Curcuma FDA

GRAS Notice (GRN) No.
686
http://www.fda.gov/Food/IngredientsPackagingLabeling/GRAS/NoticeInventory/default.htm
ORIGINAL SUBMISSION
Form Approved: OMB No. 0910-0342; Expiration Date: 03/31/2019
(See last page for OMB Statement)
FDA USE ONLY
GRN NUMBER DATE OF RECEIPT
000686 01/05/2017
DEPARTMENT OF HEALTH AND HUMAN SERVICES
ESTIMATED DAILY INTAKE INTENDED USE FOR INTERNET
Food and Drug Administration
GENERALLY RECOGNIZED AS SAFE

NAME FOR INTERNET
(GRAS) NOTICE
KEYWORDS
Transmit completed form and attachments electronically via the Electronic Submission Gateway (see Instructions); OR Transmit
completed form and attachments in paper format or on physical media to: Office of Food Additive Safety (HFS-200), Center for
Food Safety and Applied Nutrition, Food and Drug Administration, 5100 Paint Branch Pkwy., College Park, MD 20740-3835.
PART I – INTRODUCTORY INFORMATION ABOUT THE SUBMISSION

1. Type of Submission (Check one)
New Amendment to GRN No. Supplement to GRN No.
2. All electronic files included in this submission have been checked and found to be virus free. (Check box to verify)
3a. For New Submissions Only: Most recent presubmission meeting (if any) with
FDA on the subject substance (yyyy/mm/dd): NA
3b. For Amendments or Supplements: Is your (Check one)
amendment or supplement submitted in Yes If yes, enter the date of
response to a communication from FDA? No communication (yyyy/mm/dd):
PART II – INFORMATION ABOUT THE NOTIFIER
Name of Contact Person Position

KG Rao President
Company (if applicable)

1a. Notifier DolCas Biotech, LLC
Mailing Address (number and street)

9 Lenel Road
City State or Province Zip Code/Postal Code Country

Landing New Jersey 07850 United States of America
Telephone Number Fax Number E-Mail Address
973-347-1958 973-347-0433 grao@dolcas-biotech.com
Name of Contact Person Position

N/A
1b. Agent
Company (if applicable)
or Attorney
(if applicable)
Mailing Address (number and street)
City State or Province Zip Code/Postal Code Country
Telephone Number Fax Number E-Mail Address
FORM FDA 3667 (5/16) Page 1 of 5

PART III – GENERAL ADMINISTRATIVE INFORMATION
1. Name of Substance
BCM 95 (curcumin)
2. Submission Format: (Check appropriate box(es)) 3. For paper submissions only:
Electronic Submission Gateway Electronic files on physical media
with paper signature page Number of volumes 1
Paper
If applicable give number and type of physical media
one copy on CD virus free Total number of pages 128
4. Does this submission incorporate any information in FDA’s files by reference? (Check one)
Yes (Proceed to Item 5) No (Proceed to Item 6)
5. The submission incorporates by reference information from a previous submission to FDA as indicated below (Check all that apply)
a) GRAS Notice No. GRN
b) GRAS Affirmation Petition No. GRP
c) Food Additive Petition No. FAP
d) Food Master File No. FMF
e) Other or Additional (describe or enter information as above)
6. Statutory basis for determination of GRAS status (Check one)
Scientific Procedures (21 CFR 170.30(b)) Experience based on common use in food (21 CFR 170.30(c))
7. Does the submission (including information that you are incorporating by reference) contain information that you view as trade secret
or as confidential commercial or financial information?
Yes (Proceed to Item 8)
No (Proceed to Part IV)
8. Have you designated information in your submission that you view as trade secret or as confidential commercial or financial information
(Check all that apply)
Yes, see attached Designation of Confidential Information
Yes, information is designated at the place where it occurs in the submission
No
9. Have you attached a redacted copy of some or all of the submission? (Check one)
Yes, a redacted copy of the complete submission
Yes, a redacted copy of part(s) of the submission
No
PART IV – INTENDED USE
1. Describe the intended use of the notified substance including the foods in which the substance will be used, the levels of use in such
foods, the purpose for which the substance will be used, and any special population that will consume the substance (e.g., when a sub-
stance would be an ingredient in infant formula, identify infants as a special population).
DolCas intends to incorporate BCM-95® into selected food categories (yogurt, nutrition bars, smoothies and medical foods)
as a nutrient supplement as defined by FDA in 21 CFR 170.30 at use levels described in Section IV (B)
2. Does the intended use of the notified substance include any use in meat, meat food product, poultry product, or egg product?
(Check one)
Yes No

PART V – IDENTITY
1. Information about the Identity of the Substance

Registry
Biological Source Substance Category
Name of Substance 1 Used Registry No.2
(if applicable) (FOR FDA USE ONLY)
(CAS, EC)
BCM-95®( Curcuma longa L.) 458-37-7 turmeric rhizome
1
1 Include chemical name or common name. Put synonyms (whether chemical name, other scientific name, or common name) for each respective
item (1 - 3) in Item 3 of Part V (synonyms)
2
Registry used e.g., CAS (Chemical Abstracts Service) and EC (Refers to Enzyme Commission of the International Union of Biochemistry (IUB), now
carried out by the Nomenclature Committee of the International Union of Biochemistry and Molecular Biology (IUBMB))
2. Description
Provide additional information to identify the notified substance(s), which may include chemical formula(s), empirical formula(s), structural
formula(s), quantitative composition, characteristic properties (such as molecular weight(s)), and general composition of the substance. For
substances from biological sources, you should include scientific information sufficient to identify the source (e.g., genus, species, variety,
strain, part of a plant source (such as roots or leaves), and organ or tissue of an animal source), and include any known toxicants that
could be in the source.
BCM-95® is a reconstituted, purified and standardized turmeric extract,from the rhizome,which enhances the oral
bioavailability of curcumin in blood. It contains a specialized unique blend of curcuminoids (curcumin, demethoxy curcumin
and bisdemethoxy curcumin) and essential oil of turmeric.
BCM-95® consists of no less than 85% curcuminoids and 5-7% volatile oils.
3. Synonyms
Provide as available or relevant:
1 curcumin
2 turmeric
3 Biocurcumax™ and Biocurcumin™

