Certificate of Analysis

BASF SE

Please note that the certificates of analysis are also conveniently available on your BASF online portal.

BASF INDIA LIMITED

2021-02-23
B WING, COMMERCIAL PLAZA ENT/OQA
Hr. Dr. Florian Wildschek
110037 NEW DELHI florian.wildschek@basf.com
Certificate No 2680
India

Inspection Certificate 3.1 according to EN 10204

Bisabolol rac. Material 50564398

Order 6009256741 000010
5KG Plastic jerricans Delivery 3194222466 000010
Purchase Order/Customer Product# Lot 23310268E0
SSI/BASF/918 Lot/Qty 100.000 KG
000000000050564398 Total 100.000 KG
Transport 00000000001022454898

Manufacturing Location: DE, 67056 Ludwigshafen, Carl-Bosch-Str. 38

Test Parameter Requirements UoM Results

--------------------------------------------------------------------------------
Appearance colourless to slightly conforms
yellowish, clear liquid

purity Min.: 85.0 area-% 86.2

Refractive index n(D/20) Min.: 1.492 1.495

Max.: 1.498

QC-Reference-No. 20C04178

Production date (YYYY-MM-DD) 2020-03-24

Release date (YYYY-MM-DD) 2020-03-27

Best before/Retest date (YYYY-MM-DD) 2022-09-22

The aforementioned data shall constitute the agreed contractual quality of the product at the time of passing of risk. The data are controlled at regular intervals as
part of our quality assurance program. Neither these data nor the properties of product specimens shall imply any legally binding guarantee of certain properties
or of fitness for a specific purpose. No liability of ours can be derived therefrom.

This is a computer-generated document. No signature is required.

Safety data sheet

Page: 1/13
BASF Safety data sheet according to Regulation (EC) No. 1907/2006 as amended from time to time.
Date / Revised: 24.04.2017 Version: 3.0
Product: Bisabolol rac.
(ID no. 30035139/SDS_COS_EU/EN)
Date of print 25.04.2017

SECTION 1: Identification of the substance/mixture and of the

company/undertaking
1.1. Product identifier

Bisabolol rac.
Chemical name: 3-Cyclohexene-1-methanol, .alpha.,4-dimethyl-.alpha.-(4-methyl-3- pentenyl)-,
(R*,R*)-
CAS Number: 515-69-5

1.2. Relevant identified uses of the substance or mixture and uses advised against

Relevant identified uses: cosmetic ingredient

Recommended use: for industrial use only

1.3. Details of the supplier of the safety data sheet

Company:
BASF SE
67056 Ludwigshafen
GERMANY
Operating Division Care Chemicals

Telephone: +49 211 7940-2222

E-mail address: emc-ehs-masterdata@basf.com

1.4. Emergency telephone number

International emergency number:

Telephone: +49 180 2273-112

SECTION 2: Hazards Identification

2.1. Classification of the substance or mixture

 Page: 2/13
BASF Safety data sheet according to Regulation (EC) No. 1907/2006 as amended from time to time.
Date / Revised: 24.04.2017 Version: 3.0
Product: Bisabolol rac.
(ID no. 30035139/SDS_COS_EU/EN)
Date of print 25.04.2017

According to Regulation (EC) No 1272/2008 [CLP]

Aquatic Chronic 2

H411

For the classifications not written out in full in this section the full text can be found in section 16.

2.2. Label elements

According to Regulation (EC) No 1272/2008 [CLP]

Pictogram:

Hazard Statement:
H411 Toxic to aquatic life with long lasting effects.

Precautionary Statements (Prevention):

P273 Avoid release to the environment.

Precautionary Statements (Response):

P391 Collect spillage.

Precautionary Statements (Disposal):

P501 Dispose of contents/container to hazardous or special waste collection
point.

2.3. Other hazards

According to Regulation (EC) No 1272/2008 [CLP]

No specific dangers known, if the regulations/notes for storage and handling are considered.

SECTION 3: Composition/Information on Ingredients

3.1. Substances

Chemical nature

INCI Name: Bisabolol

(R*,R*)-.alpha.,4-Dimethyl-.alpha.-(4-methyl-3-pentenyl)cyclohex-3-ene-1-methanol
 Page: 3/13
BASF Safety data sheet according to Regulation (EC) No. 1907/2006 as amended from time to time.
Date / Revised: 24.04.2017 Version: 3.0
Product: Bisabolol rac.
(ID no. 30035139/SDS_COS_EU/EN)
Date of print 25.04.2017
CAS Number: 515-69-5
EC-Number: 208-205-9

For the classifications not written out in full in this section, including the hazard classes and the
hazard statements, the full text is listed in section 16.

3.2. Mixtures

Not applicable

SECTION 4: First-Aid Measures

4.1. Description of first aid measures
Remove contaminated clothing. If adverse health effects develop seek medical attention.

If inhaled:
Keep patient calm, remove to fresh air.

On skin contact:
Wash thoroughly with soap and water.

On contact with eyes:

Wash affected eyes for at least 15 minutes under running water with eyelids held open.

On ingestion:
Rinse mouth and then drink plenty of water.

4.2. Most important symptoms and effects, both acute and delayed
Symptoms: No significant symptoms are expected due to the non-classification of the product.

Hazards: No hazard is expected under intended use and appropriate handling.

4.3. Indication of any immediate medical attention and special treatment needed
Treatment: Symptomatic treatment (decontamination, vital functions).

SECTION 5: Fire-Fighting Measures

5.1. Extinguishing media
Suitable extinguishing media:
foam, dry powder

5.2. Special hazards arising from the substance or mixture

Evolution of fumes/fog.
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BASF Safety data sheet according to Regulation (EC) No. 1907/2006 as amended from time to time.
Date / Revised: 24.04.2017 Version: 3.0
Product: Bisabolol rac.
(ID no. 30035139/SDS_COS_EU/EN)
Date of print 25.04.2017

5.3. Advice for fire-fighters

Special protective equipment:
Wear a self-contained breathing apparatus.

Further information:
Keep containers cool by spraying with water if exposed to fire. Collect contaminated extinguishing
water separately, do not allow to reach sewage or effluent systems. Dispose of fire debris and
contaminated extinguishing water in accordance with official regulations.

SECTION 6: Accidental Release Measures

6.1. Personal precautions, protective equipment and emergency procedures
Avoid contact with the skin, eyes and clothing. Handle in accordance with good industrial hygiene
and safety practice.

6.2. Environmental precautions

Do not discharge into drains/surface waters/groundwater.

6.3. Methods and material for containment and cleaning up

For large amounts: Dike spillage. Pump off product.
For residues: Pick up with suitable absorbent material (e.g. sand, sawdust, general-purpose binder,
kieselguhr).
Dispose of absorbed material in accordance with regulations.

6.4. Reference to other sections

Information regarding exposure controls/personal protection and disposal considerations can be
found in section 8 and 13.

SECTION 7: Handling and Storage

7.1. Precautions for safe handling
Avoid contact with the skin, eyes and clothing. No special measures necessary if stored and handled
correctly.

Protection against fire and explosion:

Take precautionary measures against static discharges. Avoid all sources of ignition: heat, sparks,
open flame.

