiratory Effects. The respiratory system, particularly the upper portion of the respiratory system,
is the target for exposure to chlorine gas, and there is a considerable amount of information to support this
observation. Chlorine is a respiratory irritant and its effects depend on its concentration, as well as the
duration of exposure and the water content of the tissue involved.
Table 3-2 lists clinical effects associated with exposure concentrations compiled from epidemiological
and toxicological studies by Ellenhorn and Barceloux (1988). Whether acute exposure to high levels of
chlorine induces long-term respiratory effects is still a matter of debate. As mentioned below, some
studies have reported a clinical picture of persistent airflow obstruction as well as increased bronchial
reactivity, while many others have not found significant persistent alterations. There are many factors
that can determine whether residual effects are detected, including exposure level and duration of
exposure, medical treatment following exposure, length of the follow-up, underlying respiratory disease,
and smoking status. The preponderance of the evidence suggests that no serious long-term respiratory
alterations result from acute exposure to low to moderate (up to approximately 20 ppm) concentrations of
chlorine gas.
Effects caused by several types of exposures are summarized below including exposure to high
concentrations as it occurred during gassing attacks in World War I, accidental exposures of the general
population, occupational exposures, and acute, low-level, controlled exposure in volunteers. Information
on odor perception is also summarized. Due to the high volume of studies in some of these categories,
representative examples are presented.
Odor Perception. A study in which a trained odor panel of four members was exposed to chlorine under
controlled laboratory conditions reported that the first concentration at which all members cold detect the
odor was 0.314 ppm (Leonardos et al. 1968). Ryazanov (1962) reported that the odor threshold of a
group of volunteers was 0.3–0.4 ppm. In a study by Rupp and Henschler (1967), chlorine was slowly
introduced to a test room so that the concentration increased from 0 to 1.3 ppm in a 50-minute period.
CHLORINE 47
3. HEALTH EFFECTS
Table 3-2. Acute Effects of Chlorine Exposure on the Respiratory Tract of
Humans
Concentration (ppm) Effects

0.2–3.5 Odor detection
1–3 Mild mucous membrane irritation tolerated up to 1 hour
5–15 Moderate irritation
30 Immediate chest pain, dyspnea, cough
40–60 Toxic pneumonitis and pulmonary edema
430 Lethal over 30 minutes
1,000 Lethal within minutes
Source: Ellenhorn and Barceloux 1988

CHLORINE 48
3. HEALTH EFFECTS
The odor of chlorine was first detected at 0.06 ppm and all the subjects (number not specified) could
smell 0.2 ppm chlorine. In a summary of information on odor perception, NIOSH (1976) states that
Stayzhkin reported a threshold of 0.2 ppm for chlorine in a group of 12 subjects who were asked to
discern clean air from chlorine by inhaling from two tanks and that Beck found that subjects who were
exposed to increasing concentrations of chlorine the length of time of perception was positively related to
the exposure concentrations (i.e., the perception of higher concentrations lasted longer than that of low
concentrations suggesting that tolerance to low chlorine concentrations may develop). In general, there
seems to be consensus that the mean odor threshold lies between 0.2 and 0.4 ppm, which is between
1/25 and 1/50 of the concentration considered to represent immediate danger to life and health of 10 ppm
(NIOSH 2005). This means that individuals with a normal sense of smell should be able to take
appropriate avoidance measures before serious health effects due to chlorine exposure can occur.
War Exposures. A review of the effects of chlorine as a result of its use during World War I indicates
that subjects exposed to very high concentrations (not specified, but presumably >100 ppm) experienced
burning of the throat, cough, and feeling of suffocation, dyspnea, and usually death within 24 hours of
acute pulmonary edema (DOA 1933). Those surviving 48 hours usually recovered, but bronchitis
persisted for weeks and, in some cases, there was evidence of pulmonary emphysema. Data summarized
by DOA (1933) on studies that evaluated residual effects indicate that bronchitis and asthma were
common months to years after gassing. Dyspnea and chest pain after exercise were also frequent
complaints. Citing a study of 838 U.S. soldiers who had been subjected to chlorine gassing, DOA (1933)
states that 9 soldiers were discharged due to conditions attributable to gassing; these conditions included
pulmonary tuberculosis, bronchitis, pleurisy, and dyspnea. An additional 39 cases were found to have
been disabled at the time of discharge, and bronchitis and pleurisy were among the disabling conditions.
The extent to which these residual effects were truly due to chlorine gassing is difficult to ascertain due to
lack of information on pre-existing conditions, smoking status, and even factors such as the climatic
conditions that existed at the time.
Exposures of the General Population. There is considerable information on the effects of exposures of
the general population to chlorine derived from various types of situations, including storage tank leaks,
railroad accidents, mishandling of bleach cleaning solutions, accidents involving swimming pool
chemicals, and accidents in high school chemistry laboratories. Representative examples are summarized
below.
CHLORINE 49
3. HEALTH EFFECTS
Chasis et al. (1947) provided a comprehensive description of immediate and delayed respiratory effects in
a group of subjects exposed to chlorine that leaked from a defective cylinder that was carried in a truck in
Brooklyn, New York. The accident involved several hundred people. Although the exposure
concentration was not known, it was high enough to cause a visible cloud. Chasis et al. (1947) report on
33 persons admitted to a local hospital. Immediate symptoms included rhinorrhea, cough, choking
sensation, and substernal burning, pain, and constriction. Substernal pain, burning, and constriction, and
choking sensation were present within 2 hours of exposure and, in most patients, subsided completely
within 72 hours. Respiratory distress subsided within 3 days in 27 patients and within 6 days in
5 patients. During the first week, almost all 33 patients complained of substernal soreness, which was
interpreted as indicating the presence of tracheobronchitis. Physical examination on admission revealed
acutely ill patients in moderate to marked respiratory distress, increased respiratory rate of costal
abdominal type, and both dry and moist rales. Laboratory data showed sputum with large numbers of
epithelial cells showing pronounced degenerative changes. Most cultures showed microorganisms
representative of the normal pharyngeal flora. Chest x-rays showed mottling of the lungs and patches of
irregular density and differences in the degree of aeration between the two pulmonary fields. Spirometry
was conducted on 8 patients 48 hours after exposure and showed markedly reduced vital capacity (VC)
and maximal breathing capacity (1 minute); these changes showed improvement in subsequent days. The
diagnosis of pulmonary changes was: pulmonary edema, tracheobronchitis, and pneumonia. In
29 patients who were followed for up to 16 months after exposure, there was no evidence of permanent
pulmonary disease.
Hasan et al. (1983) reported that exposure of 28 subjects to chlorine that leaked from a storage tank
caused cough, dyspnea, and nasopharyngeal irritation. Pulmonary tests conducted 18 hours after
exposure showed diminished forced expiratory volume in 1 second (FEV1), and low forced expiratory
flow rate at 50 and 25% vital capacity (FEF50 and FEF25) and FEF25–75%. These abnormalities were still
present 14 days after exposure in subjects whose chief initial complaint was dyspnea. Evaluation of nine
subjects 5 months after chlorine exposure showed pulmonary parameters within normal limits.
In contrast to the findings of the above two studies, some studies have reported long-term effects of acute
high chlorine exposure. For example, Chester et al. (1977) reported the case of a woman who was
exposed following a leak in a liquid storage tank and suffered severe cough and chest pain within minutes
after exposure. Chest x-rays at the time showed bilateral infiltrates in the midpulmonary zones, but 1 year
after the accident x-rays were normal. However, dyspnea and chronic cough with occasional production
of white to yellow sputum persisted over the next 4 years. Schönhofer et al. (1996) studied three cases
CHLORINE 50
3. HEALTH EFFECTS
that experienced nose and throat irritation, cough, shortness of breath, wheezing, chest tightness, and a
feeling of suffocation minutes after exposure to chlorine gas that leaked from a tank. Chest x-rays
showed no evidence of pulmonary edema. Four months after the accident, bronchoalveolar lavage
showed inflammatory changes, but no such changes were seen 16 months later. However, moderate to
severe bronchial hyperresponsiveness was observed up to 30 months after the accident. Schönhofer et al.
(1996) noted that the condition showed the typical feature of the reactive airways dysfunction syndrome
(RADS), defined as an asthma-like occupational illness after an acute exposure to concentrated
respiratory irritants characterized by increased responsiveness to methacholine (Brooks et al. 1985).
Weill et al. (1969) studied 12 subjects who were exposed to chlorine after the derailment of a tank car
containing 30 tons of liquid chlorine near the town of Morganza, Louisiana. Chlorine concentrations of
400 ppm were measured 75 yards from the wreck 7 hours after the accident. Immediate effects included
shortness of breath, cough, and x-rays revealed pulmonary edema. Three and/or 7 years after the
accident, all patients were free of respiratory symptoms and pulmonary tests, including total lung capacity
(TLC), VC, residual volume (RV), FEV1, and single-breath diffusing capacity for carbon monoxide
(DLCO) were within 2 standard deviations of the predicted value. Weill et al. (1969) concluded that acute
exposure to chlorine does not result in significant permanent lung damage. A previous account of this
accident was given by Joyner and Durel (1962).
The Agency for Toxic Substances and Disease Registry (1998) conducted a health assessment of a
population in Alberton, Montana after tanker cars derailed and released chlorine gas, solid sodium
chlorate, and potassium cresylate. Readings at the site of the accident occasionally reached 1,000 ppm,
but it was estimated that members of the community had been exposed to up 20 ppm chlorine. Analysis
of soil and wipe samples determined that chemicals other than chlorine had not migrated offsite. A total
of 682 persons were interviewed within 2 weeks of the accident. The most frequent conditions were
cough, nose and throat irritation, and difficulty breathing. The report also indicates that children aged 0–
5 years had the highest prevalence of respiratory infections, that persons who had previous respiratory
problems (i.e., asthma, chronic bronchitis, hay fever) reported a higher prevalence of respiratory health
problems, and that the reported frequencies of respiratory symptoms were higher among current and
former smokers than in nonsmokers.
Accidental domestic exposure to chlorine gas can occur when bleach (sodium hypochlorite) is mixed with
other cleaning substances that contain an acid, for example, phosphoric acid cleaners (used to remove
hard water deposits); the chemical reaction generates chlorine gas. Many such incidents have been
CHLORINE 51
3. HEALTH EFFECTS
reported. For example, CDC (1991) reported five episodes in which subjects experienced nose irritation,
sore throat, chest tightness, cough, and difficulty breathing; in most cases, respiratory symptoms subsided
within a day. Gapany-Gapanavičius et al. (1982) reported two similar cases in which subjects inhaled
chlorine after mixing bleach and hydrochloric acid and immediately experienced a burning sensation in
the throat, cough, and shortness of breath. Chest x-rays taken hours after the accident showed air in the
mediastinal space (space in the middle of the chest separating the two pleurae), probably the result of
severe coughing, which resolved 7–10 days after the accident. None of these cases were followed to
evaluate possible long-term effects. Additional information from similar exposure scenarios can be found
in a review by Mrvos et al. (1993).
Chlorine gas can be released around swimming pools when chlorinating agents are handled improperly or
due to malfunction of the chlorination equipment, which underscores a strong need for training pool
owners and operators in pool maintenance. Pertinent information can be found in CDC (2009).
Sexton and Pronchik (1998) described the effects of such an exposure on 13 children who presented to the
emergency department. On admission to the emergency department, most patients complained of throat
irritation, chest pain, shortness of breath, wheezing, and chest tightness. Five patients who were admitted
to the hospital had normal chest x-rays. At follow-up interviews 2 weeks later, the patients did not
complain of residual respiratory symptoms. Ploysongsang et al. (1982) studied four patients who inhaled,
for 2–5 minutes, an undetermined amount of chlorine gas that leaked from a container at a public
swimming pool and experienced cough, a feeling of irritation of the upper respiratory tract, and tightness
in the chest. Pulmonary function studies conducted 12–14 hours after the accident showed values within
normal ranges. However, tests done 1 month later showed a significant increase in measurements of
volumes, suggesting that there had been an acute reduction of lung volumes after the exposure.
Ploysongsang et al. (1982) concluded that exposure to chlorine had produced an insignificant and
inconsistent obstruction in large airways. Agabiti et al. (2001) reported the effects of accidental
inhalation of chlorine gas among a total of 282 subjects attending a pool. Cough and shortness of breath
were common acute symptoms after the accident and 27% reported some respiratory symptoms 15–
30 days after exposure. Lung function measurements at that time revealed a tendency to lower levels
among those with the highest perceived exposure, but only a decrease in FEV1 was significant. The study
also found that among children (approximately half the sample), the incidences of all symptoms tended to
be higher among those who had a history of chronic respiratory disease, among those who were engaged
in physical exercise when the accident occurred, among those who were slow to evacuate the pool, and
among those who reported higher exposure (as judged by eye irritation). Also, incidences were higher
CHLORINE 52
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among smokers and former smokers than among never smokers. A recent study of 18 children exposed to
chlorine in a swimming pool accident found that a biomarker of pulmonary inflammation, leukotriene B4,
was still significantly increased in exhaled breath condensate 2 months after exposure, long after
pulmonary function parameters had returned to normal values (Bonetto et al. 2006). Immediately after
exposure, the children had experienced dyspnea and burning of the throat and spirometry tests done
within the first 24 hours showed reduced forced vital capacity (FVC) and FEV1. The authors also found
that hours after exposure a Clara cell-specific protein, CC16, was significantly elevated in serum
compared to non-exposed children, and suggested that this may be interpreted as a sign of injury to the
lung epithelial permeability barrier. Transient increases in serum CC16 have been reported following
exposure to certain pulmonary irritants (see Lakind et al. 2007 for review). Additional information
regarding swimming pool accidents can be found in Almagro et al. (2008), Babu et al. (2008), Grasemann
et al. (2007), and Thomas and Murray (2008).
Controlled Low-level Exposure of Volunteers. Anglen (1981) exposed up to 29 male and female
volunteers to 0, 0.5, 1, or 2 ppm chlorine for either 4 or 8 hours. Sensations were recorded before and
during exposure and pulmonary function was monitored by measuring FVC and FEV1 before and at
various times during exposure. Itching and burning of the throat were the highest responses and were
most prevalent by the end of an 8-hour exposure to 1 ppm chlorine. Responses for sensations of itching
or burning of the nose and eyes were also prevalent at 1 ppm chlorine. In general, males provided
stronger irritation responses than females. Exposure to 1 or 2 ppm chlorine for 8 hours produced
significant changes in pulmonary function but similar exposures to 0.5 ppm did not. Exposure to 2 ppm
for up to 30 minutes produced no increase in subjective irritation and exposure to 2 ppm for 2 hours did
not alter pulmonary function. In another study from the same group of investigators (it is unclear whether
a follow-up to Anglen [1981] or a separate study), eight healthy male volunteers exposed to target
concentrations of 0, 0.5, or 1 ppm chlorine (Rotman et al. 1983). Pulmonary tests were conducted before
exposure, after a 4- and 8-hour exposure period and again 2 and 24 hours after exposure ceased. During
exposure, the subjects exercised on a treadmill for 15 minutes of each hour to simulate light-to-moderate
work that raised the heart rate to 100 beats per minute. Specific respiratory parameters measured
included FVC, FEV1, forced expired volume in 1 second as percent FVC (FEV1%), peak expiratory flow
rate (PEFR), FEF50 and FEF25, TLC, expiratory reserve volume (ERV), functional residual capacity
(FRC), residual volume, airway resistance (Raw), single-breath DLCO, closing volume, and difference in
nitrogen concentrations between 750 and 1,250 mL of inhaled vital capacity (ΔN2). Exposure to 1 ppm
chlorine caused runny nose and mild burning in the throat, but no such effects were reported at 0.5 ppm.
Significant changes in pulmonary function tests were mostly restricted to the 1 ppm exposure level and
CHLORINE 53
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were evident after 4 hours of exposure. Changes were observed in FEV1, PEFR, FEF50, FEF25, TLC,
Raw, and ΔN2. Greater changes in some of these parameters were seen after 8 hours of exposure. Few
changes were still evident 24 hours after exposure, but most parameters had returned to pre-exposure
values by that time. It should be noted that one volunteer who was atopic experienced severe distress
during exposure to 1 ppm and was forced to exit the chamber before the full 8-hour period due to
shortness of breath and wheezing.
D’Alessandro et al. (1996) evaluated pulmonary function in subjects with (n=10) and without (n=5)
airway hyperresponsiveness (HR, defined by baseline methacholine hyperresponsiveness). The HR
subjects were exposed to 0.4 or 1.0 ppm chlorine, whereas the healthy subjects were exposed to 1.0 ppm
chlorine. All exposures lasted 60 minutes. Airflow and airway resistance were measured immediately
before and immediately after exposure. Also, lung volumes, airflow, diffusing capacity, airway
resistance, and responsiveness to methacholine were measured 24 hours before and 24 hours after
exposure. Exposure of the HR group to 0.4 ppm chlorine resulted in no significant change in airflow or
resistance either immediately or 24 hours after exposure. Exposure to 1.0 ppm chlorine resulted in an
immediate decrease in FEV1 and FEF25–75% and increase in airway resistance among normal and HR
subjects, but the magnitude of the effects among HR subjects was significantly greater than in healthy
subjects. Twenty-four hours after exposure, there were no significant changes for healthy or HR subjects
in airflow, lung volumes, diffusing capacity, resistance, or methacholine responsiveness. Comparing
relative changes from baseline immediately after exposure between normal and HR subjects showed that
HR subjects had much greater changes in pulmonary function tests.
A similar study was conducted in eight volunteers exposed to chlorine 6 hours/day on 3 consecutive days
to each of the four exposure conditions, 0, 0.1, 0.3, and 0.5 ppm chlorine (Schins et al. 2000). Pulmonary
function including effort-dependent parameters and effort-independent parameters were evaluated before
and after exposures. In addition, nasal lavage measurements were performed before and after each
exposure and 1 and 4 days after each exposure. The nasal lavage fluid was examined for total cells,
epithelial cells, neutrophils, lymphocytes, eosinophils, monocytes, albumin (an indicator of epithelial
permeability), and interleukin-8 (indicator of inflammatory response). Subjective complaints by the
subjects were judged to be not treatment-related, but objective physiological measures of nasal irritant
response were not included. Examination of the nasal lavages gave no indication of an inflammatory
response or irritant effects on the nasal epithelium. The results of the pulmonary function tests showed
that the only significant effect related to chlorine exposure was a difference in maximal mid expiratory
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flow (MMEF) between 0 and 0.5 ppm exposure; however, this was attributed to an unexplained shift in
baseline values during control exposure (0 ppm).
Shusterman et al. (2003b) measured nasal airway resistance in 52 healthy adults (24 males and
28 females) before and after exposure to 0 or 1 ppm chlorine for 15 minutes. Subjects were stratified on
age (18–34, 35–51, 52–69 years), gender, and allergic rhinitis status (27 were positive). Nasal airway
resistance was measured by active posterior rhinomanometry. Exposures to air and chlorine were a week
apart. Subjects with allergic rhinitis showed a significantly greater increase in nasal airway resistance
(49% increase from baseline) than healthy subjects (10% increase from baseline) 15 minutes after
exposure. The increase in nasal airway resistance was most pronounced in older subjects and least
pronounced in the youngest group. No significant differences were seen between males and females. In
an earlier study, the same group of investigators had reported that subjects with SAR exposed to 0.5 ppm
chlorine for 15 minutes experienced a much greater increase in nasal airway resistance than subjects
without SAR, as measured by active posterior rhinomanometry (Shusterman et al. 1998). However, when
subjective responses to odor, nasal irritation, and nasal congestion were analyzed separately by rhinitis
status, no significant exposure-related changes were observed for rhinorrhea, postnasal drip, or headache
either on a pool or stratified basis. In addition, within either the SAR or non-SAR group, there was no
relationship between subjective and objective congestion after chlorine exposure. Pulmonary peak flow
tests showed that none of the subjects exhibited clinically significant changes in peak flow, nor did they
complain of cough, wheezing, or chest tightness on chlorine exposure days.
As a whole, these studies indicate that acute-duration exposures to 1 ppm chlorine can induce upper
respiratory tract irritation and transient alterations in parameters of respiratory function and exposure
concentrations of 0.5 ppm are generally devoid of such effects and, therefore, 0.5 ppm can be considered
an acute (1–8 hours) NOAEL for sensory irritation and pulmonary function. The 0.5 ppm level caused no
significant effects in an atopic subject (Rotman et al. 1983) or in subjects with airway hyper-
responsiveness (D’Alessandro et al. 1996), and, while increased nasal airway resistance measured
instrumentally in subjects with SAR, the latter did not clearly perceive the effect as an adverse effect
(Shusterman et al. 1998). These studies also show that individuals with compromised respiratory
function constitute a susceptible group for exposure to chlorine. The NOAEL of 0.5 ppm and LOAEL of
1 ppm from these studies as a group, serve as the basis for derivation of an acute-duration inhalation MRL
for chlorine.
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Long-term, Low-level Occupational Exposures. Relatively few studies have examined the effects of
long-term exposure to low levels of chlorine in humans, and the ones that have done so have not provided
conclusive answers largely because of study limitations.
Patil et al. (1970) studied the health effects of chlorine in 600 workers from 25 plants producing chlorine
in North America. A group of 382 workers not considered to be routinely exposed to chlorine served as
controls. The average duration of exposure was 11.9 years. Each worker received one physical
examination that included evaluation of medical and occupational histories, blood and urine tests,
pulmonary function tests and electrocardiogram (EKG). Tobacco and alcohol use were also monitored.
The concentration of chlorine was monitored in each plant every 2 months over a period of 1 year in
several representative areas, but otherwise unspecified. Exposure data were available for 332 workers
and showed a time-weighted average (TWA) 8-hour mean of 0.15±0.29 ppm (range, 0.006–1.42 ppm). It
also showed that almost all workers were exposed to <1 ppm chlorine, 94% were exposed to ≤0.5 ppm,
and 70% were exposed to ≤0.2 ppm. Evaluation of the 332 workers who had exposure data showed that
none of the end points examined (those subjected to recall or measured) showed a dose-response
relationship. The mean concentration of 0.15 ppm may be considered a NOAEL for the study, but there
are limitations such as unclear analytical methodology, no clear definition of the case/control populations,
and insufficient detail regarding the method of analysis that render the NOAEL questionable; thus, it is
not included in Table 3-1.
Ferris et al. (1967) examined the prevalence of chronic respiratory disease among 147 workers in a pulp
mill and 124 controls who worked in a paper mill and found no significant differences in respiratory
symptoms or in tests for FVC and FEV1 (tests were conducted without a nose clip) between the two
groups. Duration of exposure was not provided. Chlorine levels were measured on three different
occasions in 3 years; in one occasion, the mean was 7.4 ppm and only traces were reported in the other
two occasions. The limit of detection of the method was 1 ppm. Examination of the same cohort
10 years later did not reveal any increased mortality or increased specific cause of death (Ferris et al.
1979). Evaluation of 200 men seen at both times did not reveal any differences in respiratory symptoms
or chronic nonspecific respiratory disease.
Enarson et al. (1984) evaluated respiratory effects and pulmonary function in a group of 392 male pulp
mill workers exposed to chlorine, sulfur dioxide, hydrogen sulfide, and methylmercaptan, in addition to
various particulates (i.e., wood dust, ash, lime dust), for a mean duration of 101.5±86.6 months. A
control, unexposed group, consisted of 310 male rail yard workers who lived in the same community and
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who performed similar manual labor. End points examined included prevalence of respiratory symptoms
(usual cough, usual phlegm, wheezing without a cold, dyspnea when hurrying, chest tightness, and chest
illness). Pulmonary function tests conducted included FEC, FEV1, FEF25–75%, and FEV1/FVC ratio.
Chlorine was the main contaminant in two areas of the pulp mill, the bleach plant and the machine room
(mean 8-hour TWA 0.18 and 0.02 ppm, respectively). Overall, pulp mill workers complained more
frequently of usual phlegm, wheeze without cold, and chest illness than rail workers. However, the most
significant finding was that among bleach workers (n=15) and machine room workers (n=22),
nonsmokers (n=4) had a significantly lower FEF25–75% and FEV1/FVC ratio than rail yard workers. Given
the small number of workers involved, the possibility of exposure to multiple chemicals, and the lack of
information on chlorine peak exposure levels, the validity of the 0.18 ppm as an effect level is
questionable.
A study at a chlorine plant in Sweden compared the changes in vital capacity (VC) and FEV1 that
occurred between measurements separated by 10 years among 44 workers exposed to chlorine and
33 white-collar workers matched for age and smoking status (Hyback 1999). The author stated that the
concentration of chlorine was measured continuously over the years and was always below 0.5 ppm, as a
set standard. The results of the tests showed that in fact, over the years, VC and FEV1 declined more in
white-collar workers (significantly for FEV1) than in the workers exposed to chlorine. Hyback (1999)
speculated that perhaps the low concentrations of chlorine gas may protect workers from contracting
respiratory infections that over time contribute to a decline in respiratory function.
The limited information available does not suggest that long-term exposure to low levels of chlorine gas
affects respiratory function, but additional, better-conducted studies are necessary to confirm this view.
High-level Occupational Exposure. Schwartz et al. (1990) studied a group of 20 workers who were
briefly (minutes) exposed in a pulp mill to chlorine gas when liquid chlorine leaked from a tank and
evaporated. Acute symptoms included burning of the nose and throat, and dry cough with chest tightness.
Pulmonary tests were conducted within 24 hours of exposure and several times over the next 12 years.
The most significant findings were a high prevalence of airflow obstruction (FEV1/VC ratio <65%) that
persisted over the observation period and a prevalence of low residual volume (RV) that increased during
the follow-up period. Schwartz et al. (1990) also found that 5 of 13 subjects tested at year 12 had
increased airway reactivity to inhaled methacholine. While the findings were suggestive of long-term
pulmonary complication, the investigators acknowledged that without pre-exposure pulmonary function
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tests and individual measures of exposure, it is difficult to determine whether the changes were due to
chlorine exposure.
Moulick et al. (1992) evaluated 82 patients exposed to approximately 66 ppm chlorine that leaked from a
storage tank at a chemical factory in Bombay, India. Acute symptoms of exposure included dyspnea,
cough, and irritation of the throat. Pulmonary tests performed in 62 cases within 48 hours of exposure
indicated obstruction in 17 cases, restriction in 2 cases, and a mixed pattern in 33 cases. Also,
bronchoscopy showed tracheobronchial mucosal congestion and hemorrhagic spots. Four out of
16 patients who were followed for 1 year showed persistent cough 4–6 weeks after exposure, but after
1 year, there were no residual symptoms and x-rays and pulmonary function tests were normal.
Evaluation of five nonsmoking patients 3 years after exposure did not reveal any residual symptoms and
pulmonary function tests were normal (tests were not specified).
Lemière et al. (1997) reported the case of a nonsmoking worker at a water-filtration plant man who was
exposed to chlorine levels high enough to induce immediate burning of the nose and throat and
retrosternal burning and wheezing. Five years earlier, he experienced similar symptoms after chlorine
inhalation, but the symptoms had been transient. Two days after exposure, FEV1 was significantly
reduced (66% of predicted) and the response to methacholine provocation was slightly abnormal. A
bronchial biopsy showed almost complete replacement of the epithelium by a fibrinohemorrhagic
exudate. Subsequent biopsies taken over a 5-month period showed considerable epithelial desquamation
15 days after exposure followed by signs of regeneration 5 weeks after exposure and considerable
improvement 5 months after exposure, although an inflammatory infiltrate was still present. The airway
responsiveness to methacholine paralleled the inflammatory changes, but could be significantly improved
by inhaled steroids.
Kowitz et al. (1967) described the effects of chlorine exposure that occurred when a cylinder containing
chlorine that was being unloaded from a freighter leaked. Neither exposure concentration nor exposure
duration was available. At least 150 men were involved and almost all experienced acute symptoms.
Eleven of 17 subjects who were admitted to a hospital were evaluated over a 3-year period. All showed
respiratory distress on admission; other common signs included rales, wheeze, or rhonchi, or both, and
pulmonary edema. Pulmonary function testing conducted over the 3-year evaluation period showed a
persistent decrease in lung volume and diffusing capacity and increased airway resistance. According to
Kowitz et al. (1967), these alterations were compatible with an alveolar-capillary injury.
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There are also a number of studies that describe the effects of occasional occupational exposures to
elevated concentrations of chlorine over a background of low level exposure (“gassing” incidents). Some
examples are summarized below.
In a study of 321 workers at a British Columbia pulp mill, 189 reported one or more gassing incidents,
although no data were available to determine the severity of the exposure incidents (Kennedy et al. 1991).
The average chlorine levels in the pulp mill were <1 ppm, but estimates of concentrations during the
gassing incidents are not available. Pulp mill workers who reported having being gassed were
significantly more likely to report wheezing on occasion than individuals who had not been gassed.
While there were no significant differences in lung function tests between the overall pulp mill group and
a control group, nonsmoking and formerly smoking pulp mill workers who reported being gassed had
significantly lower MMEF and FEV1/FVC ratio than those who had not been gassed. Kennedy et al.
(1991) hypothesized that the first accidental high exposure incident may cause an inflammatory reaction
in the small airways that does not completely resolve because of continuous or repeated presence of the
stimulus. A longitudinal analysis over a 7-year period (1981–1988) of 67 pulp mill workers that
underwent pulmonary function tests both in 1981 and 1988 reported that there was a significantly greater
decline in FEV1/FVC ratio and MMEF in the gassed group than in the unexposed group matched for age
and smoking status (Salisbury et al. 1991).
In a survey of 281 construction workers involved in renovation work at a pulp mill, 257 workers reported
an average of 24 gassing episodes over a 3–6-month period (Courteau et al. 1994). Exposure data during
the gassings were not available, but 36% of 483 air samples taken in the bleach plant after the episodes
showed chlorine concentrations of <0.5 ppm, 58% were between 0.5 and 8 ppm, and 6% were >8 ppm.
The most commonly reported symptoms were irritation of the throat (78%), cough (67%), and shortness
of breath (54%); the latter was not associated with age, smoking state, or history of asthma or chronic
bronchitis. Over 60% of the workers described a flu-like syndrome that lasted for an average of 11 days.
Visits to the first aid department were associated with greater reporting of most symptoms including
dyspnea and cough. Seventy-one workers identified as having moderate to high risk based on exposure
data and onset of respiratory symptoms were evaluated 18–24 months later (Bhérer et al. 1994). At this
time, a questionnaire completed by 64 workers (90%) suggested that 58 (91%) still had respiratory
symptoms and 51 underwent spirometry and methacholine challenge tests. Bronchial obstruction (FEV1
<80% predicted) was observed in 16 workers, whereas 29 showed significantly increased airway
responsiveness. Based on the fact that workers who had been to an emergency room were more likely to
be left with airway hyper-responsiveness, Bhérer et al. (1994) speculated that severity of one or more
CHLORINE 59
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gassing episodes may be a more significant determinant of the likelihood of developing permanent
alterations than the number of episodes.
In a study of 300 pulp and paper workers in New Hampshire, 105 reported ever having experienced an
episode of high exposure to chlorine gases (Henneberger et al. 1996). Spirometry (FEV1, FVC,
FEV1/FVC, MMEF) showed that the prevalence of obstructive pattern was >3 times greater for the gassed
subjects compared with the others. For workers who had 26-pack years of cigarette smoking, an
obstructive pattern (abnormally low FEV1 and FEV1/FVC) was observed only among those with a history
of gassing. In addition, the combination of high cigarette smoking and gassing had a greater-than-
additive effect on obstruction. Monitoring data were not available in this report.
Gautrin et al. (1999) evaluated 239 workers in a metal production plant who, 3 years earlier, had taken
part in a cross-sectional study (Gautrin et al. 1995). In the first evaluation, the authors reported that FVC
was higher in workers who had no symptoms after a gassing episode compared with those who had mild
symptoms. Also, FEV1 and FVC were significantly lower in workers who experience >10 gassing
incidents with mild symptoms than in workers who experienced no symptoms. In both cases, the
differences were significant only in workers who had ever smoked. Increased airway responsiveness was
also found in subjects who experienced >10 gassing incidents with mild symptoms. In 98% of the
accidental exposures, chlorine was reported as the gas involved. Among 211 workers seen at follow-up
(Gautrin et al. 1999), heavy smokers showed a decrease in FEV1/FVC% that was predicted by the number
of gassing episodes causing mild symptoms between the two evaluations. Nineteen workers showed
increased airway responsiveness which was associated with accidents reported to the first aid unit during
the previous 2 years. The same group of investigators also reported that chronic rhinitis reported in the
second assessment was significantly associated with acute exposure to chlorine and that chronic lower
airway symptoms were more frequent in the second assessment among workers reporting chronic rhinitis
on both assessments than in others (Leroyer et al. 1999).
Effects in Animals. The studies in animals support the findings in humans, particularly the nature of the
acute effects of exposure to high concentrations of chlorine gas. A great deal of information regarding the
toxicity of chlorine in animals was generated during World War I and the years that followed triggered by
the use of chlorine as a chemical weapon during the war. A summary of the earlier studies conducted in
various European countries as well as in the United States and Russia can be found in Withers and Lees
(1985b). Additional information on the early literature, particularly from extensive studies in dogs, can
be found in DOA (1933).
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More recently, studies in rodents have confirmed the earlier observations regarding high exposures and
have provided valuable information regarding the irritant properties of chlorine.
Acute exposure to low-to-moderate concentrations of chlorine induces a reduction in the respiratory rate,
a protective reflex response mediated by stimulation of trigeminal nerve endings in the nasal mucosa.
The concentration of the chemical that induces a 50% decrease in respiratory rate is termed RD50. For
example, RD50 values of 9.3 and 3.5 ppm were determined in mice exposed for 10 and 60 minutes,
respectively (Barrow et al. 1977; Gagnaire et al. 1994). An RD50 of 25 ppm was determined in male
F344 rats exposed to chlorine for 10 minutes (Barrow and Steinhagen 1982). This study also
demonstrated the development of tolerance to chlorine since in rats pre-exposed to chlorine at 1, 5, or
10 ppm intermittently for 32 weeks, the RD50 values were 90, 71, and 454 ppm, respectively, measured
16–24 hours after the last day of pre-exposure. Barrow and Steinhagen (1982) speculated that the
mechanism of tolerance may involve reactions of chlorine with sulfhydryl groups in the receptors or that
chlorine exposure may damage the free nerve endings in the respiratory nasal mucosa. Rats pre-exposed
to chlorine also developed cross-tolerance to formaldehyde (Chang and Barrow 1984). Interestingly, rats
pre-exposed to 15 ppm formaldehyde did not develop tolerance to formaldehyde, but did develop cross-
tolerance to chlorine, which suggested the existence of different reactive sites for the two gases (Chang
and Barrow 1984).
A study by the same group of investigators examined the effects of chlorine on lung -SH content and on
the enzymes that maintain non-protein -SH levels, glucose-6-phosphate dehydrogenase (G6PD) and
glutathione reductase (GSSG-RED) in rats exposed to 0 or 12 ppm chlorine for up to 2 weeks and
sacrificed at various times after cessation of exposure (Dodd et al. 1980). The results showed no
significant alterations in lung protein -SH, non-protein -SH, G6PD, or GSSG-RED in rats sacrificed
immediately after 1, 5, or 10 days of exposure. Rats sacrificed 3 or 6 days after exposure showed an
increase in lung -SH, G6PD, and GSSG-RED. These parameters returned to control values after 10 days
of recovery. The investigators concluded that the increase in lung -SH and enzymatic activities observed
during the recovery periods may reflect reparative processes subsequent to damage induced by chlorine.
A different study by the same group showed that exposures to up to 10 ppm chlorine for 12 hours did not
alter the total sulfhydryl content (TSH) of the olfactory mucosa but lower concentrations did reduce TSH
in the respiratory mucosa, suggesting that inhaled chlorine can oxidize tissue sulfhydryl groups at the
point of entry, but not at deeper regions of the respiratory tract (McNulty et al. 1983). McNulty et al.
(1983) also found that exposure to 5 ppm for 6 hours or 10 ppm for 3 hours (concentration times
CHLORINE 61
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exposure=30) produced similar reductions in TSH, but exposure to 2.5 ppm for up to 12 hours did not
significantly affect TSH content. The investigators speculated that a threshold concentration may be
needed to overwhelm the protective mechanism in the respiratory mucosa (perhaps the mucociliary flow)
allowing chlorine to penetrate deeper into the underlying tissue.
Acute studies also have examined respiratory function in animals.
Barrow and Smith (1975) evaluated inspiratory-expiratory flow rate ratios (Vi/Ve) and volume-pressure
relationships (lung compliance) in rabbits exposed to 0, 50, 100, and 200 ppm chlorine for 10 minutes.
The tests were conducted 0.5 hours after exposure and after 3, 14, and 60 days without exposure. After
the last test, the rabbits were killed and the lungs were removed for gross and microscopic examination.
Rabbits exposed to 50 ppm showed mild pneumonitis, which was also observed in control animals; this
exposure level did not induce significant changes in air flow ratios, but transiently decreased lung
compliance. Exposure to 100 or 200 ppm induced transient concentration related increases in Vi/Ve and
a decrease, followed by an increase, in pulmonary compliance; these changes are related to gross signs of
pulmonary edema and microscopic changes characterized by chronic pneumonitis and anatomic
emphysema. Rabbits allowed to recover for 14 or 60 days showed no “specific airway pathology.”
In another study, mice exposed for 15 minutes to 0.8, 2, 3.1, or 3.8 ppm chlorine showed concentration-
related decreases in respiratory frequency and increases in specific airway resistance (Morris et al. 2005).
Pretreatment with atropine did not alter the increase in airway resistance, suggesting that this response
does not involve parasympathetic cholinergic endings. However, pretreatment with capsaicin, a sensory
nerve toxin, dramatically reduced respiratory irritation and the obstructive response, suggesting the
involvement of sensory nerves. Mice exposed to much higher concentrations of chlorine (100–800 ppm)
for 15 minutes showed increased airways resistance and increased responsiveness to methacholine and
microscopic examination of the lungs showed flattening of the epithelium and epithelial cell loss and
changes associated with oxidative stress (Martin et al. 2003). Since the increased responsiveness to
methacholine could be prevented by inhibition of nitric oxide synthase, it appeared that nitric oxide (NO)
production may have contributed to the airway response to inhaled chlorine.
Jiang et al. (1983) studied the time course of the histopathological alterations in the respiratory tract of
rats and mice exposed to the RD50 of 9.1 ppm chlorine 6 hours/day for 1–5 days. The animals were killed
immediately after the last exposure and the nose, larynx, trachea, and lungs were processed for
microscopic examination. In both species, lesions were seen in the nasal passages with less severe
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changes in the nasopharynx, larynx, trachea, and lungs. The lesions in the nasal passages involved both
the olfactory and respiratory epithelia; the nasal squamous epithelium showed minimal change. Lesions
in the respiratory epithelium included acute epithelial degeneration with epithelial cell exfoliation,
erosion, and ulceration after 1 and 3 days of exposure, infiltration by neutrophils after 3 and 5 days, and
squamous metaplasia after 5 days. After 3 and 5 days of exposure, the epithelial lesions and
inflammatory response found in the respiratory and olfactory mucosa became progressively more severe
and extended more posteriorly. The most severe changes occurred in the olfactory mucosa of the anterior
portion of the dorsal meatus, which showed extensive epithelial erosion and ulceration. Less severely
affected areas showed necrosis and variable loss of sensory cells. Scanning electron microscopy showed
loss of olfactory cilia and cellular exfoliation. The larynx and trachea showed acute degeneration of
respiratory epithelial cells, whereas the lungs showed moderate to severe peribronchiolitis. Exposure of
mice to the RD50 of 9.3 ppm for 5 days induced severe exfoliation, erosion, ulceration, and necrosis of the
nasal respiratory epithelium (Buckley et al. 1984). It also induced minimal inflammation and squamous
metaplasia. In the olfactory epithelium, chlorine induced severe ulcerations and necrosis and
degeneration of sensory nerve endings. In the trachea, the lesions ranged from mild to moderate epithelial
exfoliation, hyperplasia, and squamous metaplasia. In the lungs, chlorine induced a moderately severe
terminal bronchiolitis with occlusion of affected bronchioles by serocellular exudate. Mice killed
72 hours after the last exposure had reduced inflammation and exudate, but there was little difference in
the extent of ulceration and degenerative lesions, suggesting that the 3-day period was insufficient for
complete repair of the lesions.
Exposure of rats to much higher concentrations of chlorine (50–1,500 ppm for 1–10 minutes) induced
increasing lung damage that partially resolved within 24 hours of exposure (Demnati et al. 1995). In rats
exposed to 1,330 ppm chlorine for 15 minutes, pulmonary changes observed 45 days after exposure
included interstitial fibrosis and thickening of the alveolar septa due to thickening of the basement
membrane (Yildirim et al. 2004). Exposure of rats to ≥184 ppm chlorine for 30 minutes induced
hypoxemia, respiratory acidosis, and hypercapnia, and increased the surfactant surface tension and protein
content of the bronchoalveolar lavage fluid, suggesting alveolar epithelial injury (Leustik et al. 2008).
Less evidence of lung injury was seen in rats that were injected before exposure to chlorine with a
mixture of ascorbate, deferoxamine, and N-acetyl-L-cysteine, suggesting that damage could be
ameliorated by low-molecular antioxidants (Leustik et al. 2008). Exposure of mice to 221–289 ppm
chlorine for 60 minutes caused severe lung inflammation as evidenced by widespread neutrophil influx
into the lung parenchyma 6 hours after exposure followed by a clustering of neutrophils around damaged
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airways 24 hours after exposure (Tian et al. 2008). Histologically, chlorine caused massive sloughing of
the airway epithelium that was evident 6 hours after exposure.
Two intermediate-duration studies in animals were located.
Barrow et al. (1979) evaluated the respiratory response in F344 rats exposed to 0, 1, 3, or 9 ppm chlorine
6 hours/day, 5 days/week for 6 weeks. Nasal discharge was seen occasionally in rats exposed to 1 ppm,
but was common in rats exposed to 3 and 9 ppm. Respiratory difficulty was also apparent in some rats
exposed to 9 ppm. At termination, gross necropsy revealed accumulation of inflammatory reactions in
the upper nasal passages in rats exposed to 3 and 9 ppm chlorine. Microscopic evaluations showed
indications of inflammatory reactions in the upper and lower respiratory tract of high-dose males and
females. The nasal turbinates showed mucopurulent inflammation with secretory material and erosions of
the mucosal epithelium. Changes in the trachea and bronchi consisted mostly of hyperplasia of the
epithelial lining and inflammatory reactions. The alveolar sacs contained macrophages and secretory
material and epithelial cells showed necrosis, hypertrophy and hyperplasia. Alterations in rats exposed to
1 and 3 ppm were less extensive and were limited to focal mucopurulent inflammation of the nasal
turbinates in females. Males exposed to 1 or 3 ppm showed deeper pulmonary changes consisting of
slight to moderate inflammatory reaction around the respiratory bronchioles and alveolar ducts, increased
alveolar macrophages, and isolated areas of atelectasis (incomplete expansion). A LOAEL of 1 ppm for
respiratory effects can be defined in this study based on the presence of inflammatory changes in the nasal
turbinates of females and in the lungs of males; no NOAEL was established.
A similar study examined clinical signs, lung function, and histopathology of the nasal turbinates and
lungs from F344 rats exposed to 0, 0.5, 1.5, or 5 ppm chlorine 6 hours/day, 5 days/week for 62 days
(Kutzman 1983). Pulmonary function tests (plethysmograph-based assessment of multiple end points,
including lung and tidal volumes, breathing frequency, transpulmonary pressure, lung compliance, N2
washout, diffusing capacity for CO, maximum expiratory flow volume, peak expiratory flow, and airway
resistance) were conducted in 21–24 anesthetized males 6 hours after the last exposure. Respiratory
tissues from these rats were prepared for histopathology. The lungs from some of these rats were also
examined for collagen, elastin, total protein, and DNA. Exposure to 5 ppm cause severe upper respiratory
irritation; exposure to 1.5 ppm showed occasionally less severe signs of irritation, whereas exposure to
0.5 ppm caused no obvious signs of irritation or discomfort. The tests of pulmonary function did not
reveal marked abnormalities. The most significant effect was a reduction in airflow at 75% of exhaled
vital capacity in all exposed groups, indicating some degree of small airway involvement. There were no
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histopathological alterations in the lungs and nasal turbinates, but there was a tendency in the trachea for
loss of cilia and epithelium at 0.5 and 5 ppm chlorine. The lung biochemistry only showed an increased
collagen concentration at 1.5 and 5 ppm. Based on upper respiratory irritation and loss of cilia and
epithelium in the trachea, the exposure level of 0.5 ppm can be defined as a LOAEL for respiratory
effects; no NOAEL was defined in this study. This study was used as the basis for derivation of an
intermediate-duration inhalation MRL for chlorine.
Two studies have examined the effects of chronic exposure to chlorine on respiratory parameters in
animals.
Wolf et al. (1995) exposed groups of F344 rats and B6C3F1 mice (approximately 70/sex/exposure level)
to 0, 0.4, 1, or 2.5 ppm chlorine gas for 2 years. Males from both species and female mice were exposed
6 hours/day, 5 days/week, whereas female rats were exposed 6 hours/day, 3 days/week. The reduced
exposure of female rats was based on unpublished data from the investigators that showed female rats to
have a greater sensitivity to repeated long-term exposure to chlorine. End points evaluated included gross
and microscopic examination of the respiratory tract; the nasal passages were examined microscopically
at five different levels. Both in rats and mice, there were no gross lesions attributable to exposure to
chlorine, and microscopic evaluation of the respiratory tract showed that chlorine-related effects were
restricted to the nasal passages. In the study, the incidences were presented as percentages of all animals
for which the nasal passages were adequate for microscopic examination, but the numbers of animals
examined were not provided. No lesions were seen in the larynx, trachea, bronchi, or bronchioles. In
general, rats and mice exhibited similar types of lesions. For the most part, the nasal lesions were site-
specific, but the severity and/or incidence were not always concentration-dependent. The majority of the
nasal responses exhibited a rostral-to-caudal severity gradient. The lesions rarely extended to the
nasopharyngeal meatus. Lesions observed included respiratory and olfactory epithelial degeneration,
septal fenestration, mucosal inflammation, respiratory epithelial hyperplasia, squamous metaplasia, and
goblet cell (rats only) hypertrophy and hyperplasia, and secretory metaplasia of the transitional epithelium
of the lateral meatus. Also observed was intracellular accumulation of eosinophilic proteinaceous
material involving the respiratory, transitional, and olfactory epithelia. Lesions were also observed in
controls, but the incidences were significantly lower than in the treated groups. One of the lesions with
the lowest incidence in controls was goblet cell hyperplasia in female rats (4%); the respective incidences
in the 0.4, 1, and 2.5 ppm group were 71, 90, and 91%. In mice, olfactory epithelium atrophy exhibited
one of the lowest incidences in controls (3%); the respective incidences in the 0.4, 1, and 2.5 ppm group
were 20, 21, and 39%. In both cases, severity also was concentration-related. Based on the increased
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incidence of various types of lesions in the nasal passages, the exposure level of 0.4 ppm constitutes a
LOAEL for respiratory effects in rats and mice; a NOAEL was not defined.
Klonne et al. (1987) exposed Rhesus monkeys to 0, 0.1, 0.5, or 2.3 ppm chlorine 6 hours/day,
5 days/week for 1 year. Pulmonary diffusing capacity for CO and distribution of ventilation were
evaluated monthly during the study. At termination, the nasal tissues (at the first palatine ridge and just
posterior to the third, fifth, and seventh palatine ridges), trachea, and lungs were examined. There was no
evidence of treatment-related effects on pulmonary function at any interval during the study. The only
treatment-related histopathological effects consisted of focal epithelial hyperplasia characterized by
increased cell numbers and loss of cilia and goblet cells in the respiratory epithelium of the nose and
trachea. The affected areas of the nasal passages showed hypercellularity with loss of goblet cells and
cilia. In some of these areas, the nuclei showed altered polarity. Lesions were more frequent on the
angular margins of the turbinates and less frequent on the lateral wall or septum adjacent to these margins.
In some cases, the respiratory epithelial hyperplasia was associated with mild suppurative inflammatory
response. Lesions in the trachea resembled those in the nose, but were less severe and involved only a
small circumferential section of the ventral and ventrolateral trachea. The combined incidences of lesions
in the nasal mucosa, characterized as trace and mild in males and females, were 1/8, 3/8, 6/8, and 8/8 in
the control, 0, 0.1, 0.5, and 2.3 ppm exposure groups, respectively. The lowest exposure concentration of
0.1 ppm chlorine is a LOAEL for nasal lesions in monkeys. This study was used as the basis for
derivation of a chronic-duration inhalation MRL for chlorine.
Ibanes et al. (1996) re-examined the respiratory tissues from the chronic studies in monkeys, rats, and
mice summarized above to better characterize the lesions and to improve human risk assessments based
on these data sets. In general, the re-evaluation found a good correlation between the subjective scores of
tissue responses in the original studies and quantitative analyses in the re-evaluation. The investigators
also noted that the lesions in monkeys and rodents exhibited both differences and similarities. One
notable difference was that monkeys showed less severe lesions, but extended more distally in the
respiratory tract. The investigators concluded that respiratory tract airflow characteristics play a major
role in lesion distributions in monkeys and rodents. Yet, with appropriate exposure and response
adjustments, both rodents and Rhesus monkeys appear to be valid models for human risk assessment.
Cardiovascular Effects. It is not uncommon to find reports of tachycardia and elevated blood
pressure in individuals admitted to emergency rooms following accidental exposure to high
concentrations of chlorine, but how much of this can be attributed to chlorine exposure or to a stressful
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situation is not clear. Some cases in which EKGs were performed shortly after exposure found no
significant alterations (Chasis et al. 1947; Güloğlu et al. 2002; Ramachandran et al. 1990). Tachypnea
and hypertension were frequently observed in persons who were hospitalized following a train derailment
that released chlorine gas in South Carolina in 2005 (Van Sickle et al. 2009). In most persons in whom
the conditions were observed, tachypnea and tachycardia persisted across examination. No specific
mention of cardiovascular effects was found in studies that evaluated possible long-lasting effects of
chlorine exposure.
Rats and mice that were exposed to lethal concentrations of chlorine had distended hearts (Weedon et al.
1940), but little additional information is available regarding cardiovascular effects in animals following
exposure to chlorine. It is reasonable to assume that some cardiovascular parameters would be affected
after acute exposure to high concentrations of chlorine as a result of the severe ventilation-perfusion
mismatching and hypoxia caused by pulmonary edema; however, no evaluations were made in the studies
available.
In an intermediate-duration study, rats exposed to 5 ppm chlorine for 62 days had no significant gross or
microscopic alterations in the heart (Kutzman 1983). Intermittent exposure of monkeys to 2.3 ppm
chlorine for 1 year (Klonne et al. 1987) or of rats and mice to 2.5 ppm chlorine for 2 years (Wolf et al.
1995) did not cause any significant gross or microscopic alterations in the heart and aorta.
Gastrointestinal Effects. Nausea and vomiting are common acute symptoms following exposure to
high concentrations of chlorine and are believed to be reflex reactions and not a specific effect of
chlorine.
Barrow et al. (1979) reported that rats exposed to 9 ppm chlorine 6 hours/day, 5 days/week for 6 weeks
had focal erosion of the gastric mucosa, which was usually accompanied by focal inflammation of the
adjacent submucosal areas. No such effects were seen in rats exposed to 3 ppm chlorine. The
investigators suggested that general stress or perhaps ingestion of hydrochloric acid and/or hypochlorous
acid as a result of grooming or deposition in the oral cavity may have caused the condition. The results of
Barrow et al. (1979) could not be confirmed or refuted in a study of very similar design by Kutzman
(1983) because the latter did not examine the gastrointestinal tract.
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Intermittent exposure of monkeys to up to 2.3 ppm chlorine for 1 year or of rats and mice to up to
2.5 ppm for 2 years did not produce gross or microscopic alterations in the gastrointestinal tract (Klonne
et al. 1987; Wolf et al. 1995).
Hematological Effects. Leukocytosis is a common finding in individuals acutely exposed to high