PART VI – OTHER ELEMENTS IN YOUR GRAS NOTICE
(check list to help ensure your submission is complete – check all that apply)
Any additional information about identity not covered in Part V of this form
Method of Manufacture
Specifications for food-grade material
Information about dietary exposure
Information about any self-limiting levels of use (which may include a statement that the intended use of the notified substance is
not-self-limiting)
Use in food before 1958 (which may include a statement that there is no information about use of the notified substance in food
prior to 1958)
Comprehensive discussion of the basis for the determination of GRAS status
Bibliography
Other Information
Did you include any other information that you want FDA to consider in evaluating your GRAS notice?
Yes No
Did you include this other information in the list of attachments?
Yes No
PART VII – SIGNATURE
1. The undersigned is informing FDA that DolCas Biotech, LLC

(name of notifier)
has concluded that the intended use(s) of BCM 95 (curcumin)

(name of notified substance)
described on this form, as discussed in the attached notice, is (are) exempt from the premarket approval requirements of section 409 of the
Federal Food, Drug, and Cosmetic Act because the intended use(s) is (are) generally recognized as safe.
2. DolCas Biotech, LLC agrees to make the data and information that are the basis for the
(name of notifier) determination of GRAS status available to FDA if FDA asks to see them.
DolCas Biotech, LLC agrees to allow FDA to review and copy these data and information during
customary business hours at the following location if FDA asks to do so.
(name of notifier)
9 Lenel Road, Landing, NJ 07850

(address of notifier or other location)
DolCas Biotech, LLC agrees to send these data and information to FDA if FDA asks to do so.
(name of notifier)
OR
The complete record that supports the determination of GRAS status is available to FDA in the submitted notice and in GRP No.
(GRAS Affirmation Petition No.)
3. Signature of Responsible Official, Printed Name and Title Date (mm/dd/yyyy)

Agent, or Attorney
K G Rao
Digitally signed by K G Rao
DN: cn=K G Rao, o=DolCas Biotech, ou=President,
email=grao@dolcas-biotech.com, c=US
KG Rao, President 10/13/2016
Date: 2016.10.27 13:12:36 -04'00'

PART VIII – LIST OF ATTACHMENTS
List your attached files or documents containing your submission, forms, amendments or supplements, and other pertinent information.
Clearly identify the attachment with appropriate descriptive file names (or titles for paper documents), preferably as suggested in the
guidance associated with this form. Number your attachments consecutively. When submitting paper documents, enter the inclusive page
numbers of each portion of the document below.
Attachment Folder Location (select from menu)

Attachment Name
Number (Page Number(s) for paper Copy Only)
Summary of Safety Data And Food usage conditions For

conclusion of General Recognition of Safety of BCM 95 5-74
(Curcumin)
Appendix A - Flow chart of manufacturing Process for BCM 95 75
Appendix B - Certificates of Analysis for Five Production Batches

of BCM 95 77
Appendix C - JECFA Specifications for Curcumin 83
Appendix D - Accelerated and Long-Term Stability Report for

BCM 95 87
Appendix E - Elevated Temperature Stability Report 94
Appendix F - Human Studies on Other Curcumin Preparations 99
OMB Statement: Public reporting burden for this collection of information is estimated to average 150 hours per response, including
the time for reviewing instructions, searching existing data sources, gathering and maintaining the data needed, and completing and
reviewing the collection of information. Send comments regarding this burden estimate or any other aspect of this collection of information,
including suggestions for reducing this burden to: Department of Health and Human Services,Food and Drug Administration, Office of Chief
Information Officer, 1350 Piccard Drive, Room 400, Rockville, MD 20850. (Please do NOT return the form to this address.). An agency may
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control number.

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DolCas Biotech, LLC.
9 Lenel Road
Landing, N.J. 074850
973-347-1958
www.dolcas-biotech.com
Food and Drug Administration

Center for Food Safety & Applied Nutrition
Office of Food Additive Safety (HFS-255)
5100 Paint Branch Parkway
College Park, MD 20740-3835
Attention: Dr. Paulette Gaynor

Re: GRAS Notification - BCM -95® (Curcumin)
Dear Dr. Gaynor,
On behalf of DoiCas Biotech, LLC, we are submitting for FDA review, Form 3667, one paper copy and the
enclosed CD, free of vi ruses, containing a GRAS notification for BCM-95® (Curcumin).
An Expert Panel of independent qualified persons was assembled to assess the composite safety
information of the subject substance with the intended use in select foods as outlined in the
notification.
The attached documentation contains the specific information that addresses the safe human food uses
for the subject notified substance as discussed in the GRAS final rul e, 21 CFR Part 170.30(a)(b),
Subpart E.
If additional information or clarification is needed as you and your colleagues proceed with the review,
please feel free to contact us via telephone or email.
We look forward to your feedback.
(b) (6) J~"'
DoiCas Biotech, LLC

9 Lenel Road
Landing, N.J. 074850
973-347-1958 Ext. 201
grao@dolcas-biotech.com
Enclosure: GRAS Notification for DoiCas Biotech, LLC- BCM-95® (Curcumin)

1 paper copy/1 virus- free electronic media
SUMMARY OF SAFETY DATA
AND FOOD USAGE CONDITIONS FOR
CONCLUSION OF GENERAL RECOGNITION OF
SAFETY
of
BCM-95® (Curcumin)
for
DolCas Biotech, LLC
DolCas Biotech, LLC