7.2. Conditions for safe storage, including any incompatibilities

Suitable materials for containers: Stainless steel 1.4301 (V2), Stainless steel 1.4401, High density
polyethylene (HDPE), Low density polyethylene (LDPE), Aluminium, Stove-lacquer RDL 50, glass,
tinned carbon steel (Tinplate)

7.3. Specific end use(s)

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BASF Safety data sheet according to Regulation (EC) No. 1907/2006 as amended from time to time.
Date / Revised: 24.04.2017 Version: 3.0
Product: Bisabolol rac.
(ID no. 30035139/SDS_COS_EU/EN)
Date of print 25.04.2017
For the relevant identified use(s) listed in Section 1 the advice mentioned in this section 7 is to be
observed.

SECTION 8: Exposure Controls/Personal Protection

8.1. Control parameters

Components with occupational exposure limits

No occupational exposure limits known.

PNEC
Chemical Safety Assessment not yet performed due to registration timelines

DNEL
Chemical Safety Assessment not yet performed due to registration timelines

8.2. Exposure controls

Personal protective equipment
Respiratory protection:
Wear respiratory protection if ventilation is inadequate.

Hand protection:
Suitable chemical resistant safety gloves (EN 374) also with prolonged, direct contact
(Recommended: Protective index 6, corresponding > 480 minutes of permeation time according to
EN 374): E.g. nitrile rubber (0.4 mm), chloroprene rubber (0.5 mm), butyl rubber (0.7 mm) etc.
Supplementary note: The specifications are based on tests, literature data and information of glove
manufacturers or are derived from similar substances by analogy. Due to many conditions (e.g.
temperature) it must be considered, that the practical usage of a chemical-protective glove in
practice may be much shorter than the permeation time determined through testing.

Eye protection:
Safety glasses with side-shields (frame goggles) (e.g. EN 166)

Body protection:
Body protection must be chosen depending on activity and possible exposure, e.g. apron, protecting
boots, chemical-protection suit (according to EN 14605 in case of splashes or EN ISO 13982 in case
of dust).

General safety and hygiene measures

Handle in accordance with good industrial hygiene and safety practice.

Environmental exposure controls

For information regarding environmental exposure controls, see Section 6.
 Page: 6/13
BASF Safety data sheet according to Regulation (EC) No. 1907/2006 as amended from time to time.
Date / Revised: 24.04.2017 Version: 3.0
Product: Bisabolol rac.
(ID no. 30035139/SDS_COS_EU/EN)
Date of print 25.04.2017
SECTION 9: Physical and Chemical Properties
9.1. Information on basic physical and chemical properties

Form: liquid
Colour: clear
colourless
slightly yellow
Odour: faint odour, flowery, sweetish
Odour threshold:
not determined
pH value: 7.0
Boiling point: 287 °C
Flash point: 148 °C (DIN 51758)
Evaporation rate:
Value can be approximated from
Henry's Law Constant or vapor
pressure.
Flammability: not flammable
Flammability of Aerosol Products:
not applicable, the product does not
form flammable aerosoles
Lower explosion limit: 0.8 %(V)
(146 °C, 8.0 hPa)

For liquids not relevant for

classification and labelling.
Upper explosion limit: 3.8 %(V)
(180 °C, 37.5 hPa)

For liquids not relevant for

classification and labelling.
Ignition temperature: approx. 250 °C (DIN 51794)
Vapour pressure: approx. 1.6 hPa
(approx. 110 °C)
approx. 79.3 hPa
(approx. 200 °C)
Density: 0.924 g/cm3
(20 °C)
Relative vapour density (air):
not applicable
Solubility in water: sparingly soluble
Solubility (qualitative) solvent(s): organic solvents
soluble
Partitioning coefficient n-octanol/water (log Kow): 4.8 (Directive 92/69/EEC, A.8)
Thermal decomposition: > 330 °C
Viscosity, dynamic: 133 mPa.s
(20 °C)
Viscosity, kinematic: 144.5 mm2/s (DIN 51562)
(20 °C)
 Page: 7/13
BASF Safety data sheet according to Regulation (EC) No. 1907/2006 as amended from time to time.
Date / Revised: 24.04.2017 Version: 3.0
Product: Bisabolol rac.
(ID no. 30035139/SDS_COS_EU/EN)
Date of print 25.04.2017
Explosion hazard: Based on the chemical structure
there is no indicating of explosive
properties.
Fire promoting properties: Based on its structural properties
the product is not classified as
oxidizing.

9.2. Other information

Molar mass: 222.37 g/mol

Other Information:
If necessary, information on other physical and chemical parameters is indicated in this section., No
further information available.

SECTION 10: Stability and Reactivity

10.1. Reactivity
No hazardous reactions if stored and handled as prescribed/indicated.

10.2. Chemical stability

The product is stable if stored and handled as prescribed/indicated.

Peroxides: The product does not contain peroxides.

10.3. Possibility of hazardous reactions

No hazardous reactions if stored and handled as prescribed/indicated.

10.4. Conditions to avoid

Avoid all sources of ignition: heat, sparks, open flame.

10.5. Incompatible materials

Substances to avoid:
No data available.

10.6. Hazardous decomposition products

Hazardous decomposition products:

No hazardous decomposition products if stored and handled as prescribed/indicated.

SECTION 11: Toxicological Information

11.1. Information on toxicological effects

Acute toxicity

Assessment of acute toxicity:

 Page: 8/13
BASF Safety data sheet according to Regulation (EC) No. 1907/2006 as amended from time to time.
Date / Revised: 24.04.2017 Version: 3.0
Product: Bisabolol rac.
(ID no. 30035139/SDS_COS_EU/EN)
Date of print 25.04.2017
Virtually nontoxic after a single ingestion. The inhalation of a highly enriched/saturated vapor-air-
mixture represents an unlikely acute hazard.

Experimental/calculated data:
LD50 rat (oral): > 5,000 mg/kg (BASF-Test)

rat (by inhalation): 7 h (IRT)

No mortality within the stated exposition time as shown in animal studies.

Irritation

Assessment of irritating effects:

Not irritating to the skin. Not irritating to the eyes.

Experimental/calculated data:
Skin corrosion/irritation rabbit: non-irritant (OECD Guideline 404)

Serious eye damage/irritation rabbit: non-irritant (OECD Guideline 405)

Respiratory/Skin sensitization

Assessment of sensitization:
Skin sensitizing effects were not observed in animal studies.

Experimental/calculated data:
Non-sensitizing.
No sensitizing effect.

Germ cell mutagenicity

Assessment of mutagenicity:
No mutagenic effect was found in various tests with microorganisms and mammalian cell culture.

Carcinogenicity

Assessment of carcinogenicity:
The chemical structure does not suggest a specific alert for such an effect.

Reproductive toxicity

Assessment of reproduction toxicity:

The chemical structure does not suggest a specific alert for such an effect.

Developmental toxicity

Assessment of teratogenicity:
Animal studies gave no indication of a developmental toxic effect at doses that were not toxic to the
parental animals.

Specific target organ toxicity (single exposure)

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BASF Safety data sheet according to Regulation (EC) No. 1907/2006 as amended from time to time.
Date / Revised: 24.04.2017 Version: 3.0
Product: Bisabolol rac.
(ID no. 30035139/SDS_COS_EU/EN)
Date of print 25.04.2017

Assessment of STOT single:

Based on available Data, the classification criteria are not met.

Repeated dose toxicity and Specific target organ toxicity (repeated exposure)

Assessment of repeated dose toxicity:

None known

Aspiration hazard

No aspiration hazard expected.