concentrations of chlorine, and is most likely a clinical manifestation of acute inflammation and tissue
destruction rather than a specific effect of chlorine. Hypoxemia is also characteristic of exposures high
enough to cause pulmonary edema and consequently, interference in gas exchange.
Experiments in dogs conducted by Underhill (1920) following World War I showed that following
gassing with high concentrations of chlorine, there was a relative increase in red blood cells and
hemoglobin that reached a peak approximately 5 hours after exposure and was due to a decrease in
intravascular fluid content. He also observed that in dogs exposed to relatively low concentrations of
chlorine, there was slight leukocytosis, which was caused solely by an increase in polymorphonuclear
cells. An intermediate-duration study in rats reported that exposure to 9 ppm chlorine for 6 weeks
induced a significant increase in hematocrit (females) and segmented neutrophils (males and females)
(Barrow et al. 1979). No significant changes in hematological parameters were observed in monkeys,
rats, or mice exposed to 2.3–2.5 ppm chlorine in chronic duration studies (Klonne et al. 1987; Wolf et al.
1995).
Musculoskeletal Effects. The only information regarding musculoskeletal effects and exposure to
chlorine is a report in which a 25-year-old man was diagnosed with myasthenia gravis manifested as
laryngeal stridor after accidental exposure to chlorine gas (Foulks 1981). Myasthenia gravis is an
autoimmune disorder that causes a reduction in the number and/or sensitivity of acetylcholine receptors at
the neuromuscular junction resulting in muscle weakness. Foulks (1981) speculated that the massive
exposure of the laryngeal muscles to chlorine may have altered the neuromuscular junction in a way that
caused an autoimmune stimulus that resulted in myasthenia gravis.
Exposure of monkeys to up to 2.3 ppm chlorine for 1 year or of rats and mice to up to 2.5 ppm for 2 years
did not produce gross or microscopic alterations in skeletal muscle (Klonne et al. 1987; Wolf et al. 1995).
Hepatic Effects. Very limited information was located regarding evaluation of liver end points in
patients after acute high exposure to chlorine. Leube and Kreiter (1971) reported that 1 day after exposure
to chlorine, 26 out of 65 patients (40%) had elevated serum ALT and 2 out of 13 (15%) had elevated
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serum aspartate aminotransferase (AST) values. Without any information on other factors that impact the
levels of these enzymes in serum, such as alcohol consumption, it is difficult to ascertain the toxicological
significance of this finding. Moulick et al. (1992) mention that measurements of serum AST activity in
patients admitted to the hospital following exposure to chlorine did not show any significant abnormality.
The exposure concentration was not known, but 2 hours after the massive leak, the level of chlorine was
found to be 66 ppm. Hasan et al. (1983) reported that subjects exposed to chlorine gas following a leak
from a liquid storage tank had normal liver function tests; the tests were not specified.
Liver congestion has been observed in rodents exposed to acute lethal concentrations of chlorine (i.e.,
Weedon et al. 1940), but generally, other low-concentration, acute-duration studies did not examine the
liver, or if they did, the findings were not reported. In an intermediate-duration study, rats exposed to
≥3 ppm chlorine, but not 1 ppm, 6 hours/day, 5 days/week for 6 weeks had cytoplasmic vacuolation in the
hepatocytes (Barrow et al. 1979). This was accompanied by a significant increase in serum alkaline
phosphatase at 3 and 9 ppm in males and females and an increase in serum alanine aminotransferase
(ALT) in females exposed to 9 ppm. In contrast, in a study of very similar design, rats exposed to up to
5 ppm chlorine 6 hours/day, 5 days/week for 62 days showed no significant histological alterations in the
liver (Kutzman 1983). The reason for this apparent discrepancy is not apparent.
Intermittent exposure of monkeys to up to 2.3 ppm chlorine for 1 year or of rats and mice to up to
2.5 ppm for 2 years did not produce gross or microscopic alterations in the liver (Klonne et al. 1987; Wolf
et al. 1995).
Renal Effects. No reports were located of renal effects in humans following inhalation exposure to
chlorine. However, it would have not been unexpected to find some abnormal indices of renal function in
individuals acutely exposed to high levels of chlorine as a consequence of severe cardiopulmonary
alterations.
Slight to moderate congestion of the kidneys was reported in male and female rats exposed intermittently
to 9 ppm chlorine for 6 weeks, but no significant alterations were seen in rats exposed to 3 ppm (Barrow
et al. 1979). Kutzman (1983) examined the kidneys of rats exposed to up to 5 ppm chlorine for 62 days
and reported no significant gross or microscopic alterations. Intermittent exposure of monkeys to up to
2.3 ppm chlorine for 1 year or of rats and mice to up to 2.5 ppm for 2 years did not produce gross or
microscopic alterations in the kidney (Klonne et al. 1987; Wolf et al. 1995).
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Endocrine Effects. No information was located regarding endocrine effects in humans following
inhalation exposure to chlorine. No gross or microscopic alterations were reported in the adrenals,
pancreas, parathyroid, pituitary, or thyroid gland from monkeys exposed to up to 2.3 ppm chlorine for
1 year (Klonne et al. 1987). Similarly, no gross or histological alterations were found in the pancreas,
parathyroid, pituitary, or thyroid from rats and mice exposed to up to 2.5 ppm chlorine for 2 years (Wolf
et al. 1995). No further information on endocrine effects in animals exposed to chlorine was located in
the literature.
Dermal Effects. Considering that chlorine is an irritating gas, very few reports have described skin
effects in subjects exposed to high concentrations of the gas. A health assessment of a population that
may have been exposed to up to 200 ppm chlorine after tanker cars derailed reported that skin rashes and
skin burns affected 16–25% of a total of 682 persons interviewed 2 weeks after the accident (Agency for
Toxic Substances and Disease Registry 1998). In another train derailment, some exposed subjects had
minor first-degree skin burns resulting from the vapor exposure (Joyner and Durel 1962). A health
evaluation report of firefighters that responded to a chlorine gas leak in Henderson, Nevada, mentions that
many of the firefighters complained of skin irritation (NIOSH 1995). During the incident, chlorine
concentrations in the air ranged from <0.2 to 17 ppm.
Studies in animals have not described skin alterations following exposure to chlorine gas, even in high
exposure acute-duration studies in which animals experienced whole-body exposures. In monkeys
exposed to up 2.3 ppm chlorine for 1 year, histological examination of samples of skin did not reveal any
significant exposure-related alterations (Klonne et al. 1987). The same negative observations were made
in rats and mice exposed to up to 2.5 ppm chlorine for 2 years (Wolf et al. 1995).
Ocular Effects. Almost all reports of acute exposure to high concentrations of chlorine mention eye
irritation (lacrimation, conjunctivitis, burning sensation) as one of the most prevalent complains among
the patients. These effects usually resolve within a few days after exposure. In a controlled exposure
study with volunteers, complaints of itching or burning of the eyes were significantly greater during
exposures to 1 ppm chlorine than during control exposures (Anglen 1981).
Swelling around the eyes was reported in rats exposed to 12 ppm chlorine 6 hours/day, 5 days/week for
10 days, but not for 5 days (Dodd et al. 1980). Ocular irritation was also reported in rats exposed
intermittently to 3 ppm chlorine for 6 weeks, but no irritation was apparent at 1 ppm (Barrow et al. 1979).
This is more or less consistent with the results of another intermediate-duration study that reported
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occasional signs of eye irritation in rats exposed to 1.5 ppm for 62 days and severe irritation in rats
exposed to 5 ppm chlorine (Kutzman 1983). Monkeys exposed intermittently to 2.3 ppm for 1 year
showed conjunctival irritation with some exudation at the end of the study, but there was no gross or
microscopic evidence of chronic changes in the conjunctiva or in the cornea (Klonne et al. 1987). No
ocular effects were observed in rats or mice exposed to up to 2.5 ppm chlorine for 2 years (Wolf et al.
1995).
Body Weight Effects. No relevant information was located regarding body weight effects in humans
following inhalation exposure to chlorine. Reduced body weight gain or weight loss has been commonly
reported in acute high-exposure studies in animals of enough duration to allow evaluation of weight
changes. Although rarely reported, the reduced growth or weight loss is largely due to reduced food
consumption. For example, rats exposed to 12 ppm chlorine 5 days/week for 2 weeks lost approximately
20% of their body weight during the second week relative to their starting weight (Dodd et al. 1980).
Pair-fed rats also lost weight, confirming that the effect in the chlorine-exposed rats was due to reduced
food intake. In another acute-duration study, rats exposed to 9.1 ppm chlorine for 3 or 5 days lost 11 and
13%, respectively, of the initial body weight (Jiang et al. 1983). Under the same exposure conditions,
mice lost 17 and 21% of the initial body weight (Jiang et al. 1983).
Similar results have been obtained in intermediate-duration studies. Final body weight of rats exposed to
9 ppm chlorine for 6 weeks (Barrow et al. 1979) or to 5 ppm for 62 days (Kutzman 1983) were >30%
lower than controls. Even a relatively low concentration of chlorine of 0.5 ppm for 62 days lowered body
weight in female rats by approximately 11% relative to controls (Kutzman 1983). Neither study provided
information on food or water consumption. Exposure of monkeys to 2.3 ppm chlorine for 1 year (Klonne
et al. 1987) or of rats and mice to 2.5 ppm for 2 years (Wolf et al. 1995) reduced body weight gain during
the studies, but the final weights, judging by figures in the papers, appeared to be <10% lower than the
respective controls.
3.2.1.3 Immunological and Lymphoreticular Effects
No studies were located that evaluated immunocompetence or effects on lymphoreticular organs in

humans following exposure to chlorine gas.
Minimal information is available from studies in animals. Barrow et al. (1979) reported that the spleen
and thymus from rats exposed to 9 ppm chlorine for 6 weeks had a decreased content of lymphoid
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elements, but no such changes were seen in rats exposed to 1 or 3 ppm. According to the investigators,
this may have been a function of the poor physical condition and decreased nutritional state of the rats in
that dosing group. In a very similar study, no histological alterations were reported in the spleen and
peribronchial lymph nodes from rats exposed to up to 5 ppm chlorine for 62 days (Kutzman 1983).
Studies in monkeys, rats, and mice also have found no gross or microscopic lesions in lymphoreticular
organs and tissues following intermittent chronic exposure to 2.3–2.5 ppm chlorine (Klonne et al. 1987;
Wolf et al. 1995).
The highest NOAEL values and all LOAEL values from each reliable study for lymphoreticular effects in
each species and duration category are recorded in Table 3-1 and plotted in Figure 3-1.
3.2.1.4 Neurological Effects
Symptoms effects such as headache, dizziness, anxiety, and syncope are commonly reported following
acute high exposures to chlorine and are thought to be due, at least in part, to asphyxia induced by
chlorine.
In a case of high exposure to chlorine that resulted in the death of the patient, postmortem examination
showed a swollen brain with flattening of convolutions and subarachnoid hemorrhage (Adelson and
Kaufman 1971). The investigators speculated that the lesions could have been caused by hypoxia that
resulted from the severe pulmonary effects. In another case report, a 60-year-old man who accidentally
inhaled chlorine gas in a swimming pool accident had a magnetic resonance scan of the head conducted
2 years after the accident that showed multiple areas of decreased signal in the periventricular white
matter (Levy et al. 1986). Other neurological tests showed no evidence of cranial nerve abnormalities or
sensory deficits. This brief communication does not mention what might have prompted the subject to
undergo the scan.
Kilburn (1995, 2000, 2003b) published a series of reports describing long-lasting neurological effects in
subjects accidentally exposed to high concentrations of chlorine gas under various scenarios. The earliest
study (Kilburn 1995) reported that six subjects exposed to an undetermined concentration of chlorine for
3 minutes to 5 hours had difficulty concentrating and sleeping, dizziness, loss of balance, excessive
fatigue, loss of strength, depression, and irritability during a period of 1–3 years after the accident.
Neurobehavioral tests were conducted 15–50 months after exposure and the results were compared to a
control group matched for sex, age, and education. It should be noted that the testers were aware of the
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exposure status of the subjects. The results showed impaired balance with the eyes closed and hearing
loss in all of the exposed subjects. Five had decreased vibration sensitivity, color discrimination, and
verbal recall; four had prolonged blink reflex latency; three had prolonged simple and choice reaction
times, and three had nerve defects or constricted visual fields. In a subsequent study, 22 patients exposed
briefly (the reports mentions seconds to a few minutes in one section and minutes to a few hours in
another section) to chlorine gas were evaluated with a battery of tests 7–48 months after exposure. A
total of 296 unexposed subjects served as controls. The results showed significant impairment among the
exposed group in a number of areas including balance, reaction time, color identification, visual field
performance, blink latency, cognition, verbal recall, and making trails. A similar study was conducted
with subjects exposed to chlorine as a result of a train derailment (see Agency for Toxic Substances and
Disease Registry [1998] under Respiratory Effects) (Kilburn 2003b). Ninety-seven subjects were tested
7 weeks after exposure and 57 were tested 3 years later; 26 were tested on both occasions. Seven weeks
after exposure, the exposed subjects showed impairment in five neurobehavioral functions compared with
unexposed subjects recruited for the 3-year testing. At 3 years, the patients showed impairment in seven
additional tests compared with controls. Because of lack of exposure data, these studies are not listed in
Table 3-1.
There are no studies in animals that could confirm or refute Kilburn’s findings mentioned above. The
only information regarding neurological effects of chlorine in animals is limited to reports of no gross or
microscopic alterations in the brain of rats exposed intermittently to up to 5 ppm chlorine for 62 days
(Kutzman 1983), or in the brain, spinal cord, and sciatic nerve of rats and mice exposed to up to 2.5 ppm
chlorine for 2 years (Wolf et al. 1995). Also, in monkeys exposed intermittently for 1 year to up to
2.3 ppm chlorine, there were no gross or histological alterations in central or peripheral nervous system
tissues (Klonne et al. 1987). The investigators also mentioned that clinical observational neurological
examinations conducted in the monkeys prior to sacrifice were unremarkable, but the scope of these tests
was not specified.
The highest NOAEL values from each reliable study for neurological effects in each species and duration
category are recorded in Table 3-1 and plotted in Figure 3-1.
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3.2.1.5 Reproductive Effects
The only information available regarding effect in humans is that evaluation of the outcome of
15 pregnancies among female workers at a chlorine plant in 1932–1933 did not provide any evidence of
reproductive toxicity (Skljanskaya et al. 1935).
In an intermediate-duration inhalation study, male and female rats were exposed intermittently to up to
5 ppm chlorine for 62 days (Kutzman 1983). At the end of the exposure period, 8 exposed males were
mated with unexposed females and 10 exposed females were mated with unexposed males and all females
were sacrificed on gestation day 19 for evaluation of reproductive end points. The results showed no
significant effects of chlorine exposure on fertility, number of corpora lutea, viable embryos, early or late
deaths, or pre-implantation loses. In addition, in males exposed for 62 days, there were no histological
alterations in the testes, and sperm morphology was unremarkable.
In chronic-duration studies, exposure of male and females monkeys for 1 year or male and female rats and
male mice for 2 years to up to 2.5 ppm chlorine did not result in gross or microscopic alterations of the
reproductive organs (Klonne et al. 1987; Wolf et al. 1995). Female mice developed a concentration-
related increase in ovarian abscesses and of suppurative inflammation of the uterus. Without a further
discussion, the investigators stated that it was unlikely that chlorine induced the inflammatory response,
but no alternative explanation was provided.
The highest NOAEL values from each reliable study for reproductive effects in each species and duration
3.2.1.6 Developmental Effects
In a summary of the limited information available, WHO (1982) reports that early studies from the
Russian literature found no evidence of teratogenic in offspring from effects female workers at a chlorine
plant in 1932–1933 and that rabbits exposed to low chlorine concentrations (0.6–1.6 ppm) during
pregnancy gave birth to healthy offspring. No additional information was located regarding
developmental effects in animals following inhalation exposure to chlorine.
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3.2.1.7 Cancer
There are several studies of cancer in humans that involve exposure to chlorine, among other chemicals,
in occupational settings.
A study of 28 employees at a Texas chemical plant who had died of primary intracranial neoplasms found
no evidence that exposure to chlorine may have played a role (Bond et al. 1983). Chlorine was one of the
chemicals to which cases and controls had the most frequent potential for exposure. Bond et al. (1985)
conducted a case-control study of 26 renal cancer deaths among employees of a multiple process
chemical production facility. Although an increased odds ratio (OR) for renal cancer was found in a
chlorine production area, it was not attributed to chlorine exposure, but to asbestos and caustic materials.
In addition, in the magnesium processing area, where large amounts of chlorine were used, there was a
decreased risk of renal cancer. A nested case-control study of 306 lung cancer deaths among
19,608 employees of a chemical plant provided no evidence that chlorine had a role in the deaths (Bond et
al. 1986). The OR for chlorine exposure was 1.08 (95% confidence interval [CI], 0.81–1.44).
A study of 51 lung cancer cases at a dye and resin manufacturing plant reported an increased OR for lung
cancer for employees who were seen at the plant infirmary for acute exposure to chlorine after adjusting
for smoking (OR=27; 95% CI, 3.5–205) (Barbone et al. 1992). However, the number of cases was small
(6 cases versus 3 out of 102 controls), and four of the six cases worked in the anthraquinone dye and
epichlorohydrin production area. Barbone et al. (1992) stated that based on small number of cases, the
small association between lung cancer and acute exposure to chlorine may be due to chance or to
confounding by other unidentified exposures.
In a larger study of 2,391 male workers producing magnesium metal, Heldaas et al. (1989) found 4 cases
of lung cancer versus 1.3 expected in a subset of workers who experienced chlorine intoxication and had
at least 20 years since first employment (95% CI, 0.8–7.8). However, the rate ratios for lung cancer were
higher in those workers who were not registered in the chlorine exposure list. The authors speculated that
the use of respiratory protective gear (mouthpieces) may have been a reason for the difference.
In a study of 1,190 workers at chlor alkali plants, there was a marginally significant excess of lung
cancers (10 observed versus 4.9 expected; 95% CI, 1.0–3.8) which, according to the authors, was possibly
due to previous use of asbestos (Barregård et al. 1990). Jäppinen et al. (1987) conducted a retrospective
cohort study of 3,545 workers in the Finnish pulp and paper industry and found 78 cases of lung cancer
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versus 62.6 expected (95% CI, 98–155). The excess was most prominent in board mill workers
(40 observed versus 18.1 expected; 95% CI, 158–302), particularly after 20 years of latency (25 observed
versus 7.8 expected; 95% CI, 209–476). However, there is no mention in the study of the chemicals to
which the various subcohorts (based on work histories) may have been more intensely exposed.
Only the study by Wolf et al. (1995) provided information on carcinogenicity of inhaled chlorine in
animals. In that study, male and female rats and mice were exposed intermittently to up to 2.5 ppm
chlorine for 2 years. Gross and histological examination of all major tissues and organs, including the
nasal cavity at five levels did not show any biologically or statistically significant increase in neoplasms.
The EPA, the International Agency for Research on Cancer (IARC), and the Department of Health and
Human Services (DHHS) have not classified chlorine gas as to its carcinogenicity.
3.2.2 Oral Exposure
Studies that used tap water as the medium for delivery of chlorine to experimental animals are not
included in this section to eliminate potential confounding effects of chlorination byproducts.
Although people are not likely to be exposed to chlorine itself through oral routes, there are reports of
accidental or intentional exposure to bleach (typically a 3–6% solution of sodium hypochlorite).
Information from some of those reports is also included in this section.
3.2.2.1 Death
Human deaths have been reported following ingestion of sodium hypochlorite. In a review of the
literature, Racioppi et al. (1994) state that the lethal dose of sodium hypochlorite in adults has been
reported to be approximately 200 mL of a solution containing 3–6% chlorine. Racioppi et al. (1994) also
indicate that the aspiration of bleach in the lungs following ingestion as been reported as the cause of
fatalities. Ross and Spiller (1999) described a fatal case of a 66-year-old woman who ingested an
unknown quantity of bleach and died of cardiac arrest 4.5 hours after the bleach ingestion. Autopsy
revealed esophageal and gastric mucosal erosions, perforations at the gastroesophageal junction, and
extensive necrosis of adjacent soft tissue. Jakobsson et al. (1991) reported the case of a fatal poisoning in
a 1-year-old girl after ingestion of a household cleanser containing 4.5% sodium hypochlorite in an
alkaline solution. Examination of the upper gastrointestinal tract showed severe gross and microscopic
damage. According to unpublished information reviewed by Racioppi et al. (1994), the oral LD50 for a
CHLORINE 76
3. HEALTH EFFECTS
5.25% solution of sodium hypochlorite household bleach in rats is 13,000 mg/kg; for a 13% solution,
LD50 values of 5,000 and 8,200 mg/kg are listed. A review of the literature by BG-Chemie (1991)
indicates that LD50 values of 6,800 and 5,800 mg/kg were determined for male and female ddY rats,
respectively.
The highest NOAEL values and all LOAEL values from each reliable study for systemic effects in each
species and duration category are recorded in Table 3-3 and plotted in Figure 3-2.
Respiratory Effects. Respiratory rate was not altered in a group of 10 volunteers who drank
0.5 L/day of drinking water containing 5 mg/L chlorine for 12 weeks (Lubbers et al. 1982). This
corresponds approximately to doses of 0.036 mg Cl/kg/day, assuming a body weight of 70 kg.
Evaluations of the respiratory rate were done weekly during the dosing period and continued for an
additional 8 weeks post-dosing. Since the study did not control for non-experimental ingestion of
chlorine by the volunteers, the total daily dose of chlorine consumed is likely to have been higher than
0.036 mg Cl/kg/day. In a review of the literature, Racioppi et al. (1994) mention the case of a woman
who developed aspiration pneumonitis after ingesting an unknown amount of hypochlorite bleach.
Bracco et al. (2005) described a similar case. In this case, chest x-rays performed 2 hours after
intoxication showed bilateral bibasal infiltrate suggestive of aspiration pneumonia. Over the next
24 hours, the patient’s respiratory condition declined and she required ventilatory support. The patient
eventually recovered after 26 days of mechanical ventilation. In the fatal case of bleach ingestion
described by Jakobsson et al. (1991), microscopic examination of the lungs showed aspiration of
epithelium derived from the upper respiratory tract, and signs of acute bronchitis.
Limited data on respiratory effects are available in animals. Ninety-day drinking water studies in
Sprague-Dawley rats (Daniel et al. 1990) and B6C3F1 mice (Daniel et al. 1991) dosed with up to 24.9 and
39.2 mg Cl/kg/day, respectively, reported no gross or microscopic alterations in the lungs, trachea, and
nasal turbinates. Furukawa et al. (1980) also reported no significant histological alterations in the lungs
and bronchial tube of F344 rats dosed with up to 85 mg Cl/kg/day for 92 days. Similar results were
reported in chronic-duration studies in F344 rats (Hasegawa et al. 1986; NTP 1992) and B6C3F1 mice
(NTP 1992). Rats received doses of up to 133 mg Cl/kg/day and mice received doses up to 24.2 mg
Cl/kg/day for 2 years.
Table 3-3 Levels of Significant Exposure to Hypochlorite Solution - Oral
CHLORINE
Exposure/ LOAEL
Duration/
(Route)
Figure (Strain) System (mg/kg/day) (mg/kg/day) (mg/kg/day) Chemical Form Comments
ACUTE EXPOSURE
Systemic
1 Rat once Chang et al. 1981 No other end points
Hepatic 20 M (increased
(Sprague- (G) triacylglycerols in whole were evaluated.
Dawley) liver homogenate)
20
88
2 Rat 14 d Cunningham 1980 Only organ weight was

Cardio 200 F
(Wistar) (GW) 200
assessed.
79
Hepatic 200 F
200
Renal 200 F
3. HEALTH EFFECTS
200
Bd Wt 200 F
200
Neurological
3 Rat 14 d Cunningham 1980 Only brain weight was
200 F
(Wistar) (GW) 200
assessed.
80
INTERMEDIATE EXPOSURE
Systemic
4 Human 4 wk Wones et al. 1993 NOAELs are for serum
Hepatic 0.4
(W) 0.4
thyroid hormones and
serum lipid profile.
85
Endocr 0.4
0.4
5 Rat 12 mo Abdel-Rahman et al. 1984

Hemato 12 M
(Sprague- (W) 12
Dawley)
73
77
Table 3-3 Levels of Significant Exposure to Hypochlorite Solution - Oral (continued)
CHLORINE
Exposure/ LOAEL
Duration/
a
Frequency Reference
(Route)
6 Rat 66-76 d Carlton et al. 1986 NOAELs are for blood

Hemato 3.4
(Long- Evans) (GW) 3.4
counts and serum
thyroid hormone
levels.
82
Endocr 3.4
3.4
Bd Wt 3.4
3.4
7 Rat 6 wk Cunningham 1980
Bd Wt 15.7 M
(Wistar) (W)
15.7
3. HEALTH EFFECTS
78
8 Rat 90 d Daniel et al. 1990 NOAELs are for gross

Resp 24.9 F
(Sprague- (W) 24.9
and microscopic
Dawley) evaluation of tissues
and organs, and
hematology and clinical
chemistry.
65
Cardio 24.9 F
24.9
Gastro 24.9 F
24.9
Hemato 24.9 F
24.9
Musc/skel 24.9 F
24.9
Hepatic 24.9 F
24.9
Renal 24.9 F
24.9
Endocr 24.9 F
24.9
Dermal 24.9 F
24.9
Bd Wt 24.9 F
24.9
78
CHLORINE
Exposure/ LOAEL
Duration/
a
Frequency Reference
(Route)
9 Rat 8 wk Exon et al. 1987
Bd Wt 4.1 M
(Sprague- (W)
4.1
Dawley)
74
10 Rat 92 d Furukawa et al. 1980 NOAELs are for

Resp 85 M
(Fischer- 344) (W) 85
histopathology of
hypochlorous acid and sodium tissues and organs,
hypochlorite clinical chemistry and
hematology.
99
Cardio 52 F 84 F (endocardial hyperplasia;
3. HEALTH EFFECTS
myocardial fibrosis)
52
84
Gastro 85 M
85
Hemato 85 M
85
Hepatic 85 M
85
Renal 85 M
85
Endocr 85 M
85
Dermal 85 M
85
Bd Wt 26 M 50 M (19% reduction in final 85 M (46% reduction in final

body weight) body weight)
26
50 85
11 Rat 13 wk Hasegawa et al. 1986 Only body weight is

Bd Wt 76 152 M (final body weight 305 M (final body weight
(Fischer- 344) (W) 76
reduced 19%) reduced 47%) listed due to

incomplete reporting of
152 305
other end points.
86
79
CHLORINE
Exposure/ LOAEL
Duration/
a
Frequency Reference
(Route)
12 Mouse 90 d Daniel et al. 1991 NOAELs are for gross

Resp 39.2 F
(B6C3F1) (W) 39.2
and histological
evaluation of tissues
and organs, adn
hematology and clinical
chemistry.
69
Cardio 39.2 F
39.2
Gastro 39.2 F
39.2
Hemato 39.2 F
3. HEALTH EFFECTS
39.2
Musc/skel 39.2 F
39.2
Hepatic 39.2 F
39.2
Renal 39.2 F
39.2
Endocr 39.2 F
39.2
Dermal 39.2 F
39.2
Bd Wt 39.2 F
39.2
13 Gn Pig 5 wk Cunningham 1980
Bd Wt 26 M
(albino) (W)
26
77
Immuno/ Lymphoret
14 Rat 90 d Daniel et al. 1990 NOAEL is for gross and
24.9 F
(Sprague- (W) 24.9
microscopic evaluation
Dawley) of lymphoreticular
organs.
66
80
CHLORINE
Exposure/ LOAEL
Duration/
a
Frequency Reference
(Route)
15 Rat 8 wk Exon et al. 1987 Some reported

4.1 M
(Sprague- (W) 4.1
changes in immune
Dawley) parameters of unknown
toxicological
significance were not
considered adverse.
75
16 Rat 92 d Furukawa et al. 1980 NOAEL is for gross and

85 F
(Fischer- 344) (W) 85
hypochlorous acid and sodium of lymphoreticular
hypochlorite organs.
3. HEALTH EFFECTS
100
17 Mouse 90 d Daniel et al. 1991 NOAEL is for gross and

39.2 F
(B6C3F1) (W) 39.2
histological evaluation
of lymphoreticular
organs.
70
Neurological
24.9 F
(Sprague- (W) 24.9
Dawley) of the brain and sciatic
nerve.
67

85 F
(Fischer- 344) (W) 85
microscopic
hypochlorous acid and sodium examination of the
hypochlorite brain.
101
81
CHLORINE
Exposure/ LOAEL
Duration/
a
Frequency Reference
(Route)

39.2 F
(B6C3F1) (W) 39.2
of the brain and sciatic
nerve.
71
Reproductive
21 Rat 66-76 d Carlton et al. 1986 NOAEL is for fertility
3.4
and histopathology of
the reproductive tract.
81
3. HEALTH EFFECTS
24.9 F
(Sprague- (W) 24.9
Dawley) of reproductive organs.
68

85 F
(Fischer- 344) (W) 85
hypochlorous acid and sodium of reproductive organs.
hypochlorite
102

39.2 F
(B6C3F1) (W) 39.2
of reproductive organs.
72
Developmental
25 Rat 42 d Carlton et al. 1986 NOAEL is for litter
3.4
viability and size and
pup weight.
83
82
CHLORINE
Exposure/ LOAEL
Duration/
a
Frequency Reference
(Route)
CHRONIC EXPOSURE
Systemic
26 Rat 2 yr Hasegawa et al. 1986 NOAELs are for gross
Resp 133 F
(Fischer- 344) (W) 133
and microscopic
alterations in organs
and tissues.
58
Cardio 133 F
133
Gastro 133 F
133
Hemato 133 F
133
Hepatic 133 F
3. HEALTH EFFECTS
133
Renal 133 F
133
Endocr 133 F
133
Dermal 133 F
133
Ocular 133 F
133
Bd Wt 67 F (11% reduction in final
body weight)
67
83
CHLORINE
Exposure/ LOAEL
Duration/
a
Frequency Reference
(Route)
27 Rat 2 yr NTP 1992 NOAELs are for

Resp 14.4 F
(Fischer- 344) (W) 14.4
histopathology of
tissues and organs and
hematology
parameters.
48
Cardio 14.4 F
14.4
Gastro 14.4 F
14.4
Hemato 14.4 F
14.4
3. HEALTH EFFECTS
Hepatic 14.4 F
14.4
Renal 14.4 F
14.4
Endocr 14.4 F
14.4
Dermal 14.4 F
14.4
Bd Wt 14.4 F
14.4
Other 14.4 F
14.4
84
CHLORINE
Exposure/ LOAEL
Duration/
a
Frequency Reference
(Route)
28 Mouse 2 yr NTP 1992 NOAELs are for

Resp 24.2 F
(B6C3F1) (W) 24.2
histopathology of
tissues and organs and
hematology
parameters.
49
Cardio 24.2 F
24.2
Gastro 24.2 F
24.2
Hemato 24.2 F
24.2
3. HEALTH EFFECTS
Hepatic 24.2 F
24.2
Renal 24.2 F
24.2
Endocr 24.2 F
24.2
Dermal 24.2 F
24.2
Bd Wt 24.2 F
24.2
Other 24.2 F
24.2
Immuno/ Lymphoret
29 Rat 2 yr Hasegawa et al. 1986 NOAEL is for gross and
133 F
(Fischer- 344) (W) 133
microscopic
appearence of the
spleen.
59
30 Rat 2 yr NTP 1992 NOAEL is for

14.4 F
(Fischer- 344) (W) 14.4
histopathology of
lymphoreticular organs.
50
85
CHLORINE
Exposure/ LOAEL
Duration/
a
Frequency Reference
(Route)
31 Mouse 2 yr NTP 1992 NOAEL is for

24.2 F
(B6C3F1) (W) 24.2
histopathology of
lymphoreticular organs.
53
Neurological
133 F
(Fischer- 344) (W) 133
microscopic
appearence of the
brain.
60
3. HEALTH EFFECTS
14.4 F
(Fischer- 344) (W) 14.4
histopathology of
various brain areas.
51
34 Mouse 2 yr NTP 1992 NOAELs are for

24.2 F
(B6C3F1) (W) 24.2
histopathology of
various brain areas.
54
Reproductive
133 F
(Fischer- 344) (W) 133
microscopic
appearence of the
reproductive organs.
61

14.4 F
(Fischer- 344) (W) 14.4
histopathology of
52
86
CHLORINE
Exposure/ LOAEL
Duration/
a
Frequency Reference
(Route)
37 Mouse 2 yr NTP 1992 NOAEL is for

24.2 F
(B6C3F1) (W) 24.2
histopathology of
55
a The number corresponds to entries in Figure 3-2.
Bd Wt = body weight; Cardio = cardiovascular; d = day(s); Endocr = endocrine; F = Female; Gastro = gastrointestinal; Gn pig = guinea pig; (GW) = gavage in water; Hemato =
hematological; Immuno/Lymphoret = immunological/lymphoreticular; LOAEL = lowest-observed-adverse-effect level; M = male; mo = month(s); Musc/skel = musculoskeletal; NOAEL
= no-observed-adverse-effect level; Resp = respiratory; (W) = drinking water; wk = week(s); yr = year(s)
3. HEALTH EFFECTS
87
Figure 3-2 Levels of Significant Exposure to Hypochlorite Solution - Oral
Acute (≤14 days)
CHLORINE
Systemic
r
cula ht al
as eig gic
iov tic al yW ro
lo
rd pa n d u
Ca He Re Bo Ne
mg/kg/day
1000
3. HEALTH EFFECTS
2r 2r 2r 2r 3r
100
1r
10
88
Figure 3-2 Levels of Significant Exposure to Hypochlorite Solution - Oral (Continued)
Intermediate (15-364 days)