Landing, NJ
October 21, 2016
DolCas Biotech, LLC

DolCas Biotech, LLC
GRAS Assessment – BCM-95® October 21, 2016
Table of Contents
I. GRAS EXEMPTION CLAIM .............................................................................................................................. 5
A. Claim of Exemption From Requirement for Premarket Approval .................................................................. 5
B. Name & Address of Notifier ........................................................................................................................... 5
C. Common Name & Identity of Notified Food Substance ................................................................................. 5
D. Conditions of Intended Use in Food .............................................................................................................. 6
E. Basis for GRAS Conclusion .......................................................................................................................... 6
F. Availability of Information .............................................................................................................................. 6
G. Confidentiality................................................................................................................................................ 6
H. INTRODUCTION ........................................................................................................................................... 6
1. Objective ................................................................................................................................................... 6
2. Foreword................................................................................................................................................... 6
3. FDA GRAS Regulatory Framework .......................................................................................................... 7
4. Regulatory Background for Curcumin ....................................................................................................... 7
II. INGREDIENT IDENTITY, CHEMICAL CHARACTERIZATION, MANUFACTURING PROCESS & PURITY 11
A. Turmeric Botanical Classification ................................................................................................................ 11
B. Common or Usual Name of BCM-95® (Also known as Biocurcumax™ and Biocurcumin™) ...................... 11
C. Chemical and Identity Characterization of BCM-95® ................................................................................... 12
1. Identity and Chemical Characterization of the Turmeric Rhizome (Curcuma spp.) from which BCM 95® is
Derived ................................................................................................................................................... 12
2. Identity and Chemical Characterization of Curcuminoids and Essential Oil in BCM 95® ........................ 13
D. Manufacturing Process................................................................................................................................ 18
E. Product Specifications ................................................................................................................................. 18
F. Stability of BCM-95® .................................................................................................................................... 21
III. INTENDED FOOD USES & ANTICIPATED DIETARY EXPOSURES............................................................ 22
A. Introduction ................................................................................................................................................. 22
B. Intended Dietary Uses ................................................................................................................................. 22
IV. SELF-LIMITING LEVELS OF USE ................................................................................................................. 24
V. COMMON USE OF BCM95® PRIOR TO 1958 ............................................................................................... 25
VI. NARRATIVE- GRAS CONCULSION ............................................................................................................. 26
A. GRAS Criteria ............................................................................................................................................. 26
B. Discussion of Safety of BCM-95® ................................................................................................................ 27
1. JECFA Safety Review............................................................................................................................. 27
2. Safety of the Combination of Turmerone with Curcumin ........................................................................ 28
C. Common Knowledge Elements Supporting GRAS Conclusion ................................................................... 28
D. Panel Findings ............................................................................................................................................ 29
1. Safety Discussion on BCM-95® By An Independent Panel Of Qualified Experts ................................... 29
2. Expert Panel Review of Manufacturing Process for Safety..................................................................... 30
3. Panel Opinion ......................................................................................................................................... 30
4. Common Knowledge Elements Supporting GRAS Conclusion .............................................................. 30
5. Expert Panel Conclusions ....................................................................................................................... 32
E. Dolcas Biotech’s Conclusion of Generally Recognized As Safe for Notified .............................................. 33
Substance, BCM 95® ........................................................................................................................................... 33
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VII. SUPPORTING DATA FOR THE SAFETY ASSESSMENT ON BCM-95® & CURCUMIN TO SUPPORT A
GRAS CONSULSION .............................................................................................................................................. 34
A. Safety Data on Curcumin ............................................................................................................................ 34
B. Biological Activity of Curcumin .................................................................................................................... 35
1. Gastrointestinal System .......................................................................................................................... 35
2. Cardiovascular System ........................................................................................................................... 36
3. Nervous System...................................................................................................................................... 36
4. Lipid Metabolism ..................................................................................................................................... 36
5. Anti-Inflammatory Activity ....................................................................................................................... 37
6. Antioxidant Effects .................................................................................................................................. 37
7. Anticarcinogenic Effects.......................................................................................................................... 37
8. Anticoagulant Activity .............................................................................................................................. 38
9. Antifertility Activity ................................................................................................................................... 38
C. Metabolism of Curcumin.............................................................................................................................. 39
D. Toxicology Studies on (BCM-95®) ............................................................................................................... 40
1. Acute Study ............................................................................................................................................ 40
2. Subchronic Studies ................................................................................................................................. 41
3. Genotoxicity & Mutagenicity Studies on BCM-95® .................................................................................. 41
4. Other Studies in Animals on BCM-95®.................................................................................................... 42
E. Clinical Studies on BCM-95® ....................................................................................................................... 44
1. Joint Health ............................................................................................................................................. 44
2. Urinary Health ......................................................................................................................................... 44
3. Mood and Depression ............................................................................................................................. 45
4. Cognitive Function .................................................................................................................................. 45
5. Chemoprotection..................................................................................................................................... 46
6. Studies in Progress ................................................................................................................................. 47
F. Toxicology Studies on Other Sources of Curcumin ..................................................................................... 48
1. Acute Study ............................................................................................................................................ 48
2. Short-Term Study.................................................................................................................................... 48
3. Genotoxicity & Mutagenicity Studies....................................................................................................... 49
4. Reproductive Study................................................................................................................................. 49
5. Human Studies ....................................................................................................................................... 50
G. Studies Conducted by National Toxicology Program on Curcumin ............................................................. 50
H. JECFA Review of Curcumin & Turmeric ..................................................................................................... 52
I. Safety Studies on Desmethoxycurcumin..................................................................................................... 53
J. Safety Studies on Bisdesmethoxycurcumin ................................................................................................ 53
K. Other Studies on Turmerone ....................................................................................................................... 54
L. Allergenicity ................................................................................................................................................. 55
VIII. REFERENCES ................................................................................................................................................ 57
APPENDIX A FLOW CHART OF MANUFACTURING PROCESS FOR BCM-95® ......................................... 75
APPENDIX B CERTIFICATES OF ANALYSIS FOR FIVE PRODUCTION BATCHES OF BCM-95® ........ 77
APPENDIX C JECFA SPECIFICATIONS FOR CURCUMIN ........................................................................... 83
APPENDIX D ACCELERATED AND LONG-TERM STABILITY REPORT FOR BCM-95® ............................ 87
APPENDIX E ELEVATED TEMPERATURE STABILITY REPORT ................................................................ 94
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APPENDIX F HUMAN STUDIES ON OTHER CURCUMIN PREPARATIONS ...............................................99
TABLES
Table 1. Turmeric Use Levels Set Forth by Health Canada ................................................................................................................. 9