SECTION 12: Ecological Information

12.1. Toxicity

Assessment of aquatic toxicity:

Acutely toxic for aquatic organisms. The inhibition of the degradation activity of activated sludge is
not anticipated when introduced to biological treatment plants in appropriate low concentrations.

Toxicity to fish:
LC50 (96 h) > 4,6 < 10 mg/l, Leuciscus idus (DIN 38412 Part 15, static)
The details of the toxic effect relate to the nominal concentration.

Aquatic invertebrates:
EC50 (48 h) 1.3 mg/l, Daphnia magna (OECD Guideline 202, part 1, static)
The statement of the toxic effect relates to the analytically determined concentration. The product
has low solubility in the test medium. An eluate has been tested.

Aquatic plants:
EC50 (72 h) > 1 - 10 mg/l (growth rate), Pseudokirchneriella subcapitata (OECD Guideline 201,
static)
The statement of the toxic effect relates to the analytically determined concentration.

EC10 (72 h) > 1 - 10 mg/l (growth rate), Pseudokirchneriella subcapitata (OECD Guideline 201,
static)
The statement of the toxic effect relates to the analytically determined concentration.

Microorganisms/Effect on activated sludge:

EC10 (16 h) > 10,000 mg/l, Pseudomonas putida (DIN 38412 Part 27 (draft), aerobic)

EC20 (180 min) approx. 100 mg/l, activated sludge (OECD Guideline 209, aerobic)

12.2. Persistence and degradability

Assessment biodegradation and elimination (H2O):

Readily biodegradable (according to OECD criteria).
 Page: 10/13
BASF Safety data sheet according to Regulation (EC) No. 1907/2006 as amended from time to time.
Date / Revised: 24.04.2017 Version: 3.0
Product: Bisabolol rac.
(ID no. 30035139/SDS_COS_EU/EN)
Date of print 25.04.2017

Elimination information:
70 - 80 % BOD of the ThOD (28 d) (OECD 301F; ISO 9408; 92/69/EEC, C.4-D) (aerobic, activated
sludge, domestic)

12.3. Bioaccumulative potential

Bioaccumulation potential:
Accumulation in organisms is expected.

12.4. Mobility in soil

Assessment transport between environmental compartments:

Adsorption in soil: Adsorption to solid soil phase is possible. The product has not been tested. The
statement has been derived from the properties of the individual components.

12.5. Results of PBT and vPvB assessment

According to Annex XIV of Regulation (EC) No.1907/2006 concerning the Registration, Evaluation,
Authorisation and Restriction of Chemicals (REACH): The product does not contain a substance
fulfilling the PBT (persistent/bioaccumulative/toxic) criteria or the vPvB (very persistent/very
bioaccumulative) criteria. Self classification

12.6. Other adverse effects

The substance is not listed in Regulation (EC) 1005/2009 on substances that deplete the ozone
layer.

SECTION 13: Disposal Considerations

13.1. Waste treatment methods

Must be disposed of or incinerated in accordance with local regulations.

Contaminated packaging:
Uncontaminated packaging can be re-used.
Packs that cannot be cleaned should be disposed of in the same manner as the contents.

SECTION 14: Transport Information

Land transport

ADR
UN number UN3082
UN proper shipping name: ENVIRONMENTALLY HAZARDOUS SUBSTANCE, LIQUID,
 Page: 11/13
BASF Safety data sheet according to Regulation (EC) No. 1907/2006 as amended from time to time.
Date / Revised: 24.04.2017 Version: 3.0
Product: Bisabolol rac.
(ID no. 30035139/SDS_COS_EU/EN)
Date of print 25.04.2017
N.O.S. (contains BISABOLOL)
Transport hazard class(es): 9, EHSM
Packing group: III
Environmental hazards: yes
Special precautions for
user:

RID
UN number UN3082
UN proper shipping name: ENVIRONMENTALLY HAZARDOUS SUBSTANCE, LIQUID,
N.O.S. (contains BISABOLOL)
Transport hazard class(es): 9, EHSM
Packing group: III
Environmental hazards: yes
Special precautions for None known
user:

Inland waterway transport

ADN
UN number UN3082
UN proper shipping name: ENVIRONMENTALLY HAZARDOUS SUBSTANCE, LIQUID,
N.O.S. (contains BISABOLOL)
Transport hazard class(es): 9, EHSM
Packing group: III
Environmental hazards: yes
Special precautions for None known
user:

Transport in inland waterway vessel

Not evaluated

Sea transport

IMDG
UN number: UN 3082
UN proper shipping name: ENVIRONMENTALLY HAZARDOUS SUBSTANCE, LIQUID,
N.O.S. (contains BISABOLOL)
Transport hazard class(es): 9, EHSM
Packing group: III
Environmental hazards: yes
Marine pollutant: YES
Special precautions for None known
user:
 Page: 12/13
BASF Safety data sheet according to Regulation (EC) No. 1907/2006 as amended from time to time.
Date / Revised: 24.04.2017 Version: 3.0
Product: Bisabolol rac.
(ID no. 30035139/SDS_COS_EU/EN)
Date of print 25.04.2017
Air transport

IATA/ICAO
UN number: UN 3082
UN proper shipping name: ENVIRONMENTALLY HAZARDOUS SUBSTANCE, LIQUID,
N.O.S. (contains BISABOLOL)
Transport hazard class(es): 9, EHSM
Packing group: III
Environmental hazards: yes
Special precautions for None known
user:

14.1. UN number
See corresponding entries for “UN number” for the respective regulations in the tables above.

14.2. UN proper shipping name

See corresponding entries for “UN proper shipping name” for the respective regulations in the tables
above.

14.3. Transport hazard class(es)

See corresponding entries for “Transport hazard class(es)” for the respective regulations in the
tables above.

14.4. Packing group

See corresponding entries for “Packing group” for the respective regulations in the tables above.

14.5. Environmental hazards

See corresponding entries for “Environmental hazards” for the respective regulations in the tables
above.

14.6. Special precautions for user

See corresponding entries for “Special precautions for user” for the respective regulations in the
tables above.

14.7. Transport in bulk according to Annex II of MARPOL and the IBC Code
Regulation: Not evaluated
Shipment approved: Not evaluated
Pollution name: Not evaluated
Pollution category: Not evaluated
Ship Type: Not evaluated

SECTION 15: Regulatory Information

15.1. Safety, health and environmental regulations/legislation specific for the
substance or mixture
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BASF Safety data sheet according to Regulation (EC) No. 1907/2006 as amended from time to time.
Date / Revised: 24.04.2017 Version: 3.0
Product: Bisabolol rac.
(ID no. 30035139/SDS_COS_EU/EN)
Date of print 25.04.2017

15.2. Chemical Safety Assessment

Advice on product handling can be found in sections 7 and 8 of this safety data sheet.

Chemical Safety Assessment not required

SECTION 16: Other Information

Full text of the classifications, including the hazard classes and the hazard statements, if mentioned
in section 2 or 3:
Aquatic Chronic Hazardous to the aquatic environment - chronic
H411 Toxic to aquatic life with long lasting effects.