CHLORINE
Systemic

r
lar na
l l tal ho l
u ti gic
a le t
ym
p l ve nta
ry sc tes ke igh gic
a ti e
ato va in olo los c r ine l e o/L lo uc pm
pir dio tro at cu ati al oc ma yW un ro od lo
s r s m s p n d r d m u pr ve
Re Ca Ga He Mu He Re En De Bo Im Ne Re De
mg/kg/day
1000
11r
11r
100
10r 10r 10r 10r 10r 10r 10r 10r 10r 16r 19r 23r
11r
3. HEALTH EFFECTS
10r 10r
12m 12m 12m 12m 12m 12m 12m 12m 12m 12m 17m 20m 24m
8r 8r 8r 8r 8r 8r 8r 8r 8r 13g 8r 10r 14r 18r 22r
7r
5r
10
9r 15r
6r 6r 6r 21r 25r
4 4
0.1
89
Figure 3-2 Levels of Significant Exposure to Hypochlorite Solution - Oral (Continued)
CHLORINE
Systemic

r
lar n al a l p ho
u ti gic
t
ym al e
ry sc tes ne igh gic tiv
ato va in to lo c ri l e o/L lo duc
spir rdio str
o
ma p ati nal doc rma ula
r
dyW h er mu
n
uro pro
Re Ca Ga He He Re En De Oc Bo Ot Im Ne Re
mg/kg/day
1000
3. HEALTH EFFECTS
26r 26r 26r 26r 26r 26r 26r 26r 26r 29r 32r 35r
100
26r
28m 28m 28m 28m 28m 28m 28m 28m 28m 28m 31m 34m 37m
27r 27r 27r 27r 27r 27r 27r 27r 27r 27r 30r 33r 36r
10
90
CHLORINE 91
3. HEALTH EFFECTS
Cardiovascular Effects. In the study by Lubbers et al. (1982) in volunteers mentioned above,
drinking water that provided 0.036 mg Cl/kg/day for 12 weeks did not alter systolic or diastolic blood
pressure or pulse rate, and electrocardiograms were unremarkable. No additional relevant information
was located regarding cardiovascular effects in humans following oral exposure to hypochlorite solutions.
A 14-day study in which Wistar rats were dosed by gavage with sodium hypochlorite in milk (up to
200 mg Cl/kg/day) reported no significant alterations in heart weight, but no additional cardiovascular
parameters were examined (Cunningham 1980). Two intermediate-duration studies reported no
significant gross or microscopic alterations in the heart and aorta from rats and mice exposed to up to
24.9 and 39.2 mg Cl/kg/day, respectively, for 90 days (Daniel et al. 1990, 1991). Furukawa et al. (1980)
reported that endocardial hyperplasia and fibrosis of the myocardium were observed in male and female
F344 rats dosed with approximately 84 mg Cl/kg/day in the drinking water for 92 days. No such effects
were seen in rats dosed with approximately 50 mg Cl/kg/day. Two-year studies also did not find
histological alterations in the heart from rats and mice that received doses of up to 133 and 24.2 mg
Cl/kg/day, respectively (Hasegawa et al. 1986; NTP 1992).
Gastrointestinal Effects. In general, ingestion of small amounts (less than a cup) of sodium
hypochlorite bleach (approximately 5.3% sodium hypochlorite) does not cause serious or permanent
damage to the upper gastrointestinal tract. Pike et al. (1963) reviewed 129 cases of children who ingested
Clorox® and reported that no complications of consequences were found. Sixty-five cases were examined
by esophagoscopy within 96 hours of the ingestion and only 2 showed evidence of esophageal injury.
The children were between 12 month and 7 years old and the amounts of bleach ingested ranged from
“½ ounce to 1 cup.” Landau and Saunders (1964) state that among 393 children who ingested bleach and
were seen at a hospital, there were no esophageal strictures or perforations, and about 50% of the patients
received no treatment. Hook and Lowry (1974) reported that among 23 definite cases of children who
ingested Clorox®, severe irritation of the esophageal mucosa was observed in only 1 case. Minor
transient irritation was observed in some of the patients. A report from the German literature of
23 children who accidentally ingested 3–5% sodium hypochlorite indicates that there was only 1 case
with signs of superficial burns in the esophagus, which had disappeared 2 weeks later when controlled by
esophagoscopy (Mühlendahl et al. 1978). Liquid bleach is a strong emetic, which helps reduce the time
of residence in the stomach, but on the other hand, it increases the potential for aspiration.
CHLORINE 92
3. HEALTH EFFECTS
Examination of fatal cases following ingestion of unknown quantities has revealed esophageal and gastric
mucosal erosions, perforations at the gastroesophageal junction, and extensive necrosis of adjacent soft
tissue (Ross and Spiller 1999). In a fatal case of a child who drank 4.5% sodium hypochlorite in an
alkaline solution (pH 12), severe gross lesions were seen in the mouth, tongue, glottis, epiglottis,
esophagus, and stomach (Jakobsson et al. 1991). Glottic and subglottic edema was described by Babl et
al. (1998) in a child who drank household bleach from a cup.
In some earlier studies in animals, commercial bleach was administered through a tube directly into the
esophagus and, in some cases, the distal end of the esophagus was artificially occluded to prolong and
control the contact time between the solution and the mucosa (Hook and Lowry 1974; Landau and
Saunders 1964; Strange et al. 1951; Yarington 1970). For example, commercial bleach placed in the
esophagus of 151 dogs for several minutes caused the immediate death of 8 dogs from perforations into
their pleural cavities (Landau and Saunders 1964). Necropsy performed 3 months later on the seven dogs
that survived revealed no abnormalities. Yarington (1970) reported that, in dogs, the minimum amount of
bleach that caused a burn in the esophagus was 10 cm3 applied over a 5-minute period. A volume of
30 cm3 applied for 2 minutes caused minimal edema of the esophagus.
Few more recent studies are available. Gross and microscopic examination of multiple levels of the
gastrointestinal tract of Sprague-Dawley rats that drank water that provided up to 24.9 mg Cl/kg/day for
90 days did not reveal any significant gross or microscopic alterations (Daniel et al. 1990). The same
negative results were reported in F344 rats and B6C3F1 mice that drank water with up to 85 mg Cl/kg/day
or 39.2 mg Cl/kg/day, respectively, for 90 days (Daniel et al. 1991; Furukawa et al. 1980). Two-year
studies also did not find histological alterations in the gastrointestinal tract from F344 rats and B6C3F1
mice that received doses of up to 133 and 24.2 mg Cl/kg/day, respectively (Hasegawa et al. 1986; NTP
1992).
Hematological Effects. No significant treatment-related alterations in a comprehensive number of

hematological parameters were reported in volunteers who drank 0.5 L/day of drinking water containing
5 mg/L chlorine (approximately 0.036 mg Cl/kg/day) for 12 weeks (Lubbers et al. 1982).
A 12-month study in Sprague-Dawley rats exposed to approximately 12 mg Cl/kg/day reported alterations

in red blood cell fragility at various times during the study; however, the alterations were sporadic and not
dose- or duration-related, and varied in direction suggesting that they may have not been caused by
exposure to chlorine (Abdel-Rahman et al. 1984). Red blood cell count and hematocrit were reduced
CHLORINE 93
3. HEALTH EFFECTS
significantly after 3 months of treatment with 12 mg Cl/kg/day, but not at lower doses of chlorine
(0.12 and 1.2 mg Cl/kg/day). Evaluations conducted after 6 months of treatment showed no significant
difference in hematology parameters between treated and control groups (Abdel-Rahman et al. 1984). In
another intermediate-duration study, exposure of male and female Long-Evans rats to up to 3.4 mg
Cl/kg/day did not induce significant alterations in blood cell counts (Carlton et al. 1986). In yet
additional studies, standard hematology parameters were not significantly altered in rats or mice dosed
with up to 85 and 39.2 mg Cl/kg/day, respectively, for 90 days (Daniel et al. 1990, 1991; Furukawa et al.
1980). Hematology parameters were also evaluated in F344 rats and B6C3F1 mice after 14–15 and
66 months of treatment with chlorine in the 2-year drinking water bioassay (NTP 1992) and at termination
in the Hasegawa et al. (1986) study in F344 rats. The results showed no significant treatment-related
alterations in rats dosed with ≤133 mg Cl/kg/day or in mice dosed with ≤24.2 mg Cl/kg/day.
Musculoskeletal Effects. No information was located regarding musculoskeletal effect in humans

following oral exposure to hypochlorite and limited information is available in animals. No significant
gross or microscopic alterations were seen in skeletal muscle and sternebrae from Sprague-Dawley rats
following exposure to up to 24.9 mg Cl/kg/day in the drinking water for 90 days (Daniel et al. 1990).
Similar results were reported in B6C3F1 mice exposed to up to 39.2 mg Cl/kg/day for 90 days (Daniel et
al. 1991). The 2-year NTP (1992) study reported no significant alterations in the femur from F344 rats or
B6C3F1 mice that received up to 14.4 or 24.2 mg Cl/kg/day, respectively, in the drinking water.
Hepatic Effects. Serum chemistry tests used to evaluate liver function did not reveal any significant
alteration in volunteers during 12 weeks of exposure to approximately 0.036 mg Cl/kg/day in the drinking
water and during a period of 8 weeks after exposure ceased (Lubbers et al. 1982). In another study of
controlled exposure in volunteers, exposure to approximately 0.4 mg Cl/kg/day in the drinking water for
4 weeks had no significant effect on the lipid profile in serum (Wones et al. 1993).
Very limited information is available regarding liver effects in acute-duration oral studies in animals.
Liver weight was not significantly altered in Wistar rats after 14 days of daily gavage doses of sodium
hypochlorite in milk (up to 200 mg Cl/kg/day) (Cunningham 1980); no other liver parameter was
monitored in this study. In another study of limited scope, triacylglycerols were significantly increased in
whole liver homogenates from rats 2 days after a single gavage dose of approximately 20 mg Cl/kg
(Chang et al. 1981). Ten days after dosing, the levels of triacylglycerols had returned to pre-dosing
levels.
CHLORINE 94
3. HEALTH EFFECTS
No significant gross or microscopic alterations were seen in the liver of Sprague-Dawley rats, F344 rats,
or B6C3F1 mice exposed to up to 24.9, 85, and 39.2 mg Cl/kg/day, respectively, in the drinking water for
90 days (Daniel et al. 1990, 1991; Furukawa et al. 1980). Levels of serum liver enzymes also were not
significantly affected by treatment. Similarly, no significant hepatic effects were reported in F344 rats or
B6C3F1 mice that received up to 133 or 24.2 mg Cl/kg/day, respectively, in the drinking water for 2 years
(Hasegawa et al. 1986; NTP 1992). Clinical chemistry tests conducted at termination in rats in the
Hasegawa et al. (1986) study did not provide any indication of liver toxicity.
Renal Effects. The only relevant information regarding renal effects in humans following oral
exposure to hypochlorite is that urinalysis performed weekly on volunteers during a 12-week controlled
intake of approximately 0.036 mg Cl/kg/day and during a subsequent period of 8 weeks after treatment
was unremarkable (Lubbers et al. 1982).
The only information available in acute-duration oral studies in animals is that kidney weight was not
altered in rats in a 14-day study in which received daily doses of up to 200 Cl/kg/day by gavage in milk
(Cunningham 1980). No other renal parameter was evaluated. No significant gross or microscopic
alterations were seen in the kidney of Sprague-Dawley rats, F344 rats, or B6C3F1 mice exposed to up to
24.9, 85, and 39.2 mg Cl/kg/day, respectively, in the drinking water for 90 days (Daniel et al. 1990, 1991;
Furukawa et al. 1980). However, Furukawa reported increased incidence of gross abnormalities (no
further details provided) in the bladder of rats in all treated groups (8–85 mg Cl/kg/day) in the 90-day
study. No significant kidney effects were reported in F344 rats or B6C3F1 mice that received up to 133 or
24.2 mg Cl/kg/day, respectively, in the drinking water for 2 years (Hasegawa et al. 1986; NTP 1992).
Endocrine Effects. A study in male and female volunteers who consumed daily for 4 weeks 1.5 L of
distilled water that provided a dose of approximately 0.4 mg Cl/kg/day reported that there was a slight
reduction in serum levels of thyroxine (T4) and triiodothyronine (T3) in men, which was not accompanied
by any meaningful change in thyroid-stimulating hormone (TSH) levels (Wones et al. 1993). In another
study in volunteers, ingestion of approximately 0.036 mg Cl/kg/day in the drinking water for 12 weeks
did not significantly alter serum levels T3 or T4 (Lubbers et al. 1982).
No information was located regarding endocrine effects in acute-duration studies in animals. In an

intermediate-duration reproductive study in male and female Long-Evans rats, dosing with up to
3.4 mg Cl/kg/day by gavage (hypochlorous acid) had no significant effect on serum thyroid hormone
(unspecified) levels in males or females (Carlton et al. 1986). In the 90-day drinking water studies in
CHLORINE 95
3. HEALTH EFFECTS
Sprague-Dawley and F344 rats and B6C3F1 mice administered up to 24.9, 85, and 39.2 mg Cl/kg/day,
respectively, there were no gross or microscopic alterations in the pancreas, adrenals, pituitary, thyroid,
and parathyroid glands (Daniel et al. 1990, 1991; Furukawa et al. 1980). Similar results were obtained in
the 2-year drinking water bioassay in F344 rats and B6C3F1 mice (NTP 1992). Rats were exposed to up
to 14.4 mg Cl/kg/day and mice were exposed to up to 24.2 mg Cl/kg/day. Hasegawa et al. (1986) also
reported no alterations in the adrenal glands from F344 rats exposed to up 133 mg Cl/kg/day in the
drinking water for 2 years.
Dermal Effects. No information was located regarding dermal effects in humans following oral
exposure to hypochlorite solutions. The skin of rats and mice was examined in the 90-day (Daniel et al.
1990, 1991; Furukawa et al. 1980) and 2-year drinking water studies (Hasegawa et al. 1986; NTP 1992)
and no significant gross or microscopic alterations related to treatment with chlorine were reported. In
the 90-day studies, high doses in rats and mice were approximately 85 and 39.2 mg Cl/kg/day,
respectively. In the 2-year studies, high doses in rats and mice were 133 and 24.2 mg Cl/kg/day.
Ocular Effects. No studies were located regarding ocular effects in humans following oral exposure
to hypochlorite solutions. The only information from studies in animals is that exposure of F344 rats to
up to 133 mg Cl/kg/day for 2 years did not increase the incidence of cataracts (Hasegawa et al. 1986).
The eyes were not examined in rats or mice in the 90-day studies (Daniel et al. 1990, 1991) or in the NTP
(1992) 2-year study.
Body Weight Effects. No studies were located regarding body weight effects in humans following
oral exposure to hypochlorite solutions. Reduced growth was not observed in Wistar rats that received
200 mg Cl/kg/day (from sodium hypochlorite) by gavage in milk for 14 days (Cunningham 1980). Body
weight was also not affected in Sprague-Dawley rats and B6C3F1 mice exposed to up to 24.9 and 39.2 mg
Cl/kg/day, respectively, in the drinking water for 90 days (Daniel et al. 1990, 1991) or in F344 rats and
B6C3F1 mice exposed to up to 14.4 and 24.2 mg Cl/kg/day, respectively, in the drinking water for 2 years
(NTP 1992). Hasegawa et al. (1986) reported that male Fisher-24 rats exposed to approximately 152 or
305 mg Cl/kg/day (from sodium hypochlorite) in the drinking water for 90 days had reductions of 19 and
47% in final body weight compared with control rats; however, neither food nor water consumption data
were provided in the study. In another 90-day study, male F344 dosed with approximately 50 mg
Cl/kg/day (as sodium hypochlorite) in water had a final body weight 19% lower than controls; this group
of rats also consumed 42% less water daily than controls (Furukawa et al. 1980). Rats dosed with 84 mg
Cl/kg/day consumed 66% less water than controls and their final body weight was 46% lower than
CHLORINE 96
3. HEALTH EFFECTS
controls (Furukawa et al. 1980). In the 2-year study conducted by the same investigators, final body
weights were reduced 11 and 20% in female rats dosed with 67 and 133 mg Cl/kg/day, respectively. The
investigators stated that in high-dose females water intake was somewhat lower (no quantitative data
provided) during the first year, but not in the second year.
Metabolic Effects. Hypernatremia and hyperchloremic acidosis were reported in a woman who
intentionally drank about 500 mL of a strong bleach solution (10% sodium hypochlorite) (Ward and
Routledge 1988). Treatment with 5% dextrose gradually improved her electrolytes and 5 days later, she
had recovered. Hyperchloremic metabolic acidosis also was reported in a woman who intentionally
ingested an unknown amount of bleach (5.25% sodium hypochlorite, pH 11.4) and eventually died of
cardiac arrest 4.5 hours after ingestion of the bleach solution (Ross and Spiller 1999). No other relevant
information was located regarding metabolic effects in humans or animals following oral exposure to
hypochlorite solutions.
No studies were located regarding immunological effects in humans following oral exposure to
hypochlorite solutions. Limited information is available in animals. In an 8-week study in Sprague-
Dawley rats, exposure to 4.1 mg Cl/kg/day (the highest dose tested) in the drinking water (as sodium
hypochlorite) resulted in alterations in several immunological parameters including reduced delayed-type
hypersensitivity (DTH) reaction, increased prostaglandin E2 synthesis by macrophages, and reduced
oxidative metabolism by macrophages following stimulation with phorbol myristate acetate (Exon et al.
1987). In the absence of systemic toxicity in rats dosed with much higher dose of chlorine in longer-term
studies, the toxicological significance of these changes is unknown. In 90-day (Daniel et al. 1990, 1991;
Furukawa et al. 1980) and 2-year (Hasegawa et al. 1986; NTP 1992) studies in rats and mice dosed with
chlorine in the drinking water, there were no significant gross or microscopic alterations in the spleen,
thymus, and lymph nodes. In the 90-day studies Sprague-Dawley and F344 rats and B6C3F1 mice were
exposed to up to 24.9, 85, and 39.2 mg Cl/kg/day, respectively. In the 2-year studies, high-doses in
F344 and rats and B6C3F1 mice were 133 and 24.2 mg Cl/kg/day, respectively. In none of these long-
term studies was immunocompetence evaluated.
The highest NOAEL values from each reliable study for immunological and lymphoreticular effects in
each species and duration category are recorded in Table 3-3 and plotted in Figure 3-2.
CHLORINE 97
3. HEALTH EFFECTS
No studies were located regarding neurological effects in humans following exposure to hypochlorite
solutions. One acute-duration study reported that exposure of Wistar rats to up to 200 mg Cl/kg/day (as
sodium hypochlorite) by gavage in milk had no significant effect on brain weight, but no other
neurological end point was evaluated in this study (Cunningham 1980). No gross or microscopic
alterations were reported in the brain and sciatic nerve of Sprague-Dawley or F344 rats and B6C3F1 mice
in 90-days drinking water studies (Daniel et al. 1990, 1991; Furukawa et al. 1980). In these studies, rats
and mice received doses of up to 85 and 39.2 mg Cl/kg/day, respectively. In the NTP (1992) 2-year
drinking water study in F344 rats and B6C3F1 mice, gross and microscopic examination of several brain
areas did not show any significant alteration that could be attributed to treatment with chlorine.
Hasegawa et al. (1986) also reported no histological alterations in the brain of F344 rats dosed with up to
133 mg Cl/kg/day (as sodium hypochlorite) in the drinking water for 2 years. None of these studies
reported any adverse neurological sign in the animals throughout the studies, but no neurological tests
were performed.
The highest NOAEL values from each reliable study for neurological effects in each species and duration
No information was located regarding reproductive effects in humans following oral exposure to
hypochlorite solutions. In an acute-duration drinking water study, exposure of male B6C3F1 mice to
≥1.6 mg Cl/kg/day (as sodium hypochlorite) for 5 days resulted in significant increases in sperm
abnormalities in mice sacrificed 3 weeks after dosing ceased, but not in mice sacrificed 1 or 5 weeks after
dosing (Meier et al. 1985). In addition, no sperm abnormalities were seen in mice that were treated in the
same manner with hypochlorous acid. According to the investigators, the results were somewhat
surprising since sodium hypochlorite should be converted in to hypochlorous acid in acid pH of the
stomach. In the absence of corroborating information from other studies and lack of internal consistency
of the results, the toxicological significance of these results is difficult to ascertain; therefore, this study is
not listed in Table 3-3.
In an intermediate-duration study, exposure of male and female Long-Evans rats to up to 3.4 mg

Cl/kg/day (as hypochlorous acid) by gavage before and during breeding and of the females throughout
gestation and lactation did not affect fertility, the gross and microscopic appearance of the reproductive
CHLORINE 98
3. HEALTH EFFECTS
organs of males or females, and did not induce sperm abnormalities (Carlton et al. 1986). Neither the
90-day (Daniel et al. 1990, 1991; Furukawa et al. 1980) nor the 2-year (Hasegawa et al. 1986; NTP 1992)
drinking water studies reported any gross or histological alterations in the reproductive organs of male
and female rats and mice. These studies, however, did not assess fertility.
The highest NOAEL values from each reliable study for reproductive effects in each species and duration
No information was located regarding developmental effects in humans following oral exposure to
hypochlorite solutions. Abdel-Rahman et al. (1982) exposed female Sprague-Dawley rats to 0, 0.1, 1, or
10 mg Cl/kg/day (as hypochlorous acid) in the drinking water for 2.5 months before mating with
untreated males and continuing throughout pregnancy until sacrifice on gestation day 20. Exposure to
chlorine had no significant effects on fetal viability or on mean fetal body weight. Skeletal anomalies
were increased at 1 and 10 mg/kg/day and total soft tissue defects at 10 mg/kg/day relative to controls.
However, since neither maternal body weight nor water consumption data were provided in the study, it
also appeared that the incidence of fetal anomalies in the control group were higher than in the low-dose
group, interpretation of these results is problematic; therefore, this study is not listed in Table 3-3. In the
study by Carlton et al. (1986) mentioned above under Reproductive Effects, exposure of rats during
gestation to maternal doses of 3.4 mg Cl/kg/day had no significant effect on neonate viability, weight
gain, or on the incidence of gross external abnormalities. Pups sacrificed at 21 days of age had normal
blood counts and serum levels of thyroid hormones. Developmental landmarks such as mean day of eye
opening and average day of observed vaginal patency were unaltered in pups evaluated at age 28 and
40 days. The developmental NOAEL of 3.4 mg Cl/kg/day is listed in Table 3-3 and plotted in Figure 3-2.
3.2.2.7 Cancer
Studies of the carcinogenicity of trihalomethanes or other organic chemicals that form in water as a result
of the chlorination of drinking water are not discussed in this section since these studies were not intended
to assess whether chlorine itself is responsible for cancer. For reviews on this issue, the reader is referred
to IARC (1991), Koivusalo and Vartiainen (1997), and EPA (1994b).
Cancer bioassays of chlorine in drinking water have been conducted in rats and mice. In the NTP (1992)
bioassay, F344 rats (70/sex/dose group) were exposed to 0, 70, 140, or 275 ppm sodium hypochlorite in
CHLORINE 99
3. HEALTH EFFECTS
the drinking water for 103–104 weeks. This provided doses of 0, 4.2, 7.3, or 13.6 mg Cl/kg/day to males
and 0, 4.2, 7.8, or 14.4 mg Cl/kg/day to females. The water used in the study was deionized charcoal-
filtered water. Interim sacrifices (10 rats/sex/dose) were conducted at 14 and 66 weeks. The only
significant finding was an increased incidence of leukemia in female rats. The incidences were: 8/50,
7/50/, 19/51, and 16/50 in the control, low-, mid-, and high-dose females, respectively. Pair-wise
comparison showed a statistically significant difference between controls and the mid-dose (p=0.014) and
a trend test was also significant (p=0.037). In males, the respective incidences were 25/51, 25/51, 27/50,
and 29/51. These results led NTP (1992) to conclude that there was equivocal evidence of
carcinogenicity in female rats based on the fact that there was no clear dose-related response or reduced
latency, there was no decrease in tumor latency, and the incidence in concurrent controls (16%) was
significantly lower than in historical controls (25%). In a similar study, Hasegawa et al. (1986)
administered sodium hypochlorite in distilled water to groups of F344 rats (50/sex/dose) in concentrations
of 0, 500, or 1,000 ppm to males and 0, 1,000, or 2,000 ppm to females for 104 weeks; this was followed
by a period of 8 weeks of drinking untreated water. This corresponds to doses of approximately 0, 33, or
67 mg Cl/kg/day for males and 0, 67, or 133 mg Cl/kg/day for females. The results showed no significant
treatment-related increased incidence of neoplasms or alterations in latency of neoplasms.
In the NTP (1992) study, B6C3F1 mice (70/sex/dose group) drank water with 0, 70, 140, or 275 ppm
sodium hypochlorite for 103–104 weeks. This corresponds to doses of approximately 0, 7.4, 14, or 24 mg
Cl/kg/day for males and 0, 7.6, 14.2, or 24.2 mg Cl/kg/day for females. The water used in the study was
deionized charcoal-filtered water. Interim sacrifices (10 mice/sex/dose) were conducted at 15 and
66 weeks. The results showed that treatment with chlorine did not induce significant treatment-related
increases in neoplasms. In a study by Kurokawa et al. (1986), groups of B6C3F1 mice (50/sex/dose) were
exposed to sodium hypochlorite in drinking water in concentrations of 0, 0.5, or 1% for 103 weeks.
These concentrations provided doses of approximately 0, 33, or 55 mg Cl/kg/day to males and 0, 27, or
52 mg Cl/kg/day to females. Controls consisted of 73 males and 72 females. At termination,
examination of tissues and organs did not show any statistically significant differences in tumor
incidences between controls and treated mice.
Neither the EPA nor the DHHS has classified chlorine (elemental) or hypochlorite salts as to their
carcinogenicity. Based on inadequate evidence for carcinogenicity of hypochlorite salts in animals and
no data from studies in humans, IARC determined that hypochlorite salts are not classifiable as to their
carcinogenicity in humans (Group 3) (IARC 1991).
CHLORINE 100
3. HEALTH EFFECTS
3.2.3 Dermal Exposure
3.2.3.1 Death
No studies were located regarding death in humans or in animals following dermal exposure to
No studies were located regarding respiratory, cardiovascular, gastrointestinal, hematological,

musculoskeletal, hepatic, renal, endocrine, and body weight effects in humans or in animals following
dermal exposure to hypochlorite solutions.
The highest NOAEL values and all LOAEL values from each reliable study for systemic effects in each
species and duration category are recorded in Table 3-4.
Dermal Effects. Nixon et al. (1975) reported that patch application of bleach containing 5.25%
sodium hypochlorite, pH 10.7, to intact human skin for 4 hours was severely irritating. Habets et al.
(1986) reported that a solution of 2% sodium hypochlorite in water caused weak to moderate skin
irritation in 15 out of 69 individuals tested; the volume applied was not disclosed. Twenty individuals
who were tested with 0.1 and 0.5% solutions showed no irritation. Hostynek et al. (1989) tested
10 subjects with 100 μL of a 6% strength sodium hypochlorite solution (pH 11.2) and 4 of them
developed a non-immunologic form of contact urticaria within 20 minutes of the application to skin of the
forehead. The same group of investigators studied the skin irritation of 20 or 100 μL of hypochlorite
bleach containing 1% sodium hypochlorite and various amounts of sodium hydroxide following 24 hours
exposure under occluded patch conditions in 50 volunteers (Hostynek et al. 1990). The results showed
that 20 μL 1% sodium hypochlorite and 1% sodium hydroxide produced no irritation, whereas 100 μL
produced significant irritation. Goffin et al. (1997) reported that patch test exposure of 15 women to
150 μL of a commercial bleaching agent containing 4% sodium hypochlorite and 0.2% sodium hydroxide
for up to 90 minutes produced no clinical signs of irritation. However, instrumental tests (reflectance
colorimetry, transepidermal water loss, and skin conductance) revealed subclinical damage to the stratum
corneum. The investigators concluded that a 4% solution of sodium hypochlorite can alter the superficial
part of the stratum corneum without modifying the barrier function of the skin.
Table 3-4 Levels of Significant Exposure to Hypochlorous Acid and/or Sodium Hypochlorite - Dermal
CHLORINE
Exposure/ LOAEL
Duration/
Species Frequency Reference
(Strain) (Route)
System NOAEL Less Serious Serious Chemical Form Comments
ACUTE EXPOSURE
Systemic
Human 90 min Dermal Goffin et al. 1997 Instrumental tests
4F
(C) revealed subclinical
93
Percent (%) damage to the stratum
Percent (%) corneum.
93
Human 48 hr Dermal Habets et al. 1986 90

0.5 2 (weak to moderate skin
(C)
90
Percent (%) Percent (%) irritation)
Percent (%) Percent (%)
Human 20 min Dermal Hostynek et al. 1989 Non-immunologic

6 (non-immunologic
3. HEALTH EFFECTS
(C) contact urticaria
91 Percent (%) contact urticaria) developed within 20
Percent (%) minutes of application.
91
Human 24 hr Dermal Hostynek et al. 1990 Application of 100

1
(C) microliters induced
92
Percent (%) irritation; 20 microliters
Percent (%) did not.
92
Human 4 hr Dermal Nixon et al. 1975 89
(C) 5.25 (severe skin irritation in

89 Percent (%) 4/7 subjects)
Percent (%)
Mouse 2d Dermal Hess et al. 1991 The solution was

(CD-1) 8 x/d
(C) 0.53 F (histologic changes
applied as a spray.
96 Percent (%) indicating moderate 96
irritation response)
Percent (%)
101
Table 3-4 Levels of Significant Exposure to Hypochlorous Acid and/or Sodium Hypochlorite - Dermal (continued)
CHLORINE
Exposure/ LOAEL
Duration/
Species Frequency Reference
(Strain) (Route)
System NOAEL Less Serious Serious Chemical Form Comments
Gn Pig 4 hr Dermal Nixon et al. 1975 94

5.25
(Hartley) (C)
94
Percent (%)
Percent (%)
Rabbit once Ocular Griffith et al. 1980 Median day to clear

(New (C) 5 B (moderate eye irritation)
varied from 7 to over
Zealand) Percent (%) 21 depending on
97 Percent (%) volume applied.
97
Rabbit 4 hr Dermal Nixon et al. 1975 95

5.25
3. HEALTH EFFECTS
(NS) (C)
95
Percent (%)
Percent (%)
B = both male and female; (C) = capsule; d = day; F = female; Gn pig = guinea pig; hr = hour; LOAEL = lowest-observed-adverse-effect level; min = minute; NOAEL =
no-observed-adverse-effect level
102
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3. HEALTH EFFECTS
Nixon et al. (1975) conducted 4-hour patch tests with a 5.25% hypochlorite bleach solutions in rabbits
and guinea pigs and reported that in both species, hypochlorite caused only slight irritation to both intact
and abraded skin and concluded that neither species provide an accurate model for human skin. Strange
et al. (1951) studied the effect of Clorox® mixed with various biological media on the skin of rabbits and
rats. Clorox® was mixed with water, saliva, gastric juice, or plasma in ratios of 2:1, 1:1, and 1:2 and
applied to the shaved abdominal skin of anesthetized rabbits in inverted tubes for 15 and 30 minutes. The
mixtures with saliva and water were the most damaging, whereas the mixture with plasma was the least
damaging, regardless of the dilution. Strange et al. (1951) speculated that the proteins in solutions
containing plasma had a buffer effect on the harmful action of Clorox® on tissue. Strange et al. (1951)
also reported that submerging the feet of anesthetized rats for 15 minutes into Clorox® mixed with
proteins (plasma, egg white, milk) protected the tissue from the action of Clorox®. Mixtures of Clorox®
with saliva or Clorox® with water induced edema, bleeding, and actual ulceration and destruction of
tissue.
Hess et al. (1991) sprayed 0.8 mL of a 1:10 dilution of a commercial bleach solution onto a shaved
abdominal area of female CD-1 mice 8 times/day for 2 consecutive days. Eighteen to 24 hours after the
last application, the mice were sacrificed and the skin was processed for microscopic examination of the
epidermis, dermis, and hypodermis. Exposure to bleach caused a “moderate” response. Grossly, the skin
appeared dry with scattered brown crusty patches. Acanthosis, intraepithelial edema, hyperkeratosis, and
atypical epithelial cells were seen in the epidermis. The dermis showed some evidence of edema,
whereas the hypodermis showed a mild infiltration of neutrophils, macrophages, and lymphocytes.
Ocular Effects. Very limited information was located regarding ocular effects of direct contact of the
eye with hypochlorite solutions. In their text Toxicology of the Eye, Grant and Schuman (1993) state that
“because most accidental splashes in the eye have been with the relatively weak 5% household solutions
of sodium hypochlorite, very few human eye injuries have been reported, and recovery has been rapid and
complete.”
Experiments conducted in male and female New Zealand albino rabbits showed that instillation of 0.1 mL
of household bleach directly to the central corneal surface and followed over a 21-day period produced
moderate irritation (Griffith et al. 1980). The median day to clear was 7 days. In a review of the
literature, Racioppi et al. (1994) mention unpublished data indicating that in rabbits, 0.1 mL of an 8%
solution of sodium hypochlorite (without rinsing) caused moderate irritation and that the recovery time
CHLORINE 104
3. HEALTH EFFECTS
was 7 days; under similar conditions, 0.01 mL of the same solution had low irritation potential and the
recovery time was 3 days.
Although sodium hypochlorite generally is not considered a contact sensitizer, several cases of allergic
contact dermatitis have been reported. Osmundsen (1978) reported that case of a woman had a strong
reaction to patch testing with 0.5% sodium hypochlorite in water years after having had dermal contact
with chloramine. Further tests showed positive reactions to sodium hypochlorite in 3 out of 225 patients.
Habets et al. (1986) reported two cases of hand dermatitis related to sodium hypochlorite allergy, as
diagnosed by patch tests. Both patients showed a positive reaction to sodium hypochlorite up to a
concentration of 0.1%. Van Joost et al. (1987) reported one additional case among 40 housewives who
apparently had used bleaching agents for long periods. Eun et al. (1984) also reported a case of allergic
contact dermatitis in a veterinarian who occasionally washed his hands with a commercial solution
containing 4–6% sodium hypochlorite.
No information was located regarding immunological and lymphoreticular effects in animals following
dermal exposure to hypochlorite solutions.
No studies were located regarding the following effects in humans or animals after dermal exposure to

3.2.3.7 Cancer
No information was located regarding cancer in humans due to dermal exposure to hypochlorite solutions.
No bioassays have been conducted in animals by the dermal route of exposure, but the co-carcinogenic
properties of hypochlorite have been examined. In a two-stage study in female ddN mice using
4-nitroquinoline 1-oxide in benzene as initiator, application of a commercial sodium hypochlorite solution
(45 times) to a shaved area in the back of the mice after 20 applications of the nitroquinoline solution
resulted in an incidence of 9/32 skin tumors compared with 0/29 in the nitroquinoline alone group and
0/27 in the hypochlorite group alone (Hayatsu et al. 1971). Although there is suggestive evidence of
CHLORINE 105
3. HEALTH EFFECTS
promotion activity for sodium hypochlorite, the study is limited by insufficient information on dose,
survival, and age at termination. In another initiation-promotion study, skin application of single
initiating doses of 7,12-dimethylbenz[a]anthracene in acetone to female Sencar mice followed by twice
weekly applications of sodium hypochlorite resulted in squamous cell carcinomas in one mouse initiated
with 7,12-dimethylbenz[a]anthracene followed by sodium hypochlorite applications (Kurokawa et al.
1984). No skin carcinomas were seen in uninitiated mice promoted with sodium hypochlorite or in
control groups. In yet another study, application of sodium hypochlorite to the shaved back of female
NMRI mice twice per week for 10 weeks before the mice were applied benzo[a]pyrene twice per week
for 10 weeks resulted in a decrease (approximately 40%) in the number of skin carcinomas induced by
benzo[a]pyrene (Pfeiffer 1978). Mice that were treated with sodium hypochlorite during or after
benzo[a]pyrene had tumor incidences comparable to benzo[a]pyrene alone.
3.3 GENOTOXICITY
No studies were located regarding genotoxic effects of chlorine gas in humans. The only information
available in animals exposed to chlorine gas is that from an intermediate-duration study by Kutzman
(1983). In that study, rats were exposed to 0, 0.5, 1.5, or 5 ppm chlorine 6 hours/day, 5 days/week for
62 days. At termination, samples of blood and bone marrow were collected and evaluated for cytogenetic
effects. The results showed no evidence on increased incidence of sister chromatid exchanges or of
cellular proliferation in the bone marrow from exposed rats. There was also no evidence of increased
sister chromatid exchanges or of chromosomal aberrations in peripheral lymphocytes.
There is limited information regarding the in vivo genotoxicity of hypochlorite ions. A study in which
male B6C3F1 mice were administered chlorine in the drinking water as sodium hypochlorite or
hypochlorous acid for 5 days and that provided doses of up to 8 mg Cl/kg/day found no evidence of
increased incidences of chromosomal aberrations or micronuclei in bone marrow (Meier et al. 1985). In
another study, administration of a single intraperitoneal dose of up to 2,500 mg/kg sodium hypochlorite
(1,175 mg Cl/kg/day) to male ddY mice did not increase the incidence of micronuclei in bone marrow
evaluated 24 hours after dosing (Hayashi et al. 1988). Exposure of newt larvae to sodium hypochlorite in
the surrounding water (0.12 or 0.25 μg/mL) for 12 days increased the frequency of micronuclei in blood
erythrocytes (Le Curieux et al. 1993). However, the study did not specify in what type of water the larvae
were kept. If the larvae were kept in tap water, it is possible that chlorination byproducts rather than
chlorine or the hypochlorite anion were the clastogenic agents. Table 3-5 summarizes the genotoxicity of
sodium hypochlorite in vivo. Studies of the genotoxicity of sodium hypochlorite in vitro are summarized
CHLORINE 106
3. HEALTH EFFECTS
Table 3-5. Genotoxicity of Sodium Hypochlorite In Vivo
Species (test system) End point Results Reference

Mice bone marrow cells Micronuclei − Meier et al. 1985
Mice bone marrow cells Chromosomal aberrations − Meier et al. 1985
Mice bone marrow Micronuclei − Hayashi et al. 1988
erythrocytes
Newt (Pleurodeles waltl) Micronuclei + Le Curieux et al. 1993
larvae erythrocytes
– = negative result; + = positive result

CHLORINE 107
3. HEALTH EFFECTS
in Table 3-6. As the table shows, the results have been mixed and no general statements can be made.
The variability of the results may be due to differences in the experimental protocols used.
3.4 TOXICOKINETICS
3.4.1 Absorption
3.4.1.1 Inhalation Exposure
Nodelman and Ultman (1999a) measured the fraction of an inspired chlorine bolus cleared during a single
breath as a function of the bolus penetration into the respiratory system of five nonsmoker males and
females during both nasal and oral breathing at a respiratory flow of 250 mL/second using a noninvasive
procedure. Measurements of the chlorine concentrations were made by means of a fast-responding
thermionic chlorine analyzer. Peak concentrations of 0.5 and 3 ppm chlorine were used in nasal breathing
experiments and 3 ppm in oral breathing experiments. The results indicated that almost all of the chlorine
inhaled was absorbed in the upper airways (above the cords) whether the subjects inhaled through the
nose or through the mouth. By comparing mass transfer parameters, the investigators also determined
that total absorption rates for the mouth and nose were similar. When the peak concentration in the nasal
breathing experiments was increased from 0.5 to 3 ppm, the mass transfer parameters remained
unchanged, indicating that the dissolution, diffusion, and chemical reactions governing the absorption of
the gas by the nasal mucosa are all linear processes. In other words, over the 0.5–3 ppm concentration
range, absorption appeared to be non-saturable. In a separate experimental series, the investigators
determined the longitudinal distribution of a bolus of 3 ppm chlorine as a function of the flow rate
(Nodelman and Ultman 1999b). Using flow rates of 150, 250, or 1,000 mL/second, the authors
determined that irrespective of the mode of breathing, nasal or oral, and respiratory flow rate, >95% of
the inspired chlorine was absorbed in the upper airways and <5% was delivered to the lower airways.
Some studies in animals also have provided indirect evidence that the upper respiratory tract is an
efficient scrubber of chlorine. For example, Alarie (1981) reported that the 10-minute LC50 in intact mice
was 302 ppm, but in mice that breathed through a cannula in the trachea, the LC50 was only 131 ppm. In
another study, the surgically isolated upper respiratory tract of anesthetized mice was shown to scrub
chlorine with a mean efficiency of approximately 98% (Morris et al. 2005). Preliminary studies in F344
rats similar to those conducted by Nodelman and Ultman (1999a, 1999b) in humans also showed that
>90% of a chlorine dose (0.5, 1.0, 2.5 ppm) is cleared in the upper respiratory tract (Roberts et al. 2007).
CHLORINE 108
3. HEALTH EFFECTS
Table 3-6. Genotoxicity of Sodium Hypochlorite In Vitro
Results
With Without
Species (test system) End point activation activation Reference
Salmonella typhimurium Gene mutation Not tested − Le Curieux et al. 1993
(TA100, TA102, TA98)
S. typhimurium (TA100) Gene mutation Not tested + Ishidate et al. 1984
S. typhimurium (TA1530) Gene mutation Not tested + Wlodkowski and
Rosenkranz 1975
S. typhimurium (TA1538) Gene mutation Not tested − Wlodkowski and
Rosenkranz 1975
Escherichia coli (PQ37) DNA repair Not tested − Le Curieux et al. 1993
E. coli (DNA polymerase DNA damage Not tested + Rosenkranz 1973
deficient)
Human fibroblasts cell line Sister chromatid Not tested + Sasaki et al. 1980
HE2144 exchange
Humans fibroblasts cell line Chromosome Not tested − Sasaki et al. 1980
HE1244 breakage
Syrian hamster embryo cells Sister chromatid Not tested + Miyachi and Tsutsui 2005
exchange
Chinese hamster fibroblast cell Chromosomal Equivocal + Ishidate et al. 1984
line aberrations
Chinese hamster lung cell line Chromosomal Toxic + Matsuoka et al. 1979
aberrations
Syrian hamster embryo cells Chromosomal + − Hagiwara et al. 2006
aberratons
C = negative result; + = positive result; DNA = deoxyribonucleic acid

CHLORINE 109
3. HEALTH EFFECTS
3.4.1.2 Oral Exposure
No relevant data were located regarding oral absorption of hypochlorite ions in humans and limited
information exists in studies in animals. Administration of a single dose of approximately 3.3 mg/kg of
radiolabeled hypochlorous acid (36Cl) to fasted Sprague-Dawley resulted in a peak 36Cl in plasma of
7.9 μg/mL 2 hours after dosing (Abdel-Rahman et al. 1983). In non-fasted rats, administration of the
same dose resulted in a peak concentration of 10.7 μg/mL 36Cl in plasma 4 hours after dosing, suggesting
that food residues slow down absorption perhaps due to the reaction of chlorine with food components
(Fukayama et al. 1986). For both fasted and non-fasted rats, the absorption half-life was 2.2 hours. The
elimination half-life from plasma was 44.1 and 88.5 hours in fasted and non-fasted rats, respectively.
3.4.1.3 Dermal Exposure
No information was located regarding absorption of hypochlorite ions in humans or in animals after
dermal exposure to hypochlorite solutions. Studies of dermal exposure of humans or animals to aqueous
chlorine have focused almost exclusively of effects on the skin; therefore, no systemic effects have been
described that could provide indirect evidence of dermal absorption of hypochlorite ions.
3.4.2 Distribution
No information was located regarding distribution of chlorine following inhalation exposure to chlorine
gas.
In rats, 96 hours after the administration of a single gavage dose of approximately 3 mg/kg of
hypochlorous acid labeled with 36Cl, the plasma had the highest amount of radioactivity (1.92 μg/g)
followed by whole blood, bone marrow, testes, skin, kidneys, lungs, packed cells, duodenum, stomach,
spleen, thyroid, thymus, liver, carcass, and fat (0.09 μg/g) (Abdel-Rahman et al. 1983). Examination of
the subcellular distribution of radioactivity in the liver 24 hours after dosing with hypochlorous acid
showed that 75% of the total radioactivity of the whole homogenate was associated with the cytosol,
2.5% with the microsomal fraction, 1.5% with the nuclear fraction, and <0.1% with the mitochondrial
fraction.
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No information was located regarding distribution of chlorine following dermal exposure to chlorine gas
or hypochlorite ions.
3.4.3 Metabolism
Limited information is available regarding the metabolism of chlorine. In a study in which rats received a
single oral gavage dose of radiolabeled (36Cl) hypochlorous acid showed that, 96 hours after dosing,
81% of radioactivity detected in plasma was chloride ion (Abdel-Rahman et al. 1983).
Hypochlorous acid is a very reactive chemical and has been shown to react with biomolecules found in
food (Fuyakama et al. 1986). Hypochlorous acid reacts with proteins, amino acids, and unsaturated lipids
to form chlorinated compounds, whereas the reaction with carbohydrates yields oxidation products.
Scully et al. (1986) reported that chlorination of the stomach from rats resulted in the production of
N-chloramines, tentatively identified as N-chloroalanine, N-chloroglycine, and N-chlorophenylalanine.
Chemicals such as chloroform, dichloroacetonitrile and di- and trichloroacetic acids were shown to form
in vivo in the stomach of rats following oral administration of sodium hypochlorite (Mink et al. 1983).
3.4.4 Elimination and Excretion
No information was located regarding elimination and excretion of chlorine following inhalation exposure
to the gas.
The excretion of 36Cl was studied in rats following administration of a single gavage dose of
approximately 2.6 mg/kg of radiolabeled hypochlorous acid (Abdel-Rahman et al. 1983). Urine, feces,
and expired air were collected over a 4-day period after dosing. During the first 24 hours, 7 and 7.5% of
the administered radioactivity was excreted in the urine and feces, respectively. At the end of the 4-day
period, 36 and 15% of the administered radioactivity had been recovered in the urine and feces,
respectively, for a combined total of about 51% of the administered dose. No radioactivity was recovered
in expired air during the study period. Since all or some of the amount recovered in the feces could have
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been un-absorbed radioactivity, the 36% recovered in the urine represents the minimum that was
absorbed.
No information was located regarding elimination and excretion of chlorine gas or hypochlorite ions in
humans or in animals following dermal exposure to these chemicals.
3.4.5 Physiologically Based Pharmacokinetic (PBPK)/Pharmacodynamic (PD) Models
Physiologically based pharmacokinetic (PBPK) models use mathematical descriptions of the uptake and
disposition of chemical substances to quantitatively describe the relationships among critical biological
processes (Krishnan et al. 1994). PBPK models are also called biologically based tissue dosimetry
models. PBPK models are increasingly used in risk assessments, primarily to predict the concentration of
potentially toxic moieties of a chemical that will be delivered to any given target tissue following various
combinations of route, dose level, and test species (Clewell and Andersen 1985). Physiologically based
pharmacodynamic (PBPD) models use mathematical descriptions of the dose-response function to
quantitatively describe the relationship between target tissue dose and toxic end points.
PBPK/PD models refine our understanding of complex quantitative dose behaviors by helping to
delineate and characterize the relationships between: (1) the external/exposure concentration and target
tissue dose of the toxic moiety, and (2) the target tissue dose and observed responses (Andersen and
Krishnan 1994; Andersen et al. 1987). These models are biologically and mechanistically based and can
be used to extrapolate the pharmacokinetic behavior of chemical substances from high to low dose, from
route to route, between species, and between subpopulations within a species. The biological basis of
PBPK models results in more meaningful extrapolations than those generated with the more conventional
use of uncertainty factors.
The PBPK model for a chemical substance is developed in four interconnected steps: (1) model
representation, (2) model parameterization, (3) model simulation, and (4) model validation (Krishnan and
Andersen 1994). In the early 1990s, validated PBPK models were developed for a number of
toxicologically important chemical substances, both volatile and nonvolatile (Krishnan and Andersen
1994; Leung 1993). PBPK models for a particular substance require estimates of the chemical substance-
specific physicochemical parameters, and species-specific physiological and biological parameters. The
numerical estimates of these model parameters are incorporated within a set of differential and algebraic
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equations that describe the pharmacokinetic processes. Solving these differential and algebraic equations
provides the predictions of tissue dose. Computers then provide process simulations based on these
solutions.
The structure and mathematical expressions used in PBPK models significantly simplify the true
complexities of biological systems. If the uptake and disposition of the chemical substance(s) are
adequately described, however, this simplification is desirable because data are often unavailable for
many biological processes. A simplified scheme reduces the magnitude of cumulative uncertainty. The
adequacy of the model is, therefore, of great importance, and model validation is essential to the use of
PBPK models in risk assessment.
PBPK models improve the pharmacokinetic extrapolations used in risk assessments that identify the
maximal (i.e., the safe) levels for human exposure to chemical substances (Andersen and Krishnan 1994).
PBPK models provide a scientifically sound means to predict the target tissue dose of chemicals in
humans who are exposed to environmental levels (for example, levels that might occur at hazardous waste
sites) based on the results of studies where doses were higher or were administered in different species.
Figure 3-3 shows a conceptualized representation of a PBPK model.
If PBPK models for chlorine exist, the overall results and individual models are discussed in this section
in terms of their use in risk assessment, tissue dosimetry, and dose, route, and species extrapolations.
A computational fluid dynamics-physiologically based pharmacokinetic model is being developed for

chlorine (Jarabek et al. 2007). The model is intended to address experimental dosimetry data on chlorine
in rats, including uptake of chlorine delivered unidirectionally at various flow rates and concentrations
measured in the isolated upper respiratory tract of F344 rats, and measurement of chlorotyrosines (as
biomarkers) in samples taken from four regions from the respiratory and olfactory tissues.
3.5 MECHANISMS OF ACTION
3.5.1 Pharmacokinetic Mechanisms
Chlorine is a strong oxidizer that hydrolyzes in water forming hydrochloric and hypochlorous acids.
Because of the high water content of the epithelial lining fluid and the local concentration of chloride and
pH, the hydrolysis reaction of chlorine has a large equilibrium constant, such that the concentration of
chlorine in the form of hypochlorite is 120,000 times that of chlorine gas (Nodelman and Ultman 1999a,
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Figure 3-3. Conceptual Representation of a Physiologically Based
Pharmacokinetic (PBPK) Model for a Hypothetical
Chemical Substance
In h a le d c h e m ic a l E x h a le d c h e m ic a l
In g e s tio n
Lungs
L iv e r
V max
Km GI
T ra c t A
V R
E F at T
N E
O R
U S lo w ly I
S p e rfu s e d A
tis s u e s L
R ic h ly
B
p e rfu s e d
L B
tis s u e s
O L
F eces
O O
D O
K id n e y
D
U rin e
S k in
C h e m ic a ls
c o n ta c tin g s k in
Note: This is a conceptual representation of a physiologically based pharmacokinetic (PBPK) model for a
hypothetical chemical substance. The chemical substance is shown to be absorbed via the skin, by inhalation, or by
ingestion, metabolized in the liver, and excreted in the urine or by exhalation.
Source: Adapted from Krishnan and Andersen 1994