Table 2. Typical Composition of Turmeric Rhizome ........................................................................................................................... 12
Table 3. Chemical Composition of Turmeric ....................................................................................................................................... 13
Table 4. Chemical Composition of Turmeric Essential Oil .................................................................................................................. 13
Table 5. Chemical Identity of Curcumin .............................................................................................................................................. 14
Table 6. Chemical Identity of Desmethoxycurcumin ........................................................................................................................... 16
Table 7. Chemical Identity of Bisdesmethoxycurcumin ...................................................................................................................... 16
Table 8. Chemical Identity of Ar-Turmerone ....................................................................................................................................... 17
Table 9. Finished Product Specifications and Analysis for BCM-95® (5 Batches) ............................................................................. 19
Table 10. Proposed Food Categories and Intended Use Levels for BCM-95® .................................................................................. 23
Table 11. Examples of Curcumin Preparations in Published Scientific Literature .............................................................................. 34
Table 12. Current Clinical Studies Using BCM-95® (from ClinicalTrials.gov) ..................................................................................... 47
Table 13. Summary of Select Curcumin Studies .............................................................................................................................. 100
FIGURES
Figure 1. Chemical Structure of Curcumin .......................................................................................................................................... 14
Figure 2. Chemical Structure of Desmethoxycurcumin ...................................................................................................................... 16
Figure 3. Chemical Structure of Bisdesmethoxycurcumin .................................................................................................................. 17
Figure 4. Chemical Structure of Ar-Turmerone ................................................................................................................................... 17
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DolCas Biotech, LLC
I. GRAS EXEMPTION CLAIM
A. Claim of Exemption From Requirement for Premarket Approval

(Pursuant to Proposed 21 CFR 170.36(c)(1)1 )
DolCas Biotech, LLC (“DolCas”) has concluded that BCM-95® curcumin complex (also
known as Biocurcumax™ and Biocurcumin™), meeting the specifications described in
Table 9 of Section II (E), is Generally Recognized As Safe (GRAS) in accordance with
Section 201(s) of the Federal Food, Drug, and Cosmetic Act. This determination was
made by DolCas in concert with an appropriately convened panel of experts who are
qualified by scientific training and experience to make such safety determinations. The
GRAS evaluation is based on scientific procedures as described in the following
sections, and the evaluation accurately reflects the conditions of the ingredient’s
intended use in foods.
(b) (6)
Signed:
K G Rao, President
DolCas Biotech, LLC
9 Lenel Rd.
Landing, NJ 07850
B. Name & Address of Notifier
DolCas Biotech, LLC

9 Lenel Rd.
Landing, NJ 07850
Person Responsible for the Notification:
K G Rao, President
DolCas Biotech, LLC
9 Lenel Rd.
Landing, NJ 07850
C. Common Name & Identity of Notified Food Substance
The common or usual name of BCM-95® is curcumin.
1 See 62 FR 18938 (17 April 1997) which is accessible at http://www.gpo.gov/fdsys/pkg/FR-1997-04-17/pdf/97-9706.pdf.

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D. Conditions of Intended Use in Food
DolCas intends to incorporate BCM-95® into selected food categories (yogurt, nutrition
bars, smoothies and medical foods) as a nutrient supplement as defined by United
States Food and Drug Administration (FDA) in 21 CFR 170.30 at use levels described in
Section III (B).
E. Basis for GRAS Conclusion
Pursuant to 21 CFR 170.30 (a)(b), BCM-95® has been determined to be GRAS on the
basis of scientific procedures as discussed in the detailed description provided below
with corroborating information provided from the documented history of food use. A
comprehensive scientific literature search conducted through September 25, 2016 was
used in the preparation of this safety evaluation.
F. Availability of Information
The complete data and information that serve as the basis for this GRAS notice are
available to the Food and Drug Administration for review upon request during normal
business hours from DolCas Biotech, LLC.
G. Confidentiality
The data and information contained herein is not confidential nor comprised of trade
secret(s) or contains commercial or financial information that is privileged or confidential
and is therefore not exempt from disclosure under the Freedom of Information Act, 5
U.S.C.552.
H. INTRODUCTION
1. Objective
DolCas has undertaken a comprehensive GRAS evaluation of its product, BCM-95®.

The primary purpose of this evaluation was to ascertain whether or not sufficient safety
documentation is available to conclude that the selected human food uses of the
curcumin preparation can be considered to be generally recognized as safe (GRAS).
2. Foreword
Background information needed to enable the subject GRAS evaluation was compiled to
address the safety/toxicity of curcumin extracts, the intended food uses, and
compositional details, specifications, and method of preparation. The information
compiled also included any adverse reports as well as information that support
conclusions of safety. Determining how much curcumin can be safely consumed (i.e. the
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DolCas Biotech, LLC
use levels) is critical in the determination of the safe exposure levels for curcumin when
consumed as a food ingredient. The composite safety/toxicity studies, in concert with
exposure information, ultimately provided the specific scientific foundation for the GRAS
evaluation.
The safety/toxicity studies, consumption/exposure information, and other related

documentation were augmented with an independent search of the scientific and
regulatory literature conducted through September 25, 2016. Based upon the composite
information, the GRAS notification was developed, using primarily publically available
safety information. Those references that were deemed pertinent to the objective at hand
are listed in Section VIII.
3. FDA GRAS Regulatory Framework
Ingredients for use in conventional foods must undergo premarket approval by FDA as
food additives or, alternatively, the ingredients to be incorporated into such foods must
be determined to be GRAS. The authority to make GRAS determinations is not
restricted to FDA. In fact, GRAS determinations may be provided by experts who are
qualified by scientific training and experience to evaluate the safety of food and food
ingredients under the intended conditions of use.
In 1997, FDA altered the GRAS determination process by eliminating the formal GRAS
petitioning process and replacing the petitioning process with a notification procedure.
Effective October 17, 2016, FDA issued a final rule, Subpart E—Generally Recognized
as Safe (GRAS) Notice, amending and clarifying the criteria for the use of a substance
in food for humans and amending the regulations for a voluntary GRAS affirmation
petition process with a voluntary notification process.
4. Regulatory Background for Curcumin
a. U.S. FDA
Curcumin is a constituent of Turmeric, the dried powdered rhizome of Curcuma longa L.