The data contained in this safety data sheet are based on our current knowledge and experience and
describe the product only with regard to safety requirements. This safety data sheet is neither a
Certificate of Analysis (CoA) nor technical data sheet and shall not be mistaken for a specification
agreement. Identified uses in this safety data sheet do neither represent an agreement on the
corresponding contractual quality of the substance/mixture nor a contractually designated use. It is the
responsibility of the recipient of the product to ensure any proprietary rights and existing laws and
legislation are observed.

Vertical lines in the left hand margin indicate an amendment from the previous version.
Final Report on the Safety Assessment of Bisabolol
1

that up to 50% of the essential oil of chamomile is comprised

Bisabolol is a naturally occuring unsaturated monocyclic ter- of (-)-a-Bisabolol. Literature available regarding the safety of
pene alcohol, the alpha form of which is used in a wide range Bisabolol concerns the (-)-a-Bisabolol configuration and it is
of cosmetic formulations as a skin conditioning agent at low con- this stereoisomer that is discussed in this review unless otherwise
centrations ranging from 0.001% in lipstick to 1% in underarm
deodorants. Animal studies demonstrate that Bisabolol is well ab-
noted.
sorbed following dermal exposure and one study using cadaver
skin demonstrated that Bisabolol can enhance the penetration of CH EMISTRY
5-fluorouracil. Bisabolol was relatively nontoxic in acute oral stud-
ies in rats, dogs, and monkeys. Short-term oral exposure using rats Definition and Structure
did produce inflammatory changes in several organs, and reduced
Bisabolol (CAS No. 515-69-5) is an unsaturated monocyclic
body weight and increased liver weights relative to body weight
in dogs. The no-observable-adverse-effect level in a 28-day dermal sesquiterpene alcohol that conforms to the formula shown in
toxicity study using rats was 200 mdkg/day. No evidence of sensi- Figure 1 (Isaac 1979; Wenninger and McEwen 1997). Synonyms
tization or photosensitization was found. Bisabolol was negative in for Bisabolol include: a, 4-I~imethyl-a-(4-Methyl-3-Pentenyl)-
bacterial and mammalian genotoxicity tests, and it did not produce
reproductive or developmental toxicity in rats. The results of oral
3-Cyc1ohexene-l-Methanol; alpha-Bisabolol; and 6-Methyl-2-
and dermal toxicity, genotoxicity, reproductive/developmental toxi- (4-Methyl-3-Cyclohexen-1 -YL)-5-Hepten-2-ol (Wenninger and
city, sensitization, and photosensitization studies show little toxicity McEwen 1997; RTECS 1993; Chemline 1993). In Japan it is
at levels expected in cosmetic formulafions. Formulators should be listed as I-Methyl-4-(I-hydroxy-1,5,5-trimethyl-4-pentenyl)-
alert to the possibility that use of Bisabolol may increase the pen- cyclohex-1-ene (Rempe and Santucci 1997).
etration of other components of a cosmetic formulation. Based on
the available data it was concluded that Bisabolol is safe as used in
cosmetic formulafions. Method of Manufacture
Alpha-Bisabolol can be synthesized by stirring ketodiene in
ether into a solution of methyl magnesium iodide at room tem-
perature for 2 hours as shown in Figure 1. The mixture is worked
INTRODUCTION up by adding saturated aqueous ammonium acetate solution and
Bisabolol is a naturally occurring sesquiterpenoid. It exists in separating the ether and aqueous layers. Washing the aqueous
both a beta and alpha configuration. Beta-Bisabolol (CAS No. phase with ether and evaporation of the combined ether washes
15352-77-9) is found in the Zea mays L. plant (corn) and is a ma- extracts the a-Bisabolol as a colorless oil (Forrester and Money
jor volatile component of cotton (Thompson et al. 1974; Dickens 1972).
1986). However, Bisabolol as it appears in the International Cos-
metic Ingredient Dictionary (Wenninger and McEwen 1997)
Analytical Methods
refers to the alpha-formation identified by the CAS No. 515-69- Bisabolol can be detected by gas chromatography (Andre
5. This a-Bisabolol itself possesses four stereoisomers which et al. 1991; Guenther et al. 1993).
are as follows: (l)-a-Bisabolol (CAS No. 23089-26-1); (d)-a-
Bisabolol (CAS No. 23178-88-3); (l)-epi-a-Bisabolol (CAS No.
Impurities
78148-59-1); and (d)-epi-cx-Bisabolol (CAS No. 76738-75-5). A of Bisabolol reports that it offers 95%
supplier a opti-
Although the (+), (-)-epi, and (+)-epi isomers have been cally [(-)-a-Bisabolol, natural] isolated from a natural
pure
isolated as naturally occurring in various plants, their rarity
source, as well as an 85% pure synthetic racemic mixture [(=b)-
(especially that of (+ )-a- Bisabolol) is noted (Brunke and a-Bisabolol, racemic]. Other components identified are bisabo-
Hammerschmidt 1985; Thappa and Agarwal 1989). (-)-a-Bisa-
lene, bisabolol oxide, farnesol, chemazulene, and nerolidol at
bolol is the main active principle of the herb chamomile, Matri-
concentrations of <0.1 % and <0.5% in the natural and syn-
caria chamomilla (Habersang et al. 1979). Isaac ( 1979) reported
thetic material, respectively (BASF 1995).

USE
1
R eviewed by the Cosmetic Ingredient Review Expert Panel. Bindu
Nair Madhavan, former Scientific Analyst and Writer, prepared this Cosmetic
report. Address correspondence to Dr. F. Alan Andersen, Director, CIR, Bisabolol is used in cosmetic formulations as a skin condi-
1101 17th Street, NW, Suite 310, Washington, DC 20036, USA. tioning agent-miscellaneous (Wenninger and McEwen 1997).

33
34

FIGURE 1
Synthesis of Bisabolol from Ketodiene (Forrester and Money 1972).