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1999b). This means that the effective solubility of chlorine between the inhaled gas and the mucus phase
is 5 orders of magnitude larger than the physical solubility, which explains why >95% of the inhaled
chlorine was absorbed in the upper airways in the studies with volunteers mentioned above (Nodelman
and Ultman 1999a).
In a review of the toxicological significance of the chemical reactions of hypochlorite ions, Scully et al.
(1989) point out that because hypochlorite is a potent oxidant, pharmacokinetic studies of radiolabeled
hypochlorous acid (36Cl) in animals do not reveal what happens to the parent compound, but rather to the
product of the reactions of these compounds in vivo. However, as discussed by Scully et al. (1986), since
hypochlorous acid undergoes rapid isotope exchange with unlabeled chloride, it is unclear whether the
radioactive chloride detected in plasma of rats in the study by Abdel-Rahman et al. (1983) is due to
complete reduction of the hypochlorous acid or to isotope exchange followed by elimination of chloride.
3.5.2 Mechanisms of Toxicity
Chlorine Gas. The toxicity of chlorine is strongly related to its oxidizing capacity. Chlorine reacts with
water in the epithelial lining of the upper respiratory airways according to the following equation:
Cl2 + H2O ↔ HCl + HOCl
Chlorine gas has been shown to be 33 times more potent as a sensory irritant in mice than hydrochloric
acid (HCl) (Barrow et al. 1977), which led the investigators to suggest that, in terms of sensory irritation,
the response observed must be due to hypochlorous acid (HOCl) rather than to hydrochloric acid. More
recently, Morris et al. (2005) reported that in mice, (a) an aerosol of sodium hypochlorite and (b) chlorine
gas, at equivalent air concentrations, induced similar decreases in respiratory rate and increases in specific
airway resistance, which suggested to the investigators that the oxidant properties of chlorine alone are
sufficient to account for the observed responses. The precise mechanism by which this might occur is not
known, but the assumption is that products of the reaction of chlorine with water are able to interact with
functional groups in components from cells in the respiratory epithelium. At low concentrations, only
sensory receptors may be affected, triggering only changes in respiratory dynamics, but higher
concentrations produce frank tissue damage due to disruption of cellular components.
Hypochlorous Acid/Hypochlorite. The mechanism of toxicity of hypochlorous acid/hypochlorite is

basically the same as that for chlorine gas. However, hypochlorous acid is a stronger oxidant than
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chlorine gas as reflected by its higher redox potential. Damage to the upper gastrointestinal tract, as may
occur following ingestion of sodium hypochlorite bleach, is likely the result of oxidation reactions of
hypochlorous acid with a range of biological molecules. Exposure to dilute solutions of bleach usually
result in only minor esophageal irritation, but ingestion of concentrated solutions of bleach can produce
serious tissue damage. These properties of hypochlorous acid form the basis for the use of this chemical
as a disinfectant (i.e., Lapenna and Cuccurullo 1996; Schraufstätter et al. 1990; Wang et al. 2007). Due to
its high reactivity, ingested hypochlorous acid also reacts with organic compounds present in the stomach
fluid such as proteins, polysaccharides, lipids, and vitamins, which may result in the formation of
potentially harmful compounds (for review, see Fukayama et al. 1986; Mink et al. 1983; Scully et al.
1989).
3.5.3 Animal-to-Human Extrapolations
The respiratory system is the target for exposure to chlorine gas in humans and animals, and for the most
part, humans and animals exhibit similar effects, particularly following acute-duration high exposures.
Less is known regarding long-term effects of acute high exposures and of prolonged low level exposures,
especially with regard to pulmonary function parameters. An evaluation of respiratory lesions in
monkeys, rats, and mice following chronic exposure to comparable concentrations of chlorine noted that
respiratory tract airflow characteristics play a major role in the distribution of the lesions and that the
lesions in monkeys and rodents exhibited both differences and similarities (Ibanes et al. 1996). The
conclusion was that with appropriate exposure and response adjustments, both rodents and Rhesus
monkeys appear to be valid models for human risk assessment.
The gastrointestinal tract is the target for oral exposure to hypochlorite in humans and animals. Ingestion
of concentrated solutions of hypochlorite bleach induces similar effects in humans and animals, and no
single animal species has emerged as a preferred animal model for human gastric toxicity. A comparative
study of dermal exposure of humans, rabbits, and guinea pigs to a 5.25% hypochlorite bleach solution
reported that rabbits and guinea pigs were much more sensitive to the irritating properties of sodium
hypochlorite, and therefore, neither species provide an accurate model for human skin (Nixon et al. 1975).
3.6 TOXICITIES MEDIATED THROUGH THE NEUROENDOCRINE AXIS
Recently, attention has focused on the potential hazardous effects of certain chemicals on the endocrine
system because of the ability of these chemicals to mimic or block endogenous hormones. Chemicals
with this type of activity are most commonly referred to as endocrine disruptors. However, appropriate
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terminology to describe such effects remains controversial. The terminology endocrine disruptors,
initially used by Thomas and Colborn (1992), was also used in 1996 when Congress mandated the EPA to
develop a screening program for “...certain substances [which] may have an effect produced by a
naturally occurring estrogen, or other such endocrine effect[s]...”. To meet this mandate, EPA convened a
panel called the Endocrine Disruptors Screening and Testing Advisory Committee (EDSTAC), and in
1998, the EDSTAC completed its deliberations and made recommendations to EPA concerning endocrine
disruptors. In 1999, the National Academy of Sciences released a report that referred to these same types
of chemicals as hormonally active agents. The terminology endocrine modulators has also been used to
convey the fact that effects caused by such chemicals may not necessarily be adverse. Many scientists
agree that chemicals with the ability to disrupt or modulate the endocrine system are a potential threat to
the health of humans, aquatic animals, and wildlife. However, others think that endocrine-active
chemicals do not pose a significant health risk, particularly in view of the fact that hormone mimics exist
in the natural environment. Examples of natural hormone mimics are the isoflavinoid phytoestrogens
(Adlercreutz 1995; Livingston 1978; Mayr et al. 1992). These chemicals are derived from plants and are
similar in structure and action to endogenous estrogen. Although the public health significance and
descriptive terminology of substances capable of affecting the endocrine system remains controversial,
scientists agree that these chemicals may affect the synthesis, secretion, transport, binding, action, or
elimination of natural hormones in the body responsible for maintaining homeostasis, reproduction,
development, and/or behavior (EPA 1997). Stated differently, such compounds may cause toxicities that
are mediated through the neuroendocrine axis. As a result, these chemicals may play a role in altering,
for example, metabolic, sexual, immune, and neurobehavioral function. Such chemicals are also thought
to be involved in inducing breast, testicular, and prostate cancers, as well as endometriosis (Berger 1994;
Giwercman et al. 1993; Hoel et al. 1992).
There are no studies that have tested whether chlorine gas has properties of endocrine disruptor, but given
its mechanism of toxicity, such effects are very unlikely.
Oral exposure to hypochlorite solutions has provided no evidence of endocrine disruption in humans or in
animals, but the available studies have not been designed to carefully evaluate that possibility. A study in
male and female volunteers who consumed for 4 weeks 1.5 L of distilled water that provided a dose of
approximately 0.4 mg Cl/kg/day reported that there was a slight reduction in serum levels of T4 and T3 in
men which was not accompanied by any meaningful change in thyroid-stimulating hormone levels
(Wones et al. 1993). In another study in volunteers, ingestion of approximately 0.036 mg Cl/kg/day in
the drinking water for 12 weeks did not significantly alter serum levels T3 or T4 (Lubbers et al. 1982).
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Relevant information in animals is very limited. Exposure of rats during gestation to maternal doses of
up to 3.4 mg Cl/kg/day (as hypochlorous acid) had no significant effect on pups’ serum levels of thyroid
hormones at 21 days of age (Carlton et al. 1986). In addition, developmental landmarks such as mean day
of eye opening and average day of observed vaginal patency were unaltered in pups evaluated at
age 28 and 40 days. Studies in rats and mice found no significant gross or microscopic alterations in
endocrine glands following long-term exposure to chlorine the drinking water (Daniel et al. 1990, 1991;
Furukawa et al. 1980; Hasegawa et al. 1986; NTP 1992).
3.7 CHILDREN’S SUSCEPTIBILITY
This section discusses potential health effects from exposures during the period from conception to
maturity at 18 years of age in humans, when all biological systems will have fully developed. Potential
effects on offspring resulting from exposures of parental germ cells are considered, as well as any indirect
effects on the fetus and neonate resulting from maternal exposure during gestation and lactation.
Relevant animal and in vitro models are also discussed.
Children are not small adults. They differ from adults in their exposures and may differ in their
susceptibility to hazardous chemicals. Children’s unique physiology and behavior can influence the
extent of their exposure. Exposures of children are discussed in Section 6.6, Exposures of Children.
Children sometimes differ from adults in their susceptibility to hazardous chemicals, but whether there is
a difference depends on the chemical (Guzelian et al. 1992; NRC 1993). Children may be more or less
susceptible than adults to health effects, and the relationship may change with developmental age
(Guzelian et al. 1992; NRC 1993). Vulnerability often depends on developmental stage. There are
critical periods of structural and functional development during both prenatal and postnatal life, and a
particular structure or function will be most sensitive to disruption during its critical period(s). Damage
may not be evident until a later stage of development. There are often differences in pharmacokinetics
and metabolism between children and adults. For example, absorption may be different in neonates
because of the immaturity of their gastrointestinal tract and their larger skin surface area in proportion to
body weight (Morselli et al. 1980; NRC 1993); the gastrointestinal absorption of lead is greatest in infants
and young children (Ziegler et al. 1978). Distribution of xenobiotics may be different; for example,
infants have a larger proportion of their bodies as extracellular water, and their brains and livers are
proportionately larger (Altman and Dittmer 1974; Fomon 1966; Fomon et al. 1982; Owen and Brozek
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1966; Widdowson and Dickerson 1964). The infant also has an immature blood-brain barrier (Adinolfi
1985; Johanson 1980) and probably an immature blood-testis barrier (Setchell and Waites 1975). Many
xenobiotic metabolizing enzymes have distinctive developmental patterns. At various stages of growth
and development, levels of particular enzymes may be higher or lower than those of adults, and
sometimes unique enzymes may exist at particular developmental stages (Komori et al. 1990; Leeder and
Kearns 1997; NRC 1993; Vieira et al. 1996). Whether differences in xenobiotic metabolism make the
child more or less susceptible also depends on whether the relevant enzymes are involved in activation of
the parent compound to its toxic form or in detoxification. There may also be differences in excretion,
particularly in newborns who all have a low glomerular filtration rate and have not developed efficient
tubular secretion and resorption capacities (Altman and Dittmer 1974; NRC 1993; West et al. 1948).
Children and adults may differ in their capacity to repair damage from chemical insults. Children also
have a longer remaining lifetime in which to express damage from chemicals; this potential is particularly
relevant to cancer.
Certain characteristics of the developing human may increase exposure or susceptibility, whereas others
may decrease susceptibility to the same chemical. For example, although infants breathe more air per
kilogram of body weight than adults breathe, this difference might be somewhat counterbalanced by their
alveoli being less developed, which results in a disproportionately smaller surface area for alveolar
absorption (NRC 1993).
The respiratory tract is also the target for chlorine gas toxicity in children, and children exposed to
chlorine exhibit the same signs and symptoms observed in adults detailed in Section 3.2.1.2. Whether
children are more susceptible than adults to the effects of chlorine exposure is not known with certainty,
but there are some reports that suggest that they might be. There are many reports of intoxication of
children following a variety of exposure scenarios: tank explosions, train derailments, accidents at
swimming pools, and accidents during school science class. Some representative examples are
summarized below.
Following a train derailment in which members of a community, including over 100 children, may have
been exposed to up 20 ppm chlorine, the most frequent conditions were coughing, headache, throat
irritation, and a burning sensation in the eyes (Agency for Toxic Substances and Disease Registry 1998).
Children aged 0–5 years had the highest prevalence of respiratory infections, rash, and vomiting. Fleta et
al. (1986) reported the case of a leak of chlorine from a tank that exposed 76 children. The most
prevalent symptoms were irritative cough (91%), nasal-pharyngeal pruritus (66%), chest pain (25%),
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tachypnea (20%), and dyspnea (14%). Other conditions included headache, vomiting, and nausea. The
report indicates that the symptoms of most children subsided naturally upon leaving the center of
contamination. Seventy of the 76 children were released within 2 hours of the accident. In a similar case,
106 individuals were affected and 60 of them were children and adolescents <18 years (Güloğlu et al.
2002). Of those hospitalized due to their severe condition, patients 0–1 and 2–7 years had the longest
duration of hospitalization, suggesting an increased susceptibility among children than adults.
Sexton and Pronchik (1998) described the case of 13 children, ages 6–18, who were overcome by chlorine
gas at two swimming pools. On admission to the Emergency Department, most children complained of
eye and throat irritation, chest pain, anxiety, shortness of breath, wheezing, and chest tightness. Five
patients were admitted to the hospital with hypoxia, but all were released after 2 days. Two weeks after
the exposures, no patients complained of residual symptoms. In another swimming pool accident,
134 children inhaled chlorine vapors and acute respiratory symptoms occurred in 72% (Agabiti et al.
2001). The incidence of all symptoms tended to be higher among those who had a history of chronic
respiratory disease and among those who were engaged in physical exercise during the accident.
Lung function tests conducted in 82 children 15–30 days after exposure showed lower FVC, FEV1, and
FEF25–75%. A study of 10 children exposed to chlorine gas at a swimming pool reported that all children
had respiratory distress and reduced lung function on admission to the hospital (Bonetto et al. 2006).
Although lung function returned to normal values 15 days after the accident, biochemical markers of
pulmonary inflammation were still elevated in exhaled breath condensate several months after the
accident. Persistent respiratory alterations were also observed in a child who developed dyspnea,
hypoxemia, and pneumonitis approximately 12 hours after exposure to chlorine gas (Vohra and Clark
2006). Pulmonary testing 4 months after the episode revealed the presence of mild obstructive reactivity
of the airways. After being exposed to excess chlorine in an indoor pool, 18 children were followed for
up to 28 days (Grasemann et al. 2007). Fractional exhaled NO (a measure of airway inflammation) was
significantly increased on day 1 compared to days 8 and 28 in 13 of the children who had lower airway
symptoms with cough or shortness of breath on day 1, but not in the total study group or in asymptomatic
children. In the total group of children, FVC was decreased on day 1 compared to days 8 and 28, whereas
a marker of pulmonary hyperinflation was elevated on day 1 compared to day 8 or 28.
There are no studies in animals that addressed possible differential susceptibilities to exposure to chlorine
gas between young and older animals.
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In children, as in adults, the gastrointestinal tract is the target for oral exposure to hypochlorite bleach.
Children usually constitute a significant percentage of the reported cases of accidental ingestion of
chlorine bleach. In general, ingestion of small amounts (less than a cup) of household bleach (5–
5.5% sodium hypochlorite) does not result in serious effects, but fatalities have been reported. For
example, a review of 129 cases of children who ingested Clorox® reported that no complications of
consequences were found (Pike et al. 1963). Sixty-five cases were examined by esophagoscopy within
96 hours of the ingestion and only 2 showed evidence of esophageal injury. Another review of
393 children seen at a hospital who ingested bleach reported that there were no esophageal strictures or
perforations and that about 50% of the patients received no treatment (Landau and Saunders 1964). Hook
and Lowry (1974) reported that among 23 definite cases of children who ingested Clorox®, severe
irritation of the esophageal mucosa was observed in only one case. Minor transient irritation was
observed in some of the patients. A report from the German literature of 23 children who accidentally
ingested 3–5% sodium hypochlorite indicates that there was only one case with signs of superficial burns
in the esophagus, which had disappeared 2 weeks later when controlled by esophagoscopy (Mühlendahl
et al. 1978). Severe gross lesions were seen in the mouth, tongue, glottis, epiglottis, esophagus, and
stomach in a child who died after drinking an unknown amount of a 4.5% sodium hypochlorite solution in
alkali (pH 12.0) (Jakobsson et al. 1991). The information available does not suggest that children are
more or less sensitive to oral exposure to chlorine than adults.
There are no studies in animals that have examined whether young animals are more susceptible to the
effects of ingestion of hypochlorite bleach than adult animals.
3.8 BIOMARKERS OF EXPOSURE AND EFFECT
Biomarkers are broadly defined as indicators signaling events in biologic systems or samples. They have
been classified as markers of exposure, markers of effect, and markers of susceptibility (NAS/NRC
1989).
A biomarker of exposure is a xenobiotic substance or its metabolite(s) or the product of an interaction

between a xenobiotic agent and some target molecule(s) or cell(s) that is measured within a compartment
of an organism (NAS/NRC 1989). The preferred biomarkers of exposure are generally the substance
itself, substance-specific metabolites in readily obtainable body fluid(s), or excreta. However, several
factors can confound the use and interpretation of biomarkers of exposure. The body burden of a
substance may be the result of exposures from more than one source. The substance being measured may
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be a metabolite of another xenobiotic substance (e.g., high urinary levels of phenol can result from
exposure to several different aromatic compounds). Depending on the properties of the substance (e.g.,
biologic half-life) and environmental conditions (e.g., duration and route of exposure), the substance and
all of its metabolites may have left the body by the time samples can be taken. It may be difficult to
identify individuals exposed to hazardous substances that are commonly found in body tissues and fluids
(e.g., essential mineral nutrients such as copper, zinc, and selenium). Biomarkers of exposure to chlorine
are discussed in Section 3.8.1.
Biomarkers of effect are defined as any measurable biochemical, physiologic, or other alteration within an
organism that, depending on magnitude, can be recognized as an established or potential health
impairment or disease (NAS/NRC 1989). This definition encompasses biochemical or cellular signals of
tissue dysfunction (e.g., increased liver enzyme activity or pathologic changes in female genital epithelial
cells), as well as physiologic signs of dysfunction such as increased blood pressure or decreased lung
capacity. Note that these markers are not often substance specific. They also may not be directly
adverse, but can indicate potential health impairment (e.g., DNA adducts). Biomarkers of effects caused
by chlorine are discussed in Section 3.8.2.
A biomarker of susceptibility is an indicator of an inherent or acquired limitation of an organism's ability

to respond to the challenge of exposure to a specific xenobiotic substance. It can be an intrinsic genetic or
other characteristic or a preexisting disease that results in an increase in absorbed dose, a decrease in the
biologically effective dose, or a target tissue response. If biomarkers of susceptibility exist, they are
discussed in Section 3.10, Populations That Are Unusually Susceptible.
3.8.1 Biomarkers Used to Identify or Quantify Exposure to Chlorine
There are no biomarkers that can be used to quantify exposure to chlorine gas or sodium hypochlorite in
humans. However, a recent study documented a statistically significant exposure concentration-
dependent increase in 3-chlorotyrosine (CY) and 3,5-dichlorotyrosine (dCY) in nasal tissue from
F344 rats exposed to chlorine gas concentrations ranging from 0.5 to 2.5 ppm for 90 minutes (Sochaski et
al. 2008). Preferential formation of CY and dCY was found in the respiratory and transitional epithelium
versus the olfactory epithelium of the nasal cavity. The investigators point out that the method presented
in the study is only applicable to animals, as the collection of tissue samples would be too invasive for use
in humans; nevertheless, it represents a good starting point for future method development. It is not
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known whether exposure to other chlorinated compounds could also produce CY and dCY, thus
compromising the specificity of these biomarkers.
3.8.2 Biomarkers Used to Characterize Effects Caused by Chlorine
There are no specific biomarkers that can be used to characterize the effects of chlorine. Chlorine gas is a
sensory and pulmonary irritant, and similar effects can be observed after exposure to many other irritants.
Ingestion of sodium hypochlorite can irritate the upper gastrointestinal tract, but this effect is not specific
to chlorine.
3.9 INTERACTIONS WITH OTHER CHEMICALS
The only relevant information is that exposure to chlorine gas may result in the development of cross-
tolerance to other chemicals. A study showed rats pre-exposed to chlorine developed cross-tolerance to
formaldehyde and vice versa, and the development of tolerance was a function of the duration of pre-
treatment (Chang and Barrow 1984). Slight loss of cross-tolerance was observed following a recovery
period of a few days. Interestingly, exposure of rats to 15 ppm formaldehyde did not induce tolerance to
formaldehyde, but resulted in cross-tolerance to chlorine and, according to Chang and Barrow (1984),
suggested the existence of different reactive sites at the trigeminal nerve endings.
As previously mentioned, hypochlorous acid is a very reactive chemical and has been shown to react with
biomolecules found in food (Fuyakama et al. 1986). Hypochlorous acid reacts with proteins, amino acids,
and unsaturated lipids to form chlorinated compounds, whereas the reaction with carbohydrates yields
oxidation products. Scully et al. (1986) reported that chlorination of the stomach from rats resulted in the
production of N-chloramines, tentatively identified as N-chloroalanine, N-chloroglycine, and N-chloro-
phenylalanine. Chemicals such as chloroform, dichloroacetonitrile, and di- and trichloroacetic acids were
shown to form in vivo in the stomach of rats following oral administration of sodium hypochlorite (Mink
et al. 1983).
3.10 POPULATIONS THAT ARE UNUSUALLY SUSCEPTIBLE
A susceptible population will exhibit a different or enhanced response to chlorine than will most persons
exposed to the same level of chlorine in the environment. Reasons may include genetic makeup, age,
health and nutritional status, and exposure to other toxic substances (e.g., cigarette smoke). These
parameters result in reduced detoxification or excretion of chlorine, or compromised function of organs
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affected by chlorine. Populations who are at greater risk due to their unusually high exposure to chlorine
are discussed in Section 6.7, Populations with Potentially High Exposures.
Populations unusually susceptible to chlorine gas exposure include individuals with respiratory conditions
such as asthma, hay fever, and chronic bronchitis, heavy smokers, and children. Rotman et al. (1983)
described the case of an atopic individual who experienced severe distress during exposure to 1 ppm
chlorine, a concentration that was tolerated by healthy subjects. D’Alessandro et al. (1996) also reported
that subjects with airway hyperresponsiveness to methacholine exhibited a much more pronounced
decrease in FEV1 and FEF25–75% than healthy subjects during exposure to 1 ppm chlorine. Shusterman et
al. (1998) reported that subjects with seasonal allergic rhinitis experienced a significantly greater increase
in nasal airway resistance (congestion) than non-rhinitic subjects following exposure to 0.5 ppm chlorine
for 15 minutes. Following an accidental leak of chlorine, individuals who had a more prevent history of
smoking and asthma exhibited more hypoxemia and were more likely to have tachypnea, crackles, and
wheezes during examination than subjects without asthma and/or who smoked less (Hasan et al. 1983).
In the former, signs and symptoms of chlorine intoxication resolved more slowly reduced and flow rates
and lung volumes were still evident 2 weeks after acute exposure to chlorine. Similar observations
regarding smokers have been made in studies of workers who have experienced occasional high
exposures or “gassing” episodes (Chester et al. 1969; Gautrin et al. 1999; Henneberger et al. 1996).
In a swimming pool accident involving 126 adult and 134 children, among both children and adults, the
incidences of all symptoms (eye, nose, and throat irritation) and respiratory problems (shortness of breath,
wheezing, cough) were higher among those who had a history of chronic respiratory disease than among
healthy people (Agabiti et al. 2001). In addition, in adults, incidences were higher among smokers and
former smokers than among never smokers.
Some reports in which adults and children were accidentally exposed to high concentrations of chlorine
have suggested that children might be more susceptible to the effects of chlorine than adults. For
example, in a case involving 106 individuals, 60 of whom were children and adolescents <18 years old, of
those hospitalized due to their severe condition, patients 0–1 and 2–7 years old had the longest duration of
hospitalization, suggesting an increased susceptibility among children than adults (Güloğlu et al. 2002).
In another case in which over 100 children may have been exposed to up 20 ppm chlorine, children aged
0–5 years had the highest prevalence of respiratory infections, rash, and vomiting (Agency for Toxic
Substances and Disease Registry 1998).
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No information was located regarding populations unusually susceptible to exposure to hypochlorite

bleach.
3.11 METHODS FOR REDUCING TOXIC EFFECTS
This section will describe clinical practice and research concerning methods for reducing toxic effects of
exposure to chlorine. However, because some of the treatments discussed may be experimental and
unproven, this section should not be used as a guide for treatment of exposures to chlorine. When
specific exposures have occurred, poison control centers and medical toxicologists should be consulted
for medical advice. The following texts provide specific information about treatment following exposures
to chlorine:
Ellenhorn MJ, Barceloux DG. 1988. Medical Toxicology: Diagnosis and Treatment of Human
Poisoning. New York, NY: Elsevier, 878-879.
Ellenhorn MJ. 1997. Medical Toxicology: Diagnosis and Treatment of Human Poisoning. 2th ed.
Philadelphia, PA: Williams and Wilkins, 1521.
Goldfrank LR, Flomenbaum NE, Lewin NA, et al. 2002. Goldfrank’s Toxicologic Emergencies. 7th ed.
New York, NY: McGraw-Hill, 1458-1459.
Viccellio P, Bania T, Brent J, et al. 1998. Chlorine gas. In: Emergency toxicology. 2nd ed.
Philadelphia, PA: Lippincott-Raven Press, 444-445.
Additional information can be found in ATSDR’s Medical Management Guideline for chlorine (ATSDR
2007).
3.11.1 Reducing Peak Absorption Following Exposure
There are no specific methods for reducing absorption of chlorine gas other than removing the patient
from the source of the chlorine gas to fresh air and monitor for respiratory distress. It should be noted
that rescuers should wear self-contained breathing apparatus and have protective clothing, if needed.
Sodium hypochlorite or hypochlorous acid is not absorbed in the gastrointestinal tract as such. Either
substance will react with the acid in the stomach to form chlorine gas and/or with organic compounds
present in the stomach fluid to form chlorinated compounds (Mink et al. 1983; Scully et al. 1989).
Gastrointestinal decontamination procedures such as emesis, gastric lavage, and activated charcoal should
be avoided following ingestion of chlorine bleach. However, dilution with water or milk is
recommended, but the dilution amount should be small to avoid inducing vomiting. In case of exposure
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of the skin to hypochlorite solutions, flushing with copious amounts of plain tepid water is recommended.
In case of exposure of the eyes, irrigation with saline or Ringer’s lactate is recommended.
3.11.2 Reducing Body Burden
There are no standard methods for reducing chlorine body burden. Studies in humans have shown that
under low exposure conditions (<5 ppm), >95% of the inspired chlorine is absorbed in the upper airways
and <5% is delivered to the lower airways (Nodelman and Ultman 1999a, 1999b). Chlorine that reacts
with the mucosa of the upper respiratory airways eventually joins the pool of chloride ions in the body.
Studies in animals also have shown that most of the chlorine ingested as hypochlorous acid is transformed
and eliminated as chloride (Abdel-Rahman et al. 1983).
3.11.3 Interfering with the Mechanism of Action for Toxic Effects
The toxic effects of chlorine gas are due to its oxidant properties and also to the added tissue damage
caused by the hypochlorous and hydrochloric acids that result from the reaction of chlorine with water.
There are no established methods to interfere with the oxidant properties of chlorine, but nebulized
sodium bicarbonate has been used to neutralize the acid (Bosse 1994; Douidar 1997).
The treatment of exposure to chlorine gas is symptomatic, exposure to low concentrations may require
only treatment for sensory irritation, but exposure to high concentrations may cause serious respiratory
symptoms including pulmonary edema and respiratory failure and death. The information below has been
extracted from the texts listed above and also from Baxter et al. (1989).
Before any treatment, the patient should be assessed for signs of corrosive injury to mucous membrane,
eyes, and skin. The assessment should also include a check for lung sounds, peak flow, and vital signs.
Patients heavily exposed who show breathing difficulties at rest should undergo baseline x-ray
examination. The initial treatment consists of irrigation with water or saline and vasoconstrictive
ophthalmic solutions for eye irritation, but eye damage may require referral to a health care facility.
Nausea may be treated with Phenergan® and administration of clear liquids, whereas sore throat can be
treated with throat lozenges or spray or a humidifier. Decongestants are recommended for rhinitis and
antitussive agents for the treatment of cough. Skin burns should be treated as thermal burns. Patients
exhibiting respiratory effects should receive 100% humidified oxygen, unless it is contraindicated by the
medical history. As mentioned above, 5% nebulized bicarbonate has been used in patient with respiratory
effects with favorable responses in at least some patients (Bosse 1994; Douidar 1997). Nebulized
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bronchodilators may be used to treat bronchospasm. Therapy with corticosteroids has not been proved to
produce improvement in chlorine gas poisoning (Baxter et al. 1989). Monitoring of respiratory function
and arterial blood gases in important because pulmonary edema may occur up to 24 hours after exposure.
If pulmonary edema occurs, emergent treatment and monitoring in an intensive care unit is often required.
Caution should be exercised with the administration of intravenous fluids and because fluid overload is
extremely dangerous in such patients. If fluid overload occurs, diuretics such as furosemide may be
useful as indicated. Survivors of high chlorine exposure should be monitored periodically to determine
possible persistent loss of pulmonary function.
3.12 ADEQUACY OF THE DATABASE
Section 104(I)(5) of CERCLA, as amended, directs the Administrator of ATSDR (in consultation with the
Administrator of EPA and agencies and programs of the Public Health Service) to assess whether
adequate information on the health effects of chlorine is available. Where adequate information is not
available, ATSDR, in conjunction with the National Toxicology Program (NTP), is required to assure the
initiation of a program of research designed to determine the health effects (and techniques for developing
methods to determine such health effects) of chlorine.
The following categories of possible data needs have been identified by a joint team of scientists from
ATSDR, NTP, and EPA. They are defined as substance-specific informational needs that if met would
reduce the uncertainties of human health assessment. This definition should not be interpreted to mean
that all data needs discussed in this section must be filled. In the future, the identified data needs will be
evaluated and prioritized, and a substance-specific research agenda will be proposed.
3.12.1 Existing Information on Health Effects of Chlorine
The existing data on health effects of inhalation, oral, and dermal exposure of humans and animals to
chlorine gas and hypochlorite solutions chlorine are summarized in Figures 3-4 and 3-5, respectively.
The purpose of these figures is to illustrate the existing information concerning the health effects of
chlorine. Each dot in the figure indicates that one or more studies provide information associated with
that particular effect. The dot does not necessarily imply anything about the quality of the study or
studies, nor should missing information in this figure be interpreted as a “data need”. A data need, as
defined in ATSDR’s Decision Guide for Identifying Substance-Specific Data Needs Related to
Toxicological Profiles (Agency for Toxic Substances and Disease Registry 1989), is substance-specific
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Figure 3-4. Existing Information on Health Effects of Chlorine Gas
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Figure 3-5. Existing Information on Health Effects of Hypochlorite Solution
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information necessary to conduct comprehensive public health assessments. Generally, ATSDR defines a
data gap more broadly as any substance-specific information missing from the scientific literature.
The existing information on the health effects of chlorine gas in humans comes from accounts of soldiers
exposed during gas attacks in World War I, subjects exposed to chlorine at work, and members of the
general population accidentally exposed due to leaks or explosions of storage tanks or due to the
mishandling of bleach solutions or swimming pool chemicals. Regardless of the exposure scenario, the
target for chlorine gas toxicity is the respiratory system. Effects of exposure to low concentrations may
be limited to irritation of the eyes, upper respiratory tract, and skin, whereas exposure to high
concentrations may cause serious pulmonary effects and death. There is limited information on
neurological effects in humans exposed to chlorine gas. Oral exposure is not a relevant route of exposure
to chlorine gas in humans or animals.
Acute-, intermediate-, and chronic inhalation studies of chlorine gas in animals are available. In these
studies, the respiratory tract was also established as the target for chlorine toxicity. There are minimal
data on neurological, lymphoreticular, reproductive, and genotoxic effects, as well as cancer, in animals.
The available information on health effects of hypochlorous acid or sodium hypochlorite in humans is
derived almost exclusively from cases of accidental or intentional ingestion of chlorine bleach. These
observations indicate that the principal target for oral exposure to hypochlorite is the upper
gastrointestinal tract. Ingestion of small amounts of chlorine bleach may only cause esophageal irritation,
but ingestion of strong solutions of bleach can cause severe damage to the upper gastrointestinal tract and
even death. There are no data on long-term exposure of humans to hypochlorite bleach. Since no target
for chlorine toxicity has been identified in oral studies of various durations with dose levels much higher
than those that could be generally encountered by the general population, oral MRLs for hypochlorite
were not derived. Additional oral studies are not considered necessary except for the few exceptions
indicated in Section 3.12.2 below.
Information is available from acute-duration oral studies with hypochlorous acid or sodium hypochlorite
in animals, which also indicates that the upper gastrointestinal tract is the main target of toxicity for
concentrated bleach. Intermediate- and chronic-duration studies with hypochlorous acid or sodium
hypochlorite in animals have examined systemic end points and also have provided limited information
on immunological, neurological, reproductive, and developmental effects. There are cancer bioassays
available with sodium hypochlorite in rats and mice.
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There are data that indicate that dermal exposure to hypochlorite bleach can cause skin irritation in
humans and in animals.
3.12.2 Identification of Data Needs
Acute-Duration Exposure. Information regarding health effects of acute exposure to chlorine gas is
available from studies with volunteers (Anglen 1981; D’Alessandro et al. 1996; Rotman et al. 1983;
Schins et al. 2000; Shusterman et al. 1998, 2003b), from exposures of soldiers during World War I (i.e.,
Berghoff 1919; DOA 1933; Joy 1997; Meakins and Priestley; Sandall 1922), and from accidental
exposures of workers and the general public following chlorine leaks in a variety of scenarios (i.e.,
Agabiti et al. 2001; Agency for Toxic Substances and Disease Registry 1998; Bhérer et al. 1994; Bonetto
et al. 2006; CDC 1991, 2005; Chasis et al. 1947; Chester et al. 1977; Edwards et al. 1983; Hasan et al.
1983; Jones et al. 1986; Kowitz et al. 1967; Moulick et al. 1992; Salisbury et al. 1991; Schönhofer et al.
1996; Sexton and Pronchik 1998; Weill et al. 1969). These and many additional studies showed that the
respiratory tract is the target for chlorine toxicity and that the effects range from sensory irritation at low
exposures (<5 ppm) to severe pulmonary effects (40–60 ppm) and possibly death (>100 ppm).
Information is also available regarding long-term effects of acute high exposures to chlorine; some studies
did not find persistent effects (i.e., Chasis et al. 1947; Jones et al. 1986; Moulick et al. 1992; Weill et al.
1969), whereas others did (i.e., Bhérer et al. 1994; Kowitz et al. 1967; Salisbury et al. 1991). Further
research on this issue is needed. The studies in volunteers provided sufficient information for derivation
of an acute-duration inhalation MRL for chlorine gas. The studies in animals support the findings in
humans and provided additional information regarding histopathological changes in the respiratory tract
and duration and reversibility of the effects. Standard additional acute-duration inhalation studies of
chlorine gas in animals do not seem necessary at this time.
Information regarding health effects of hypochlorous acid and sodium hypochlorite in humans is derived
exclusively from cases of accidental or intentional ingestion of hypochlorite bleach. These reports
indicate that the upper gastrointestinal tract is the main target of toxicity for the oral route of exposure
(Landau and Saunders 1964; Pike et al. 1963; Ross and Spiller 1999). The animal data support the
findings in humans, but the available studies are inadequate for constructing dose-response relationships.
Earlier studies in animals tried to reproduce the lesions to the esophagus and/or stomach due to ingestion
of bleach. In most of these studies, commercial bleach was administered through a tube directly into the
esophagus and, in some cases, the distal end of the esophagus was artificially occluded to prolong and
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monitor the contact time between the solution and the mucosa (Hook and Lowry 1974; Landau and
Saunders 1964; Strange et al. 1951; Yarington 1970). Two more recent studies were of very limited
scope (Cunningham 1980) or reported ambiguous results (Meier et al. 1985).
Dermal effects have been reported in a few cases of direct acute contact of the skin with high
concentrations of chlorine gas in humans (Agency for Toxic Substances and Disease Registry 1998;
Joyner and Durel 1962; NIOSH 1995), and eye irritation was reported in volunteers exposed to 1 ppm
chlorine for up to 8 hours (Anglen 1981; Rotman et al. 1983). Information on dose-response for sensory
irritation was used along with data on pulmonary effects to derive the acute-duration inhalation MRL for
chlorine. Additional studies of sensory irritation with chlorine gas do not appear necessary at this time.
Chlorine gas is not absorbed through the skin, so systemic effects due to contact of the skin with chlorine
are not expected to occur. Dermal effects of hypochlorite bleach have been reported in humans and in
animals (Habets et al. 1986; Hostynek et al. 1989, 1990; Nixon et al. 1975; Strange et al. 1951); therefore,
additional dermal studies do not seem necessary at this time.
Intermediate-Duration Exposure. No studies of humans exposed specifically for intermediate

duration to chlorine gas were located. However, it is likely that in many of the occupational studies
available, some workers were exposed for intermediate durations. Only two intermediate-duration studies
in animals are available (Barrow et al. 1979; Kutzman 1983). Both studies utilized rats and in both
studies, the most sensitive target for chlorine exposure was the respiratory tract. Barrow et al. (1979)
described inflammation of the nasal turbinates in rats exposed to ≥1 ppm chlorine, whereas loss of cilia
and epithelium in the trachea was seen in rats exposed to ≥0.5 ppm in the Kutzman (1983) study. The
Kutzman (1983) study was selected as the principal study for derivation of an intermediate-duration
inhalation MRL for chlorine. Additional intermediate-duration inhalation studies in animals do not seem
necessary at this time.
Two intermediate-duration studies in which volunteers were exposed to known amounts of total chlorine
from chlorinated water provided no evidence of adverse effects (Lubbers et al. 1982; Wones et al. 1993).
Few intermediate-duration studies in animals were located that examined a wide range of end points
following exposure to hypochlorite. These studies showed that the main effect of exposure to solutions of
hypochlorous acid or sodium hypochlorite, particularly at the higher concentrations levels, is a reduction
of water intake that is due to taste aversion. The available intermediate-duration oral studies evaluated
systemic toxicity (Abdel-Rahman et al. 1984; Cunningham 1980; Daniel et al. 1990, 1991; Furukawa et
al. 1980) and also provided information, albeit limited, on immunological/lymphoreticular (Daniel et al.
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1990, 1991; Exon et al. 1987), neurological (Daniel et al. 1990, 1991), reproductive (Carlton et al. 1986;
Daniel et al. 1990, 1991), and developmental effects (Carlton et al. 1986). None of the available studies
reported effects that could be attributed directly to chlorine or only reported effects that were considered
of unknown toxicological significance. Additional intermediate-duration oral studies with hypochlorite
do not seem necessary. It is also unclear what needed information would be provided in additional
intermediate-duration dermal studies.
Chronic-Duration Exposure and Cancer. There are relatively few long-term studies in workers
exposed to chlorine gas (Enarson et al. 1984; Ferris et al. 1967, 1979; Hyback 1999; Patil et al. 1970).
Health evaluations of the workers in these studies, including pulmonary function monitoring, did not
provide evidence of significant health problems. In the Enarson et al. (1984) and Patil et al. (1970)
studies, it was estimated that the workers were exposed to a TWA mean of 0.15–0.18 ppm chlorine. Yet,
due to limitations, these long-term studies were insufficient for quantitative risk assessment. In none of
the studies available was the nasal cavity, a sensitive target of chlorine exposure in humans and animals,
examined. Therefore, evaluations of workers currently exposed to chlorine should include examination of
the nasal cavity. In addition, future studies should include more reliable methods to estimate exposure.
Two chronic-duration inhalation studies in animals are available. One of them studied the effects of
chlorine inhalation in monkeys (Klonne et al. 1987) and the other in rats and mice (Wolf et al. 1995). In
both, the upper respiratory tract was most sensitive end point and the study in monkeys was selected as
basis for derivation of a chronic-duration inhalation MRL for chlorine gas. These studies also evaluated
hematology and clinical chemistry parameters and, for the most part, no significant alterations were
found. Additional chronic-duration inhalation studies of chlorine gas in animals do not seem necessary at
this time.
No chronic-duration human studies of exposure to hypochlorous acid or sodium hypochlorite were