In the United States, turmeric has been used as a coloring agent in food because of its
bright yellow color. In India, it has been used for centuries as a food preservative and as
a spice in curry dishes (Chainani-Wu, 2003).
FDA describes turmeric as the ground rhizome of Curcuma longa L. and regulates
turmeric as a color additive; 21 CFR 73.600. Furthermore, turmeric oleoresin, described
as the solvent extract of Curcuma longa L., is regulated as a color additive (21 CFR
73.615). The use of turmeric as referenced in 21 CFR 182.10, and turmeric extract or
turmeric oleoresin (21 CFR 182.20) is considered to be GRAS by FDA for use as a spice
and a flavoring agent in foods.
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A search of FDA’s GRAS Notice Inventory website using the search terms “curcumin,”
“turmeric,” and “Curcuma longa” identified one notification, GRN 460, related to turmeric-
derived preparations. GRN 460, “Curcuminoids Purified from Turmeric (Curcuma longa
L.),” was submitted by Sabinsa and filed by FDA on February 28, 2013. The subject of
GRN 460 is a curcuminoids preparation consisting of >95% curcuminoids, with 75-81%
curcumin, 2.2-6/5% bisdemethoxy curcumin and 15-22% desmethoxy curcumin, at use
levels of up to 20 mg per serving as a flavor, flavor enhancer, or nutrient ingredient in a
number of applications (Sabinsa, 2013). FDA noted that the use of curcuminoids in foods
may require a color additive listing. FDA issued a “no questions” letter on August 23,
2013 for GRN 460.
b. Flavor & Extract Manufacturers Association (FEMA)
Turmeric, turmeric extract, and turmeric oleoresin are considered to be GRAS by the
Flavor & Extract Manufacturers Association (FEMA) (Hall and Oser, 1965)
c. Self- Determination GRAS
In 2012, it was reported that Verdure Sciences (Noblesville, IN) obtained self-determined
GRAS status for Longvida® Optimized Curcumin. As a result, Longvida® is reported to be
a safe ingredient for a variety of food categories when used as a flavor enhancer and as
an antioxidant at usage levels of 0.2% to 1.25%. The GRAS determination also covers
Longvida® SD, which is a form of curcumin with enhanced water solubility for food and
beverage applications. A review of the literature has revealed that Longvida®-optimized
curcumin is comprised of tetrahydrocurcumin (TC), a more stable metabolite of
curcumin.
d. Scientific Committee for Food (SCF)
Curcumin was evaluated by SCF in 1975. No Acceptable Dietary Intake (ADI) was set by
SCF as they found that curcumin from natural foods could be classified as a color for
which an ADI could not be established but which is nevertheless acceptable for use in
food. The SCF (1975) identified several gaps in the data at the time of their evaluation
and stated that selected additional studies---metabolic studies in several species and if
possible in man; adequate long-term studies in another species---would be needed if
considerable extension of use in food of this color was contemplated in the future.
e. Joint FAO/WHO Expert Committee on Food Additives (JECFA)
Curcumin was previously evaluated several times by the Joint FAO/WHO Expert
Committee on Food Additives (JECFA). In its latest evaluations, JECFA established food
grade specifications for curcumin in 2004 (FAO, 2004) and finalized the specifications in
2006 (FAO, 2006).
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f. European Food Safety Authority (EFSA)
The most recent safety review was conducted by the EFSA panel on Food Additives and
Nutrient Sources added to Food (EFSA, 2010). This review was a reevaluation to
consider additional literature that became available since a previous review by the EU
Scientific Committee on Food (SCF, 1975) including the new data that led the to the
JECFA establishment of an ADI (WHO, 2004). The Panel agreed with JECFA that
curcumin is not carcinogenic based on carcinogenicity bioassays conducted by NTP
(1993). The Panel also concluded that there were sufficient new data on lack of
reproductive toxicity (study later published as Ganiger et al., 2007) and agreed with
JECFA in establishing the ADI of 3 mg/kg bw/day based on the No Observed Adverse
Effect Level (NOAEL) of 250-320 mg/kg bw/day from a reproductive toxicity study for
decreased body weight gain in the F2 generation which was observed at the highest
dose level, and an uncertainty factor of 10. The Panel concluded that, at the maximum
levels of use, intake estimates from 1- to 10-year-old children at the mean and high
percentile (95th percentile) groups were determined to be less than the ADI of 3 mg per
kg bw per day for adolescents, adults and the elderly. The estimated mean exposure for
toddlers and children was at the ADI, which the high level group exceeded the ADI.
Additionally, EFSA found that the updated exposure estimates were lower than those
determined in 2010 (EFSA, 2014).
g. Health Canada
In 2010, Health Canada published a monograph on, curcumin derived from Curcuma
longa L. (rhizome) for use as a medicinal ingredient at levels not to exceed 400 mg taken
3 times per day (not more than 1,200 mg curcumin per day). No contraindications or
known adverse reactions were noted (Health Canada, 2010a). Health Canada also listed
uses as a “colour” additive and preservative antioxidant (Health Canada, 2014a).
That same year, Health Canada also published a monograph for turmeric (Curcuma
longa L.) dried rhizome for use as an orally administered medicinal ingredient at levels
indicated in Table 1. Health Canada further stipulated that “the only acceptable
potencies are: 3-5% curcuminoids.” No contraindications or known adverse reactions
were noted (Health Canada, 2010b).
Table 1. Turmeric Use Levels Set Forth by Health Canada
CATEGORY
DRY RHIZOME USE LEVEL
Antioxidant 9 g/day
Traditional Chinese Medicine (TCM) 3-9 g/day (as a decoction)
Ayurveda 1-4 g/day (topical application)
Other uses 1-9 g/day
a
Health Canada
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In June 2014, Health Canada published a monograph to serve as a guide to industry

for a Product License Application (PLA) to obtain market authorization for joint health
products. This monograph identified both curcumin and turmeric (Curcuma longa L.
rhizome) as allowable medicinal ingredients that can be used in joint health products
(Health Canada, 2014b).
Furthermore, Health Canada included both curcumin and turmeric (Curcuma longa L.
rhizome) in a list of ingredients for joint health products (Health Canada, 2014b).
h. Food Standards Australia New Zealand
Both curcumin and turmeric appear in a list of food additives prepared by Food
Standards Australia New Zealand (FSANZ, 2014). Both are also referenced in the
2008 “Draft New Zealand Food (Supplemented Food) Standard” as an approved
colorant in supplemented foods (vitamins and minerals).
Space Left Intentionally Blank
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II. INGREDIENT IDENTITY, CHEMICAL CHARACTERIZATION,