Data submitted to the Food and Drug Administration (FDA) shaved skin of mice (number and strain not specified) (Hahn
in 1997 by cosmetic firms participating in the voluntary cosmetic and H61zl 1987). Each mouse received a radioactive dose of
registration program indicated that Bisabolol was used in 184 40.6 kBq. The levomenol solution was delivered with either ar-
formulations (Table 1) (FDA 1997). latone or acetone as a solubilizer. Animals were killed after 1, 3,
Concentration of use values are no longer reported to the FDA and 5 hours of exposure. Samples of skin, fat, and muscle tissues
by the cosmetic industry (FDA 1992). One supplier notes that it were obtained from various sites and analyzed. Total radioactiv-
recommends a use level of 0.1-2% and that typical concentra- ity was measured as [14C]C02 from combusted samples of neck
tions of use are 0. i-0.2°l0 (BASF 1995). Data submitted to CIR and leg skin. Thin layer chromatography (TLC) fractionations of
indicated use at concentrations of ~Q.l% up to 1% (see Table 1) skin samples were analyzed for metabolism by autoradiography.
(CTFA 1995). After 1 hour, 80% of the applied radioactivity remained in
the arlatone solution on and in the skin at the site of applica-
International tion. By 3 hours, the radioactivity at the exposure site decreased
Bisabolol is listed (under its Japanese name) in the Compre- to 57%; by 5 hours the activity was 50%. Similar results were
hensive Licensing Standards of Cosmetics by Category (CLS). observed with the acetone solution; at 3 hours, approximately
Bisabolol which conforms to the specifications of the Japanese 60% of the administered radioactivity was detected at the ap-
Cosmetic Ingredient Codex has precedent for use without re- plication site. At 5 hours, 50% of the applied radioactivity was
striction in &dquo;nail makeup preparations.&dquo; Bisabolol has precedent detected at the application site; 90% of it was detected as intact
for use at concentrations of 0.1, 0.3, and 0.5% in the various levomenol. Densitometric measurements of skin section autora-
other CLS categories (Rempe and Santucci 1997). diograms indicated that the radioactive levomenol was detected
in both fatty and muscular tissues of the neck. About 75% of
GENERAL BIOLOGY the absorbed radioactivity penetrated to the 120-{Lm layer after
1 hour by 3 hours, radioactivity was detected at 160 Am. By
Absorption Distribution, ~rletaboii~m, and Excretion 5 hour, a concentration maximum was recorded between layers
In Zero 90 and 180 pm (corium region), and some radioactivity was
Pretreatment of epidermis obtained from abdominal human detected in the lower corium regions (Hahn and Holzl 1987).
cadaver skin with a 1:1 <x-Bisabolol:propylene glycol mixture
increased the permeability of 5-fluorouracil (5-FU) and triam-
cinolone acetonide by 17- and 73-fold, respectively. A 5.4-fold ANIMAL TOXICOLOGY
increase in the permeability of 5-FU was noted after pretreat-
ment with a-Bisabolol alone. It was determined that a-Bisabolol Acute Toxicity
did not affect the stratum corneum-vehicle partition coefficient Oral
of 5-FU. Rather the penetration enhancement was suggested to The LDso of (-)-a-Bisabolol (98% pure, oily liquid) in mice
result from an increase in the diffusion coefficient of 5-FU. Bis- was 15.1 ml/kg body weight; sedation in males and ataxia in fe-
abolol altered the transition enthalpy of skin lipids (Kadir and males was observed at a dose of 6.35 ml/kg. The values were 14.9
Barry 1991). and 15.6 ml/kg for male and female rats, respectively. Again,
sedation and ataxia were observed, initially at 6.35 ml/kg. The
In Vino LDso value could not be determined for dogs (5-10 kg) due
l~C_Levomenol ~{-)-6-~nethyl-2-(4-methyl-3-cyclohexen- to vomiting which began at a dose of 12.6 mllkg. The value
l-yl)-5-hepten-2-ol and (- )-a-Bisabolol] was applied to the could not be determined in rhesus monkeys (3-5 kg) as the gag
 35

TABLE 1
Product formulation data for Bisabolol

1 FDA 1997.
2CTFA 1995.

reflex and salivation were observed upon dosing with 0.5 ml/kg through 5 cm of the test substance. There were no deaths and no
(Habersang et al. 1979). lesions at necropsy. Details were not reported (BASF 1980b).
BASF (19$ova) reported an oral LDso for (4-)-a-Bisabolol of
>5 g/kg in rats. Dyspnea, apathy, ruffled fur, and &dquo;poor general Parenteral Toxicity
state&dquo; were noted at that dose. BASF (1 ~$Oc) reported an intraperitoneal LD50 value for (~)_
a-Bisabolol (in emulsion) of 633 mg/kg in mice. Dyspnea, apa-
Inhalation Taxicity thy, trembling, staggering gait, rolling fits, ruffled fur, and &dquo;poor
Twelve rats were exposed for 7 hours to air containing (:1::)- general state&dquo; were noted at the lowest dose, 200 mg/kg. At
a-Bisabolol. Bisabolol was aerosolized by passing 200 L air/h necroposy of mice that died during the study, no intra-abdominal
36

deposits of the test substance or adhesions were found. Sacri- significantly. No other changes were noted as compared to con-
ficed animals had intra-abdominal adhesions of the liver, blunt trols.
hepatic margins, and astringed serosa.
Dermal Toxicity
In a study by BASF (1996a), a-Bisabolol in an olive oil ve-
Short-Term Toxicity hicle was applied in a semiocclusive dressing at doses of 50,
Oral 200, and 1000 mg/kg body weight/day to the clipped skin of 10
Habersang et al. (1979) performed a short-term oral toxicity Wistar rats (five each sex). The concentrations of a-Bisabolol
study. An orientation study was first conducted in which groups (87.5% pure) used to achieve the doses were f%, 4%, and 20%,
of 20 Wistar Br 46-II rats (10 of each sex) received 1 mllkg Bis- respectively. Rats were exposed for 6 h/day, 7 days a week,
abolol (oily liquid, 85% pure) by stomach tube, 7 days a week, for for 4 weeks. Male rats weighed between 274-297 g and fe-
6 weeks. A control group received aqueous tylosis mucus (resin). male rats weighed between 209-232 g. Daily observations were
No intolerance reactions were detected. In the toxicity assay, made and feed consumption and body weight were measured
two groups of 40 Sprague-Dawley rats (20 of each sex, average weekly. Urine and blood samples were obtained towards the end
body weight 100 g) received Bisabolol (85 %) via a stomach tube, of the study. Rats were examined for gross lesions followed by
7 days a week, for 4 weeks. One group received 2 ml/kg, the histopathological examination of fixed tissues. No treatment-
other received 3 ml/kg. A control group received 4 ml of aqueous related effects were noted in rats of the low- and mid-dose
tylosis mucus. Slight motor agitation was noted in animals of the groups. A slight decrease in body weight gain and feed effi-
2 ml/kg treatment group. A positive ketone body reaction was de- ciency was noted in all rats of the high-dose group on day 7
tected in the urine. Mortality rate was 20% in the 3 ml/kg group. only. Transient moderate erythema and diffuse scale formation
Increased motor agitation and decreased body weight gain were were noted in some female rats of the high-dose group. Various
noted. A significant increased in activities of serum glutamic- changes in clinical pathology values were noted in high-dose
oxaloacetic transaminase (SGOT) and alkali phosphatase was male rats but none were considered treatment-related. Leukope-
noted in females; these activities were slightly increased in nia coupled with lymphopenia was considered questionable as
males. The positive ketone reaction in the urine was intensi- concurrent controls had &dquo;extremely high&dquo; leukocytes and lym-
fied in the 3-ml/kg group. Animals of this group were emaciated phocyte values. Values for both parameters for the control and
and had a shaggy haircoat. Postmortem findings for the 3 ml/kg high-dose group were respectively higher and lower than the
group were different from those of the control group, but the range of historical data and were thus considered &dquo;fortuitous.&dquo;
researchers noted a lack of reliable indications of substance- A significant increase in serum glucose was within historical
dependent intolerance reactions (details not reported). Inflam- range, and a significant increase in serum calcium concentra-
matory changes were observed in the liver, trachea, spleen, thy- tions was discounted because similar changes were not noted
mus, and stomach; these changes were more severe in animals in high-dose females. A significant decrease in mean absolute
of the high-dose group. The researchers characterized the in- liver weight was noted in high-dose females and an increase
flammations as an &dquo;infection defense weakness triggered by the in mean relative testes weight was noted in high-dose males.
emaciation.&dquo; The changes were considered to result from the decreased mean
Habersang et al. (1979) conducted a similarly designed study terminal body weight of female (5.4% lower than controls)
on dogs. In the orientation study two mixed breed dogs (average and male (3.7% lower than controls) high-dose rats. The no-
weight 8 kg) received 1 ml/kg body weight Bisabolol (oily liq- observable-adverse-effect level (NOAEL) was 200 mg/kg/day
uid, 85% pure) via a stomach tube, 7 days a week, for 2 weeks. (BASF 1996a).
Another two dogs received aqueous tylosis mucus and served
as controls. No intolerance reactions were observed. In the tox-