located. Three chronic-duration studies were available in rats and mice (Hasegawa et al. 1986; NTP
1992). All three studies evaluated a comprehensive number of end points including hematology and
clinical chemistry and tissue and organ histopathology and did not find any significant toxicity attributed
to exposure to hypochlorite solutions. Additional chronic-duration oral studies with hypochlorite
solutions are not necessary at this time.
There are several studies of cancer in humans exposed to chlorine gas, and probably simultaneously to
other chemicals that did not find any evidence that chlorine gas is carcinogenic (Barbone et al. 1992;
Barregård et al. 1990; Bond et al. 1983, 1985, 1986; Heldaas et al. 1989). The chronic-duration
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inhalation study in rats and mice exposed to chlorine for 2 years found no evidence of carcinogenicity at
termination (Wolf et al. 1995). It is unclear what useful information additional studies with chlorine gas
would provide. There are no studies of cancer in humans exposed to hypochlorite ions, and it is unlikely
that such a cohort can ever be found. Studies of cancer in humans exposed to chlorinated water have been
conducted, but the focus of these studies has not been the hypochlorite ion but the chlorinated byproducts
derived from the reaction of chlorine with organic matter in the water (see Kantor [1994] for review).
Long-term drinking water bioassays have been conducted in rats (Hasegawa et al. 1986; NTP 1992) and
mice (Kurokawa et al. 1986; NTP 1992) and, with one exception, the results were negative. Equivocal
evidence of increased leukemia was reported in female rats in the NTP (1992) study. A need to conduct
additional drinking water studies in the F344 strain may be unwarranted given that: (1) mononuclear cell
leukemia occurs with high incidence in F344 rats; (2) the increase in leukemia was slight and not clearly
dose-related; (3) there was no decrease in tumor latency; and (4) the incidence in concurrent controls was
less than in historical controls. Although an option would be to conduct a study in a different strain of rat,
the need would still have to be balanced with the fact that epidemiologic data do not suggest such an
effect in humans.
Genotoxicity. No studies were located regarding genotoxic effects of chlorine gas in humans. The
only information available in animals is that from a study in which blood and bone marrow from rats
exposed to chlorine gas for 62 days showed no evidence on increased incidence of sister chromatid
exchanges, chromosomal aberrations, or of cellular proliferation (Kutzman 1983). It does not appear that
there is a need for additional genotoxicity studies for chlorine gas. Studies examining the in vivo
genotoxicity of hypochlorite ions in mammals gave negative results (Hayashi et al. 1988; Meier et al.
1985) and studies in vitro in animal cells and bacteria gave mixed results (Hagiwara et al. 2006; Ishidate
et al. 1984; Le Curieux et al. 1993; Miyachi and Tsutsui 2005; Sasaki et al. 1980). It is unlikely that
additional studies with hypochlorite will settle the issue.
Reproductive Toxicity. The only information available regarding effect of chlorine gas in humans is
that evaluation of the outcome of 15 pregnancies among female workers at a chlorine plant in 1932–1933
did not provide any evidence of reproductive toxicity (Skljanskaja et al. 1935). Pre-exposure of male or
female rats to up to 5 ppm chlorine for 62 days followed by mating with untreated rats resulted in no
significant effects on fertility, number of corpora lutea, viable embryos, early or late deaths, or pre-
implantation loses. In addition, in males exposed for 62 days there were no histological alterations in the
testes, and sperm morphology was unremarkable (Kutzman 1983). Chronic-duration inhalation studies
with monkeys, rats, and mice exposed to up to 2.5 ppm chlorine did not observe gross or microscopic
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lesions in the reproductive organs (Klonne et al. 1987; Wolf et al. 1995). It is plausible that accidental
exposure of pregnant women to concentrations of chlorine high enough to produce severe hypoxia may
affect pregnancy outcomes (i.e., stillbirth, abortions). Therefore, identification and evaluation of women
who were pregnant during past chlorine accidents may provide valuable information. This can also be
tested in animal models.
There is no information regarding reproductive effects in humans exposed to hypochlorite solutions and
there are limited data in animals. An acute-duration study reported sperm abnormalities in mice treated
with sodium hypochlorite, but not in mice treated with hypochlorous acid (Meier et al. 1985). This and
other internal inconsistencies make this finding of unknown toxicological significance. A study in rats
exposed to hypochlorous acid by gavage before and during breeding reported no significant effects on
fertility or on histopathology of the reproductive organs of males or females (Carlton et al. 1986). Sperm
was examined in this study and no significant alterations were reported. Long-term drinking water
studies in rats and mice did not report any gross or microscopic alterations in the reproductive organs of
males and females (Daniel et al. 1991, 1991; Furukawa et al. 1980; Hasegawa et al. 1986; NTP 1992).
Although 2-generation reproductive studies with sodium hypochlorite (in water devoid of organic matter
to eliminate the formation of chlorination byproducts) have not been conducted, the available information
does not suggest that reproductive parameters are sensitive targets for hypochlorite. Thus, additional oral
studies do not appear necessary at this time. There are no studies that evaluated reproductive parameters
in humans or animals following dermal exposure to hypochlorite. However, dermal exposure to
hypochlorite bleach is expected to affect only the site of exposure.
Developmental Toxicity. The only information available in humans exposed to chlorine gas is that
evaluation of the outcome of 15 pregnancies among female workers at a chlorine plant in 1932–1933 did
not provide any evidence of teratogenic effects (Skljanskaja et al. 1935). The same investigators reported
that rabbits exposed to low chlorine concentrations (0.6–1.6 ppm) during pregnancy gave birth to healthy
offspring (Skljanskaja and Rappoport 1935). There are no modern developmental studies of chlorine gas
in animals. As mentioned in the preceding paragraph, exposure to high concentrations of chlorine gas
during pregnancy could affect fetal or neonatal development, although so far, no study has examined that
possibility. Therefore, identification and evaluation of women that were pregnant during past accidents in
which chlorine gas was released may provide valuable information. Again, this can also be tested in
animal models.
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There is no information regarding developmental effects in humans exposed to hypochlorite. Only one
reliable study in animals was available. In that study, exposure of pregnant rats to hypochlorous acid by
gavage had no effect on neonate viability, weight gain, incidence of gross external abnormalities, or
developmental landmarks (Carlton et al. 1986). Additional studies using a relevant means of
administering chlorine, such as drinking water rather than gavage, may be necessary to confirm or refute
the results of Carlton et al. (1986). There are no studies that evaluated developmental parameters in
humans or animals following dermal exposure to hypochlorite bleach. However, as mentioned above,
dermal exposure to bleach is expected to affect only the site of exposure.
Immunotoxicity. No studies were located that evaluated immunocompetence or effects on

lymphoreticular organs in humans following exposure to chlorine gas. Studies in workers did not provide
any evidence that exposure to chlorine gas may affect immunocompetence. A 6-week study reported that
the spleen and thymus from rats exposed to 9 ppm chlorine showed decreased content of lymphoid
elements, but according to the investigators, this may have been a function of the poor physical condition
and decreased nutritional state of the rats in that dosing group (Barrow et al. 1979). Chronic-duration
inhalation studies in moneys, rats, and mice found no gross or microscopic lesions in lymphoreticular
organs and tissues (Klonne et al. 1987; Wolf et al. 1995). The immune system does not seem to be a
sensitive target for chlorine gas toxicity; additional studies of the immune system in animals exposed by
inhalation to chlorine gas are not necessary at this time.
There is no information regarding effects on the immune system in humans following oral exposure to
chlorine. One study reported that exposure of rats to chlorine in the drinking water for 8 weeks resulted
in alterations in some immune parameters (Exon et al. 1987). The toxicological significance of these
findings is difficult to ascertain because there is no known mechanism by which oral administration of
chlorine could induce immunological effects and no additional studies that could corroborate these
findings. It is possible that oxidative reactions play a role in the effects reported by Exon et al. (1987).
Other intermediate-duration studies and chronic-duration studies in rats and mice dosed with much higher
doses of chlorine in the drinking water found no gross or microscopic alterations in lymphoreticular
organs, but did not examine immunocompetence (Daniel et al. 1990, 1991; Furukawa et al. 1980;
Hasegawa et al. 1986; NTP 1992). It would be useful to try to replicate the findings from Exon et al.
(1987) adding to the protocol challenges with microorganisms to determine whether the reported
alterations translate into decreased immunity.
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Sodium hypochlorite is generally not considered a skin sensitizer, but several cases of allergic contact
dermatitis have been reported (Eun et al. 1984; Habets et al. 1986; Osmundsen 1978; Van Joost et al.
1987). Additional dermal studies are not necessary
Neurotoxicity. A series of studies by Kilburn (1995, 2000, 2003b) suggested that brief exposures to
high concentrations of chlorine gas can result in long-term neurological alterations in humans. No other
high-exposure studies in humans have reported similar effects, but no neurobehavioral tests have been
conducted in these studies. Therefore, it would be useful to conduct neurobehavioral evaluations in
subjects known to have been exposed to high concentrations of chlorine to confirm or refute Kilburn’s
findings. The study should include comparison populations matched for the prior occurrence of a non-
chemically related traumatic event. In addition, there are several validated animal models that have been
used to test for neurobehavioral effects of chemicals (i.e., lead) that could be used to test for possible
chlorine effects. The available studies in animals have provided no evidence of gross or microscopic
alterations in tissues of the central or peripheral nervous system following exposure to chlorine gas.
There is no information regarding neurological effects in humans following exposure to hypochlorite

bleach. The only information relevant information in animals is that from 90-day and 2-year studies that
found no gross or microscopic alterations in the brain from rats and mice exposed to chlorine in the
drinking water (Daniel et al. 1990, 1991; Furukawa et al. 1980; Hasegawa et al. 1986; NTP 1992). No
further neurological end points were evaluated in these studies. Since the nervous system does not seem
to be a sensitive target for oral chlorine, there is no compelling reason to conduct additional studies.
Epidemiological and Human Dosimetry Studies. There is a considerable number of studies of

humans exposed to chlorine gas (see Section 3.2.1.2 for representative references). The effects of acute
exposure to high concentrations of chlorine gas are known and concentration-response relationships have
been established (Ellenhorn and Barceloux 1988). However, less is known about long-term effects of
high acute exposures to chlorine gas and low-level, long-term exposure. As previously mentioned, some
studies have described persistent pulmonary alterations following acute exposure to chlorine gas (i.e.,
Bhérer et al. 1994; Kowitz et al. 1967; Salisbury et al. 1991), whereas others have not (i.e., Chasis et al.
1947; Jones et al. 1986; Moulick et al. 1992; Weill et al. 1969). Better exposure data and baseline health
information would seem necessary to establish reliable correlations between exposure and effects. Also,
evaluation of the nasal cavity of low-level, long-term exposure to chlorine gas seems warranted in light of
the findings of Klonne et al. (1987) in monkeys exposed to chlorine for 1 year.
CHLORINE 137
3. HEALTH EFFECTS
Exposure to hypochlorous acid or sodium hypochlorite can occur by accidental or intentional ingestion of
chlorine bleach. This type of exposure is generally of acute duration and, in most cases, the effects are
restricted to esophageal irritation without long-term consequences (Hook and Lowry 1974; Landau and
Saunders 1964; Pike et al. 1963). As discussed in Chapters 4 and 6, the level of dissolved chlorine in
drinking water is extremely low and most of the free chlorine is as hypochlorous acid at the normal pH of
drinking water. The highest level of chlorine allowed in drinking water is 4 ppm (EPA 2006a), which is
considerably lower than the maximal concentration of chlorine used in long-term studies (275 ppm
available chlorine) in rats and mice (NTP 1992), which caused no significant toxicity. Therefore, it seems
unlikely that free chlorine in drinking water will represent a health concern for humans. It should be
noted, however, that chlorinated water contains a variety of chlorinated byproducts whose biological
effects continue to be studied.
Biomarkers of Exposure and Effect.
Exposure. There are no specific biomarkers of exposure for chlorine in humans. Chlorine gas that enters
the airways or chlorine ingested as sodium hypochlorite eventually joins the chloride pool in the body.
A recent study showed that exposure of rats to chlorine gas (0.5–2.5 ppm) for 90 minutes resulted in
dose-related formation of 3-chlorotyrosine and 3,5-dichlorotyrosine in nasal tissue (Sochaski et al. 2008).
Since the method could not be used in humans due to the invasive nature of the tissue collection,
additional research needs to be conducted to make the method less invasive. In addition, it would be
valuable to determine whether exposure to other chlorinated compounds also result in the formation of
these potential biomarkers.
Effect. There are no biomarkers of effect specific for chlorine. The sensory irritation and respiratory
alterations caused by exposure to chlorine gas or the esophageal irritation caused by ingestion of
hypochlorite bleach can also be caused by other chemicals.
Absorption, Distribution, Metabolism, and Excretion. The only information regarding

pharmacokinetics of chlorine gas is that from experiments in volunteers conducted by Nodelman and
Ultman (1999a, 1999b) that showed that almost all (>95%) of a bolus dose of chlorine gas inhaled
through the mouth or the nose is cleared by the upper respiratory tract and none reaches the lungs. This
was observed over a 0.5–3 ppm exposure range. The methodology used to generate the bolus and to
monitor the concentrations of chlorine in the airways could probably be adapted to studies in animals,
CHLORINE 138
3. HEALTH EFFECTS
particularly monkeys, to test a wider range of concentrations and to correlate internal concentrations of
chlorine with lesions in the respiratory tract.
There is only one study of the pharmacokinetics of hypochlorite, the study by Abdel-Rahman et al. (1983)
that evaluated absorption, metabolism, distribution, and excretion of chlorine in rats following gavage
doses or radiolabeled (36Cl) hypochlorous acid. Additional studies may be useful to confirm or refute the
findings of Abdel-Rahman et al. (1983). On the other hand, as Scully et al. (1989) pointed out, because
hypochlorite is a potent oxidant, pharmacokinetic studies of radiolabeled hypochlorous acid (36Cl) in
animals do not reveal what happens to the parent compound, but rather to the product of the reactions of
these compounds in vivo. Therefore, the usefulness of additional studies is questionable. As previously
mentioned, a computational fluid dynamics-physiologically based pharmacokinetic model is being
developed for chlorine (Jarabek et al. 2007).
Comparative Toxicokinetics. The nature and distribution of lesions in the respiratory tract of
monkeys were compared with those in rats and mice following chronic exposure to comparable
concentrations (Ibanes et al. 1996). The investigators noted that monkeys and rodents exhibited both
differences and similarities that were most likely related to the differences in airflow characteristics.
Intuitively, it would seem that monkeys are a better model for human risk assessment because rodents are
obligate nose breathers, whereas humans and monkeys are not. However, Ibanes et al. (1996) concluded
that with appropriate exposure and response adjustments, both rodents and Rhesus monkeys appear to be
valid models for human risk assessment.
An animal model for human exposure to hypochlorite has not been identified. Studies in rats and mice
exposed to sodium hypochlorite by the oral route for 90 days or 2 years showed practically no toxicity of
at the concentrations of chlorine tested (Daniel et al. 1990, 1991; NTP 1992). The gastrointestinal effects
observed in humans after ingestion of high amounts of hypochlorite bleach (i.e., Ross and Spiller 1999)
are similar to those described in earlier studies in dogs and rabbits exposed also to high amounts of
hypochlorite bleach (Landau and Saunders 1964; Strange et al. 1951; Yarington 1970). Additional
comparative studies do not seem necessary at this time.
Methods for Reducing Toxic Effects. The treatment of chlorine exposure is mostly supportive of
respiratory and cardiovascular functions. The efficacy of some specific agents such as corticosteroids or
nebulized sodium bicarbonate for the treatment of respiratory alterations due to exposure to chlorine gas
has not been properly documented and further studies in animal models would be valuable.
CHLORINE 139
3. HEALTH EFFECTS
Children’s Susceptibility. Data needs relating to both prenatal and childhood exposures, and
developmental effects expressed either prenatally or during childhood, are discussed in detail in the
Developmental Toxicity subsection above.
Children exposed to high concentrations of chlorine gas or hypochlorite solutions have experienced
effects similar to those observed in adults, although some reports have suggested that children may more
susceptible to chlorine gas toxicity than adults (Agency for Toxic Substances and Disease Registry 1998;
Güloğlu et al. 2002). Children may be at increased risk for exposure to chlorine gas because they have a
greater lung surface area:body weight ratio and an increased minute volume:weight ratio. Children may
also be more vulnerable than adults because of the smaller diameter of their airways. Prolonged low-level
exposures to chlorine gas are not relevant to children since this type of exposure occurs only in
occupational settings. There are no studies that have examined whether young animals are more or less
susceptible than adults to chlorine gas or hypochlorite toxicity. Additional information on this issue
would be useful.
Child health data needs relating to exposure are discussed in Section 6.8.1, Identification of Data Needs:
Exposures of Children.
3.12.3 Ongoing Studies
The following ongoing studies pertaining to chlorine were identified in the Federal Research in Progress
database (FEDRIP 2009):
Dr. M.D. Gunn and coworkers at Duke University, plan to conduct a series of murine studies to determine
the extent to which specific pulmonary inflammatory cell types contribute to chlorine-induced lung injury
and the consequent epithelial damage, bronchial reactivity, morbidity, and mortality. He will then
examine the ability of the chemokine receptor antagonist to reduce these toxicities. The research is
sponsored by the National Institute of Environmental Health Sciences (NIEHS).
Dr. S-E. Jordt and coworkers at the University of Alabama, Birmingham, intend to develop
pharmacological approaches for the treatment of asthma patients after exposure to chlorine. Based on
preliminary results indicating that the TRPA1, an ion channel of the transient receptor potential (TRP)
gene family, is strongly activated by chlorine in primary and heterologous cells, the investigators
CHLORINE 140
3. HEALTH EFFECTS
hypothesized that post-exposure administration of TRP channel antagonist, in combination with

adrenergic agonists and antioxidants, will counteract life-threatening hypersensitivity responses in asthma
patients to chlorine and other pulmonary chemical threats. Specifically the investigators intend to
(1) compare responses of wild-type and TRP-channel deficient mice to chlorine in the background of the
ovalbumin asthma model, (2) establish pharmacological measures to counteract chlorine hypersensitivity
responses and chlorine-induced tissue damage in asthma, and (3) analyze the mechanism of TRPA1
activation and sensitization by chlorine, and its reversal. The research is sponsored by the NIEHS.
Dr. S. Matalon and associates at the University of Alabama, Birmingham, plan to test the hypothesis that
the toxic effects of C12 will be heightened in animals infected with respiratory syncytial virus (RSV) or
challenged with ova albumin. For that purpose, they will perform a number of biochemical, biophysical,
physiological, and morphometric measurements in RSV infected and ova albumin challenged mice as
well as normal rats prior to and following chlorine exposure to document the onset and progression of
injury to lung epithelia and pulmonary and systemic vasculature. They will then treat the mice with
antioxidants, TRP antagonists, and nitrite administered at various intervals post chlorine exposure either
intratracheally or via aerosolization, or intraperitoneally (antioxidants and nitrite) and quantify recovery
by specific functional measurements. The research is sponsored by the NIEHS.
Dr. S. Matalon and coworkers at the University of Alabama, Birmingham, also plan to determine whether
systemic administration of reactive species scavengers, as well as agents that augment surfactant levels,
ion transport and paracellular resistance, and a recently described peptide based on the lectin region of
TNFa (tip peptide), shortly after exposure to chlorine will decrease lung injury, morbidity and mortality.
This hypothesis will be tested by exposing either confluent monolayers of rat alveolar type II (ATII)
epithelial cells or rats to chlorine (50–200 ppm for 30 minutes) and measuring a number physiological
and biochemical indices of lung function 0.5, 6, 12, and 24 hours post exposure. The measurements will
be repeated following intravenous injections of NAC, ascorbate, and deferoxamine as well as albuterol
and the tip peptide. They will also assess the efficacy of intratracheally instilled ascorbate, NAC,
deferoxamine, Infasurf (a surfactant replacement mixture), albuterol and the tip peptide, as well as
aerosolized albuterol, in prolonging survival of rats with respiratory failure following chlorine exposure.
The research is sponsored by the NIEHS.
Dr. P.R. Patel and coworkers at the University of Alabama, Birmingham, hypothesize that chlorine gas
exposure induces both pulmonary and systemic vascular injury, which will be inhibited by nitrite-
dependent NO formation. The investigators propose to test this via the following specific aims: (1) test
CHLORINE 141
3. HEALTH EFFECTS
the hypothesis that inactivation of eNOS leads to compromised pulmonary and systemic vascular
function, (2) establish protective effects of nitrite administration to rats following chlorine gas exposure
on cardiopulmonary function, and (3) determine the mechanism by which nitrite therapy protects against
C12 gas induced cardiopulmonary toxicity.
CHLORINE 142
3. HEALTH EFFECTS

CHLORINE 143
4. CHEMICAL AND PHYSICAL INFORMATION
4.1 CHEMICAL IDENTITY
Information regarding the chemical identity of chlorine is located in Table 4-1. This information includes
synonyms, chemical formula and structure, and identification numbers. For the purpose of
disambiguation, terms that are commonly used in reference to chlorinated water are defined in Table 4-2.
4.2 PHYSICAL AND CHEMICAL PROPERTIES
Information regarding the physical and chemical properties of chlorine is located in Table 4-3.
Chlorine (Cl2) is a heavier-than-air, greenish-yellow gas with a pungent, irritating odor (HSDB 2009).
The odor threshold for chlorine in air is generally between 0.2 and 0.4 ppm (Amoore and Hautala 1983;
The Chlorine Institute 1998). Perceivable sensory irritation occurs at 1.0 ppm in air (EPA 1999).
Chlorine is a nonflammable gas; however, it is a very strong oxidizing agent, reacting explosively or
forming explosive compounds or mixtures with many common chemicals (O'Neil et al. 2001). Chlorine
reacts directly with nearly all of the elements to form chlorides (Lide 2005; O'Neil et al. 2001). Chlorine
is stored and transported as a liquid in pressurized containers (EPA 1999). Chlorine is transported as
either a liquid or a gas through pipelines within chemical plants or over distances of several kilometers
(Schmittinger et al. 2006).
Chlorine hydrolyzes rapidly and almost completely in water to form hydrochloric acid, hypochlorous
acid, and hypochlorite as follows:
Cl2 + H2O HOCl + H+ + Cl-
HOCl H+ + OCl-
The equilibrium constants for these reactions are represented by:
[ HOCl ][H + ][Cl − ]

K1 = (1)
[Cl 2 ]
CHLORINE 144
Table 4-1. Chemical Identity of Chlorinea
Characteristic Information
Chemical name Chlorine
b
Synonyms/trade names Chlorine gas , Bertholite, molecular chlorine, chlorine mol, dichlorine
Chemical formula Cl2
Chemical structure Cl Cl
Identification numbers:
CAS registry 7782-50-5
NIOSH RTECS FO2100000

EPA hazardous waste No data
DOT/UN/NA/IMCO shipping UN1017; IMO 2.0
HSDB 206
EINECS 231-959-5
NCI No data
a
All information obtained from HSDB 2009 except where noted.
b
EPA 1999
c
IPCS 1996
CAS = Chemical Abstracts Service; DOT/UN/NA/IMO = Department of Transportation/United Nations/North

America/International Maritime Dangerous Goods Code; EINECS = European Inventory of Existing Commercial
Chemical Substances; EPA = Environmental Protection Agency; HSDB = Hazardous Substances Data Bank; NCI =
National Cancer Institute; NIOSH = National Institute for Occupational Safety and Health; RTECS = Registry of Toxic
Effects of Chemical Substances
CHLORINE 145
Table 4-2. Commonly Used Terms Related to Chlorinated Water
Term Meaning
Chlorinated water The solution that results when molecular chlorine or a hypochlorite salt is
added to water for the purpose of water disinfection. Molecular chlorine
reacts rapidly with water under environmental conditions to form
hypochlorous acid, hypochlorite, and hydrochloric acid; therefore,
chlorinated water does not contain molecular chlorine under normal
conditions. Some other substances that are commonly formed in
chlorinated water include oxidized inorganics, chloramines, and
trihalomethanes.
Free chlorine The combination of the equilibrium species molecular chlorine,

hypochlorous acid, and the hypochlorite ion in chlorinated water. Since
molecular chlorine is usually not present in water samples, this term
usually refers to the amount of hypochlorous acid and hypochlorite in
water.
Combined chlorine The amount of chloramines (chlorine combined with nitrogen) present in
chlorinated water.
Total chlorine The amount of free chlorine (hypochlorous acid and hypochlorite) plus
combined chlorine (chloramines) present in chlorinated water.
Available chlorine A measure of the oxidizing strength of a solution. It is equal to the

amount of molecular chlorine that when added to water would produce a
solution with equivalent oxidizing power. It is commonly reported as
weight percent.
Residual chlorine The amount of free chlorine remaining in a chlorinated water sample that
has been collected at a point of use. This indicates whether the water
has retained its disinfection properties.
Aqueous chlorine A term that usually has a meaning similar to that of free chlorine. In this
sense, “aqueous chlorine” should not be misunderstood as the amount of
molecular chlorine in water (aqueous molecular chlorine). The term
“aqueous chlorine” is commonly used in reference to a prepared aqueous
solution of hypochlorite and hypochlorous acid.
Sources: APHA 1998a; Edstrom Industries 2003; Fukayama et al. 1986; IARC 1991; The Chlorine Institute 2006;
Westerhoff et al. 2004; WHO 2007.
CHLORINE 146
Table 4-3. Physical and Chemical Properties of Chlorinea
Property Information
Molecular weight 70.905
Color Greenish-yellow
Physical state Gas
Melting point -101.00 °C
Boiling point -34.04 °C
b
Density in air 2.482 (air=1)
Density, as liquid
c
20 °C, 6.864 atm 1.4085 g/mL
c
-35 °C, 0.9949 atm 1.5648 g/mL
Odor Pungent, irritating
Odor threshold:
d
Water Not applicable

c,e,f
Air 0.2–0.4 ppm

Solubility:
c,g
Water 14.6 g/L at 0 °C; 7.3 g/L at 20 °C
Other solvents Glacial acetic acid, dimethylformamide, nitrobenzene, phosphoryl
chloride, carbon tetrachloride, tetrachloroethane, pentachloroethane,
h
hexachlorobutadiene, and chlorobenzene
Partition coefficients:
Log Kow Not applicable
Log Koc Not applicable
Vapor pressure at 25 °C 5,830 mm Hg
-2 3 i
Henry's law constant 1.17x10 atm-m /mol
Autoignition temperature Not applicable
Flashpoint Not applicable
Reactivity Strong oxidizer; reacts explosively with many materials
3 3 c
Conversion factors 1 ppm=2.9 mg/m ; 1 mg/m =0.344 ppm
a
All information obtained from HSDB 2009, except where noted.
b
O'Neil et al. 2001
c
EPA 1999
d
Amoore and Hautala (1983) reported an odor threshold of 0.002 ppm for chlorine in water; however, these authors
state that this solution lacks enough persistence for this value to be used for reference purposes.
e
Amoore and Hautala 1983
f
CI 1998
g
EPA 1994b
h
Schmittinger et al. 1996
i
Staudinger and Roberts 1996
CHLORINE 147
[ H + ][OCl − ]
K2 = (2)
[ HOCl ]
The relative percentage of Cl2, HOCl, and OCl- at some fixed concentration of Cl- can be expressed as:
[Cl 2 ]
%Cl 2 = (3)
[Cl 2 ] + [ HOCl ] + [OCl − ]
[ HOCl ]
% HOCl = (4)
[Cl 2 ] + [ HOCl ] + [OCl − ]
− [OCl − ]
%OCl = (5)
[Cl 2 ] + [ HOCl ] + [OCl − ]
Using the expressions for the equilibrium constants in Equations 1 and 2 and the relationship that pH is
equivalent to the negative logarithm of the hydronium ion concentration, Equations 3–5 can be re-written
as:
1
%Cl 2 = (6)
K1 KK
1+ −
10 pH + 1 − 2 10 2 pH
[Cl ] [Cl ]
1
% HOCl = −
(7)
[Cl ]
1+ + K 2 10 pH
K 110 pH
1
%OCl − = −
(8)
[Cl ] 1
1+ 2 pH
+
K 1 K 2 10 K 2 10 pH
Figure 4-1 illustrates the speciation as a function of pH using values for K1 = 3.9x10-4 M2 (Cotton et al.
1999; Farr et al. 2003) and K2 = 2.9x10-8 M (Farr et al. 2003) at 25 °C. This figure shows the
CHLORINE 148
Figure 4-1. Speciation of Cl2, HOCl, and OCl- as a Function of pH
100
90
80
70
% Species
60
50
Cl2
40
HOCl
OCl
30
20
10
0 1 2 3 4 5 6 7 8 9 10 11 12 13 14
pH
CHLORINE 149
pH-dependant relationship between molecular chlorine, hypochlorous acid, and hypochlorite in aqueous
solution. Sodium hypochlorite bleach solutions typically have a pH of 11–13 (The Chlorine Institute
2006). As illustrated in Figure 4-1, the addition of acid to a hypochlorite solution (e.g., mixing of sodium
hypochlorite bleach with acid drain cleaner) can drive the pH low enough to result in the release of
dangerous amounts of molecular chlorine gas.
CHLORINE 150

CHLORINE 151
5. PRODUCTION, IMPORT/EXPORT, USE, AND DISPOSAL
5.1 PRODUCTION
The element chlorine was discovered in 1774, and the first patent for its use as a bleaching agent came as
early as 1799 (Deutsch 1947). However, it wasn't until the late 1800s that adequate electrolytic
equipment became available to produce chlorine on an industrial scale. Chlorine production increased
steadily from 5,400 metric tons in 1900 to 63,500 metric tons in 1920 (Deutsch et al. 1963). U.S. chlorine
production then underwent an extremely dramatic increase over the next 50 years. Production volumes in
1930, 1940, 1950, 1960, and 1970 were 181,000, 608,000, 1,814,000, 4,172,000, and 8,800,000 metric
tons, respectively (Curlin et al. 1991; Deutsch et al. 1963; Robertson 1978). Reasons for this increase
were the demand for use of chlorine as a bleaching agent, the demand for its use in the manufacture of
other important industrial chemicals, and the further development of electrolytic cell technology, which
improved plant production capacities by almost 200% (Bommaraju et al. 2004; Deutsch et al. 1963).
Growth during this period was supported by the widespread construction of chlorine-producing plants by
alkali producers who were interested in manufacturing chlorine and caustic soda (sodium hydroxide) as
co-products, an effort that gave birth to the chlor-alkali industry (Bommaraju et al. 2004; Deutsch et al.
1963; Schmittinger et al. 2006). In 1915, there were only 15 chlorine-producing factories in the United
States; by 1960, there were 240 (Deutsch et al. 1963).
During the 1970s and 1980s, U.S. chlorine production fluctuated between 11,200,000 metric tons in 1979
and 8,300,000 metric tons in 1982 (Curlin et al. 1991). Chlorine production rose steadily through the
1990s, reaching 12,100,000 metric tons in 1999 (The Chlorine Institute 2008). With the exception of a
spike to 12,300,000 metric tons in 2004, production has steadily declined over the past decade (The
Chlorine Institute 2008). The 2008 U.S. production volume for chlorine was reported to be
10,600,000 metric tons by the U.S. Census Bureau (2009). Environmental pressures have strained the
chlorine market since the 1970s. Regulations have contributed to such changes as moving away from the
use of mercury and asbestos in chlorine production, ending the use of chlorine in pulp and paper
bleaching, and curtailing the production of certain chlorinated end products (Bommaraju et al. 2004;
CMR 1977, 1980, 1989, 1992, 1995, 2000, 2003, 2006; Robertson 1978; Schmittinger et al. 2006).
Negative effects on the market have been balanced by the development of alternative chlorine production
methods and increases in demand for other chlorine end products, especially polyvinyl chloride.
Although there are still operational facilities that use the older mercury and asbestos production methods,
the newer chlorine production facilities are based on the more efficient membrane technology
(Bommaraju et al. 2004; The Chlorine Institute 2008). The companies that produced chlorine in the
CHLORINE 152
United States, their production sites, and their annual capacities for 2008 (the most recent year for which
figures are available) are shown in Table 5-1 (SRI 2008).
Table 5-2 summarizes the number of facilities in each state that manufactured or processed chlorine (Cl2)
in 2006, the ranges of maximum amounts on site, if reported, and the activities and uses as reported in the
Toxics Release Inventory (TRI) (TRI06 2008). The data listed in this table should be used with caution
since only certain types of facilities are required to report. This is not an exhaustive list.
5.2 IMPORT/EXPORT
Annual U.S. chlorine import and export quantities reported for different years are listed in Table 5-3. The
available data indicate that annual imports of chlorine into the United States have increased steadily over
the past 20 years, rising from 251,000 metric tons in 1984 to 429,000 metric tons in 2007 (CMR 1989,
1992, 2000; HSDB 2009; ITA 2007; U.S. Census Bureau 2008). The decline in U.S. chlorine exports
during the early 2000s (24,200 metric tons in 2000 to 10,400 metric tons in 2004) has been attributed to
increasing energy costs, which have rendered the chlorine produced in the United States uncompetitive,
especially in the Asian market (CMR 2006; ITA 2007). However, U.S. chlorine exports in 2006 were
bolstered by a 9-fold increase in shipments to Mexico, accounting for approximately 82% (32,201 metric
tons) of the 39,481 metric tons of chlorine exported during that year (ITA 2007). U.S. exports of chlorine
fell to 25,740 in 2007 (US Census Bureau 2008).
5.3 USE
The major uses of chlorine during 2006 were the manufacturing of vinyl chloride to make polyvinyl
chloride (PVC) plastics (36%), the manufacturing of other organic compounds (41%), the manufacturing
of inorganic chemicals (15%), water treatment (4%), and pulp and paper bleaching (1%) (CMR 2006).
Other miscellaneous uses accounted for 3% of total chlorine use during 2006. Chlorine is used in the
production of a large number of commercial products (Bommaraju et al. 2004; Schmittinger et al. 2006).
Some of the important end products for which chlorine plays a role in the production stream include
refrigerants, aerosols, silicones, silicone rubber, plastics, solvents, polyethers, varnishes, foams,
chlorinated rubber, polyurethane, detergents, dyes, insecticides, pesticides, disinfectants, bleaches, and
white pigment enamel (Schmittinger et al. 2006). Chlorine has been used in the food industry as a
bleaching agent for flour (Fukayama et al. 1986). Chlorine was used as a war gas during World War I
(Compton 1987). Chlorine is also used to manufacture phosgene (O’Neil et al. 2001).
CHLORINE 153
Table 5-1. Companies that Produce Chlorine in the United States and Annual
Capacities for 2006
Capacity (thousands Capacity

Company Location of short tons)a (metric tons)a
ASHTA Chemicals, Inc. Ashtabula, Ohio 44 40,000
Bayer MaterialScience LLC Baytown, Texas 400 363,000
The Dow Chemical Company Freeport, Texas 3,240 2,939,000
Plaquemine, Louisiana 1,070 971,000
E.I. du Pont de Nemours and Niagara Falls, New York 85 77,000
Company; DuPont Coatings and
Color Technologies; DuPont
Performance Coatings
Equa-chlor LLC Longview, Washington 87 79,000
ERCO Worldwide, Inc. Port Edwards, Wisconsin 106 96,000
Formosa Plastics Corporation Point Comfort, Texas 811 736,000
Georgia Gulf Corporation Plaquemine, Louisiana 450 408,000
Georgia-Pacific Chemicals LLC Green Bay, Wisconsin 9 8,000
Muskogee, Oklahoma 6 5,000
Rincon, Georgia 7 6,000
Kuehne Chemical Corporation Delaware City, Delaware 16 15,000
Occidental Chemical Corporation; Convent, Louisiana 389 353,000
Chloro-Vinyls Group
Corpus Christi, Texas 604 548,000
Geismar, Louisiana 268 243,000
Hahnville, Louisiana 750 680,000
Mobile, Alabama 50 45,000
Muscle Shoals, Alabama 150 136,000
New Castle, Delaware 90 82,000
Niagara Falls, New York 335 304,000
Wichita, Kansas 263 239,000
Olin Corporation; Olin Chlor Alkali Augusta, Georgia 120 109,000
Products Division Charleston, Tennessee 245 222,000
Henderson, Nevada 152 138,000
McIntosh, Alabama 735 667,000
Niagara Falls, New York 286 259,000
St. Gabriel, Louisiana 180 163,000
OxyVinyls, L.P. La Porte, Texas 580 526,000
PPG Industries, Inc.; Lake Charles, Louisiana 1,375 1,247,000
Chemical Group Natrium, West Virginia 510 463,000
CHLORINE 154
Table 5-1. Companies that Produce Chlorine in the United States and Annual
Capacities for 2006
Capacity (thousands Capacity

Company Location of short tons)a (metric tons)a
SABIC Innovative Plastics Burkville, Alabama 90 82,000
Mount Vernon, Indiana 96 87,000
Titanium Metals Corporation Henderson, Nevada 5 5,000
Trans Carolina Products LLC Hamlet, North Carolina Not available Not available
U.S. Magnesium, LLC Rowley, Utah 47 43,000
Westlake Vinyls, Inc. Calvert City, Kentucky 205 186,000
Total 13,856 12,570,000
a
Much of the capacity is consumed captively.
Source: SRI 2008; The Chlorine Institute 2008

CHLORINE 155
Table 5-2. Facilities that Produce, Process, or Use Chlorine
Minimum Maximum
Number of amount on site amount on site
Statea facilities in poundsb in poundsb Activities and usesc
AK 13 0 9,999,999 1, 2, 3, 5, 6, 7, 10, 11, 12, 13, 14
AL 134 0 499,999,999 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14
AR 67 0 49,999,999 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13
AS 2 1,000 9,999 11, 12
AZ 44 100 9,999,999 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 14
CA 143 0 499,999,999 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13
CO 19 0 49,999,999 1, 2, 3, 4, 5, 6, 9, 10, 11, 12
CT 28 0 999,999 1, 2, 3, 4, 5, 6, 7, 10, 11, 12
DC 1 100,000 999,999 12
DE 31 100 499,999,999 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12
FL 109 0 499,999,999 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13
GA 105 0 9,999,999 1, 2, 3, 4, 5, 6, 7, 9, 10, 11, 12, 13
GU 2 10,000 999,999 9, 12
HI 18 0 9,999,999 1, 2, 3, 4, 6, 8, 10, 11, 12
IA 46 0 9,999,999 1, 2, 3, 5, 6, 7, 8, 10, 11, 12
ID 36 0 9,999,999 1, 2, 3, 5, 6, 7, 10, 11, 12, 13, 14
IL 72 0 49,999,999 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13
IN 67 0 9,999,999 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13
KS 37 0 9,999,999 1, 2, 3, 4, 5, 6, 7, 9, 10, 11, 12
KY 81 0 999,999,999 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13
LA 180 0 499,999,999 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14
MA 25 0 999,999 1, 2, 3, 5, 6, 7, 9, 10, 11, 12
MD 41 100 49,999,999 1, 2, 3, 5, 6, 7, 8, 9, 10, 11, 12, 13
ME 63 0 49,999,999 1, 2, 3, 4, 5, 6, 7, 10, 11, 12, 13
MI 104 0 499,999,999 1, 2, 3, 5, 6, 7, 8, 9, 10, 11, 12, 13
MN 67 0 9,999,999 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13
MO 55 0 9,999,999 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14
MS 76 0 49,999,999 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14
MT 11 1,000 9,999,999 1, 4, 5, 7, 10, 11, 12, 13
NC 118 0 499,999,999 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13
ND 9 100 999,999 1, 2, 3, 5, 6, 10, 11, 12
NE 18 100 49,999,999 1, 2, 3, 4, 6, 9, 10, 11, 12
NH 12 0 9,999,999 1, 2, 3, 5, 6, 9, 12, 13
NJ 66 0 49,999,999 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14
NM 19 0 9,999,999 1, 2, 3, 4, 5, 6, 9, 11, 12
NV 31 0 49,999,999 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13
CHLORINE 156
Table 5-2. Facilities that Produce, Process, or Use Chlorine
Minimum Maximum
Number of amount on site amount on site
Statea facilities in poundsb in poundsb Activities and usesc
NY 106 0 49,999,999 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13
OH 120 0 499,999,999 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13
OK 48 0 49,999,999 1, 2, 3, 5, 6, 7, 8, 9, 10, 11, 12, 13
OR 55 0 9,999,999 1, 2, 3, 4, 5, 6, 8, 10, 11, 12, 13
PA 102 0 9,999,999 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14
PR 27 0 49,999,999 2, 3, 4, 6, 7, 10, 11, 12
RI 15 100 9,999,999 1, 2, 3, 4, 6, 9, 10, 11, 12
SC 94 0 99,999,999 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13
SD 9 100 999,999 7, 10, 11, 12
TN 99 0 499,999,999 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14
TX 197 0 499,999,999 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14
UT 40 0 9,999,999 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13
VA 66 0 49,999,999 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13
VT 2 1,000 9,999 11, 12
WA 102 0 499,999,999 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13
WI 107 0 9,999,999 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14
WV 52 0 499,999,999 1, 2, 3, 4, 5, 6, 9, 10, 11, 12, 13
WY 13 1,000 999,999 1, 2, 3, 5, 10, 11, 12, 13
a
Post office state abbreviations used
b
Amounts on site reported by facilities in each state
c
Activities/Uses:
1. Produce 6. Impurity 11. Chemical Processing Aid
2. Import 7. Reactant 12. Manufacturing Aid
3. Onsite use/processing 8. Formulation Component 13. Ancillary/Other Uses
4. Sale/Distribution 9. Article Component 14. Process Impurity
5. Byproduct 10. Repackaging
Source: TRI06 2008 (Data are from 2006)

CHLORINE 157
Table 5-3. U.S. Chlorine Imports and Exports by Year in Metric Tons
Year Imports Exports Reference