MANUFACTURING PROCESS & PURITY
A. Turmeric Botanical Classification
Curcuma longa L., a member of the ginger family Zingaberaceae (Peirce, 1999), is a
perennial herb commonly referred to as turmeric. It grows in tropical areas, including
Hawaii, Puerto Rico, and India. The aboveground portion of the plant consists of
large, elliptic leaves and yellow flowers, which can grow to a height of over 3 feet.
The rhizome is bright orange and is often boiled and dried for culinary purposes
(Bremness, 2002; USDA, 2015).
The botanical classification (USDA, 2015) is as follows:
Kingdom Plantae
Subkingdom Tracheobionta
Superdivision Spermatophyta
Division Magnoliophyta
Class Liliopsida
Subclass Zingiberidae
Order Zingiberales
Family Zingiberaceae
Genus Curcuma L.
Species Curcuma longa L.
The dried root is commonly used as an ingredient in curry powders that are added to
many Indian dishes and piccalilli. In Thai cuisine, the shoots and flowers are eaten as
vegetables. In Indonesia, the leaves are used to flavor fish (Bremness, 2002).
Turmeric is thought to be native to Southeast Asia where many related species of
Curcuma occur in the wild, though turmeric itself is not known to occur in the wild.
B. Common or Usual Name of BCM-95® (Also known as Biocurcumax™ and

Biocurcumin™)
The DolCas product with the commercial name of BCM-95®, also known as
Biocurcumax™ and Biocurcumin™ and the subject of this safety evaluation, has the
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common or usual name of Curcumin Complex from Curcuma longa L., as produced and
sold by DolCas.
C. Chemical and Identity Characterization of BCM-95®
BCM-95® is a reconstituted, purified and standardized turmeric extract from Curcuma

longa L., designed to enhance the oral bioavailability of curcumin in blood. It contains a
specialized unique blend of curcuminoids (curcumin, desmethoxycurcumin and
bisdesmethoxycurcumin) and essential oils of turmeric (turmerone, atlantone, and
Zingiberene). BCM-95® consists of no less than 85% curcuminoids and 5-7% essential
oils. Below describes the chemical composition of turmeric, from which BCM 95 ® is
derived, along with the chemical composition of the turmeric constituent that also
comprise the subject substance.
1. Identity and Chemical Characterization of the Turmeric Rhizome (Curcuma

spp.) from which BCM 95® is Derived
Turmeric (Curcuma longa L.), species has been the subject of extensive research and
chemical characterization, identifying, to date, identifying at a minimum, 235
compounds. These compounds are comprised primarily of phenolic compounds and
terpenoids including 22 diarylheptanoids and diarylpentanoids, eight phenylpropene and
other phenolic compounds, 68 monoterpenes,109 sesquiterpenes, five diterpenes, three
triterpenoids, four sterols, two alkaloids, and 14 other compounds with the curcuminoids
and essential oils as the major bioactive ingredients (Li, S., 2011).
DolCas has determined the typical composition of the turmeric rhizome (from which
BCM 95® is derived) and essential oils (also referred to as volatile oils in the scientific
literature) as represented in Table 2, 3 and 4. The information below is representative of
the physical and chemical information for the major components of BCM 95 ®.
a. Turmeric Rhizome (Curcuma spp.)
DolCas has determined the typical composition of the turmeric rhizome as

represented in Table 2 and 3.
Table 2. Typical Composition of Turmeric Rhizome
Component Percentage (%)

Curcuminoids 4.5
Essential oil of turmeric 5
Turmerones 1.5
Fixed oils 4
Resin 3
Fiber 5.1
Protein 10.1
Starch 52
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Table 3. Chemical Composition of Turmeric
COMPONENT CONCENTRATION
Protein 6.3%
Fat 5.1%
Minerals 3.5%
Carbohydrates 69.4%
Moisture 13.1%
a
Adapted from Chattopadhyay et al., (2004).
b. Turmeric Essential Oils
The typical chemical composition of turmeric essential oils is provided, as described in

the literature, in Table 4. It has been noted in the scientific literature that the main
bioactive components of the Curcuma longa L. essential oil are the sesquiterpines ar-
turmerone (16.7- 25.7%), α-turmerone (14.7- 18.3%), and β-turmerone (14.70-
18.4%)(Ferreira et al., 2013).
Table 4. Chemical Composition of Turmeric Essential Oil
COMPONENT CONCENTRATION
1%
α-phellandrene
0.6%
Sabinene
1%
Cineol
0.5%
Borneol
25%
Zingiberene
Sesquiterpenes 53%
ar-turmerone 16.7- 25.7%
α-turmerone 14.7- 18.3%
β-turmerone 14.70-18.4%
a
Adapted from Chattopadhyay et al., (2004) and Ferreira et al., (2013), Naz, S., (2010).
2. Identity and Chemical Characterization of Curcuminoids and Essential Oil in