icity assay groups of six dogs (three of each sex) received ei- Dermal Irritation
ther 2.0 or 3.0 ml Bisabolol/kg, 7 days a week, for 4 weeks. Semiocclusive patches containing undiluted (-)-a-Bisab-
Two weeks into the study, the 3.0 ml/kg dose was increased to olol were applied for 4 hours contact to the clipped back or
4.0 ml/kg. A control group received 4 ml of aqueous tylosis flank of three white Vienna rabbits. Very slight erythema was
mucus/kg body weight. A loss of appetite, reduced feed intake, noted in all rabbits at the 4-hour reading. By 24 hours, the re-
and vomiting were observed in two of the six dogs receiving action increased to well-defined erythema in two rabbits, one
2 mal Bisabolol/kg. No other toxic reactions were noted in this of which also developed very slight edema. By 48 hours, the
treatment group. The reactions were more severe in animals of erythema was no longer observed in rabbit 1, had decreased to
the 4.0-ml/kg group. Body weight gain was reduced. By the very slight in rabbit 2, and remained well-defined in rabbit 3.
4th week, creatine concentrations and serum glutamate pyru- The edema which had been noted at 24 hours in rabbit 3 cleared.
vate transaminase (SGPT) activity had significantly increased By 72 hours, very slight erythema was noted only in rabbit 3.
as did liver function (details not reported). At necropsy it was However, scaling was noted in rabbits 2 and 3. At 7 days scaling
noted that the liver weight relative to body weight was increased was noted in all three rabbits (BASF 1989a).
 37

Ocular Irritation 2. (+)-a-Bisabolol (naturally occurring)

Undiluted (-)-a-Bisabolol was instilled into one conjuncti- 3. (+)-a-Bisabolol (racemate produced by unfixing the above
val sac of each of three rabbits. Eyes were not rinsed. No changes two naturally occurring isomers)
were noted in the cornea or iris at any observation. Well-defined 4. (+ )-a -Bisabolol (synthetic, contains 77% isopropylidene and
conjunctival redness was noted in all rabbits at the 1, 24, and 23% isopropenyl isomers)
48 hours readings. None was noted at the 72 hours reading. In- 5. Commercial Bisabolol preparation (78.7% (+)-a-Bisabolol
creased discharge was noted in all animals at the 1 hour reading; in isopropylidene form and 5.7% in the isoprenyl form)
the reaction cleared in two rabbits and was reduced to a &dquo;slight 6. Bisabolol Oxide A
increase&dquo; in one rabbit at the 24 hours reading, and thereafter 7. Bisabolol Oxide B
was not noted in any rabbit at subsequent observations (BASF
The test substances were administered at doses of 500, 1000,
1989b). and 2000 mg/kg. The commercial Bisabolol preparation (5) was
tested at a high dose of 3000 mg/kg. Olive Oil was tested as a
Photosensitization control. One hour after dosing the animals received an injection
In a photosensitization assay, Bisabolol (3 and 15% v/v) was of 1 % carrageenin suspension (0.1 ml) into the right rear paw.
applied to the shaved neck skin of groups of five male white Pir- Two hours later the animals were killed and the rear paws re-
bright guinea pigs (291-365 g). The test material was dissolved moved and weighed. The weight difference yielded the amount
in absolute alcohol. Following application the guinea pigs were of edema in milligram.
irradiated for 15 minutes with 7.9 kilolumen of 240-540 nm Naturally occurring (-)-a-Bisabolol at a dose of 1465 mg/kg
light emitted from a quartz lamp at a distance of 65 cm between inhibited edema development by 50% (ED so). In comparison, a
the light source and the experimental animal. The protocol of similar effect was not produced by even the highest dose tested
dermal treatment followed by radiation was followed for 5 days. of the other Bisabolol isomers and oxides and olive oil. However
A group which was treated with 15% vlv Bisabolol but not ir- an EDso of 3164 mg/kg was determined for Bisabolol Oxide A.
radiated was maintained to monitor the effect of the high dose. Using (-)-cx-Bisabolol as the standard, the commercial prepa-
The vehicle control was treated with alcohol followed by irradia- ration had about 25% the antiphlogistic effect, Bisabolol Oxide
tion, and the positive control was treated with tetrachlorosalicy- A was 33% as effective, and the other forms of Bisabolol were
lanilide followed by irradiaton. Following a 9-day nontreatment half as effective.
period the protocol was repeated on 2 successive days. In this
phase, the protocol was modified in that the test material and
the positive control material were now dissolved in olive oil and Test on Adjuvant Arthritis in Rats
the vehicle control was olive oil. After a 12-day nontreatment Arthritis was induced in female SIV-50 albino rats (90-100 g)
period the hind legs were shaved and a commercial soap solu- by injecting dead Mycobacterium butyricum suspended in paraf-
tion was applied to the right leg of all animals. The 3 and 15% fin oil into the plantar side of the right rear paw. (-)-a-Bisabolol
Bisabolol solutions were dissolved in the commercial soap so- was administered daily perorally in 1.5% aqueous tragacanth
lution and applied to the left leg of Bisabolol-treated animals. gum solution. A control group received the gum solution alone.
The left leg of positive-control animals was treated with tetra- Feed and water were provided ad libitum. The volume of the in-
chlorosalicylanilide dissolved in the soap solution. Irradiation jected paw was measured daily by plethysmography a few hours
followed and the procedure was repeated for 3 days. Animals after the test substance was administered. A clear inhibition in
continued to be observed during a 3-day follow-up period. No the increase of paw volume was noted with a dose of 250 mg
indication of photosensitization was noted in Bisabolol-treated (- )-a-Bisabolol/kg. A dose of 500 mg/kg corresponded in ac-
animals (BASF 1981). tion to about 1.5 mg/kg of the steroid prednisolone (which was
used as the standard).
Anti-Inflammatory Effects
There are numerous articles concerning the anti-inflamma-
Testing of Ultraviolet Erythema in the Guinea Pig
tory action of Bisabolol (Fernandes, Periera, and Paulo 1992;
Jakovlev et al. 1979; Thiele et al. 1969; Yakovlev and Von- (-)-a-Bisabolol (in a 1% aqueous tylose mucous) was ad-
ministered either orally or applied to the back of groups of nine
Schlichtegroll 1969). Jakovlev et al. (1979) reported the follow- shaved white male Pirbright guinea pigs (200-260 g). The dose
ing three studies and results.
range was 125-~000 mg/kg. Salicylamide was used as the com-
Testing on Carrageenin Edema of Rat Paws parison substance. Thirty minutes post application, the animals
were irradiated for 15 seconds at a distance of 40 cm from the
Groups of 30-50 male SIV-50 rats (95-130 g) were orally
dosed with one of the following test substances (mixed with light source (PQ 600, Hanauer Quarzlampen GmbH, Hanau).
A plastic sleeve containing six (1-cm) holes was used to direct
methylcarboxyl cellulose):
exposure. Erythema was assessed 2 hours after irradiation and
1. (-)-a-Bisabolol (naturally occurring, 99.5% pure, no iso- erythema inhibition was rated when at least three fields had no
propylene polymers) reddening.
38