1975 67,000 15,000 Robertson 1978
1984 251,000 39,500 HSDB 2007
1986 298,739 Not available HSDB 2007
1987 Not available 3,787 HSDB 2007
1988 280,840 58,073 CMR 1989
1991 272,160 Not available CMR 1992
1998 373,766 22,680 CMR 2000
1999 325,685 21,773 CMR 2000
2000 358,015 24,231 ITA 2007
2001 358,060 20,964 ITA 2007
2002 409,695 18,566 ITA 2007
2003 412,117 15,361 ITA 2007
2004 470,884 10,448 ITA 2007
2005 476,103 12,306 ITA 2007
2006 454,414 39,481 ITA 2007
2007 429,440 25,740 U.S. Census Bureau 2008
CHLORINE 158
5.4 DISPOSAL
Chlorine is disposed of via a salt-forming reaction followed by neutralization (HSDB 2009). Chlorine
gas is first introduced into a large volume solution of a reducing agent such as sodium thiosulfate,
bisulfite, or ferrous salts or aqueous sodium hydroxide (HSDB 2009). The resulting salt solution is then
neutralized and routed to a sewage treatment plant (HSDB 2009).
CHLORINE 159
6. POTENTIAL FOR HUMAN EXPOSURE
6.1 OVERVIEW
Although it has multiple uses and is released to the environment, chlorine is too reactive to be identified
in any of the 1,704 hazardous waste sites that have been proposed for inclusion on the EPA National
Priorities List (NPL) (HazDat 2007).
Chlorine may be released into the environment during accidents such as a chlorine gas leak from an
industrial facility or a chlorine tank spill or rupture. Low concentrations of chlorine gas (<600 ppt)
appear to be produced by the photolysis of seawater aerosol. Chlorine gas injected into the water during
water chlorination quickly dissolves and forms chloride and hypochlorous acid within seconds. Liquid
chlorine in a ruptured tank or spilled onto the ground or into water during an accident is expected to
volatilize rapidly, forming a greenish-yellow cloud of chlorine gas. This gas cloud can be carried several
miles away from the source of release while maintaining dangerous levels of chlorine.
Since chlorine gas is so reactive, it is not expected to remain in the environment very long after it is
released. Chlorine immediately reacts with both organic and inorganic materials that it comes into
contact with. As mentioned above, it is converted within seconds once it dissolves in water. Chlorine
undergoes direct photolysis in the air and its half-life in the troposphere is on the order of several minutes.
Chlorine levels in the ambient atmosphere, water, soil, or sediment are not available.
Exposure of the general population to chlorine gas is not expected except in the case of an accidental spill
or industrial mishap. There have been several documented incidents in which large amounts of chlorine
gas have been released, thereby exposing workers and the members of the general population following
the derailment of trains carrying liquefied chlorine gas (Agency for Toxic Substances and Disease
Registry 1998; NTSB 1998, 2005, 2006). Other accidental exposures may occur when individuals mix
acidic household chemicals with bleach or pool sanitizing agents (see Section 6.3.2.2). Occupational
exposure to low levels of chlorine gas may occur for individuals who work at facilities where it is
produced or used. These individuals may be exposed to higher levels if an accidental release occurs
within the facility. Children are expected to be affected by the same routes of exposure as adults, except
for occupational exposure.
The general public is not exposed to molecular chlorine in drinking water as a result of water sanitation
practices, even though chlorine gas may be used in these processes. Free chlorine in drinking water is
CHLORINE 160
defined as the sum of dissolved chlorine gas, hypochlorous acid, and hypochlorite anion. As discussed in
Chapter 4 and in Section 6.3.2.2, the level of dissolved chlorine in water is very low, except under acidic
conditions. As a consequence, the term free chlorine in public water systems or swimming pools usually
refers to the concentration of hypochlorous acid and hypochlorite anion (APHA 1998a, 1998b).
6.2 RELEASES TO THE ENVIRONMENT
The Toxics Release Inventory (TRI) data should be used with caution because only certain types of
facilities are required to report (EPA 2005). This is not an exhaustive list. Manufacturing and processing
facilities are required to report information to the TRI only if they employ 10 or more full-time
employees; if their facility is included in Standard Industrial Classification (SIC) Codes 10 (except 1011,
1081, and 1094), 12 (except 1241), 20–39, 4911 (limited to facilities that combust coal and/or oil for the
purpose of generating electricity for distribution in commerce), 4931 (limited to facilities that combust
coal and/or oil for the purpose of generating electricity for distribution in commerce), 4939 (limited to
facilities that combust coal and/or oil for the purpose of generating electricity for distribution in
commerce), 4953 (limited to facilities regulated under RCRA Subtitle C, 42 U.S.C. section 6921 et seq.),
5169, 5171, and 7389 (limited S.C. section 6921 et seq.), 5169, 5171, and 7389 (limited to facilities
primarily engaged in solvents recovery services on a contract or fee basis); and if their facility produces,
imports, or processes ≥25,000 pounds of any TRI chemical or otherwise uses >10,000 pounds of a TRI
chemical in a calendar year (EPA 2005).
6.2.1 Air
Estimated releases of 5,050,000 pounds (2,290 metric tons) of chlorine to the atmosphere from
915 domestic manufacturing and processing facilities in 2006, accounted for about 88% of the estimated
total environmental releases from facilities required to report to the TRI (TRI06 2008). These releases are
summarized in Table 6-1.
Chlorine may be released into the air in fugitive emissions from industrial facilities where it is produced
or used. It may also be released into the air as a result of a spill or tank rupture (Henry et al. 2005; Horton
et al. 2002). Between January 1993 and December 2000, 952 chlorine-related events (865 involved
chlorine only) were reported to the ATSDR's Hazardous Substances Emergency Events Surveillance
system (Horton et al. 2002). Of the 865 chlorine-only events, 592 (68.4%) involved air emissions. Of the
564 events for which release amount information was available in pounds, 511 events involved releases of
≤250 pounds. Examples of some recent large scale accidents involving the release of chlorine gas follow.
CHLORINE 161
Table 6-1. Releases to the Environment from Facilities that Produce, Process, or
Use Chlorinea
b
Reported amounts released in pounds per year
Total release
c d e f g h i j k
State RF Air Water UI Land Other On-site Off-site On- and off-site
AK 2 0 No data 0 0 0 0 0 0
AL 39 43,765 1,208 0 0 0 44,973 0 44,973
AR 23 54,016 637 0 0 0 54,653 0 54,653
AZ 10 668 250 0 517 0 1,435 0 1,435
CA 28 3,192 0 0 8,100 0 11,292 0 11,292
CO 9 45,635 0 0 0 0 45,635 0 45,635
CT 4 972 816 0 0 0 1,788 0 1,788
DC 2 1,008 0 0 0 0 1,008 0 1,008
DE 5 4,662 No data 0 0 0 4,662 0 4,662
FL 34 5,749 22 0 27,734 0 18,055 15,450 33,505
GA 34 5,332 2,702 0 0 0 8,034 0 8,034
HI 1 5 No data 0 0 0 5 0 5
IA 16 12,873 16,825 0 1,620 0 31,318 0 31,318
ID 6 8,965 250 0 5 0 9,215 5 9,220
IL 31 186,356 121,209 0 0 0 307,565 0 307,565
IN 34 77,356 1,501 0 278 0 78,862 273 79,135
KS 10 2,681 0 146,240 0 0 148,921 0 148,921
KY 21 78,635 490 0 0 0 79,125 0 79,125
LA 63 179,943 13,056 0 269 72 192,999 341 193,340
MA 5 385 No data 0 0 0 385 0 385
MD 9 781 0 0 0 0 781 0 781
ME 5 1,510 0 0 0 0 1,510 0 1,510
MI 26 30,950 679 0 0 0 31,628 0 31,628
MN 16 12,165 0 0 0 0 12,165 0 12,165
MO 20 15,545 1,157 0 0 0 16,702 0 16,702
MS 18 61,839 676 0 0 0 62,515 0 62,515
NC 23 121,870 12,308 0 8 0 134,186 0 134,186
ND 4 715 0 0 0 0 715 0 715
NE 9 2,126 220 0 0 0 2,346 0 2,346
NH 2 11 0 0 0 0 11 0 11
NJ 12 8,251 6,431 0 0 0 14,682 0 14,682
NM 6 3,133 No data 3,166 0 109 6,299 109 6,408
NV 9 5,246 No data 0 252,035 0 257,281 0 257,281
NY 23 61,884 1,209 0 0 694 63,093 694 63,787
OH 42 51,278 1,206 0 0 7 52,484 7 52,491
CHLORINE 162
Table 6-1. Releases to the Environment from Facilities that Produce, Process, or
Use Chlorinea
b
Reported amounts released in pounds per year
Total release
c d e f g h i j k
State RF Air Water UI Land Other On-site Off-site On- and off-site
OK 12 1,448 250 0 0 0 1,698 0 1,698
OR 10 10,744 301 0 0 0 11,045 0 11,045
PA 31 68,834 2,919 0 0 0 71,753 0 71,753
PR 7 3,644 No data 0 0 0 3,644 0 3,644
RI 3 1,796 No data 0 0 0 1,796 0 1,796
SC 18 12,836 23 0 0 0 12,859 0 12,859
SD 2 0 186 0 144 0 330 0 330
TN 26 138,054 0 0 0 0 138,054 0 138,054
TX 116 242,531 31,610 13,908 160 0 288,209 0 288,209
UT 6 3,330,619 0 0 0 0 3,330,619 0 3,330,619
VA 25 31,766 11,173 0 0 0 42,939 0 42,939
VT 1 0 No data 0 0 0 0 0 0
WA 18 2,268 17,006 0 5 0 19,279 0 19,279
WI 21 40,691 3,540 0 14 0 44,245 0 44,245
WV 14 17,997 4,000 0 0 0 21,997 0 21,997
WY 4 57,019 0 0 114 0 57,133 0 57,133
Total 915 5,049,751 253,859 163,314 291,003 882 5,741,931 16,879 5,758,810
a
The TRI data should be used with caution since only certain types of facilities are required to report. This is not an
exhaustive list. Data are rounded to nearest whole number.
b
Data in TRI are maximum amounts released by each facility.
c
Post office state abbreviations are used.
d
Number of reporting facilities.
e
The sum of fugitive and point source releases are included in releases to air by a given facility.
f
Surface water discharges, waste water treatment-(metals only), and publicly owned treatment works (POTWs) (metal
and metal compounds).
g
Class I wells, Class II-V wells, and underground injection.
h
Resource Conservation and Recovery Act (RCRA) subtitle C landfills; other on-site landfills, land treatment, surface
impoundments, other land disposal, other landfills.
i
Storage only, solidification/stabilization (metals only), other off-site management, transfers to waste broker for
disposal, unknown
j
The sum of all releases of the chemical to air, land, water, and underground injection wells.
k
Total amount of chemical transferred off-site, including to POTWs.
RF = reporting facilities; UI = underground injection
Source: TRI06 2008 (Data are from 2006)

CHLORINE 163
A freight train derailment, which took place on April 11, 1996, 2 miles west of Alberton, Montana
resulted in a spill releasing 64.8 tons of chlorine into the environment (Agency for Toxic Substances and
Disease Registry 1998; NTSB 1998). On January 6, 2005, a train carrying sodium hydroxide, cresol, and
liquefied chlorine collided with another train in Graniteville, South Carolina releasing approximately
120,000 pounds of chlorine gas to the surrounding atmosphere (NTSB 2005). On June 28, 2004, a
westbound Union Pacific Railroad freight train collided with an eastbound freight train in Macdona,
Texas (NTSB 2006). Consequently, a tank car carrying 180,000 pounds of liquefied chlorine was
punctured, releasing a cloud of chlorine gas to the immediate area (NTSB 2006). An accident involving a
broken cargo transfer pipe at the ATOFINA Chemicals plant in Riverview, Michigan, resulted in the
release of flammable methyl mercaptan gas (NTSB 2002). A subsequent fire resulted in damage to an
adjacent tank car loaded with chlorine. It was estimated that approximately 26,500 of the 178,560 pounds
of chlorine in the tank car were released in this incident, which occurred in July 2001 (NTSB 2002).
Chlorine appears to be generated in very low concentrations by the photolysis of seawater aerosols above
seawater (California Environmental Protection Agency 2002; Chang et al. 2004; Knipping and Dabdub
2003).
Based on its instability and reactivity, it is not expected to be identified in air at any of the
1,704 hazardous waste sites that have been proposed for inclusion on the EPA National Priorities List
(NPL) (HazDat 2007).
6.2.2 Water
Estimated releases of 254,000 pounds (115 metric tons) of chlorine to surface water from 915 domestic
manufacturing and processing facilities in 2006, accounted for about 4% of the estimated total
environmental releases from facilities required to report to the TRI (TRI06 2008). These releases are
summarized in Table 6-1.
Activities at industrial facilities where chlorine is produced or used may result in its unintentional release
to surface water. Chlorine may also be released into water as a result of a spill or tank rupture. Chlorine
gas is injected directly into water during certain disinfection processes; however, these processes take
place under controlled conditions within treatment facilities to prevent the release of chlorine into the
environment (Das 2002; Tchobanoglous and Schroeder 1985). Furthermore, the chlorine gas is
CHLORINE 164
immediately converted into hypochlorous acid, chloride ion, and hypochlorite as soon as it enters the
water. Chlorine may be formed in waters containing hypochlorite if the pH is lowered to levels below 4
(Farr et al. 2003).
Chlorine is too reactive to be identified in surface water or groundwater at any of the 1,704 hazardous
waste sites that have been proposed for inclusion on the EPA National Priorities List (NPL) (HazDat
2007).
6.2.3 Soil
Estimated releases of 291,000 pounds (132 metric tons) of chlorine to soils from 915 domestic
manufacturing and processing facilities in 2006, accounted for about 5% of the estimated total
environmental releases from facilities required to report to the TRI (TRI06 2008). An additional
163,000 pounds (74 metric tons), constituting about 3% of the total environmental emissions, were
released via underground injection (TRI06 2008). These releases are summarized in Table 6-1.
Activities at industrial facilities where chlorine is produced or used may result in its release to soil.
Chlorine may also be released onto soil as a result of a spill. Of the 865 chlorine-only events reported to
the ATSDR's Hazardous Substances Emergency Events Surveillance system between January 1993 and
December 2000, 134 (15.5%) involved spills (Horton et al. 2002).
Chlorine is too reactive to be identified in soil or sediment at any of the 1,704 hazardous waste sites that
have been proposed for inclusion on the EPA National Priorities List (NPL) (HazDat 2007).
6.3 ENVIRONMENTAL FATE
6.3.1 Transport and Partitioning
The boiling point of chlorine is -34.04 °C; therefore, chlorine is a gas under environmental conditions
(HSDB 2009). Chlorine gas dissolves in water (7.3 g/L at 20 °C) and is immediately converted to
hypochlorous acid and chloride ion at environmental pH. However, this conversion is hindered under
very acidic conditions (pH<4). Molecular chlorine in water at this low pH is expected to volatilize
rapidly based on a Henry's law constant of 1.17x10-2 atm-m3/mol (Staudinger and Roberts 1996).
Chlorine is not expected to bioaccumulate in plants or animals since it reacts with the moist tissues of
living systems (Compton 1987; Schreuder and Brewer 2001; Schmittinger et al. 2006). Schreuder and
Brewer (2001) observed severe damage to the foliage of two conifer species exposed to a chlorine gas
CHLORINE 165
cloud released during an accidental spill. All buds on exposed trees located within 50 m of the release
were killed.
If a large amount of liquid chlorine is released to a body of water, such as during a spill or an underwater
release from a ruptured tank, some of the chlorine is expected to escape into the air before it can mix and
react with the water. Similarly, when liquid chlorine is spilled onto the ground or when a tank containing
liquid chlorine is ruptured, much of the chlorine will volatilize rapidly into the air creating a greenish-
yellow cloud of chlorine gas (Agency for Toxic Substances and Disease Registry 1998; DOE 2005b).
Since chlorine gas is heavier than air, a chlorine gas cloud will remain low to the ground. Movement and
dissipation of the gas cloud is determined by such factors as the release volume, type of release, terrain,
topography, temperature, humidity, atmospheric stability, and wind speed and direction (DOE 2005b;
U.S. Chemical Safety and Hazard Investigation Board 2003).
Analysis of the chlorine gas cloud released during the 2005 Graniteville, South Carolina train derailment
indicates that the dense cloud was initially driven southwest by gravity toward lower elevation, but was
later dispersed by the wind toward the north and northeast as the boundary layer of the plume grew and as
the gas began to mix with the surrounding air (DOE 2005a, 2005b). Wenck et al. (2007) reported that
there were approximately 40 severe outcomes (≥3 nights of hospitalization and 9 deaths) and
approximately 120 less severe outcomes (≤2 nights hospitalization) that occurred within a half-mile
radius of the incident (Wenck et al. 2007). According to these authors, only a few less severe outcomes
occurred between a half-mile and three-quarters of a mile from incident.
Movement of chlorine through soil is not expected to be relevant since chlorine will react and volatilize
so quickly when spilled onto the ground (Agency for Toxic Substances and Disease Registry 1998;
Schulte 1999).
6.3.2 Transformation and Degradation
6.3.2.1 Air
The primary removal mechanism for chlorine in air is direct photolysis (EPA 1993; Graedel 1978;
Graedel et al. 1986). Sunlight at tropospheric wavelengths (<430 nm) breaks apart the chlorine molecule
to form two chlorine radicals. These radicals then react with any available organic molecule to form
hydrochloric acid. The mean atmospheric lifetime of chlorine has been reported as 440 seconds (the
atmospheric half-life can be approximated by multiplying the lifetime by the natural logarithm of 2)
CHLORINE 166
(Graedel 1978). A tropospheric lifetime of <15 minutes was calculated by Tanaka et al. (2003) under
smog conditions in Houston, Texas. The rate of direct photolysis for any chemical species is dependent
upon the intensity of sunlight, and therefore, factors such as time of year, geographic location, and time of
day affect the photolysis rate. Hov (1985) discussed the diurnal variation of the photolysis rate of
chlorine in an analysis of the effect that atmospheric chlorine had on the formation of various
photochemical oxidants in southern Telemark, Norway. It was generally concluded that the
photodissociation rate is rapid under both winter and summer sunlight conditions. Using absorption cross
section data for chlorine at 330 nm, a maximum photodissociation rate constant of approximately
1.6x10-3 second-1 was calculated for midsummer, midday sunlight conditions. This corresponds to a
tropospheric half-life of approximately 7.2 minutes and a mean lifetime of slightly over 10 minutes.
Using a photodissociation rate constant of approximately 0.2x10-3 second-1 calculated for midday winter
sunlight conditions, a half-life of 58 minutes is estimated.
Chlorine is also expected to react with cloud particulates and rain drops that it comes into contact with in
the atmosphere, forming hydrochloric and hypochlorous acids (Vetrano 2001). These acids can then be
washed out of the atmosphere by precipitation (Vetrano 2001).
6.3.2.2 Water
Water disinfection through chlorination has been in regular use since the early 1900s; consequently, the
fate of chlorine in water has been well studied (Das 2002). Chlorine gas released into water first
dissolves and then undergoes a disproportionation within seconds at environmental pH to form
hydrochloric (H+ + Cl-) and hypochlorous acid (HOCl) (Cotton et al. 1999; Das 2002; EPA 1999; Farr et
al. 2003; Morris 1946; Snoeyink and Jenkins 1980; Tchobanoglous and Schroeder 1985; Wang and
Margerum 1994). The equilibrium that exists between hypochlorous acid and the hypochlorite anion is
controlled by the pH of the water. Since the pKa of hypochlorous acid is 7.49 (O’Neil et al. 2001), the
formation of the conjugate base (hypochlorite anion) is favored under alkaline conditions and the
protonated species (hypochlorous acid) is favored under neutral and mildly acidic conditions. Under
strongly acidic conditions (pH≤2), the formation of molecular chlorine is possible (see Chapter 4).
As illustrated in Figure 4-1, the equilibrium between chlorine, hypochlorous acid, and hypochlorite acid is
dependant on the pH of the solution (Farr et al. 2003). As the pH is lowered to 4, the equilibrium begins
to shift to the left, and small amounts of Cl2 are present. At pH below 2, chlorine becomes the dominant
species. Therefore, molecular chlorine will be formed in chlorinated water (containing hypochlorous
CHLORINE 167
acid) that has been made very acidic. Under these conditions, chlorine is expected to react rapidly with
both organic and inorganic mater that it comes into contact with in the water; it is also expected to
volatilize rapidly into the air based on a Henry's law constant of 1.17x10-2 atm-m3/mol (Staudinger and
Roberts 1996). Chlorine is toxic to microbial communities; therefore, biodegradation is not considered to
be a relevant fate process (Vetrano 2001). The hypochlorous acid formed during the disproportionation
of chlorine in natural waters reacts with organic and inorganic materials, ultimately forming chloride,
oxidized inorganics, chloramines, trihalomethanes, oxygen, and nitrogen (IARC 1991; Vetrano 2001).
6.3.2.3 Sediment and Soil
If liquid chlorine is spilled onto soil, it will react with both organic and inorganic mater in the soil;
however, much of the chlorine is expected to volatilize immediately (Agency for Toxic Substances and
Disease Registry 1998; Schulte 1999). Chlorine is expected to dissolve and disproportionate in the water
of moist soils to form chloride and hypochlorite (Cotton et al. 1999). Chlorine in a gas cloud is expected
to react with soil surfaces that it comes into contact with. Chlorine is toxic to microbial communities;
therefore, biodegradation is not considered to be a relevant fate process (Vetrano 2001).
When released into water, chlorine is expected to react with suspended solids and sediments that it comes
into contact with.
6.3.2.4 Other Media
Specific information on the transformation of chlorine in other media is not available; however, chlorine
is very unstable and is expected to react with most substances that it comes into contact with.
6.4 LEVELS MONITORED OR ESTIMATED IN THE ENVIRONMENT
Reliable evaluation of the potential for human exposure to chlorine depends in part on the reliability of
supporting analytical data from environmental samples and biological specimens. Concentrations of
chlorine in unpolluted atmospheres and in pristine surface waters are often so low as to be near the limits
of current analytical methods. In reviewing data on chlorine levels monitored or estimated in the
environment, it should also be noted that the amount of chemical identified analytically is not necessarily
equivalent to the amount that is bioavailable. The analytical methods available for monitoring chlorine in
a variety of environmental media are detailed in Chapter 7.
CHLORINE 168
6.4.1 Air
Levels of chlorine monitored in the ambient atmosphere have not been located. Scientists have proposed
that chlorine is generated during the photolysis of seawater aerosol (California Environmental Protection
Agency 2002; Chang et al. 2004; Knipping and Dabdub 2003). According to California Environmental
Protection Agency (2002), chlorine was detected in the air at a New York coastal site with a maximum
concentration of 150 ppt. Chang et al. (2004) reported a maximum chlorine concentration of 580 ppt in
air samples collected from coastal locations in Taiwan.
Little information is available regarding the levels of chlorine measured in air surrounding areas of
accidental release. The concentrations of chlorine monitored in the air surrounding a chlorine release
from a railroad tank car near Festus, Missouri were >1,000 ppm (U.S. Chemical Safety and Hazard
Investigation Board 2003). Chlorine concentrations as high as 1,000 ppm were measured in the air at a
train derailment chemical spill near Alberton, Montana that released chlorine gas in April 1996 (Agency
for Toxic Substances and Disease Registry 1998).
6.4.2 Water
Levels of chlorine monitored in water are not available. Chlorine is not a predominant species in water at
environmental pH since it disproportionates within seconds to form chloride anion and hypochlorous
acid; therefore, chlorine is not expected to be detected in the aquatic environment (Das 2002; Morris
1946; Wang and Margerum 1994).
6.4.3 Sediment and Soil
Levels of chlorine monitored in sediment and soil are not available. Chlorine is not expected to be found
in soil since it reacts and volatilizes so rapidly.
6.4.4 Other Environmental Media
Levels of chlorine monitored in food, animals, vegetation, and consumer products are not available.
Chlorine is not expected to be found in these media because of its very high reactivity.
CHLORINE 169
6.5 GENERAL POPULATION AND OCCUPATIONAL EXPOSURE
Chlorine is not normally detected in ambient air, soil, surface water, groundwater, or drinking water.
Therefore, background exposure of the general population to chlorine is not expected. Greater than
95% of the chlorine that is inhaled (over a 1–5 ppm range) reacts in the upper respiratory tract (Nodelman
and Ultman 1999a, 1999b; Winder 2001) and eventually joins the chloride pool in the body. Therefore,
analysis of human biological materials such as blood, urine, and body tissue for chlorine is not considered
relevant. The amount of chlorine that needs to be inhaled to induce a significant increase in extracellular
chloride in the body is probably a lethal amount. Current procedures for gauging an individual's exposure
to chlorine gas involve analysis of the lungs and respiratory airways for physical and functional damage
(Lawson 1981; Winder 2001).
Members of the general population may be exposed to chlorine if they mix an acid with a solution
containing sodium hypochlorite (CDC 1991). Examples include mixing toilet bowl cleaners containing
hydrochloric, phosphoric, or oxalic acid with bleach (Becker and Forrester, 2008; CDC 1991; Gapany-
Gapanavicius et al. 1982; Howard et al. 2007; Mrvos et al. 1993). If enough acid is added to lower the
pH of the hypochlorite solution to below 4, chlorine gas will be released (Farr et al. 2003). Individuals
may also be exposed to chlorine if swimming pool chemicals are accidentally mixed with acids or too
much sodium hypochlorite is added to the water over a short period of time (Agabiti et al. 2001; Becker
and Forrester 2008; Bonetto et al. 2006; Ngo et al. 2007; Sexton and Pronchik 1998). On
October 22, 1998, hydrochloric acid accidentally spilled onto chlorinated swimming pool water at a
recreational facility in Rome, Italy causing the liberation of chlorine gas to the entire center and exposing
nearly 300 people to the gas (Agabiti et al. 2001). The exact amount of chlorine released in this accident
was not reported. A similar accident occurred on February 17, 2004 in Parma, Italy in which 18 children
were exposed to chlorine gas (Bonetto et al. 2006). In this case, the improper addition of an excessive
amount of sodium hypochlorite was added to a chlorinated swimming pool to shock the system, resulting
in the emission of chlorine gas.
Occupational exposure to low levels of chlorine gas in air may occur for individuals who work at
facilities that produce, transport, or use chlorine (Gautrin et al. 1995). These individuals may also be
exposed to high chlorine concentrations if an accidental release occurs at the facility (Beach et al. 1969;
Chester et al. 1969; Gautrin et al. 1999; Kennedy et al. 1991; NTSB 2002, 2005, 2006; USB 2007).
CHLORINE 170
Of the 865 chlorine-only events reported to the ATSDR's Hazardous Substances Emergency Events
Surveillance system between January 1993 and December 2000, 275 events involved victims
(1,071 individuals) (Horton et al. 2002). Of these, 759 were occupational exposures and 68 were first
responders.
6.6 EXPOSURES OF CHILDREN
This section focuses on exposures from conception to maturity at 18 years in humans. Differences from
adults in susceptibility to hazardous substances are discussed in Section 3.7, Children’s Susceptibility.
Children are not small adults. A child’s exposure may differ from an adult’s exposure in many ways.
Children drink more fluids, eat more food, breathe more air per kilogram of body weight, and have a
larger skin surface in proportion to their body volume. A child’s diet often differs from that of adults.
The developing human’s source of nutrition changes with age: from placental nourishment to breast milk
or formula to the diet of older children who eat more of certain types of foods than adults. A child’s
behavior and lifestyle also influence exposure. Children crawl on the floor, put things in their mouths,
sometimes eat inappropriate things (such as dirt or paint chips), and spend more time outdoors. Children
also are closer to the ground, and they do not use the judgment of adults to avoid hazards (NRC 1993).
As with adults, biomonitoring is not considered relevant for assessing childhood exposure to chlorine.
Therefore, information on chlorine levels in blood, urine, tissue, breast milk, neonatal blood, cord blood,
and meconium fluid is not available. Children may be exposed to chlorine through the same routes that
affect adults, except for occupational exposures. Children located near an accidental release of chlorine
such as a leak from a factory or a chlorine tank spill or rupture may be exposed to high concentrations of
chlorine through inhalation, skin contact, or eye contact. Children may be exposed to high levels of
chlorine if they are in an area where swimming pool chemicals are being improperly used or where
certain household chemicals are mixed together. Mixing an acid, such as toilet cleaner, with bleach can
generate chlorine gas if the pH of the bleach is lowered to below 4.
6.7 POPULATIONS WITH POTENTIALLY HIGH EXPOSURES
Individuals located near an accidental release of chlorine may be exposed to high concentrations of this
gas through inhalation, skin contact, and eye contact if the cloud travels in their direction (Horton et al.
2002; Wenck et al. 2007). Individuals who live near industrial facilities where chlorine gas is produced
or used may be exposed to high concentrations if there is an accidental release of a large amount of
CHLORINE 171
chlorine gas from the facility (USB 2007). Of the 865 chlorine-only events reported to ATSDR's
Hazardous Substances Emergency Events Surveillance system between January 1993 and December
2000, 275 events involved victims (1,071 individuals) (Horton et al. 2002). Of these, 235 were members
of the general public. A train derailment near Alberton, Montana on April 11, 1996 released
approximately 130,000 pounds of chlorine gas to the atmosphere (NTSB 1998). According to the
National Transportation Safety Board (NTSB), approximately 350 people were treated for chlorine
inhalation. Nine people, including members of the train crew, were hospitalized. The NTSB reported
that a transient riding the train died from acute chlorine toxicity (NTSB 1998). On January 6, 2005, a
northbound Norfolk Southern Railway Company freight train traveling through Graniteville, South
Carolina, encountered an improperly lined switch that diverted the train from the main track onto an
industrial track, where it struck an unoccupied, parked train releasing approximately 120,000 pounds of
chlorine gas from one of the cars of the northbound train (NTSB 2005). The train engineer and 8 other
people died as a result of chlorine gas exposure and an additional 554 nearby residents were treated at
local hospitals for respiratory illness as a result of this accident. On June 28, 2004 a westbound Union
Pacific Railroad freight train collided with an eastbound freight train in Macdona, Texas (NTSB 2006).
Consequently, a tank car loaded with liquefied chlorine was punctured, releasing a cloud of chlorine gas
that surrounded the accident area. Three persons, including the conductor of the Union Pacific train and
two local residents, died as a result of acute chlorine gas inhalation. The Union Pacific train engineer,
23 local residents, and 6 emergency responders were treated for respiratory illness or other injuries related
to the collision and derailment.
Section 104(i)(5) of CERCLA, as amended, directs the Administrator of ATSDR (in consultation with the
available, ATSDR, in conjunction with NTP, is required to assure the initiation of a program of research
designed to determine the health effects (and techniques for developing methods to determine such health
effects) of chlorine.
CHLORINE 172
Physical and Chemical Properties. The important chemical and physical properties for elemental
chlorine are available (EPA 1999; HSDB 2009; Staudinger and Roberts 1996), as well as the important
equilibrium constants describing the equilibrium reaction of chlorine in water (Cotton et al. 1999; Farr et
al. 2003). No data need is identified at this time.
Production, Import/Export, Use, Release, and Disposal. According to the Emergency Planning
and Community Right-to-Know Act of 1986, 42 U.S.C. Section 11023, industries are required to submit
substance release and off-site transfer information to the EPA. The TRI, which contains this information
for 2005, became available in May of 2007. This database is updated yearly and should provide a list of
industrial production facilities and emissions.
Current production and U.S. import/export volumes are available for chlorine (CMR 2006; HSDB 2009;
ITA 2007; The Chlorine Institute 2008; U.S. Census Bureau 2008), as well as adequate disposal methods
(HSDB 2009). No data need is identified at this time.
Environmental Fate. The environmental fate of chlorine is understood. Chlorine is extremely

reactive and will not remain in environmental media for long periods of time. The important equilibrium
properties of chlorine in water are understood (Cotton et al. 1999; Farr et al. 2003). Scientists have
proposed that minute quantities of chlorine are generated naturally during the photolysis of seawater
aerosols (California Environmental Protection Agency 2002; Chang et al. 2004; Knipping and Dabdub
2003). Sunlight at tropospheric wavelengths (<430 nm) dissociates the chlorine molecule to form two
chlorine radicals; a lifetime of <15 minutes (half-life of <11 minutes) was calculated for this reaction
(Tanaka et al. 2003). No data need is identified at this time.
Bioavailability from Environmental Media. Chlorine is too reactive to be bioavailable from soil,
water, or other environmental media. No data need is identified at this time.
Food Chain Bioaccumulation. Chlorine is too reactive to bioaccumulate in the food chain. No data
need is identified at this time.
CHLORINE 173
Exposure Levels in Environmental Media. Reliable monitoring data for the levels of chlorine in
contaminated media at hazardous waste sites are needed so that the information obtained on levels of
chlorine in the environment can be used in combination with the known body burden of chlorine to assess
the potential risk of adverse health effects in populations living in the vicinity of hazardous waste sites.
Chlorine is too reactive to monitor for background levels in the environment. In the case of an accidental
spill, levels >1,000 ppm have been observed in air around the accident site (U.S. Chemical Safety and
Hazard Investigation Board 2003). Very low levels of chlorine (parts per trillion) are generated naturally
during the photolysis of seawater aerosols (California Environmental Protection Agency 2002; Chang et
al. 2004). No data need is identified at this time.
Exposure Levels in Humans. Humans can be exposed to chlorine following the accidental release
at a manufacturing facility or an accident involving the transportation of liquefied chlorine gas (NTSB
1998, 2002, 2005, 2006); however, molecular chlorine levels in human tissues cannot be quantitatively
assessed (see Chapter 7). In addition, people may be exposed to chlorine if they mix common household
chemicals that are acidic with bleach or pool sanitizing chemicals (Agabiti et al. 2001; Bonetto et al.
2006). Continued monitoring of accidental chlorine releases and the health affects observed in humans is
necessary.
This information is necessary for assessing the need to conduct health studies on these populations.
Exposures of Children. Similar to adults, exposure of children to chlorine gas primarily occurs from
accidental industrial or transportation releases (NTSB 1998, 2002, 2005, 2006), or the inadvertent mixing
of common household chemicals with bleach or pool sanitizing chemicals, resulting in the liberation of
chlorine (Agabiti et al. 2001; Bonetto et al. 2006). Continued monitoring of accidental chlorine releases
and the health affects observed in children is necessary.
Child health data needs relating to susceptibility are discussed in Section 3.12.2, Identification of Data
Needs: Children’s Susceptibility.
Exposure Registries. No exposure registries for chlorine were located. This substance is not
currently one of the compounds for which a sub-registry has been established in the National Exposure
Registry. The substance will be considered in the future when chemical selection is made for sub-
CHLORINE 174
registries to be established. The information that is amassed in the National Exposure Registry facilitates
the epidemiological research needed to assess adverse health outcomes that may be related to exposure to
this substance.
Two ongoing studies have been located in the Federal Research in Progress Database (FEDRIP 2009) that
will measure levels of chlorine in the marine atmosphere. These are listed in Table 6-2. No other
ongoing studies regarding the potential for human exposure to chlorine were located.
CHLORINE 175
Table 6-2. Ongoing Studies Regarding the Potential for Human Exposure to
Chlorine
Investigator Affiliation Research description Sponsor

R. Talbot and University of New Study of reactive halogens in the marine National Science
A. Pszenny Hampshire boundary layer overlying the eastern Foundation
tropical north Atlantic Ocean. This
research will include measurement of
inorganic chlorine gases.
E. Saltzman University of Study of the source, presence, and National Science
California-Irvine distribution of inorganic dihalogen gases in Foundation
the marine atmosphere. This research will
include measurement of chlorine gas in
coastal and marine air.
Source: FEDRIP 2009

CHLORINE 176

CHLORINE 177
7. ANALYTICAL METHODS
The purpose of this chapter is to describe the analytical methods that are available for detecting,
measuring, and/or monitoring chlorine, its metabolites, and other biomarkers of exposure and effect to
chlorine. The intent is not to provide an exhaustive list of analytical methods. Rather, the intention is to
identify well-established methods that are used as the standard methods of analysis. Many of the
analytical methods used for environmental samples are the methods approved by federal agencies and
organizations such as EPA and the National Institute for Occupational Safety and Health (NIOSH). Other
methods presented in this chapter are those that are approved by groups such as the Association of
Official Analytical Chemists (AOAC) and the American Public Health Association (APHA).
Additionally, analytical methods are included that modify previously used methods to obtain lower
detection limits and/or to improve accuracy and precision.
7.1 BIOLOGICAL MATERIALS
Inhaled chlorine gas forms hypochlorous acid and hydrochloric acid upon contact with the moist mucous
membranes of the upper respiratory tract (Vetrano 2001; Winder 2001). Since molecular chlorine reacts
so quickly inside living systems, it is not found in biological materials. Therefore, analysis of these
materials for chlorine is not relevant. Once they have been absorbed into the body, hypochlorous and
hydrochloric acid are expected to react with proteins and nucleotides to produce a wide variety of
chlorinated organic compounds (EPA 1999; Winder 2001). Based on a study that traced radiolabeled
chlorine (as hypochlorite) through metabolism inside rats, it is expected that chlorine is ultimately
converted to chloride in the blood and eliminated in the urine and feces of humans and animals primarily
as the chloride ion (Abdel-Rahman et al. 1982, 1983; EPA 1999; Suh and Abdel-Rahman 1983).
Chloroform has also been detected in the blood of rats exposed to hypochlorous acid (Abdel-Rahman et
al. 1984). Since chloride is a natural component of blood, urine, and feces, monitoring chloride
concentrations in these materials would not be helpful for assessing exposure to chlorine.
7.2 ENVIRONMENTAL SAMPLES
When chlorine is released into the environment, it reacts very quickly with both organic and inorganic
matter forming chloride ion and chlorinated compounds. Therefore, aside from low levels in marine
aerosols above the open ocean, and higher concentrations in the areas surrounding recent spills and leaks,
molecular chlorine is not found in the environment.
CHLORINE 178
Standardized methods have been established for analyzing chlorinated water for free chlorine (APHA
1998a, 1998b). Free chlorine refers to the combination of the equilibrium species aqueous molecular
chlorine, hypochlorous acid, and the hypochlorite ion. These methods do not differentiate between the
molecular chlorine and the hypochlorite species. Since molecular chlorine is usually not present in water
samples, these tests typically measure the amounts of hypochlorous acid, hypochlorite, and chlorinated
derivatives. The most popular of these tests is the DPD (N,N-diethyl-p-phenyldiamine) test (APHA
1998a, 1998b). A small amount of DPD is added to a water sample, which is immediately oxidized by
free chlorine to produce a relatively stable free radical and results in a reddish-colored solution. The total
chlorine is measured spectrophotometrically at 515 nm (APHA 1998a, 1998b). Some important residuals
of water disinfection can also quantified by this method. Since chloramines are slow to react with DPD,
they are quantified by the subsequent addition of potassium iodide. The iodide ion acts catalytically
causing color production by monochloramine and dichloramine (APHA 1998a, 1998b). The free chlorine
and the chloroamines are often referred to as the total chlorine content of the water.
Aside from the DPD test, free chlorine can be measured using the amperometric titration method or the
starch-iodide titration method (APHA 1998a). The amperometric titration method involves the titration
of the buffered sample with phenylarsine oxide (APHA 1998a). The decrease of free chlorine during the
titration is detected by applying an electric potential across two electrodes and measuring the change in
current through the solution. The starch-iodide titration method involves addition of potassium iodide
and a starch indicator to the sample followed by titration with sodium thiosulfate (APHA 1998a). The
end point is reached when the blue color of the solution disappears.
It should be noted that the free chlorine test methods described here work by detecting the presence of
oxidizing species and are not actually specific and selective to free chlorine (hypochlorite and
hypochlorous acid) (APHA 1998a). Therefore, care must be taken to avoid interference due to non-free
chlorine oxidizing or reducing agents. The amperometric titration method is less affected by interference,
temperature variations, turbidity, and color; however, this method requires greater operator skill to
achieve reliable results (APHA 1998a).
Four standardized methods have been located that describe procedures for measuring molecular chlorine
in air (EPA 2000b; NIOSH 1994; OSHA 2007a, 2007b). In EPA Method OAQPS-26, the air sample is
passed through a particulate filter followed by a dilute sulfuric acid solution (EPA 2000b). Hydrogen
chloride dissolves to form chloride in the acid solution, while chlorine, which is relatively insoluble in the
acid, passes through to a dilute sodium hydroxide solution. Chlorine dissolves and disporportionates to
CHLORINE 179
form both chloride and hypochlorous acid. Sodium thiosulfate is then added to the alkaline solution to
ensure complete reaction with the hypochlorous acid, freeing the second chloride ion. Analysis is
performed using ion chromatography.
OSHA Methods ID-101 and ID-126SGX are based on the reaction between chlorine and iodide to form
iodine and chloride (OSHA 2007a, 2007b). In Method ID-101, chlorine is collected in a sulfamic acid
solution, which is then reacted with potassium iodide and analyzed using a residual chlorine ion specific
electrode. In Method ID-126SGX, chlorine is collected into a neutral solution of potassium iodide, which
is then titrated with sodium thiosulfate. A second titration involving chlorine dioxide is performed next.
The concentrations of chlorine and chlorine dioxide are determined using stoichiometric calculations.
Disadvantages of this method are that it suffers from many interferences and that temperature and strong
light affect solution solubility. Both of the OSHA methods recommend using a filter to eliminate
particulates that may cause interference.
NIOSH Method 6011 describes a way to measure chlorine in air samples via collection onto a silver
membrane filter, desorption into sodium thiosulfite, and subsequent analysis using ion chromatography
(NIOSH 1994). This method is subject to positive interference from hydrogen chloride and negative
interference from hydrogen sulfide. Also, silver chloride is photosensitive; therefore, the silver filter must
be transferred to an amber bottle in the dark. Once the silver chloride has desorbed, it is no longer
photosensitive. The detection limit for chlorine listed in this method is 0.007 ppm for a 90L air sample
collected at a flow rate of 0.3–1 L per minute; however, Chang et al. (2004) was able to measure chlorine
in air to a detection limit of 50 ppt (parts per trillion) using a Dionex DX-120 analyzer and longer
sampling times.
Standardized methods for measuring chlorine in air and water including accuracy, detection limits, and
additional details are listed in Table 7-1. Methods that analyze soil and sediment for chlorine are not
available.
Section 104(i)(5) of CERCLA, as amended, directs the Administrator of ATSDR (in consultation with the
available, ATSDR, in conjunction with NTP, is required to assure the initiation of a program of research
CHLORINE 180
Table 7-1. Analytical Methods for Determining Chlorine in Environmental Samples
Sample Analytical Sample Percent

matrix Preparation method method detection limit recovery Reference
Air Sample is passed through a EPA OAQPS 0.1 ppm NA EPA 2000b
particulate filter into a dilute 26
sulfuric acid solution followed
by a dilute sodium hydroxide
solution. Analysis is performed
using IC.
Air Sample is passed through a OSHA ID-101 0.14 ppm NA OSHA 2007b
teflon prefilter and dissolved in
a sulfamic acid solution.
Potassium iodide is added to
the acid solution. Analysis is
performed using RCE.
Air Sample is passed through a OSHA ID 0.3 ppm NA OSHA 2007a
glass giber pre-filter and 126SGX
collected into a potassium
iodide solution. The solution is
then titrated with sodium
thiosulfate in two steps to
determine concentrations of
chlorine and chlorine dioxide.
Air Sample is passed through a NIOSH 6011 0.007–0.5 ppm 98.6% NIOSH 1994;
silver membrane filter. Silver for a 90 L air Chang et al.
chloride is desorbed from the sample (flow 2004
membrane into a sodium rate 0.3–
thiosulfate solution, which is 1.0 L/minute);
then analyzed using IC. 50 ppt
Water Acetic acid and potassium APHA 4500-Cl 40 µg as free NA APHA 1998a,
iodide are added to the sample B chlorine/L 1998b
to create an acidic solution,
which is then titrated using
sodium thiosulfate.
Water Acetic acid and potassium EPA 330.3 250–4,020 µg NA CAS 1978c
iodide are added to the sample as free
to create an acidic solution, chlorine/L
which is then titrated using
sodium thiosulfate or
phenylarsine oxide.
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Table 7-1. Analytical Methods for Determining Chlorine in Environmental Samples
Sample Analytical Sample Percent

matrix Preparation method method detection limit recovery Reference
Water Phenylarsine oxide, potassium EPA 330.2 250–4,020 µg NA CAS 1978b
iodide, and acetate buffer are as free
combined with the sample. For chlorine/L
starch iodide determination, a
starch indicator is added
followed by titration with iodine
solution. For amperometric
determination, titrate with an
iodine solution using an
amperometric titrator.
Water Phosphate buffer is added to APHA 4500-Cl 200 µg as free NA APHA 1998a
the sample, which is then D chlorine/L
titrated with phenylarsine oxide
using a microammeter to
observe current changes.
Water Potassium iodide and acetate EPA 330.1 380–3,500 µg NA CAS 1978a
buffer are added to the sample, as free
which is then titrated with chlorine/L
phenylarsine oxide or sodium
thiosulfate using an
amperometer to determine the
end point.
Water Add 10 mL of water to 0.5 mL of APHA 4500-Cl 10 µg as free NA APHA 1998a,
phosphate buffer solution and G chlorine/L 1998b
0.5 mL of DPD reagent.
Quantify by UV-VIS at 515 nm
DPD = N,N-diethyl-p-phenyldiamine; IC = ion chromatography; NA = not available; RCE = residual chlorine ion specific
electrode; UV-VIS = ultraviolet-visible
CHLORINE 182
designed to determine the health effects (and techniques for developing methods to determine such health
effects) of chlorine.
Methods for Determining Biomarkers of Exposure and Effect.
Exposure. There are no biomarkers of exposure that are specific to chlorine. Chlorine reacts very
quickly inside the body; therefore, analyzing for this substance in biological materials is not relevant. The
chlorine reacts to form many chlorinated compounds that are ultimately broken down into chloride ion.
Chloride is a natural component of blood, urine, and feces. Monitoring for chloride in biological
materials would not be helpful in gauging exposure to chlorine.
Effect. There are no biomarkers of effect that are unique to chlorine exposure. The most obvious effect
of exposure to high levels of chlorine is damage to the moist mucous membranes of the lungs and
respiratory pathways. Other health effects that have been associated with exposure to chlorine include
bronchitis, asthma, pulmonary edema, dermatitis, and conjunctivitis. The odor threshold for chlorine in
air is 0.2–0.4 ppm and the lowest concentration in air at which there is perceivable sensory irritation is
1 ppm (EPA 1999; The Chlorine Institute 1998; WHO 1982). Current standardized methods for
measuring chlorine in air have detection limits ranging from 0.007 to 0.3 ppm, which are below
concentrations at which biological effects occur (EPA 2000b; NIOSH 1994; OSHA 2007a, 2007b).
Methods for Determining Parent Compounds and Degradation Products in Environmental