BCM 95®
Curcuminoids, a major naturally occurring phenol constituent of turmeric and having a

pronounced yellow color, are extracted from the ground rhizomes of Curcuma longa L.
Curcuminoids are composed of curcumin (diferloylmethane, diferulylmethane),
desmethoxycurcumin (demethoxycurcumin, monodemethoxycurcumin), and
bisdesmethoxycurcumin (bisdemethoxycurcumin; didemethoxycurcumin). These
components of the curcuminoid family are generally present at 71-77%, 10-20% and
5%, respectively (Sharma et al., 2005).
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a. Curcumin (Diferloylmethane, Diferulylmethane)
Curcumin, the major constituent of the curcuminoid class, was first isolated in 1815,
characterized in 1910 as a low molecular weight phenol comprising 2-8% of most
turmeric preparations (Sharma et al., 2005). The chemical structure was later
determined in 1973. Curcumin [1,7-bis-(4-hydroxy-3-methoxyphenyl)-1,6-
heptadiene-3,5-dione] can be further classified as a bis-a,b-unsaturated b-diketone
and exists in equilibrium with its enol tautomer. In acidic and neutral solutions, the
bis-keto form predominates. Figure 1. is representative of the bis-keto form of
curcumin (top) and the enolate form (bottom). Curcumin is insoluble in water, but
dissolves in ethanol, acetone and dimethylsulfoxide (DMSO) with a molecular weight
of 368.37 Daltons and a melting point of 176-177˚C (Chattopadhyay et al., 2004;
Sharma et al., 2005). The chemical identity of curcumin is described in Table 5.
Figure 1. Chemical Structure of Curcumin
a
Curcumin in the bis-keto form (top), which predominates at acidic and neutral
pH and the enolate form (bottom), which is found at pH ~8 (Sharma et al., 2005).
Table 5. Chemical Identity of Curcumin
CURCUMIN (Diferloylmethane Diferulylmethane; Natural Yellow 3)

Chemical Abstracts 458-37-7
Services (CAS) No:
Appearance & odor: Orange-yellow powder; mild odor or odorless
o
Melting point: 183 C
Vapor Density: 13 (Air = 1)
Solubility in water: Insoluble
Other solubility: Soluble in glacial acetic acid, ethyl acetate, methanol and
tetrahydrofuran; slightly soluble in acetone, benzene and carbon
disulfide; insoluble in ether and petroleum ether
Formula: C21H20O6
Molecular weight: 368.41 Daltons
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b. Desmethoxycurcumin (demethoxycurcumin, monodemethoxycurcumin)
The chemical identity of desmethoxycurcumin, a curcuminoid extracted from the ground

rhizomes of Curcuma longa L. is represented below in Table 6 and Figure 2.
Table 6. Chemical Identity of Desmethoxycurcumin
Desmethoxycurcumin (Demethoxycurcumin; Monodemethoxycurcumin)

Chemical Abstracts Services (CAS) No: 22608-11-3
Appearance & odor: Orange powder; mild odor
Melting range: 172-174ºC
Other solubility: Soluble in ethyl acetate, methanol and tetrahydrofuran
Formula: C20OH18O5
Figure 2. Chemical Structure of Desmethoxycurcumin
c. Bis-desmethoxycurcumin
The chemical identity of bis-desmethoxycurcumin is represented Table 7 and Figure 3.
Table 7. Chemical Identity of Bisdesmethoxycurcumin
Bisdesmethoxycurcumin (Bisdemethoxycurcumin; Didemethoxycurcumin)

Appearance & odor: Orange powder; mild odor
Melting range: 227- 229ºC
Other solubility: Soluble in ethyl acetate, methanol and tetrahydrofuran
Formula: C19H16O4
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GRAS Assessment- BCM-95® October 21 , 2016
Figure 3. Chemical Structure of Bisdesmethoxycurcumin
0 0
HO OH
d. BCM 95® ·rurmeric Essential Oil- Ar-Turmerones
The chemical identity of the key turmeric essential oil in SCM 95®, Ar-Turmerone, is
represented Table 8 and Figure 4 .
Table 8. Chemical Identity of Ar-Turmerone
Ar-Turmerone
Appearance & odor: Orange-yellow, occasionally slightly fluorescent liquid
with an odor reminiscent of tubers
Specific gravity at 15°C: 0.938 - 0.967
Optical rotation -13° to -25°
Refractive Index: 1.512 to 1.517 at 20oc
Acid number: 0.6 to 3.1
Ester number: T T 6.5 to 16
~ ~
Ester number after acetylation: 28 to 53

Solubility: v Sbl'uble in 4 to 5 volume of 80% alcohol; soluble in 0.5
r' l-T.. f"\ to 1 volume of 90% alcohol f"\r' l-T.
- .)
Synonyms: Turmerone, Tumerone, Ar-Tumerone
HO Figure 4. Chemical Structure of Ar-TurmeroneoH

C urcumm
Me 0
M Ar-Turmerone
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D. Manufacturing Process
The rhizomes of turmeric are dried and powdered to form powdered turmeric. The
powdered turmeric is extracted with ethyl acetate. After extraction, a solution and a
residue are obtained; the residue is separated from the solution, and ethyl acetate or
ethanol is again added to the residue for extraction. The resultant residue is similarly
extracted with ethyl acetate several times. The solution from each of the ethyl acetate
extraction steps is combined and filtered. The solvent from the filtered solution is stripped
to form an extract. Then the extract is cooled to obtain crystals of curcuminoid and a
liquid. The crystals of curcuminoid are isolated from the liquid by filtration. The crystals
are then powdered to form a powdered curcuminoid mixture.
The liquid after removal of crystals consists of essential oils of turmeric and a resin. The
liquid is then steam distilled to isolate the essential oils of turmeric to a 10-15% Ar-
turmerone. The 10-15% Ar-turmerone fraction is further steam distilled to an essential oil
fraction that consists of a minimum of 45% Ar-turmerone
The curcuminoid powder prepared from the crystals is blended with required quantity of
purified essential oils of turmeric and dried. A flow chart for the manufacturing process is
provided in Appendix A.
E. Product Specifications
The product specifications for BCM-95® and the results of the analyses of five production
batches are listed below in Table 9 (see certificates of analysis attached as Appendix B).
These specifications meet or exceed the requirements of JECFA specifications for
curcumin (FAO, 2006). Dolcas also has provided data that the product is essentially
oxalate free (< 5 ppm based on sensitivity of method). A copy of the JECFA specifications
is attached in Error! Reference source not found..
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Table 9. Finished Product Specifications and Analysis for BCM-95® (5 Batches)
Product name: BCM-95®