A dose-dependent inhibition of erythema development was and at >5-50 fig/plate in the preincubation test. Bisabolol was
observed following oral administration. The dose of 2000 mg/ negative in the assay (BASF 1996b).
kg was toxic. The EDso was 650 mg/kg. Bisabolol administered Bisabolol (86.8% pure) was tested in the chromosome aber-
orally was 1/3 as effective as salicylamide. ration assay using Chinese hamster V79 cells. In the first exper-
In contrast, although percutaneous administration also inhib- iment, test cells were incubated for 4 hours with 7.81, 15.63, or
ited erythema, an ED50 value was not reached even at the highest 31.25 fig Bisabolol/ml in the presence of metabolic activation
dose tested. The highest dose of 400 mg Bisabolol/kg protected (S9 from aroclor induced rat liver), or 0.78, 1.56, or 3.13 its Bis-
44% of the guinea pigs. abolollml without activation. In the second experiment, test cells
were incubated with 10.0, 20.0, 30.0, or 40.0 fig Bisabolol/ml
with activation, or 2.0, 3.0, or 4.0 ttg Bisabolollml without
REPRODUCTIVE AND DEVELOPMENTAL TOXICITY
metabolic activation. Positive control cells were treated with
Pregnant rats (number not specified; weight 200-262 g) re- ethyl methane sulfonate (EMS) (without S9) and cyclophos-
ceived Bisabolol (98%) daily by stomach tube on days 6-15 of
phamide (with S9), and negative control cells were treated with
gestation. The doses used were 0.250, 0.500, 1.0, and 3.0 ml/kg vehicle (DMSO) or left untreated. Duplicate cultures were made
body weight. (The 3.0 ml/kg dose was used to test maternal tox- at all doses. Colcemid was added prior to harvesting and chromo-
icity.) There were two control groups; one group received 1 % somes were prepared 18 hours after treatment. In addition, chro-
tylosis mucus and the second group received 1 % carboxyethyl mosomes from high-dose cells of the second experiment (both
cellulose gel and was used for the maternal range-finding aspect with and without activation) were also prepared at 28 hours.
of the study. Fetuses were removed on day 20 and examined. After staining with Giemsa, 100 metaphases of each culture
No effect on prenatal development was observed at doses of
(50 cells of the positive control) were analyzed for chromoso-
Bisabolol up to 1.0 ml/kg. A significant reduction in fetal num- mal aberrations. A significant increase in gap aberrations was
ber and subsequent increase in resorption rate was observed in noted in the first experiment in cells treated with 31.35 fix
the 3.0 ml/kg group (details not reported). No deformities were Bisabolol/ml with S9 and ~1.56 fig Bisabolol/ml without S9.
noted. Slight sedation, ataxia, reduced feed intake, and reduc- However the finding was not considered relevant because (i)
tion of body weight gain were observed in females of this dose the values were within the range for historical controls (the in-
group. The researchers considered the lowest toxic dose for both vestigators noted the low spontaneous rate in the concurrent
fetuses and dams was between 1.0 and 3.0 ml Bisabolol/kg body
negative control), (ii) the results were not duplicated, and, (iii)
weight perorally (Habersang et al. 1979). &dquo;gaps alone are generally not a suitable criterion for assessing
A similarly designed study was conducted using New Zealand
clastogenicity.&dquo; a-Bisabolol was negative in the assay (BASF
rabbits weighing between 3.6 and 4.4 kg. Pregnant rabbits re-
1996c).
ceived either 0.3, 1.0, or 3.0 ml Bisabolol/kg body weight by
stomach tube on days 6-15 of gestation. A control group re-
ceived, by way of replacement, 3 ml of 1 % tylosis mucus. Fe- CLINICAL ASSESSMENT OF SAFETY
tuses were removed on day 30 and examined. No adverse effects
on either prenatal development or on the dams were noted using
Dermal Irritation and Sensitization
Bisabolol at doses up to 1.0 ml/kg. A reduction in the number A patch testing reference book by DeGroot (1994) noted that
of living fetuses was noted in the 3.0 ml/kg group; no dead fe- the published literature does not contain data concerning Bis-
tuses or deformities were noted. Dams of this treatment group abolol. To serve as a guide to the reader, DeGroot reported that
an unpublished (and at the time, ongoing) study found no ir-
were slightly sedated and had reduced body weight gains (de-
tails not provided). Again, the lowest toxic dose for both fetuses ritant reaction in 1 to 20 patients suffering from or suspected
and dams was between 1.0 and 3.0 ml Bisabolol/kg body weight to suffer from cosmetic product contact allergy who had been

perorally (Habersang et al. 1979). patch-tested with 5% Bisabolol in petrolatum.

The Kligman maximization protocol was used in a clini-
cal sensitization assay using 25 panelists (Ivey Laboratories
MUTAGEN CITY 1992). The test substance was a commercial product containing
Bisabolol (86.8% pure) was tested in the Ames assay using 0.1 % Bisabolol. A 24-hour occlusive patch containing aqueous
Salmonella typhimurium strains TA 1535, TA 100, TA 1537, and sodium lauryl sulfate (SLS) was applied (and removed) prior
TA 98. The standard plate protocol (Ames et al. 1973; Ames, to application of a 48-hour patch containing 0.1 g of the test
McCann, and Yamasaki 1975) was used to test Bisabolol (in substance. This protocol of a 24-hour SLS patch followed by a
DMSO) at doses of z000 pg/plate and the preincubation 48-hour exposure to the test substance was continued for five in-
protocol (Yahagi et al. 1977; Matsushima et al. 1980) was used duction exposures. The patch containing the test substance was
to test Bisabolol (in DMSO) at doses of 1.5-1500 ¡Lg/plate. left in place for 72 hours if testing occurred over a weekend. No
Both test protocols were conducted with and without metabolic irritation was noted at any time during the induction phase in
activation (S9 from aroclor induced rat liver). A bacteriotoxic the 25 panelists. Induction was followed by a 10-day nontreat-
effect was noted at > 100-500 p g/plate in the standard plate test ment period. Prior to challenge panelists were pretreated with
 39