Media. Methods sensitive enough to measure background chlorine concentrations in ocean air are
available. Chang et al. (2004) used a more sensitive analyzer and larger sampling volumes with the silver
membrane filter method (NIOSH Method 6011) to lower the detection limit from 0.007 ppm to 50 ppt.
Background chlorine concentrations measured were <600 ppt. Methods are also available for measuring
chlorine in water; however, these methods do not distinguish between the equilibrium species molecular
CHLORINE 183
chlorine, hypochlorous acid, or hypochlorite (APHA 1998a, 1998b). Since hypochlorous acid and
hypochlorite are the dominant species at environmental pH, analyzing water for molecular chlorine is not
relevant except under very acidic conditions (pH<4) (APHA 1998a, 1998b; Farr et al. 2003). Methods
that analyze for chlorine in soil or sediment were not located. Chlorine is not expected to be found in
these media since it is so reactive, rapidly oxidizing both organic and inorganic materials that it comes
into contact with.
Among the analytical methods referred to in this chapter, only the detection limits reported for NIOSH
Method 6011 are sensitive enough to detect chlorine in air at levels at or below the MRL values derived
in Chapter 3. For reference, the acute, intermediate, and chronic MRLs derived for chlorine in air are
0.06 ppm, 0.002 ppm, and 50 ppt, respectively. Detection limits reported for NIOSH Method 6011 range
from 0.007–0.5 ppm, while a detection limit of 50 ppt was achieved for a modification of this method
(NIOSH 1994; Chang et al. 2004). The other detection methods for measuring chlorine levels in air
report detection limits of >0.1 ppm (EPA 2000b). Based on the lack of sensitivity of the available
methods relative to the derived MRL values, the development of standardized analytical methods that can
detect chlorine in air at levels below the MRL values (below 50 ppt) is a data need.
One ongoing study has been located in the Federal Research in Progress Database (FEDRIP 2009) related
to the development of analytical methods for chlorine. This study will be led by investigator Eric
Saltzman of the University of California-Irvine and is sponsored by the National Science Foundation
(NSF). The study will explore the source, presence, and distribution of inorganic dihalogen gases in the
marine atmosphere and will include the validation and further development of analytical methods for
dihalogens, including chlorine, in air. No other ongoing studies regarding the development of methods
for analyzing for chlorine in the environment were located in the available literature.
CHLORINE 184

CHLORINE 185
8. REGULATIONS, ADVISORIES, AND GUIDELINES
MRLs are substance specific estimates, which are intended to serve as screening levels, are used by
ATSDR health assessors and other responders to identify contaminants and potential health effects that
may be of concern at hazardous waste sites.
ATSDR has derived an acute-duration inhalation MRL of 0.06 ppm for chlorine based on a NOAEL of
0.5 ppm for sensory irritation and pulmonary effects in volunteers exposed for up to 8 hours/day (Anglen
1981; D’Alessandro et al. 1996; Rotman et al. 1983; Schins et al. 2000; Shusterman et al. 1998, 2003b).
The NOAEL was duration-adjusted for continuous exposure. An uncertainty factor of 3 was used to
account for sensitive populations.
ATSDR has derived an intermediate-duration inhalation MRL of 0.002 ppm for chlorine based on a
minimal LOAEL of 0.5 ppm for tracheal lesions in rats exposed 6 hours/day, 5 days/week for 62 days
(Kutzman 1983). An uncertainty factor of 90 was used (3 for extrapolation from animals to humans with
dosimetric adjustment, 3 for use of a minimal LOAEL, and 10 for human variability).
ATSDR has derived a chronic-duration inhalation MRL of 0.00005 ppm for chlorine based on an
increased incidence of nasal lesions in monkeys exposed to chlorine 6 hours/day, 5 days/week for 1 year
(Klonne et al. 1987). The MRL was derived using benchmark modeling of incidence data for nasal
lesions in monkeys. The predicted exposure concentration associated with a 10% extra risk (BMC10) for
nasal lesions in monkeys was 0.04 ppm; the lower 95% confidence limit on this concentration (BMCL10)
was 0.02 ppm. An uncertainty factor of 30 was used (3 for extrapolation from animals to humans with
dosimetric adjustment and 10 for human variability).
Oral MRLs were not derived for aqueous chlorine for the following reasons. MRLs are derived when
reliable and sufficient data exist to identify a target organ(s) of effect or the most sensitive health effect(s)
for a specific duration within a given route of exposure. Scientifically, as part of having sufficient and
reliable data, it is important to be able to see the full, or at least a significant range, of the dose-response
curve. In the case of the oral database for aqueous chlorine, no reliable LOAEL could be identified at
levels of aqueous chlorine that could reasonably be encountered in the environment. It is a matter of
policy of ATSDR not to derive free-standing MRLs.
CHLORINE 186
EPA (IRIS 2007) has established an oral reference dose (RfD) for chlorine of 0.1 mg/kg/day based on a
NOAEL of 14.4 mg/kg/day for systemic effects in F344/N rats exposed to chlorine in the drinking water
for 2 years (NTP 1992). The uncertainty factor used in this assessment was 100 (10 for interspecies
extrapolation and 10 for the protection of sensitive human subpopulations).
EPA has not derived an inhalation reference concentration (RfC) for chlorine gas.
The International Agency for Research on Cancer (IARC), the National Toxicology Program (NTP), and
EPA has not classified chlorine, sodium hypochlorite, or hypochlorous acid for human carcinogenicity
(IARC 2006; IRIS 2007; NTP 2005). The American Conference of Governmental Industrial Hygienists
(ACGIH) has classified chlorine as an A4 carcinogen (not classifiable as a human carcinogen) (ACGIH
2006).
OSHA has required employers of workers who are occupationally exposed to chlorine to institute
engineering controls and work practices to reduce and maintain employee exposure at or below
permissible exposure limits (PELs) (OSHA 2006c). The employer must use engineering and work
practice controls to reduce exposures to not exceed 1 ppm for chlorine at any time (ceiling) (OSHA
2006c).
EPA has designated chlorine as a hazardous air pollutant (HAP) under the Clean Air Act (CAA) (EPA
2007b). Chlorine and sodium hypochlorite are on the list of chemicals appearing in “Toxic Chemicals
Subject to Section 313 of the Emergency Planning and Community Right-to-Know Act of 1986" and has
been assigned a reportable quantity (RQ) limit of 10 and 1 pounds, respectively (EPA 2007e). Chlorine is
also considered to be an extremely hazardous substance (EPA 2007f). The RQ represents the amount of a
designated hazardous substance which, when released to the environment, must be reported to the
appropriate authority.
Under the Federal Insecticide, Fungicide, and Rodenticide Act (FIFRA), chlorine gas is exempt from the
requirement of a tolerance for pesticide chemicals in food when used as pre- or postharvest in solution on
all raw agricultural commodities (EPA 2007h) and sodium hypochlorite is exempt from the requirement
of a tolerance for residues in food (EPA 2007k).
The international and national regulations, advisories, and guidelines regarding chlorine in air, water, and
other media are summarized in Table 8-1.
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Table 8-1. Regulations, Advisories, and Guidelines Applicable to Chlorine and
Chlorine Compounds
Agency Description Information Reference

INTERNATIONAL
Guidelines:
IARC Carcinogenicity classification No data IARC 2006
WHO Air quality guidelines No data WHO 2000
Drinking water quality guidelines WHO 2004
a
Chlorine 5 mg/L
NATIONAL
Regulations and
Guidelines:
a. Air
ACGIH TLV (8-hour TWA) (chlorine) 0.5 ppm ACGIH 2006
STEL (15-minute TWA) (chlorine) 1 ppm
b
AIHA ERPG-1 (chlorine) 1 ppm AIHA 2004
b
ERPG-2 (chlorine) 3 ppm
b
ERPG-3 (chlorine) 20 ppm
Odor threshold (chlorine) 0.08 ppm
c
EPA AEGL-1 (chlorine) EPA 2007a
10 minutes 0.5 ppm
30 minutes 0.5 ppm
60 minutes 0.5 ppm
4 hours 0.5 ppm
8 hours 0.5 ppm
c
AEGL-2 (chlorine)
10 minutes 2.8 ppm
30 minutes 2.8 ppm
60 minutes 2.0 ppm
4 hours 1.0 ppm
8 hours 0.71 ppm
c
AEGL-3 (chlorine)
10 minutes 50 ppm
30 minutes 28 ppm
60 minutes 20 ppm
4 hours 10 ppm
8 hours 7.1 ppm
CHLORINE 188
Chlorine Compounds

NATIONAL (cont.)
Hazardous air pollutant (chlorine) Yes EPA 2007b
42 USC 7412
d
Regulated toxic substance and the 2,500 pounds EPA 2007d
threshold quantity for accidental release 40 CFR 68.130
prevention (chlorine)
NIOSH REL (ceiling) (chlorine) 0.5 ppm NIOSH 2005
IDLH (chlorine) 10 ppm
OSHA PEL (ceiling) for general industry 1 ppm OSHA 2006c
(chlorine) 29 CFR 1910.1000
PEL (ceiling) for shipyard industry 1 ppm OSHA 2006a
(chlorine) 29 CFR 1915.1000
PEL (ceiling) for construction industry 1 ppm OSHA 2006b
(chlorine) 29 CFR 1926.55,
Appendix A
Toxic and reactive highly hazardous 1,500 pounds OSHA 2006d
chemical which presents a potential for 29 CFR 1910.119
a catastrophic event at or above the
threshold quantity (chlorine)
b. Water
EPA Designated as hazardous substances in Yes EPA 2007i
accordance with Section 311(b)(2)(A) of 40 CFR 116.4
the Clean Water Act (chlorine)
Drinking water standards and health EPA 2006
advisories (chlorine)
1-day health advisory for a 10-kg 3 mg/L
child
10-day health advisory for a 10-kg 3 mg/L
child
DWEL 5 mg/L
Lifetime 4 mg/L
-4
10 Cancer risk No data
National primary drinking water EPA 2003
e
regulations (chlorine [as Cl2])
MRDL 4.0 mg/L
Public health goal (MRDLG) 4.0 mg/L
Reportable quantities of hazardous EPA 2007j
substances designated pursuant to 40 CFR 117.3
Section 311 of the Clean Water Act
Chlorine 10 pounds
Sodium hypochlorite 100 pounds
CHLORINE 189
Chlorine Compounds

NATIONAL (cont.)
c. Food
EPA Chlorine is exempt from the Yes EPA 2007h
requirement of a tolerance for pesticide 40 CFR 180.1095
chemicals in food when used as
preharvest or postharvest in solution on
all raw agricultural commodities
Sodium hypochlorite is exempt from the Yes EPA 2007k
requirement of a tolerance for residues 40 CFR 180.1235
in food
FDA EAFUS (ingredient added directly to Yes FDA 2007a
food that FDA has either approved as a
food additive or listed or affirmed as
GRAS) (chlorine and sodium
hypochlorite)
Food additives permitted for direct Yes FDA 2007b
addition to food for human consumption 21 CFR 172
(sodium hypochlorite)
Indirect food additives: adhesives and Yes FDA 2006
components of coatings (sodium 21 CFR 175
hypochlorite)
d. Other
f
ACGIH Carcinogenicity classification (chlorine) A4 ACGIH 2006
EPA Carcinogenicity classification (chlorine) No data IRIS 2007
RfD (chlorine) 0.1 mg/kg/day
RfC (chlorine) No data
Superfund, emergency planning, and
community right-to-know
g
Designated CERCLA hazardous Yes EPA 2007e
substance (chlorine and sodium 40 CFR 302.4
hypochlorite)
Reportable quantity
Chlorine 10 pounds
Sodium hypochlorite 1 pound
Extremely hazardous substance and 100 pounds EPA 2007f
the threshold planning quantity 40 CFR 355,
(chlorine) Appendix A
Effective date of toxic chemical 01/01/87 EPA 2007g
release reporting (chlorine) 40 CFR 372.65
CHLORINE 190
Chlorine Compounds

NATIONAL (cont.)
EPA TSCA Master Testing List EPA 2007c
h
Chlorine Yes
i
Sodium hypochlorite Yes
NTP Carcinogenicity classification No data NTP 2005
a
For effective disinfection, there should be a residual concentration of free chlorine of ≥0.5mg/litre after at least
30 minute contact time at pH <8.0 (WHO 2004).
b
ERPG-1 is the maximum airborne concentration below which it is believed nearly all individuals could be exposed for
up to 1 hour without experiencing or developing other than mild, transient adverse health effects or without perceiving
a clearly defined objectionable odor; ERPG-2 is the maximum airborne concentration below which it is believed
nearly all individuals could be exposed for up to 1 hour without experiencing or developing irreversible or other
serious health effects or symptoms that could impair an individual’s ability to take protective action; and ERPG-3 is
the maximum airborne concentration below which it is believed nearly all individuals could be exposed for up to
1 hour without experiencing or developing life-threatening health effects (AIHA 2004).
c
AEGL-1 is the airborne concentration of a substance above which it is predicted that the general population,
including susceptible individuals, could experience notable discomfort, irritation, or certain asymptomatic nonsensory
effects, however, the effects are not disabling and are transient and reversible upon cessation of exposure; AEGL-2
is the airborne concentration of a substance above which it is predicted that the general population, including
susceptible individuals, could experience irreversible or other serious, long-lasting adverse health effects or an
impaired ability to escape; and AEGL-3 is the airborne concentration of a substance above which it is predicted that
the general population, including susceptible individuals, could experience life-threatening health effects or death
(EPA 2007a).
d
Regulated toxic and flammable substance under Section 112 of the Clean Air Act
e
Potential health effects from exposure above the MCL include anemia and nervous system effects in infants and
young children; the common source of the contaminant in drinking water is the use of chlorine as a water additive
used to control microbes (EPA 2003).
f
A4: not classifiable as a human carcinogen
g
Designated CERCLA hazardous substance pursuant to Section 112 of the Clean Air Act.
h
The Office of Air and Radiation recommended chlorine for acute toxicity testing for health effects. Chlorine is a
hazardous air pollutant and was added to the Master Testing List in 1995. EPA is initiating development of a testing
action via TSCA Section 4 FRM, a TSCA Section 4 ECA, or a VTA (EPA 2007c).
i
The Organization for Economic Cooperation and Development recommended sodium hypochlorite for a "base set" of
screening level test data (SIDS), which include health effects and environmental effects and fate. Sodium
hypochlorite was added to the Master Testing List in 1995 and EPA is initiating development of a testing action via
CTPU-VTA (EPA 2007c).
ACGIH = American Conference of Governmental Industrial Hygienists; AEGL = Acute Exposure Guideline Levels;
AIHA = American Industrial Hygiene Association; CERCLA = Comprehensive Environmental Response,
Compensation, and Liability Act; CFR = Code of Federal Regulations; CTPU = Chemical Testing Program Underway;
DWEL = drinking water equivalent level; EAFUS = Everything Added to Food in the United States;
ECA = Enforceable Consent Agreement; EPA = Environmental Protection Agency; ERPG = Emergency Response
Planning Guidelines; FDA = Food and Drug Administration; FRM = Final Rule-Making; GRAS = Generally
Recognized As Safe; IARC = International Agency for Research on Cancer; IDLH = immediately dangerous to life or
health; IRIS = Integrated Risk Information System; MCL = Maximum Contanimant Level; MRDL = Maximum Residual
Disinfectant Level; MRDLG = Maximum Residual Disinfectant Level Goal; NIOSH = National Institute for
Occupational Safety and Health; NTP = National Toxicology Program; OSHA = Occupational Safety and Health
Administration; PEL = permissible exposure limit; REL = recommended exposure limit; RfC = inhalation reference
concentration; RfD = oral reference dose; SIDS = Screening Information Data Set; STEL = short-term expsoure limit;
TLV = threshold limit values; TSCA = Toxic Substances Control Act; TWA = time-weighted average; USC = United
States Code; VTA = Voluntary Testing Agreement; WHO = World Health Organization
CHLORINE 191
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_______________________
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CHLORINE 213
10. GLOSSARY
Absorption—The taking up of liquids by solids, or of gases by solids or liquids.
Acute Exposure—Exposure to a chemical for a duration of 14 days or less, as specified in the

Toxicological Profiles.
Adsorption—The adhesion in an extremely thin layer of molecules (as of gases, solutes, or liquids) to the
surfaces of solid bodies or liquids with which they are in contact.
Adsorption Coefficient (Koc)—The ratio of the amount of a chemical adsorbed per unit weight of
organic carbon in the soil or sediment to the concentration of the chemical in solution at equilibrium.
Adsorption Ratio (Kd)—The amount of a chemical adsorbed by sediment or soil (i.e., the solid phase)
divided by the amount of chemical in the solution phase, which is in equilibrium with the solid phase, at a
fixed solid/solution ratio. It is generally expressed in micrograms of chemical sorbed per gram of soil or
sediment.
Benchmark Dose (BMD)—Usually defined as the lower confidence limit on the dose that produces a
specified magnitude of changes in a specified adverse response. For example, a BMD10 would be the
dose at the 95% lower confidence limit on a 10% response, and the benchmark response (BMR) would be
10%. The BMD is determined by modeling the dose response curve in the region of the dose response
relationship where biologically observable data are feasible.
Benchmark Dose Model—A statistical dose-response model applied to either experimental toxicological
or epidemiological data to calculate a BMD.
Bioconcentration Factor (BCF)—The quotient of the concentration of a chemical in aquatic organisms

at a specific time or during a discrete time period of exposure divided by the concentration in the
surrounding water at the same time or during the same period.
Biomarkers—Broadly defined as indicators signaling events in biologic systems or samples. They have
been classified as markers of exposure, markers of effect, and markers of susceptibility.
Cancer Effect Level (CEL)—The lowest dose of chemical in a study, or group of studies, that produces
significant increases in the incidence of cancer (or tumors) between the exposed population and its
appropriate control.
Carcinogen—A chemical capable of inducing cancer.
Case-Control Study—A type of epidemiological study that examines the relationship between a
particular outcome (disease or condition) and a variety of potential causative agents (such as toxic
chemicals). In a case-controlled study, a group of people with a specified and well-defined outcome is
identified and compared to a similar group of people without outcome.
Case Report—Describes a single individual with a particular disease or exposure. These may suggest
some potential topics for scientific research, but are not actual research studies.
Case Series—Describes the experience of a small number of individuals with the same disease or
exposure. These may suggest potential topics for scientific research, but are not actual research studies.
CHLORINE 214
10. GLOSSARY
Ceiling Value—A concentration of a substance that should not be exceeded, even instantaneously.
Chronic Exposure—Exposure to a chemical for 365 days or more, as specified in the Toxicological
Profiles.
Cohort Study—A type of epidemiological study of a specific group or groups of people who have had a
common insult (e.g., exposure to an agent suspected of causing disease or a common disease) and are
followed forward from exposure to outcome. At least one exposed group is compared to one unexposed
group.
Cross-sectional Study—A type of epidemiological study of a group or groups of people that examines
the relationship between exposure and outcome to a chemical or to chemicals at one point in time.
Data Needs—Substance-specific informational needs that if met would reduce the uncertainties of human
health assessment.
Developmental Toxicity—The occurrence of adverse effects on the developing organism that may result
from exposure to a chemical prior to conception (either parent), during prenatal development, or
postnatally to the time of sexual maturation. Adverse developmental effects may be detected at any point
in the life span of the organism.
Dose-Response Relationship—The quantitative relationship between the amount of exposure to a

toxicant and the incidence of the adverse effects.
Embryotoxicity and Fetotoxicity—Any toxic effect on the conceptus as a result of prenatal exposure to
a chemical; the distinguishing feature between the two terms is the stage of development during which the
insult occurs. The terms, as used here, include malformations and variations, altered growth, and in utero
death.
Environmental Protection Agency (EPA) Health Advisory—An estimate of acceptable drinking water
levels for a chemical substance based on health effects information. A health advisory is not a legally
enforceable federal standard, but serves as technical guidance to assist federal, state, and local officials.
Epidemiology—Refers to the investigation of factors that determine the frequency and distribution of
disease or other health-related conditions within a defined human population during a specified period.
Genotoxicity—A specific adverse effect on the genome of living cells that, upon the duplication of
affected cells, can be expressed as a mutagenic, clastogenic, or carcinogenic event because of specific
alteration of the molecular structure of the genome.
Half-life—A measure of rate for the time required to eliminate one half of a quantity of a chemical from
the body or environmental media.
Immediately Dangerous to Life or Health (IDLH)—The maximum environmental concentration of a

contaminant from which one could escape within 30 minutes without any escape-impairing symptoms or
irreversible health effects.
Immunologic Toxicity—The occurrence of adverse effects on the immune system that may result from
exposure to environmental agents such as chemicals.
Immunological Effects—Functional changes in the immune response.

CHLORINE 215
10. GLOSSARY
Incidence—The ratio of individuals in a population who develop a specified condition to the total
number of individuals in that population who could have developed that condition in a specified time
period.
Intermediate Exposure—Exposure to a chemical for a duration of 15–364 days, as specified in the

Toxicological Profiles.
In Vitro—Isolated from the living organism and artificially maintained, as in a test tube.
In Vivo—Occurring within the living organism.
Lethal Concentration(LO) (LCLO)—The lowest concentration of a chemical in air that has been reported
to have caused death in humans or animals.
Lethal Concentration(50) (LC50)—A calculated concentration of a chemical in air to which exposure for
a specific length of time is expected to cause death in 50% of a defined experimental animal population.
Lethal Dose(LO) (LDLo)—The lowest dose of a chemical introduced by a route other than inhalation that
has been reported to have caused death in humans or animals.
Lethal Dose(50) (LD50)—The dose of a chemical that has been calculated to cause death in 50% of a
defined experimental animal population.
Lethal Time(50) (LT50)—A calculated period of time within which a specific concentration of a chemical
is expected to cause death in 50% of a defined experimental animal population.
Lowest-Observed-Adverse-Effect Level (LOAEL)—The lowest exposure level of chemical in a study,

or group of studies, that produces statistically or biologically significant increases in frequency or severity
of adverse effects between the exposed population and its appropriate control.
Lymphoreticular Effects—Represent morphological effects involving lymphatic tissues such as the

lymph nodes, spleen, and thymus.
Malformations—Permanent structural changes that may adversely affect survival, development, or

function.
Minimal Risk Level (MRL)—An estimate of daily human exposure to a hazardous substance that is
likely to be without an appreciable risk of adverse noncancer health effects over a specified route and
duration of exposure.
Modifying Factor (MF)—A value (greater than zero) that is applied to the derivation of a Minimal Risk
Level (MRL) to reflect additional concerns about the database that are not covered by the uncertainty
factors. The default value for a MF is 1.
Morbidity—State of being diseased; morbidity rate is the incidence or prevalence of disease in a specific
population.
Mortality—Death; mortality rate is a measure of the number of deaths in a population during a specified
interval of time.
CHLORINE 216
10. GLOSSARY
Mutagen—A substance that causes mutations. A mutation is a change in the DNA sequence of a cell’s
DNA. Mutations can lead to birth defects, miscarriages, or cancer.
Necropsy—The gross examination of the organs and tissues of a dead body to determine the cause of
death or pathological conditions.
Neurotoxicity—The occurrence of adverse effects on the nervous system following exposure to a

chemical.
No-Observed-Adverse-Effect Level (NOAEL)—The dose of a chemical at which there were no

statistically or biologically significant increases in frequency or severity of adverse effects seen between
the exposed population and its appropriate control. Effects may be produced at this dose, but they are not
considered to be adverse.
Octanol-Water Partition Coefficient (Kow)—The equilibrium ratio of the concentrations of a chemical

in n-octanol and water, in dilute solution.
Odds Ratio (OR)—A means of measuring the association between an exposure (such as toxic substances
and a disease or condition) that represents the best estimate of relative risk (risk as a ratio of the incidence
among subjects exposed to a particular risk factor divided by the incidence among subjects who were not
exposed to the risk factor). An OR of greater than 1 is considered to indicate greater risk of disease in the
exposed group compared to the unexposed group.
Organophosphate or Organophosphorus Compound—A phosphorus-containing organic compound

and especially a pesticide that acts by inhibiting cholinesterase.
Permissible Exposure Limit (PEL)—An Occupational Safety and Health Administration (OSHA)
allowable exposure level in workplace air averaged over an 8-hour shift of a 40-hour workweek.
Pesticide—General classification of chemicals specifically developed and produced for use in the control
of agricultural and public health pests.
Pharmacokinetics—The dynamic behavior of a material in the body, used to predict the fate
(disposition) of an exogenous substance in an organism. Utilizing computational techniques, it provides
the means of studying the absorption, distribution, metabolism, and excretion of chemicals by the body.
Pharmacokinetic Model—A set of equations that can be used to describe the time course of a parent
chemical or metabolite in an animal system. There are two types of pharmacokinetic models: data-based
and physiologically-based. A data-based model divides the animal system into a series of compartments,
which, in general, do not represent real, identifiable anatomic regions of the body, whereas the
physiologically-based model compartments represent real anatomic regions of the body.
Physiologically Based Pharmacodynamic (PBPD) Model—A type of physiologically based dose-

response model that quantitatively describes the relationship between target tissue dose and toxic end
points. These models advance the importance of physiologically based models in that they clearly
describe the biological effect (response) produced by the system following exposure to an exogenous
substance.
CHLORINE 217
10. GLOSSARY
Physiologically Based Pharmacokinetic (PBPK) Model—Comprised of a series of compartments

representing organs or tissue groups with realistic weights and blood flows. These models require a
variety of physiological information: tissue volumes, blood flow rates to tissues, cardiac output, alveolar
ventilation rates, and possibly membrane permeabilities. The models also utilize biochemical
information, such as air/blood partition coefficients, and metabolic parameters. PBPK models are also
called biologically based tissue dosimetry models.
Prevalence—The number of cases of a disease or condition in a population at one point in time.
Prospective Study—A type of cohort study in which the pertinent observations are made on events
occurring after the start of the study. A group is followed over time.
q1*—The upper-bound estimate of the low-dose slope of the dose-response curve as determined by the
multistage procedure. The q1* can be used to calculate an estimate of carcinogenic potency, the
incremental excess cancer risk per unit of exposure (usually μg/L for water, mg/kg/day for food, and
μg/m3 for air).
Recommended Exposure Limit (REL)—A National Institute for Occupational Safety and Health
(NIOSH) time-weighted average (TWA) concentration for up to a 10-hour workday during a 40-hour
workweek.
Reference Concentration (RfC)—An estimate (with uncertainty spanning perhaps an order of

magnitude) of a continuous inhalation exposure to the human population (including sensitive subgroups)
that is likely to be without an appreciable risk of deleterious noncancer health effects during a lifetime.
The inhalation reference concentration is for continuous inhalation exposures and is appropriately
expressed in units of mg/m3 or ppm.
Reference Dose (RfD)—An estimate (with uncertainty spanning perhaps an order of magnitude) of the
daily exposure of the human population to a potential hazard that is likely to be without risk of deleterious
effects during a lifetime. The RfD is operationally derived from the no-observed-adverse-effect level
(NOAEL, from animal and human studies) by a consistent application of uncertainty factors that reflect
various types of data used to estimate RfDs and an additional modifying factor, which is based on a
professional judgment of the entire database on the chemical. The RfDs are not applicable to
nonthreshold effects such as cancer.
Reportable Quantity (RQ)—The quantity of a hazardous substance that is considered reportable under
the Comprehensive Environmental Response, Compensation, and Liability Act (CERCLA). Reportable
quantities are (1) 1 pound or greater or (2) for selected substances, an amount established by regulation
either under CERCLA or under Section 311 of the Clean Water Act. Quantities are measured over a
24-hour period.
Reproductive Toxicity—The occurrence of adverse effects on the reproductive system that may result
from exposure to a chemical. The toxicity may be directed to the reproductive organs and/or the related
endocrine system. The manifestation of such toxicity may be noted as alterations in sexual behavior,
fertility, pregnancy outcomes, or modifications in other functions that are dependent on the integrity of
this system.
Retrospective Study—A type of cohort study based on a group of persons known to have been exposed
at some time in the past. Data are collected from routinely recorded events, up to the time the study is
undertaken. Retrospective studies are limited to causal factors that can be ascertained from existing
records and/or examining survivors of the cohort.
CHLORINE 218
10. GLOSSARY
Risk—The possibility or chance that some adverse effect will result from a given exposure to a chemical.
Risk Factor—An aspect of personal behavior or lifestyle, an environmental exposure, or an inborn or

inherited characteristic that is associated with an increased occurrence of disease or other health-related
event or condition.
Risk Ratio—The ratio of the risk among persons with specific risk factors compared to the risk among
persons without risk factors. A risk ratio greater than 1 indicates greater risk of disease in the exposed
group compared to the unexposed group.
Short-Term Exposure Limit (STEL)—The American Conference of Governmental Industrial

Hygienists (ACGIH) maximum concentration to which workers can be exposed for up to 15 minutes
continually. No more than four excursions are allowed per day, and there must be at least 60 minutes
between exposure periods. The daily Threshold Limit Value-Time Weighted Average (TLV-TWA) may
not be exceeded.
Standardized Mortality Ratio (SMR)—A ratio of the observed number of deaths and the expected
number of deaths in a specific standard population.
Target Organ Toxicity—This term covers a broad range of adverse effects on target organs or
physiological systems (e.g., renal, cardiovascular) extending from those arising through a single limited
exposure to those assumed over a lifetime of exposure to a chemical.
Teratogen—A chemical that causes structural defects that affect the development of an organism.
Threshold Limit Value (TLV)—An American Conference of Governmental Industrial Hygienists

(ACGIH) concentration of a substance to which most workers can be exposed without adverse effect.
The TLV may be expressed as a Time Weighted Average (TWA), as a Short-Term Exposure Limit
(STEL), or as a ceiling limit (CL).
Time-Weighted Average (TWA)—An allowable exposure concentration averaged over a normal 8-hour
workday or 40-hour workweek.
Toxic Dose(50) (TD50)—A calculated dose of a chemical, introduced by a route other than inhalation,
which is expected to cause a specific toxic effect in 50% of a defined experimental animal population.
Toxicokinetic—The absorption, distribution, and elimination of toxic compounds in the living organism.
Uncertainty Factor (UF)—A factor used in operationally deriving the Minimal Risk Level (MRL) or
Reference Dose (RfD) or Reference Concentration (RfC) from experimental data. UFs are intended to
account for (1) the variation in sensitivity among the members of the human population, (2) the
uncertainty in extrapolating animal data to the case of human, (3) the uncertainty in extrapolating from
data obtained in a study that is of less than lifetime exposure, and (4) the uncertainty in using lowest-
observed-adverse-effect level (LOAEL) data rather than no-observed-adverse-effect level (NOAEL) data.
A default for each individual UF is 10; if complete certainty in data exists, a value of 1 can be used;
however, a reduced UF of 3 may be used on a case-by-case basis, 3 being the approximate logarithmic
average of 10 and 1.
Xenobiotic—Any chemical that is foreign to the biological system.

CHLORINE A-1
APPENDIX A. ATSDR MINIMAL RISK LEVELS AND WORKSHEETS
The Comprehensive Environmental Response, Compensation, and Liability Act (CERCLA) [42 U.S.C.
9601 et seq.], as amended by the Superfund Amendments and Reauthorization Act (SARA) [Pub. L. 99–
499], requires that the Agency for Toxic Substances and Disease Registry (ATSDR) develop jointly with
the U.S. Environmental Protection Agency (EPA), in order of priority, a list of hazardous substances most
commonly found at facilities on the CERCLA National Priorities List (NPL); prepare toxicological
profiles for each substance included on the priority list of hazardous substances; and assure the initiation
of a research program to fill identified data needs associated with the substances.
The toxicological profiles include an examination, summary, and interpretation of available toxicological
information and epidemiologic evaluations of a hazardous substance. During the development of
toxicological profiles, Minimal Risk Levels (MRLs) are derived when reliable and sufficient data exist to
identify the target organ(s) of effect or the most sensitive health effect(s) for a specific duration for a
given route of exposure. An MRL is an estimate of the daily human exposure to a hazardous substance
that is likely to be without appreciable risk of adverse noncancer health effects over a specified duration
of exposure. MRLs are based on noncancer health effects only and are not based on a consideration of
cancer effects. These substance-specific estimates, which are intended to serve as screening levels, are
used by ATSDR health assessors to identify contaminants and potential health effects that may be of
concern at hazardous waste sites. It is important to note that MRLs are not intended to define clean-up or
action levels.
MRLs are derived for hazardous substances using the no-observed-adverse-effect level/uncertainty factor
approach. They are below levels that might cause adverse health effects in the people most sensitive to
such chemical-induced effects. MRLs are derived for acute (1–14 days), intermediate (15–364 days), and
chronic (365 days and longer) durations and for the oral and inhalation routes of exposure. Currently,
MRLs for the dermal route of exposure are not derived because ATSDR has not yet identified a method
suitable for this route of exposure. MRLs are generally based on the most sensitive chemical-induced end
point considered to be of relevance to humans. Serious health effects (such as irreparable damage to the
liver or kidneys, or birth defects) are not used as a basis for establishing MRLs. Exposure to a level
above the MRL does not mean that adverse health effects will occur.
MRLs are intended only to serve as a screening tool to help public health professionals decide where to
look more closely. They may also be viewed as a mechanism to identify those hazardous waste sites that
CHLORINE A-2
APPENDIX A
are not expected to cause adverse health effects. Most MRLs contain a degree of uncertainty because of
the lack of precise toxicological information on the people who might be most sensitive (e.g., infants,
elderly, nutritionally or immunologically compromised) to the effects of hazardous substances. ATSDR
uses a conservative (i.e., protective) approach to address this uncertainty consistent with the public health
principle of prevention. Although human data are preferred, MRLs often must be based on animal studies
because relevant human studies are lacking. In the absence of evidence to the contrary, ATSDR assumes
that humans are more sensitive to the effects of hazardous substance than animals and that certain persons
may be particularly sensitive. Thus, the resulting MRL may be as much as 100-fold below levels that
have been shown to be nontoxic in laboratory animals.
Proposed MRLs undergo a rigorous review process: Health Effects/MRL Workgroup reviews within the
Division of Toxicology and Environmental Medicine, expert panel peer reviews, and agency-wide MRL
Workgroup reviews, with participation from other federal agencies and comments from the public. They
are subject to change as new information becomes available concomitant with updating the toxicological
profiles. Thus, MRLs in the most recent toxicological profiles supersede previously published levels.
For additional information regarding MRLs, please contact the Division of Toxicology and
Environmental Medicine, Agency for Toxic Substances and Disease Registry, 1600 Clifton Road NE,
Mailstop F-62, Atlanta, Georgia 30333.
CHLORINE A-3
APPENDIX A
MINIMAL RISK LEVEL (MRL) WORKSHEET

Chemical Name: Chlorine gas
CAS Numbers: 7782-50-5
Date: June 2010
Profile Status: Final Draft Post-Public Comment
Route: [X] Inhalation [ ] Oral
Duration: [X] Acute [ ] Intermediate [ ] Chronic
Graph Key: 7, 9, 10, 11
Species: Human
Minimal Risk Level: 0.06 [ ] mg/kg/day [X] ppm
References: Anglen DA. 1981. Sensory response of human subjects to chlorine in air. Ann Arbor, MI:
University of Michigan.
D’Alessandro A, Kuschner W, Wong H, et al. 1996. Exaggerated responses to chlorine inhalation

among persons with nonspecific airway hyperreactivity. Chest 109:331-337.
Rotman HH, Fliegelman MJ, Moore T, et al. 1983. Effects of low concentrations of chlorine on
pulmonary function in humans. J Appl Physiol 54:1120-1124.
Schins RPF, Emmen H, Hoogendijk L, et al. 2000. Nasal inflammatory and respiratory parameters in
human volunteers during and after repeated exposure to chlorine. Eur Respir J 16:626-632.
Shusterman D, Murphy, MA, Balmes J. 1998. Subjects with seasonal allergic rhinitis and nonrhinitic
subjects react differentially to nasal provocation with chlorine gas. J Allergy Clin Immunol 101:732-740.
Shusterman D, Murphy, MA, Balmes J. 2003b. Influence of age, gender, and allergy status on nasal
reactivity to inhaled chlorine. Inhal Toxicol 15:1179-1189.
Experimental design and effects noted in each study: Anglen (1981) exposed up to 29 male and female
volunteers to 0, 0.5, 1, or 2 ppm chlorine for either 4 or 8 hours. Sensations were recorded before and
during exposure, and pulmonary function was monitored by measuring FVC and FEV1 before and at
various times during exposure. Itching and burning of the throat were the highest responses and were
most prevalent by the end of an 8-hour exposure to 1 ppm chlorine. Responses for sensations of itching
or burning of the nose and eyes were also prevalent at 1 ppm chlorine. In general, males provided
stronger irritation responses than females. Exposure to 1 or 2 ppm chlorine for 8 hours produced
significant changes in pulmonary function, but similar exposures to 0.5 ppm did not. Exposure to 2 ppm
for up to 30 minutes produced no increase in subjective irritation and exposure to 2 ppm for 2 hours did
not alter pulmonary function.
Rotman et al. (1983) studied eight healthy male volunteers exposed to target concentrations of 0, 0.5, or
1 ppm chlorine (Rotman et al. 1983). Pulmonary tests were conducted before exposure, after a 4- and
8-hour exposure period and again 2 and 24 hours after exposure ceased. During exposure, the subjects
exercised on a treadmill for 15 minutes of each hour to simulate light-to-moderate work that raised the
heart rate to 100 beats per minute. Specific respiratory parameters measured included FVC, FEV1,
FEV1% forced expired volume in 1 second as %FVC (FEV1%), peak expiratory flow rate (PEFR), FEF50
and FEF25, TLC, expiratory reserve volume (ERV), functional residual capacity (FRC), residual volume,
airway resistance (Raw), single-breath DLCO, closing volume, and difference in nitrogen concentrations
between 750 and 1,250 mL of inhaled vital capacity (ΔN2). Exposure to 1 ppm chlorine caused runny
CHLORINE A-4
APPENDIX A
nose and mild burning in the throat, but no such effects were reported at 0.5 ppm. Significant changes in
pulmonary function tests were mostly restricted to the 1 ppm exposure level and were evident after
4 hours of exposure. Changes were observed in FEV1, PEFR, FEF50, FEF25, TLC, Raw, and ΔN2.
Greater changes in some of these parameters were seen after 8 hours of exposure. Few changes were still
evident 24 hours after exposure, but most parameters had returned to pre-exposure values by that time. It
should be noted that one volunteer who was atopic experienced severe distress during exposure to 1 ppm
and was forced to exit the chamber before the full 8-hour period due to shortness of breath and wheezing.
D’Alessandro et al. (1996) evaluated pulmonary function in subjects with (n=10) and without (n=5)
airway hyperreactivity (HR, defined by baseline methacholine hyperresponsiveness). The HR subjects
were exposed to 0.4 or 1.0 ppm chlorine, whereas the healthy subjects were exposed to 1.0 ppm chlorine.
All exposures lasted 60 minutes. Airflow and airway resistance were measured immediately before and
immediately after exposure. Also, lung volumes, airflow, diffusing capacity, airway resistance, and
responsiveness to methacholine were measured 24 hours before and 24 hours after exposure. Exposure of
the HR group to 0.4 ppm chlorine resulted in no significant change in airflow or resistance either
immediately or 24 hours after exposure. Exposure to 1.0 ppm chlorine resulted in an immediate decrease
in FEV1 and FEF25–75% and increase in airway resistance among normal and HR subjects, but the
magnitude of the effects among HR subjects was significantly greater than in healthy subjects. Twenty-
four hours after exposure, there were no significant changes for healthy or HR subjects in airflow, lung
volumes, diffusing capacity, resistance, or methacholine responsiveness. Comparing relative changes
from baseline immediately after exposure between normal and HR subjects showed that HR subjects had
much greater changes in pulmonary function tests.
Schins et al. (2000) studied eight volunteers exposed to chlorine 6 hours/day on 3 consecutive days to
each of the four exposure conditions, 0, 0.1, 0.3, and 0.5 ppm chlorine (Schins et al. 2000). Pulmonary
function including effort-dependent parameters and effort-independent parameters were evaluated before
and after exposures. In addition, nasal lavage measurements were performed before and after each
exposure and 1 and 4 days after each exposure. The nasal lavage fluid was examined for total cells,
epithelial cells, neutrophils, lymphocytes, eosinophils, monocytes, albumin (an indicator of epithelial
permeability), and interleukin-8 (indicator of inflammatory response). Subjective complaints by the
subjects were judged to be not treatment-related. Examination of the nasal lavages gave no indication of
an inflammatory response or irritant effects on the nasal epithelium. The results of the pulmonary
function tests showed that the only significant effect related to chlorine exposure was a difference in
maximal mid expiratory flow (MMEF) between 0 and 0.5 ppm exposure; however, this was attributed to
an unexplained shift in baseline values during control exposure (0 ppm).
Shusterman et al. (2003b) measured nasal airway resistance in 52 healthy adults (24 males and
28 females) before and after exposure to 0 or 1 ppm chlorine for 15 minutes. Subjects were stratified on
age (18–34, 35–51, 52–69 years), gender, and allergic rhinitis status (27 were positive). Nasal airway
resistance was measured by active posterior rhinomanometry. Exposures to air and chlorine were a week
apart. Subjects with allergic rhinitis showed a significantly greater increase in nasal airway resistance
(49% increase from baseline) than healthy subjects (10% increase from baseline) 15 minutes after
exposure. The increase in nasal airway resistance was most pronounced in older subjects and least
pronounced in the youngest group. No significant differences were seen between males and females. In
an earlier study, the same group of investigators had reported that subjects with SAR (n=8) exposed to
0.5 ppm chlorine for 15 minutes experienced a much greater increase in nasal airway resistance than
subjects without SAR (n=8), as measured by active posterior rhinomanometry (Shusterman et al. 1998).
However, when subjective responses to odor, nasal irritation, and nasal congestion were analyzed
separately by rhinitis status, no significant exposure-related changes were observed for rhinorrhea,
postnasal drip, or headache either on a pool or stratified basis. In addition, within either the SAR or non-
SAR group, there was no relationship between subjective and objective congestion after chlorine
CHLORINE A-5
APPENDIX A
exposure. Pulmonary peak flow tests showed that none of the subjects exhibited clinically significant
changes in peak flow, nor did they complain of cough, wheezing, or chest tightness on chlorine exposure
days. The increased nasal airway resistance instrumentally detected in subjects with SAR is not
considered an adverse effect since the subjects did not perceive it as such.
Collectively, this group of studies provides evidence of sensory irritation and transient pulmonary
changes occurring in humans exposed to 1 ppm chlorine for up to 8 hours/day. The pulmonary changes
indicated increased airway resistance and reduced air flow. No such changes were reported in volunteers
exposed to 0.5 ppm chlorine
Dose and end point used for MRL derivation: 0.5 ppm is a NOAEL for sensory irritation and pulmonary
function.
The MRL is derived by adjusting for continuous exposure based on the fact that Rotman et al. (1983)
reported that exposure to 1 ppm for 8 hours induced greater changes in pulmonary function tests than
exposure to the same concentration for 4 hours, suggesting that the response was related to some function
of concentration and duration rather than to concentration alone.
MRL = 0.5 ppm (8 hours/24 hours) = 0.167 ppm
8 hours was the longest period of exposure for which there is information.
[X] NOAEL [ ] LOAEL
Uncertainty Factors used in MRL derivation:
[ ] 10 for use of a LOAEL
[ ] 10 for extrapolation from animals to humans
[X] 3 for human variability
Although sensitive individuals were tested in some of these studies, the number of individuals tested at
the region of the NOAEL (0.4–0.5 ppm) was small. Therefore, an uncertainty factor of 3 is used to
account for sensitive populations.
Was a conversion factor used from ppm in food or water to a mg/body weight dose? Not applicable.
If an inhalation study in animals, list conversion factors used in determining human equivalent dose: Not
applicable.
Was a conversion used from intermittent to continuous exposure? Yes, see above.
Other additional studies or pertinent information that lend support to this MRL: Results from the five
studies summarized above are supportive of each other.
Agency Contacts (Chemical Managers): G. Daniel Todd

CHLORINE A-6
APPENDIX A

Date: June 2010
Duration: [ ] Acute [X] Intermediate [ ] Chronic
Graph Key: 30
Species: Rat
Reference: Kutzman RS. 1983. A study of Fisher-344 rats subchronically exposed to 0, 0.5, 1.5, or
5.0 ppm chlorine. Upton, NY: Brookhaven National Laboratory. BNL 32710.
Experimental design: Groups of F344 rats (24 males, 10 females) were exposed to 0, 0.5, 1.5, or 5 ppm
chlorine 6 hours/day, 5 days/week for 62 days (Kutzman 1983). Pulmonary function tests
(plethysmograph-based assessment of multiple end points, including lung and tidal volumes, breathing
frequency, transpulmonary pressure, lung compliance, N2 washout, diffusing capacity for CO2, maximum
expiratory flow volume, peak expiratory flow, and airway resistance) were conducted in 21–
24 anesthetized males 6 hours after the last exposure. Respiratory tissues from these rats were prepared
for histopathology. The lung from some of these rats was also examined for collagen, elastin, total
protein, and DNA. Histopathology of selected organs (nasal turbinates, lungs, peribronchial lymph node,
brain, kidney, liver, spleen, testes, and heart) was evaluated in eight males per group. Also, 8 males were
mated with untreated females and 10 exposed females were mated with untreated males for reproductive
studies on females sacrificed on GD 19. In addition, 1 day after the last exposure, samples of blood and
bone marrow from 10 males per group were prepared for analysis of chromosomal aberrations and sister
chromatid exchanges.
Effects noted in study and corresponding doses: Exposure to 5 ppm cause severe eye and upper
respiratory irritation, whereas rats exposed to 1.5 ppm showed occasionally less severe signs of irritation,
and exposure to 0.5 ppm caused no obvious signs of irritation or discomfort. Female rats exposed to
5 ppm lost weight. Final weight was approximately 32% lower than controls; at 1.5 and 0.5 ppm, final
weight was approximately 15 and 11% lower than in control rats, respectively. In males exposed to
5 ppm, final weight was approximately 15% lower than controls. No information was provided regarding
food and water intake. Changes in organ weights were unremarkable. The tests of pulmonary function
did not reveal marked abnormalities. The most significant effect was a reduction in airflow at 25% vital
capacity in all exposed groups, indicating some degree of small airway involvement. An electro-
cardiogram did not reveal any significant cardiac alterations due to chlorine exposure. The lung
biochemistry only showed an increased collagen concentration at 1.5 and 5 ppm. The cytogenetic studies
showed no increased incidence of sister chromatid exchange or cellular proliferation in bone marrow and
no increase in sister chromatid exchanges or chromosomal aberrations in peripheral lymphocytes.
Analysis of sperm morphology was unremarkable. Results of the reproductive studies showed no effects
on fertility, number of corpora lutea, viable embryos, early or late deaths, or preimplantation loses. There
were no significant exposure-related increases in the incidences of animals with histological lesions in
any of the examined tissues with the exception of a loss of cilia in the trachea. The incidences of slight to
moderate loss of tracheal cilia were 1/23, 12/23, 4/23, and 13/23 in the 0, 0.5, 1.5, and 5 ppm exposure
groups, respectively. Although the incidence for this lesion in the mid-exposure group was not
significantly different from the control incidence, a statistically significant (p=0.0055) Cochran-Armitage
trend test for these data can be demonstrated. However, when attempts were made to apply dose-response
CHLORINE A-7
APPENDIX A
models to the data, no adequate fits of EPA Benchmark Dose Software models to the data were obtained
(p-values for chi-square goodness of fit statistics were <0.1).
Dose and end point used for MRL derivation: 0.5 ppm is a minimal LOAEL for tracheal lesions.
[X] 3 for use of a minimal LOAEL

[X] 3 for extrapolation from animals to humans with dosimetric adjustment
If an inhalation study in animals, list conversion factors used in determining human equivalent dose: The
intermediate-duration inhalation MRL was calculated using EPA’s methodology (EPA 1994a) for a
category 1 gas.
LOAEL[HEC] = LOAEL[ADJ] x RGDRTB

where:
LOAEL[ADJ] = 0.5 ppm x 6/24 hours x 5/7 days = 0.09 ppm and
RGDRTB = ratio of the regional gas dose in rats to that of humans for the tracheobronchial region
RGDRTB = (VE/SATB)A / (VE/SATB)H

where:
VE = minute volume (0.137 L/minute for rats, 13.8 L/minute for humans [EPA 1994a]) and
SATB = surface area of the tracheobronchial region (22.5 cm2 for rats and 3,200 cm2 for humans
[EPA 1994a])
LOAEL[HEC] = 0.09 ppm x (0.137 L/minute/22.5 cm2) / (13.8 L/minute/3,200 cm2) = 0.14 ppm
Other additional studies or pertinent information that lend support to this MRL: In a similar study,
Barrow et al. (1979) evaluated the respiratory response in F344 rats exposed to 0, 1, 3, or 9 ppm chlorine
6 hours/day, 5 days/week for 6 weeks. Nasal discharge was seen occasionally in rats exposed to 1 ppm,
but was common in rats exposed to 3 and 9 ppm. Respiratory difficulty was also apparent in some rats
exposed to 9 ppm. At termination, gross necropsy revealed accumulation of inflammatory reactions in
the upper nasal passages in rats exposed to 3 and 9 ppm chlorine. Microscopic evaluations showed
indications of inflammatory reactions in the upper and lower respiratory tract of high-dose males and
females. The nasal turbinates showed mucopurulent inflammation with secretory material and erosions of
the mucosal epithelium. Changes in the trachea and bronchi consisted mostly of hyperplasia of the
epithelial lining and inflammatory reactions. The alveolar sacs contained macrophages and secretory
material and epithelial cells showed necrosis, hypertrophy, and hyperplasia. Alterations in rats exposed to
1 and 3 ppm were less extensive and were limited to focal mucopurulent inflammation of the nasal
turbinates in females. Males exposed to 1 or 3 ppm showed deeper pulmonary changes consisting of
slight to moderate inflammatory reaction around the respiratory bronchioles and alveolar ducts, increased
alveolar macrophages, and isolated areas of atelectasis (incomplete expansion). A LOAEL of 1 ppm for
respiratory effects can be defined in this study based on the presence of inflammatory changes in the nasal
CHLORINE A-8
APPENDIX A
turbinates of females and in the lungs of males; no NOAEL was established. Incidences of animals with
respiratory lesions were not presented in this study.