10.0% aqueous SLS which was kept in contact with the skin for to the possibility of increased absorption of other ingredients
1 hour. This pretreatment was followed by a 48-hour occlusive also contained in the formulation, especially those ingredients
patch containing the test substance. Pretreatment and challenge whose safety is based on their lack of dermal absorption.
occurred on an unexposed site on the opposite arm. The chal-
lenge sites were graded at the time of patch removal and again
24 hours later. No reactions were noted. CONCLUSION
Based on the available data, the CIR Expert Panel concludes
that Bisabolol is safe as used in cosmetic formulations.
SUMMARY
(-)-a-Bisabolol is an unsaturated monocyclic terpene alco-
hol used in cosmetic formulations as a skin conditioning agent. REFERENCES
In January 1997 it was reportedly used in 184 cosmetic formu- Ames, B. N., W. W. Durston, E. Yamasaki, and F. D. Lee. 1973. Carcinogens are
mutagens: A simple test system combining liver homogenates for activation
lations, typically at concentrations of 0.1-0.2% (1995 data). and bacteria for detection. Proc. Nat. Acad. Sci. U.S.A. 70:2281-2285.
Animal studies indicated that Bisabolol is well absorbed fol- Ames, B. N., J. McCann, and E. Yamasaki. 1975. Methods for detecting carcino-
lowing dermal exposure. Bisabolol had anti-inflammatory prop- gens and mutagens with the Salmonella/mammalian-microsome mutagenicity
erties and an in vitro study demonstrated its penetration enhance- 31:347-364.
test. Mutat. Res.
Andre, D., P. Verite, R. Duclos, A. M. Orecchioni, and F. Failly. 1991. De-
ment activity. termination of &alpha;-bisabolol and D-panethenol in cosmetic products by gas
Acute oral LDso values include 15.1 ml/kg in mice, and 14.9
chromatography. Int. J. Cosmet. Sci. 13:137-142.
and 15.6 ml/kg in male and female rats, respectively. The values BASF. 1980a. Acute oral toxicity of (&plusmn;)-&alpha;-Bisabolol. Unpublished data sub-
could not be determined in dogs or rhesus monkeys. mitted by BASF. (4 2
pages.)
Short-term oral exposure produced inflammatory changes in BASF. 1980b. Acute inhalation toxicity of (&plusmn;)-&alpha;-Bisabolol. Unpublished data
submitted by BASF. (1 page.)2
the liver, trachea, spleen, thymus, and stomach in rats. A similar
BASF. 1980c. Acute intraperitoneal toxcity of (&plusmn;)-&alpha;-Bisabolol. Unpublished
study conducted using dogs noted significantly increased liver data submitted by BASF. (4 pages.)
2
weights relative to body weight and reduced body weight. BASF. 1981. Study with Bisabolol, lot B 065038, AN 101 151, for photosen-
A 28-day dermal toxicity study using rats determined the no- sitizing properties in the guinea pig. Unpublished data submitted by BASF.
observable-adverse-effect level (NOAEL) to be 200 mg/kg/day (13 2
pages.)
BASF. 1989a. Dermal irritation of (-)-&alpha;-Bisabolol in rabbits. Project No.:
(applied solution contained 4% a-Bisabolol, 87.5% pure). 18H0646/882254. Unpublished data submitted by BASF. (8 pages.)
Bisabolol was negative in a dermal photosensitization study 2
BASF. 1989b. Ocular irritation of (-)-&alpha;-Bisabolol in rabbits. Project No.:
with guinea pigs and was not teratogenic in an oral dose study 11H0646/882255. Unpublished data submitted by BASF. (7 pages.)2
using rats. BASF. 1995. Bisabolol impurities and concentration of use. Unpublished data
Bisabolol was negative in the Ames and the chromosome submitted by BASF. (1 page.)2
aberration assays using Chinese hamster cells. BASF. 1996a. &alpha;-Bisabolol: Repeated dose dermal toxicity study in Wistar rats.

In a clinical study, a commercial product containing 0.1 % Project No.: 33S0144/95020. Unpublished data submitted by BASF. (208
pages.)2
Bisabolol was negative for sensitization. BASF. 1996b. Ames Test: &alpha;-Bisabolol. Project No.: 40M0144/954069. Unpub-
lished data submitted by BASF. (16 pages.)2
BASF. 1996c. In vitro chromosome aberration assay with &alpha;-Bisabolol in V79
DISCUSSION cells. Project No.: 32M0144/954094. Unpublished data submitted by BASF.
In reviewing the safety of Bisabolol, the Cosmetic Ingredient (81 pages.)
2
Review (CIR) Expert Panel was satisfied that the results of oral Brunke, E. J., and F. J. Hammerschmidt. 1985. Constituents of the essential oil of
Salvia stenophylla&mdash;first identification of (+)-epi-alpha-bisabolol in nature.
and dermal toxicity, mutagenicity, reproductive/developmental Esent. Oils Aromat. Plants Proc. Int. Symp. 15:145-150.
toxicity, photosensitization, and clinical sensitization studies Chemline. 1993. Bisabolol entry. Chemline database. Bethesda, MD: National
cited in this report show little toxicity at levels expected in cos- Library of Medicine.
metic formulations. In particular, a 28-day dermal toxicity study Cosmetic, Toiletry, and Fragrance Association (CTFA). 1995. Use Levels for
Various Ingredients. Unpublished data submitted by CTFA. (1 PAGE.) 2
determined a NOAEL of 200 mg/kg/day which corresponded to
DeGroot, A. C. 1994. Patch testing: Test concentrations and vehicles for 3700
a 4% Bisabolol solution (87.5% pure). As reported use concen-
chemicals. 2nd ed., 11,43. Amsterdam: Elsevier.
trations were generally ::::1 %, the Panel was of the opinion that Dickens, J. C. 1986. Orientation of boll weevil, Anthonomus grandis Boh., to
the 28-day dermal toxicity study, in conjunction with findings of pheromone and volatile host compound in the laboratory. J. Chem. Ecol.
the other studies, supported the assertion that Bisabolol is safe 12:91-98.
as used. Fernandes, R. M., N. A. Periera, and L. G. Paulo. 1992. Anti-inflammatory activ-
The Panel acknowledged that the ingredient is well-absorbed ity of copaiba balsam (Copaifera cearensis, Huber). Rev. Bras. Farm. 73 :53-
56.
following dermal application. Further, an in vitro study demon-
strated that Bisabolol is a penetration enhancer and appeared to
have synergistic action with propylene glycol. Noting that Bis- available for review: Director, Cosmetic Ingredient Review, 1101 17th
abolol is used in baby lotions, the Panel cautioned formulators Street NW, Suite 310, Washington, DC 20036, USA.
40

Food and Drug Administration (FDA). 1992. Modification in Voluntary Filing Kadir, R., and B. Barry. 1991. &alpha;-Bisabolol, a possible safe penetration enhance
of Cosmetic Product Ingredient and Cosmetic Raw Composition Statements. for dermal and transdermal therapeutics. Int. J. Pharm. 7:87-94.
Fed. Register 57:3128-313Q. Matsushima, T., T. Sugimura, M. Nagao, T. Yahagi, and A. Shirai. 1980. Factors
FDA. 1997. Frequency of use of cosmetic ingredients. FDA database. modulating mutagenicity in microbial tests. In Short-Term Test Systems for
Washington: FDA. Detecting Carcinogens, ed. K. H. Norpoth and R. C. Garner. New York:
Forrester, J. M., and T. Money. 1972. Sequence studies in biosynthesis: Tri- Springer-Verlag.
chothecin. Can. J. Chem. 50:3310-3314. Registry of Toxic Effects of Chemical Substances (RTECS). 1993. Toxnet
Guenther, K., R. Carle, I. Fleischhauer, and S. Merget. 1993. Semipreparative database. Bethesda, MD: National Library of Medicine.
liquidchromatographic separation of all four stereoisomers of &alpha;-bisabolol on Rempe, J. M., and L. G. Santucci. 1997. CTFA List of Japanese Cosmetic In-
tribenzoyl cellulose. Fresenius’ J. Anal. Chem. 345:787-790. gredients. 3rd ed., 64. Washington, DC: CTFA.
Habersang, S., F. Leuschner, O. Isaac, and K. Thiemer. 1979. Pharmacological Thappa, R. K., and S. G. Agarwal. 1989. Cymbopogon flexuosus oil. A rich
studies with compounds of chamomile. IV. Studies on toxicity of (-)-alpha- source of (+)-alpha-bisabolol. J. Essent. Oil Res. 1:
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