CHLORINE A-9
APPENDIX A

Date: June 2010
Duration: [ ] Acute [ ] Intermediate [X] Chronic
Graph Key: 34
Species: Monkey
Reference: Klonne DR, Ulrich CE, Riley MG, et al. 1987. One-year inhalation toxicity study of chlorine
in Rhesus monkeys (Macaca mulatta). Fundam Appl Toxicol 9:557-572.
Experimental design: Male and female Rhesus monkeys (4/sex/exposure level) were exposed to 0, 0.1,
0.5, or 2.3 ppm chlorine 6 hours/day, 5 days/week for 1 year (Klonne et al. 1987). Pulmonary diffusing
capacity of CO and distribution of ventilation, body weights, urinalysis, EKG, hematology, and clinical
chemistry were evaluated monthly during the study. At termination, the heart, lungs plus trachea, liver,
gonads, kidneys, spleen, and brain were weighed. Histological evaluations were done on all major tissues
and organs. The nasal tissues (at the first palatine ridge and just posterior to the third, fifth, and seventh
palatine ridges), trachea, and lungs were also examined.
Effects noted in study and corresponding doses: Exposure to chlorine did not significantly affect body
weight, hematology and clinical chemistry parameters, urinalysis, or the EKG. At approximately week 6
of exposure, monkeys in the 2.3 ppm group showed overt signs of ocular irritation (tearing, reddened
eyes, rubbing the eyes) during the daily exposures; no signs of irritation were seen in the other exposure
groups. Examination of the eyes at termination showed irritation of the conjunctiva at 2.3 ppm, but no
evidence of gross changes; the corneas were not affected. During the study, there was a statistically
significant trend in each group, including controls, for increasing pulmonary diffusing capacity and
distribution of ventilation. However, there was no evidence of treatment-related effects at any interval
during the study. The only treatment-related histopathological effects consisted of focal epithelial
hyperplasia characterized by increased cell numbers and loss of cilia and goblet cells in the respiratory
epithelium of the nose and trachea. The affected areas of the nasal passages showed hypercellularity with
loss of goblet cells and cilia. In some of these areas, the nuclei showed altered polarity. Lesions were
more frequent on the angular margins of the turbinates and less frequent on the lateral wall or septum
adjacent to these margins. In some cases, the respiratory epithelial hyperplasia was associated with mild
suppurative inflammatory response. Lesions in the trachea resembled those in the nose, but were less
severe and involved only a small circumferential section of the ventral and ventrolateral trachea. The
combined incidences of hyperplasia in the nasal epithelium with loss of goblet cells and cilia,
characterized as trace and mild in males and females, were 1/8, 3/8, 6/8, and 8/8 in the control, 0.1, 0.5,
and 2.3 ppm exposure groups, respectively. The exposure concentration of 0.1 ppm is considered a
LOAEL for nasal lesions in monkeys.
were analyzed using the BMD approach for MRL derivation. Models in the EPA BMDS (version 1.4.1)
(i.e., Gamma, Logistic, Log-logistic, Multi-stage, Probit, Log-probit, Quantal linear, Weibull) were fit to
the nasal lesion data to determine potential points of departure for the MRL. A Quantal linear model
provided the best fit to the data. The predicted exposure concentration associated with a 10% extra risk
CHLORINE A-10
APPENDIX A
(BMC10) for nasal lesions in monkeys was 0.04 ppm; the lower 95% confidence limit on this
concentration (BMCL10) was 0.02 ppm.
Dose and end point used for MRL derivation: BMCL10 of 0.02 ppm for nasal lesions in monkeys.
[ ] NOAEL [ ] LOAEL [X] BMCL10
[ ] 10 for use of a LOAEL

[X] 3 for extrapolation from animals to humans with dosimetric adjustment
If an inhalation study in animals, list conversion factors used in determining human equivalent dose: The
intermediate-duration inhalation MRL was calculated using EPA’s methodology (EPA 1994a) for a
category 1 gas.
BMCL10[HEC] = BMCL10[ADJ] x RGDRET
where:
BMCL10[ADJ] = 0.02 ppm x 6/24 hours x 5/7 days = 0.004 ppm and
RGDRET = ratio of the regional gas dose in rats to that of humans for the extrathoracic region
RGDRET = (VE/SAET)A / (VE/SAET)H

where:
VE = minute volume 2.1 m3/day for monkeys, calculated using the allometric equation for
monkeys in EPA (1988) assuming a body weight of 7 kg for Rhesus monkeys with nasal
cavity surface area of 62 cm2 (Gross and Morgan 1991); 20 m3/day for humans (EPA 1994a)
and
SAET = 62 cm2 surface area of the nasal cavity in Rhesus monkeys weighing 7 kg (Gross and
Morgan 1991); 200 cm2 for humans (EPA 1994a)
RGDRET = (2.1 m3/day / 62 cm2) / (20 m3/day / 200 cm2) = 0.34
BMCL10[HEC] = 0.004 ppm x 0.34 = 0.00136 ppm
Other additional studies or pertinent information that lend support to this MRL: Wolf et al. (1995)
exposed groups of F344 rats and B6C3F1 mice (approximately 70/sex/exposure level) to 0, 0.4, 1, or
2.5 ppm chlorine gas for 2 years. Males from both species and female mice were exposed 6 hours/day,
5 days/week, whereas female rats were exposed 6 hours/day, 3 days/week. The reduced exposure of
female rats was based on unpublished data from the investigators that showed female rats to have a
greater sensitivity to repeated long-term exposure to chlorine. End points evaluated included gross and
microscopic examination of the respiratory tract; the nasal passages were examined microscopically at
CHLORINE A-11
APPENDIX A
five different levels. Both in rats and mice, there were no gross lesions attributable to exposure to
chlorine, and microscopic evaluation of the respiratory tract showed that chlorine-related effects were
restricted to the nasal passages. In the study, the incidences were presented as percentages of all animals
for which the nasal passages were adequate for microscopic examination, but the number of animals
examined was not provided. No lesions were seen in the larynx, trachea, bronchi, or bronchioles. In
general, rats and mice exhibited similar types of lesions. For the most part, the nasal lesions were site-
specific, but the severity and/or incidence were not always concentration-dependent. The majority of the
nasal responses exhibited a rostral-to-caudal severity gradient. The lesions rarely extended to the
nasopharyngeal meatus. Lesions observed included respiratory and olfactory epithelial degeneration,
septal fenestration, mucosal inflammation, respiratory epithelial hyperplasia, squamous metaplasia, and
goblet cell (only rats) hypertrophy and hyperplasia, and secretory metaplasia of the transitional epithelium
of the lateral meatus. Also observed was intracellular accumulation of eosinophilic proteinaceous
material involving the respiratory, transitional, and olfactory epithelia. Lesions were also observed in
controls, but the incidences were significantly lower than in the treated groups. One of the lesions with
the lowest incidence in controls was Goblet cell hyperplasia in female rats (4%); the respective incidences
in the 0.4, 1, and 2.5 ppm group were 71, 90, and 91%. In mice, olfactory epithelium atrophy exhibited
one of the lowest incidences in controls (3%); the respective incidences in the 0.4, 1, and 2.5 ppm group
were 20, 21, and 39%. In both cases, severity also was concentration-related. Based on the increased
incidence of various types of lesions in the nasal passages, the exposure level of 0.4 ppm constitutes a
LOAEL for respiratory effects in rats and mice; a NOAEL was not defined.

CHLORINE A-12
APPENDIX A
BENCHMARK MODELING OF NASAL LESIONS IN MONKEYS
were analyzed using the BMD approach for MRL derivation (Table A-1). Models in the EPA BMDS
(version 1.4.1) (i.e., Gamma, Logistic, Log-logistic, Multi-stage, Probit, Log-probit, Quantal linear,
Weibull) were fit to the nasal lesion data to determine potential points of departure for the MRL. A
Quantal linear model provided the best fit to the data (Table A-2).
Table A-1. Incidence of Nasal Lesions Observed in Monkeys Exposed to
Chlorine for 1 Year
Dose (ppm) Total number of monkeys Number of monkeys with lesions

0 8 1
0.1 8 3
0.5 8 6
2.3 8 8
Source: Klonne et al. 1987
Table A-2. Modeling Predictions for the Incidence of Nasal Lesions Observed in
Monkeys Exposed to Chlorine for 1 Year
BMC10 BMCL10
Model (ppm) (ppm) x2 p-value AIC
a
Gamma 0.04 0.02 0.95 29.72
Logistic 0.09 0.05 0.76 30.17
b
Log-logistic 0.05 0.009 0.53 32.21
c
Multi-stage 0.04 0.02 0.95 29.72
Probit 0.08 0.05 0.77 30.14
b
Log-probit 0.06 0.03 0.81 30.09
Quantal linear 0.04 0.02 0.95 29.72
a
Weibull 0.04 0.02 0.95 29.72
a
Restrict power ≥1.
b
Slope restricted to >1.
c
Restrict betas ≥0; lowest degree polynomial with an adequate fit is reported; degree of polynomial = 1.
Source: Klonne et al. 1987

CHLORINE A-13
APPENDIX A
From this model, the predicted exposure concentration associated with a 10% extra risk (BMC10) for nasal
lesions in monkeys was 0.04 ppm; the lower 95% confidence limit on this concentration (BMCL10) was
0.02 ppm (Figure A-1).
Figure A-1. Predicted and Observed incidence of Nasal Mucosal Lesions in
Monkeys Exposed to Chlorine for 1 Year
Quantal Linear Model with 0.95 Confidence Level
Quantal Linear
1
0.8
Fraction Affected
0.6
0.4
0.2
0
BMDL BMD
0 0.5 1 1.5 2
dose
10:34 03/30 2007
The form of the probability function is:

P[response] = background + (1-background)*[1-EXP(-slope*dose)]
Background = 0.135767
Slope = 2.67521
CHLORINE A-14
APPENDIX A

CHLORINE B-1
APPENDIX B. USER'S GUIDE

Chapter 1
Public Health Statement
This chapter of the profile is a health effects summary written in non-technical language. Its intended
audience is the general public, especially people living in the vicinity of a hazardous waste site or
chemical release. If the Public Health Statement were removed from the rest of the document, it would
still communicate to the lay public essential information about the chemical.
The major headings in the Public Health Statement are useful to find specific topics of concern. The
topics are written in a question and answer format. The answer to each question includes a sentence that
will direct the reader to chapters in the profile that will provide more information on the given topic.
Chapter 2
Relevance to Public Health
This chapter provides a health effects summary based on evaluations of existing toxicologic,
epidemiologic, and toxicokinetic information. This summary is designed to present interpretive, weight-
of-evidence discussions for human health end points by addressing the following questions:
1. What effects are known to occur in humans?
2. What effects observed in animals are likely to be of concern to humans?
3. What exposure conditions are likely to be of concern to humans, especially around hazardous
waste sites?
The chapter covers end points in the same order that they appear within the Discussion of Health Effects
by Route of Exposure section, by route (inhalation, oral, and dermal) and within route by effect. Human
data are presented first, then animal data. Both are organized by duration (acute, intermediate, chronic).
In vitro data and data from parenteral routes (intramuscular, intravenous, subcutaneous, etc.) are also
considered in this chapter.
The carcinogenic potential of the profiled substance is qualitatively evaluated, when appropriate, using
existing toxicokinetic, genotoxic, and carcinogenic data. ATSDR does not currently assess cancer
potency or perform cancer risk assessments. Minimal Risk Levels (MRLs) for noncancer end points (if
derived) and the end points from which they were derived are indicated and discussed.
Limitations to existing scientific literature that prevent a satisfactory evaluation of the relevance to public
health are identified in the Chapter 3 Data Needs section.
Interpretation of Minimal Risk Levels
Where sufficient toxicologic information is available, ATSDR has derived MRLs for inhalation and oral
routes of entry at each duration of exposure (acute, intermediate, and chronic). These MRLs are not
meant to support regulatory action, but to acquaint health professionals with exposure levels at which
adverse health effects are not expected to occur in humans.
CHLORINE B-2
APPENDIX B
MRLs should help physicians and public health officials determine the safety of a community living near
a chemical emission, given the concentration of a contaminant in air or the estimated daily dose in water.
MRLs are based largely on toxicological studies in animals and on reports of human occupational
exposure.
MRL users should be familiar with the toxicologic information on which the number is based. Chapter 2,
"Relevance to Public Health," contains basic information known about the substance. Other sections such
as Chapter 3 Section 3.9, "Interactions with Other Substances,” and Section 3.10, "Populations that are
Unusually Susceptible" provide important supplemental information.
MRL users should also understand the MRL derivation methodology. MRLs are derived using a
modified version of the risk assessment methodology that the Environmental Protection Agency (EPA)
provides (Barnes and Dourson 1988) to determine reference doses (RfDs) for lifetime exposure.
To derive an MRL, ATSDR generally selects the most sensitive end point which, in its best judgement,
represents the most sensitive human health effect for a given exposure route and duration. ATSDR
cannot make this judgement or derive an MRL unless information (quantitative or qualitative) is available
for all potential systemic, neurological, and developmental effects. If this information and reliable
quantitative data on the chosen end point are available, ATSDR derives an MRL using the most sensitive
species (when information from multiple species is available) with the highest no-observed-adverse-effect
level (NOAEL) that does not exceed any adverse effect levels. When a NOAEL is not available, a
lowest-observed-adverse-effect level (LOAEL) can be used to derive an MRL, and an uncertainty factor
(UF) of 10 must be employed. Additional uncertainty factors of 10 must be used both for human
variability to protect sensitive subpopulations (people who are most susceptible to the health effects
caused by the substance) and for interspecies variability (extrapolation from animals to humans). In
deriving an MRL, these individual uncertainty factors are multiplied together. The product is then
divided into the inhalation concentration or oral dosage selected from the study. Uncertainty factors used
in developing a substance-specific MRL are provided in the footnotes of the levels of significant exposure
(LSE) tables.
Chapter 3
Health Effects
Tables and Figures for Levels of Significant Exposure (LSE)
Tables and figures are used to summarize health effects and illustrate graphically levels of exposure
associated with those effects. These levels cover health effects observed at increasing dose
concentrations and durations, differences in response by species, MRLs to humans for noncancer end
points, and EPA's estimated range associated with an upper- bound individual lifetime cancer risk of 1 in
10,000 to 1 in 10,000,000. Use the LSE tables and figures for a quick review of the health effects and to
locate data for a specific exposure scenario. The LSE tables and figures should always be used in
conjunction with the text. All entries in these tables and figures represent studies that provide reliable,
quantitative estimates of NOAELs, LOAELs, or Cancer Effect Levels (CELs).
The legends presented below demonstrate the application of these tables and figures. Representative
examples of LSE Table 3-1 and Figure 3-1 are shown. The numbers in the left column of the legends
correspond to the numbers in the example table and figure.
CHLORINE B-3
APPENDIX B
LEGEND
See Sample LSE Table 3-1 (page B-6)
(1) Route of Exposure. One of the first considerations when reviewing the toxicity of a substance
using these tables and figures should be the relevant and appropriate route of exposure. Typically
when sufficient data exist, three LSE tables and two LSE figures are presented in the document.
The three LSE tables present data on the three principal routes of exposure, i.e., inhalation, oral,
and dermal (LSE Tables 3-1, 3-2, and 3-3, respectively). LSE figures are limited to the inhalation
(LSE Figure 3-1) and oral (LSE Figure 3-2) routes. Not all substances will have data on each
route of exposure and will not, therefore, have all five of the tables and figures.
(2) Exposure Period. Three exposure periods—acute (less than 15 days), intermediate (15–
364 days), and chronic (365 days or more)—are presented within each relevant route of exposure.
In this example, an inhalation study of intermediate exposure duration is reported. For quick
reference to health effects occurring from a known length of exposure, locate the applicable
exposure period within the LSE table and figure.
(3) Health Effect. The major categories of health effects included in LSE tables and figures are
death, systemic, immunological, neurological, developmental, reproductive, and cancer.
NOAELs and LOAELs can be reported in the tables and figures for all effects but cancer.
Systemic effects are further defined in the "System" column of the LSE table (see key number
18).
(4) Key to Figure. Each key number in the LSE table links study information to one or more data
points using the same key number in the corresponding LSE figure. In this example, the study
represented by key number 18 has been used to derive a NOAEL and a Less Serious LOAEL
(also see the two "18r" data points in sample Figure 3-1).
(5) Species. The test species, whether animal or human, are identified in this column. Chapter 2,
"Relevance to Public Health," covers the relevance of animal data to human toxicity and
Section 3.4, "Toxicokinetics," contains any available information on comparative toxicokinetics.
Although NOAELs and LOAELs are species specific, the levels are extrapolated to equivalent
human doses to derive an MRL.
(6) Exposure Frequency/Duration. The duration of the study and the weekly and daily exposure
regimens are provided in this column. This permits comparison of NOAELs and LOAELs from
different studies. In this case (key number 18), rats were exposed to “Chemical x” via inhalation
for 6 hours/day, 5 days/week, for 13 weeks. For a more complete review of the dosing regimen,
refer to the appropriate sections of the text or the original reference paper (i.e., Nitschke et al.
1981).
(7) System. This column further defines the systemic effects. These systems include respiratory,
cardiovascular, gastrointestinal, hematological, musculoskeletal, hepatic, renal, and
dermal/ocular. "Other" refers to any systemic effect (e.g., a decrease in body weight) not covered
in these systems. In the example of key number 18, one systemic effect (respiratory) was
investigated.
(8) NOAEL. A NOAEL is the highest exposure level at which no harmful effects were seen in the
organ system studied. Key number 18 reports a NOAEL of 3 ppm for the respiratory system,
which was used to derive an intermediate exposure, inhalation MRL of 0.005 ppm (see
footnote "b").
CHLORINE B-4
APPENDIX B
(9) LOAEL. A LOAEL is the lowest dose used in the study that caused a harmful health effect.
LOAELs have been classified into "Less Serious" and "Serious" effects. These distinctions help
readers identify the levels of exposure at which adverse health effects first appear and the
gradation of effects with increasing dose. A brief description of the specific end point used to
quantify the adverse effect accompanies the LOAEL. The respiratory effect reported in key
number 18 (hyperplasia) is a Less Serious LOAEL of 10 ppm. MRLs are not derived from
Serious LOAELs.
(10) Reference. The complete reference citation is given in Chapter 9 of the profile.
(11) CEL. A CEL is the lowest exposure level associated with the onset of carcinogenesis in
experimental or epidemiologic studies. CELs are always considered serious effects. The LSE
tables and figures do not contain NOAELs for cancer, but the text may report doses not causing
measurable cancer increases.
(12) Footnotes. Explanations of abbreviations or reference notes for data in the LSE tables are found
in the footnotes. Footnote "b" indicates that the NOAEL of 3 ppm in key number 18 was used to
derive an MRL of 0.005 ppm.
LEGEND
See Sample Figure 3-1 (page B-7)
LSE figures graphically illustrate the data presented in the corresponding LSE tables. Figures help the
reader quickly compare health effects according to exposure concentrations for particular exposure
periods.
(13) Exposure Period. The same exposure periods appear as in the LSE table. In this example, health
effects observed within the acute and intermediate exposure periods are illustrated.
(14) Health Effect. These are the categories of health effects for which reliable quantitative data
exists. The same health effects appear in the LSE table.
(15) Levels of Exposure. Concentrations or doses for each health effect in the LSE tables are
graphically displayed in the LSE figures. Exposure concentration or dose is measured on the log
scale "y" axis. Inhalation exposure is reported in mg/m3 or ppm and oral exposure is reported in
mg/kg/day.
(16) NOAEL. In this example, the open circle designated 18r identifies a NOAEL critical end point in
the rat upon which an intermediate inhalation exposure MRL is based. The key number 18
corresponds to the entry in the LSE table. The dashed descending arrow indicates the
extrapolation from the exposure level of 3 ppm (see entry 18 in the table) to the MRL of
0.005 ppm (see footnote "b" in the LSE table).
(17) CEL. Key number 38m is one of three studies for which CELs were derived. The diamond
symbol refers to a CEL for the test species-mouse. The number 38 corresponds to the entry in the
LSE table.
CHLORINE B-5
APPENDIX B
(18) Estimated Upper-Bound Human Cancer Risk Levels. This is the range associated with the upper-
bound for lifetime cancer risk of 1 in 10,000 to 1 in 10,000,000. These risk levels are derived
from the EPA's Human Health Assessment Group's upper-bound estimates of the slope of the
cancer dose response curve at low dose levels (q1*).
(19) Key to LSE Figure. The Key explains the abbreviations and symbols used in the figure.
CHLORINE
SAMPLE
1 → Table 3-1. Levels of Significant Exposure to [Chemical x] – Inhalation
LOAEL (effect)
Exposure
Key to frequency/ NOAEL Less serious Serious (ppm)
figurea Species duration System (ppm) (ppm) Reference
2 → INTERMEDIATE EXPOSURE
5 6 7 8 9 10
3 → Systemic ↓ ↓ ↓ ↓ ↓ ↓
b
18 Rat 13 wk Resp 3 10 (hyperplasia)
4 → 5 d/wk Nitschke et al. 1981
6 hr/d
APPENDIX B
CHRONIC EXPOSURE
Cancer 11
↓
38 Rat 18 mo 20 (CEL, multiple Wong et al. 1982

5 d/wk organs)
7 hr/d
39 Rat 89–104 wk 10 (CEL, lung tumors, NTP 1982
5 d/wk nasal tumors)
6 hr/d
40 Mouse 79–103 wk 10 (CEL, lung tumors, NTP 1982
5 d/wk hemangiosarcomas)
6 hr/d
a
12 → The number corresponds to entries in Figure 3-1.
b -3
Used to derive an intermediate inhalation Minimal Risk Level (MRL) of 5x10 ppm; dose adjusted for intermittent exposure and divided
by an uncertainty factor of 100 (10 for extrapolation from animal to humans, 10 for human variability).
B-6
CHLORINE B-7
APPENDIX B
CHLORINE B-8
APPENDIX B

CHLORINE C-1
APPENDIX C. ACRONYMS, ABBREVIATIONS, AND SYMBOLS

ACGIH American Conference of Governmental Industrial Hygienists
ACOEM American College of Occupational and Environmental Medicine
ADI acceptable daily intake
ADME absorption, distribution, metabolism, and excretion
AED atomic emission detection
AFID alkali flame ionization detector
AFOSH Air Force Office of Safety and Health
ALT alanine aminotransferase
AML acute myeloid leukemia
AOAC Association of Official Analytical Chemists
AOEC Association of Occupational and Environmental Clinics
AP alkaline phosphatase
APHA American Public Health Association
AST aspartate aminotransferase
atm atmosphere
ATSDR Agency for Toxic Substances and Disease Registry
AWQC Ambient Water Quality Criteria
BAT best available technology
BCF bioconcentration factor
BEI Biological Exposure Index
BMD/C benchmark dose or benchmark concentration
BMDX dose that produces a X% change in response rate of an adverse effect
BMDLX 95% lower confidence limit on the BMDX
BMDS Benchmark Dose Software
BMR benchmark response
BSC Board of Scientific Counselors
C centigrade
CAA Clean Air Act
CAG Cancer Assessment Group of the U.S. Environmental Protection Agency
CAS Chemical Abstract Services
CDC Centers for Disease Control and Prevention
CEL cancer effect level
CELDS Computer-Environmental Legislative Data System
CERCLA Comprehensive Environmental Response, Compensation, and Liability Act
CFR Code of Federal Regulations
Ci curie
CI confidence interval
CL ceiling limit value
CLP Contract Laboratory Program
cm centimeter
CML chronic myeloid leukemia
CPSC Consumer Products Safety Commission
CWA Clean Water Act
DHEW Department of Health, Education, and Welfare
DHHS Department of Health and Human Services
DNA deoxyribonucleic acid
DOD Department of Defense
DOE Department of Energy
DOL Department of Labor
CHLORINE C-2
APPENDIX C
DOT Department of Transportation

DOT/UN/ Department of Transportation/United Nations/
NA/IMDG North America/Intergovernmental Maritime Dangerous Goods Code
DWEL drinking water exposure level
ECD electron capture detection
ECG/EKG electrocardiogram
EEG electroencephalogram
EEGL Emergency Exposure Guidance Level
EPA Environmental Protection Agency
F Fahrenheit
F1 first-filial generation
FAO Food and Agricultural Organization of the United Nations
FDA Food and Drug Administration
FEMA Federal Emergency Management Agency
FIFRA Federal Insecticide, Fungicide, and Rodenticide Act
FPD flame photometric detection
fpm feet per minute
FR Federal Register
FSH follicle stimulating hormone
g gram
GC gas chromatography
gd gestational day
GLC gas liquid chromatography
GPC gel permeation chromatography
HPLC high-performance liquid chromatography
HRGC high resolution gas chromatography
HSDB Hazardous Substance Data Bank
IARC International Agency for Research on Cancer
IDLH immediately dangerous to life and health
ILO International Labor Organization
IRIS Integrated Risk Information System
Kd adsorption ratio
kg kilogram
kkg metric ton
Koc organic carbon partition coefficient
Kow octanol-water partition coefficient
L liter
LC liquid chromatography
LC50 lethal concentration, 50% kill
LCLo lethal concentration, low
LD50 lethal dose, 50% kill
LDLo lethal dose, low
LDH lactic dehydrogenase
LH luteinizing hormone
LOAEL lowest-observed-adverse-effect level
LSE Levels of Significant Exposure
LT50 lethal time, 50% kill
m meter
MA trans,trans-muconic acid
MAL maximum allowable level
mCi millicurie
CHLORINE C-3
APPENDIX C
MCL maximum contaminant level

MCLG maximum contaminant level goal
MF modifying factor
MFO mixed function oxidase
mg milligram
mL milliliter
mm millimeter
mmHg millimeters of mercury
mmol millimole
mppcf millions of particles per cubic foot
MRL Minimal Risk Level
MS mass spectrometry
NAAQS National Ambient Air Quality Standard
NAS National Academy of Science
NATICH National Air Toxics Information Clearinghouse
NATO North Atlantic Treaty Organization
NCE normochromatic erythrocytes
NCEH National Center for Environmental Health
NCI National Cancer Institute
ND not detected
NFPA National Fire Protection Association
ng nanogram
NHANES National Health and Nutrition Examination Survey
NIEHS National Institute of Environmental Health Sciences
NIOSH National Institute for Occupational Safety and Health
NIOSHTIC NIOSH's Computerized Information Retrieval System
NLM National Library of Medicine
nm nanometer
nmol nanomole
NOAEL no-observed-adverse-effect level
NOES National Occupational Exposure Survey
NOHS National Occupational Hazard Survey
NPD nitrogen phosphorus detection
NPDES National Pollutant Discharge Elimination System
NPL National Priorities List
NR not reported
NRC National Research Council
NS not specified
NSPS New Source Performance Standards
NTIS National Technical Information Service
NTP National Toxicology Program
ODW Office of Drinking Water, EPA
OERR Office of Emergency and Remedial Response, EPA
OHM/TADS Oil and Hazardous Materials/Technical Assistance Data System
OPP Office of Pesticide Programs, EPA
OPPT Office of Pollution Prevention and Toxics, EPA
OPPTS Office of Prevention, Pesticides and Toxic Substances, EPA
OR odds ratio
OSHA Occupational Safety and Health Administration
OSW Office of Solid Waste, EPA
OTS Office of Toxic Substances
CHLORINE C-4
APPENDIX C
OW Office of Water
OWRS Office of Water Regulations and Standards, EPA
PAH polycyclic aromatic hydrocarbon
PBPD physiologically based pharmacodynamic
PBPK physiologically based pharmacokinetic
PCE polychromatic erythrocytes
PEL permissible exposure limit
pg picogram
PHS Public Health Service
PID photo ionization detector
pmol picomole
PMR proportionate mortality ratio
ppb parts per billion
ppm parts per million
ppt parts per trillion
PSNS pretreatment standards for new sources
RBC red blood cell
REL recommended exposure level/limit
RfC reference concentration
RfD reference dose
RNA ribonucleic acid
RQ reportable quantity
RTECS Registry of Toxic Effects of Chemical Substances
SARA Superfund Amendments and Reauthorization Act
SCE sister chromatid exchange
SGOT serum glutamic oxaloacetic transaminase
SGPT serum glutamic pyruvic transaminase
SIC standard industrial classification
SIM selected ion monitoring
SMCL secondary maximum contaminant level
SMR standardized mortality ratio
SNARL suggested no adverse response level
SPEGL Short-Term Public Emergency Guidance Level
STEL short term exposure limit
STORET Storage and Retrieval
TD50 toxic dose, 50% specific toxic effect
TLV threshold limit value
TOC total organic carbon
TPQ threshold planning quantity
TRI Toxics Release Inventory
TSCA Toxic Substances Control Act
TWA time-weighted average
UF uncertainty factor
U.S. United States
USDA United States Department of Agriculture
USGS United States Geological Survey
VOC volatile organic compound
WBC white blood cell
WHO World Health Organization
CHLORINE C-5
APPENDIX C
> greater than

≥ greater than or equal to
= equal to
< less than
≤ less than or equal to
% percent
α alpha
β beta
γ gamma
δ delta
μm micrometer
μg microgram
q1 * cancer slope factor
– negative
+ positive
(+) weakly positive result
(–) weakly negative result
CHLORINE C-6
APPENDIX C

CHLORINE D-1
APPENDIX D. INDEX
absorbed dose............................................................................................................................................ 121
acetylcholine ............................................................................................................................................... 67
adrenal gland............................................................................................................................................... 95
adrenals ................................................................................................................................................. 69, 95
alanine aminotransferase (see ALT) ........................................................................................................... 68
Alberton .............................................................................................................................. 50, 163, 168, 171
ALT (see alanine aminotransferase) ..................................................................................................... 67, 68
ambient air ................................................................................................................................................ 169
anemia....................................................................................................................................................... 190
aspartate aminotransferase (see AST)......................................................................................................... 68
AST (see aspartate aminotransferase)......................................................................................................... 68
asthma ......................................................................................................... 11, 14, 48, 50, 58, 123, 139, 182
atropine ....................................................................................................................................................... 61
biodegradation........................................................................................................................................... 167
biomarker ............................................................................................ 52, 112, 120, 121, 122, 137, 177, 182
bleach ..................................... 2, 3, 4, 5, 9, 10, 12, 13, 21, 48, 50, 56, 58, 75, 76, 91, 92, 96, 100, 103, 115,
120, 124, 129, 130, 131, 134, 135, 136, 137, 138, 149, 159, 169, 170, 173
blood cell count..................................................................................................................................... 92, 93
body weight effects ....................................................................................................................... 70, 95, 100
breast milk................................................................................................................................................. 170
cancer .............................................................................................................. 13, 74, 98, 104, 118, 129, 132
carcinogen......................................................................................................................................... 186, 190
carcinogenic .................................................................................................................... 12, 14, 25, 104, 132
carcinogenicity.................................................................................................... 12, 13, 75, 98, 99, 133, 186
carcinomas ................................................................................................................................................ 105
cardiovascular ..................................................................................................... 11, 27, 29, 66, 91, 100, 138
cardiovascular effects...................................................................................................................... 65, 66, 91
chemical weapon....................................................................................................................... 10, 15, 26, 59
chromosomal aberrations .................................................................................................................. 105, 133
cleaning solutions.................................................................................................................................... 5, 48
death.............................................. 4, 10, 11, 13, 25, 26, 27, 28, 29, 48, 55, 71, 92, 100, 125, 129, 130, 190
deoxyribonucleic acid (see DNA)............................................................................................................. 108
dermal effects................................................................................................................................ 69, 95, 100
dermatitis ............................................................................................................................ 13, 104, 136, 182
disinfection.............................................................................................. 1, 2, 5, 26, 145, 163, 166, 178, 190
DNA (see deoxyribonucleic acid)............................................................................................... 63, 108, 121
endocrine............................................................................................................... 69, 94, 100, 115, 116, 117
endocrine effects ................................................................................................................................... 69, 94
erythema...................................................................................................................................................... 27
fetus........................................................................................................................................................... 117
gassing ................................................................................................ 11, 18, 26, 28, 46, 48, 58, 59, 67, 123
gastrointestinal effects .................................................................................................................. 66, 91, 138
general population........................................................................... 9, 11, 15, 18, 46, 48, 129, 159, 169, 190
genotoxic............................................................................................................................. 25, 105, 129, 133
genotoxicity................................................................................................................................. 14, 105, 133
Graniteville ............................................................................................................................... 163, 165, 171
groundwater ...................................................................................................................................... 164, 169
half-life.................................................................................................................. 9, 109, 121, 159, 165, 172
hematological effects ............................................................................................................................ 67, 92
CHLORINE D-2
APPENDIX D
hepatic effects ................................................................................................................................. 67, 93, 94
household chemicals ......................................................................................................... 3, 5, 159, 170, 173
hydrolysis.................................................................................................................................................. 112
hypochlorite ..............1, 2, 3, 4, 5, 6, 9, 10, 12, 13, 21, 22, 23, 24, 26, 50, 75, 76, 91, 92, 93, 94, 95, 96, 97,
98, 99, 100, 103, 104, 105, 109, 110, 111, 112, 114, 115, 116, 120, 121, 122,
124, 126, 129, 130, 131, 132, 133, 134, 135, 136, 137, 138, 139, 143,
145, 149, 160, 164, 166, 167, 169, 177, 178, 183, 186, 188, 189, 190
hypochlorous...................................... 2, 9, 10, 12, 22, 24, 26, 66, 94, 97, 98, 105, 109, 110, 112, 114, 117,
122, 124, 125, 129, 130, 131, 132, 134, 135, 137, 138, 143,
145, 149, 159, 160, 164, 166, 168, 177, 178, 179, 183, 186
immune system ................................................................................................................................... 12, 135
immunological ................................................................................................ 22, 25, 96, 104, 129, 131, 135
immunological effects......................................................................................................................... 96, 135
Kow ............................................................................................................................................................ 146
LD50............................................................................................................................................................. 75
leukemia........................................................................................................................................ 14, 99, 133
lymphatic .................................................................................................................................................... 11
lymphoreticular ......................................................................................... 22, 70, 71, 96, 104, 129, 131, 135
Macdona............................................................................................................................................ 163, 171
metabolic effects ......................................................................................................................................... 96
micronuclei ............................................................................................................................................... 105
milk ............................................................................................................... 21, 91, 93, 94, 95, 97, 103, 124
mucociliary ................................................................................................................................................. 61
musculoskeletal effects ......................................................................................................................... 67, 93
neonatal............................................................................................................................................. 134, 170
neurobehavioral..................................................................................................................... 12, 72, 116, 136
nuclear....................................................................................................................................................... 109
ocular effects........................................................................................................................... 13, 70, 95, 103
odds ratio..................................................................................................................................................... 74
pharmacodynamic ..................................................................................................................................... 111
pharmacokinetic........................................................................................ 111, 112, 113, 114, 117, 137, 138
photolysis ...................................................................................................... 9, 159, 163, 165, 168, 172, 173
pneumonia..................................................................................................................... 11, 26, 27, 28, 49, 76
pulmonary edema.......................................... 4, 10, 11, 27, 28, 47, 48, 49, 50, 57, 61, 66, 67, 125, 126, 182
railroad .......................................................................................................................... 27, 48, 163, 168, 171
rate constant .............................................................................................................................................. 166
reactive airway dysfunction syndrome ....................................................................................................... 11
renal effects........................................................................................................................................... 68, 94
solubility ........................................................................................................................................... 114, 179
South Carolina .............................................................................................................. 27, 66, 163, 165, 171
spirometry ............................................................................................................................................. 52, 58
storage tank ................................................................................................................. 10, 48, 49, 57, 68, 129
swimming pool...................................................... 3, 5, 9, 10, 48, 51, 71, 118, 119, 123, 129, 160, 169, 170
T3 .................................................................................................................................... 30, 77, 94, 101, 116
T4 ........................................................................................................................................................ 94, 116
thyroid......................................................................................................... 13, 22, 69, 94, 98, 109, 116, 117
thyroxine ..................................................................................................................................................... 94
toxicokinetic................................................................................................................................................ 25
triiodothyronine........................................................................................................................................... 94
TSH....................................................................................................................................................... 60, 94
tumors ....................................................................................................................................................... 104

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TOXICOLOGICAL PROFILE FOR

U.S. DEPARTMENT OF HEALTH AND HUMAN SERVICES

Public Health Service

Agency for Toxic Substances and Disease Registry

Agency for Toxic Substances and Disease Registry

Division of Toxicology and Environmental Medicine/Applied Toxicology Branch

1600 Clifton Road NE

Atlanta, Georgia 30333

This page is intentionally blank.

Each profile includes the following:

Thomas R. Frieden, M.D., M.P.H.

Agency for Toxic Substances and

QUICK REFERENCE FOR HEALTH CARE PROVIDERS

Primary Chapters/Sections of Interest

Section 3.7 Children’s Susceptibility

Section 6.6 Exposures of Children

Other Sections of Interest:

ATSDR Information Center

Case Studies in Environmental Medicine: Taking an Exposure History—The importance of taking an

Managing Hazardous Materials Incidents is a three-volume set of recommendations for on-scene

Other Agencies and Organizations

The American College of Occupational and Environmental Medicine (ACOEM) is an association of

G. Daniel Todd, Ph.D.

Patricia Ruiz, Ph.D.

Larry Cseh, R.S.

Pam Tucker, M.D.

John Doyle, M.P.A.

ATSDR, Division of Toxicology and Environmental Medicine, Atlanta, GA

Fernando T. Llados, Ph.D.

Daniel J. Plewak, B.S.

Mario Citra, Ph.D.

SRC, Inc., North Syracuse, NY

THE PROFILE HAS UNDERGONE THE FOLLOWING ATSDR INTERNAL REVIEWS:

This page is intentionally blank.

1. John Balmes, M.D., Professor in Residence, Department of Medicine, University of California,

3. Dennis Shusterman, M.D., MPH, Professor Emeritus, Department of Medicine, University of

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UPDATE STATEMENT .............................................................................................................................iii

QUICK REFERENCE FOR HEALTH CARE PROVIDERS....................................................................vii

PEER REVIEW ...........................................................................................................................................xi

LIST OF FIGURES ..................................................................................................................................xvii

1. PUBLIC HEALTH STATEMENT.......................................................................................................... 1

1.1 WHAT IS CHLORINE?................................................................................................................. 2

1.2 WHAT HAPPENS TO CHLORINE WHEN IT ENTERS THE ENVIRONMENT? ................... 2

1.3 HOW MIGHT I BE EXPOSED TO CHLORINE?........................................................................ 3

1.4 HOW CAN CHLORINE ENTER AND LEAVE MY BODY?..................................................... 3

1.5 HOW CAN CHLORINE AFFECT MY HEALTH?...................................................................... 4

1.6 HOW CAN CHLORINE AFFECT CHILDREN? ......................................................................... 5

1.8 IS THERE A MEDICAL TEST TO DETERMINE WHETHER I HAVE BEEN EXPOSED

1.9 WHAT RECOMMENDATIONS HAS THE FEDERAL GOVERNMENT MADE TO

PROTECT HUMAN HEALTH? ................................................................................................... 6

1.10 WHERE CAN I GET MORE INFORMATION? .......................................................................... 7

2. RELEVANCE TO PUBLIC HEALTH ................................................................................................... 9

2.1 BACKGROUND AND ENVIRONMENTAL EXPOSURES TO CHLORINE IN THE

UNITED STATES ......................................................................................................................... 9

2.2 SUMMARY OF HEALTH EFFECTS......................................................................................... 10

2.3 MINIMAL RISK LEVELS (MRLs) ............................................................................................ 14

3.2 DISCUSSION OF HEALTH EFFECTS BY ROUTE OF EXPOSURE ..................................... 25

3.2.1 Inhalation Exposure .............................................................................................................. 26