Latin Name: Curcuma longa L.L.
Country of Origin: India
Harvest Type: Cultivated -
Plant Part Used: Rhizome
Specificatio (b)
Description Method
n (4)
Physical
Characteristics
Identification Pass Complies Complies Complies Complies Complies TLC
Color Orange red Complies Complies Complies Complies Complies Visual
Appearance Powder Complies Complies Complies Complies Complies Visual
Characteristi Organolepti
Flavor Complies Complies Complies Complies Complies
c c
Characteristi Organolepti
Odor Complies Complies Complies Complies Complies
c c
Analytical
Assay
In House
Herb extract
25:1 Complies Complies Complies Complies Complies Specificatio
Ratioa
n
Solubility (in
Soluble Complies Complies Complies Complies Complies IP
Acetone)
Solubility (in
Insoluble Complies Complies Complies Complies Complies IP
water)
USP 24
Moisture NMT 2% 0.30% 0.35% 0.35% 0.4% 0.30%
<921>
In House
100% Ethyl
Extraction solvent Complies Complies Complies Complies Complies Specificatio
Acetate
n
Particle Size USP 24
20-30 mesh Complies Complies Complies Complies Complies
range <786>
None
Allergens Complies Complies Complies Complies Complies Elisa
detected
Tap Density USP 24
> 0.60 0.72 0.70 0.71 0.73 0.71
(g/mL) <616>
Bulk Density USP 24
> 0.39 0.54 0.55 0.56 0.55 0.54
(g/mL) <616>
Pesticide Complies USP 24
Complies Complies Complies Complies Complies
Residue with USP <561>
In House
Excipients None Complies Complies Complies Complies Complies Specificatio
n
In House
Carriers None Complies Complies Complies Complies Complies Specificatio
n
Residual
Solventsb
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Specificatio 1303 1303 1303 1303 1303

Description Method
n B-56 B-57 B-58 B-59 B-60
NMT 5000
Ethyl Acetate 3,473 3,275 3,863 2,533 1,679 USP <467>
ppm
NMT 50
Ethyl Alcohol Complies Complies Complies Complies Complies USP <467>
ppm
NMT 50
Methanol Complies Complies Complies Complies Complies USP <467>
ppm
NMT 50
Isopropanol Complies Complies Complies Complies Complies USP <467>
ppm
NMT 30
Dichloromethane Complies Complies Complies Complies Complies USP <467>
ppm
NMT 25
Hexane Complies Complies Complies Complies Complies USP <467>
ppm
NMT 30
Acetone Complies Complies Complies Complies Complies USP <467>
ppm
Heavy Metals
Total Heavy
< 10 ppm Complies Complies Complies Complies Complies ICP – MS
Metals
Arsenic < 1 ppm Complies Complies Complies Complies Complies ICP – MS
Lead < 0.5ppm Complies Complies Complies Complies Complies ICP – MS
Mercury < 1 ppm Complies Complies Complies Complies Complies ICP – MS
Microbial Assay
Total Plate AOAC,
<1,000 cfu/g 20 30 30 20 30
Count BAM
AOAC,
Yeast & Mold <100 cfu/g Complies Complies Complies Complies Complies
BAM
AOAC,
Salmonella Absent /25 g Complies Complies Complies Complies Complies
BAM
AOAC,
E. coli Absent /10 g Complies Complies Complies Complies Complies
BAM
Staphylococcus AOAC
Absent /10 g Complies Complies Complies Complies Complies
Aureus ,BAM
Pseudomonas AOAC,
Absent /10 g Complies Complies Complies Complies Complies
Aeruginosa BAM
AOAC,
Aflatoxin Absent Complies Complies Complies Complies Complies
BAM
AOAC,
Coliforms Absent /10 g Complies Complies Complies Complies Complies
BAM
Assay for
Actives
Volatile
Compounds of Present Complies Complies Complies Complies Complies UV – Vis
Turmeric
Total
Curcuminoids
Complex
Consisting of NLT 95% 95.7% 95.9% 95.7% 95.9% 95.8% HPLC
- Curcumin
- Curcuminoids
- Volatile Oils
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Specificatio 1303 1303 1303 1303 1303

Description Method
n B-56 B-57 B-58 B-59 B-60
(from Turmeric
Rhizome)
Total
NLT 86% 87.3% 87.8% 86.8% 87.7% 87.6% HPLC
Curcuminoids
Curcumin NLT 65% 68.5% 68.1% 68.3% 68.8% 68.5% HPLC
a TypicalYield of Curcumin is 4%; e.g. 25 kg of rhizomes produces 1 kg of BCM-95®

b Residue specifications are required by JECFA for acetone, hexane, methanol, ethanol, isopropanol and ethyl acetate (FAO, 2006). All other
solvents listed are customer-driven specifications.
F. Stability of BCM-95®
As demonstrated in an accelerated stability study, BCM-95® is stable and exhibits a room

temperature shelf life of 3 years and 5 months with respect to its curcuminoid content.
Based on the stability study at different temperatures, BCM-95® is stable at elevated
temperatures (up to 60oC) for more than 24 hours. Both accelerated and long-term
stability reports on BCM-95® are provided in Appendix D. Appendix E contains the
Elevated Temperature Stability Report on BCM-95® at temperatures 400C, 500C, and
600C.
Space left Intentionally Blank
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III. INTENDED FOOD USES & ANTICIPATED DIETARY EXPOSURES
A. Introduction
The average intake of turmeric in the diet in India is about 2-2.5 g by a 60 kg individual,
and this corresponds to an intake of about 60-100 mg of curcumin per person per day
(Chainani-Wu, 2003). Another author estimates that the average intake of turmeric by
Asians ranges from 0.5 to 1.5 g/person/day (Chattopadhyay et al., 2004). According to
the Food and Agriculture Organization of the United Nations, over 2,400 metric tons of
turmeric is imported each year into the US for use in cooking and coloring and for other
purposes (Sharma et al., 2005).
B. Intended Dietary Uses
Table 10 lists proposed food categories and intended uses levels for BCM-95®. FDA’s
methodology was used to estimate mean and high total consumption of curcumin from
proposed uses using USDA survey data on daily consumption of various food types (FDA,
2006). FDA’s methodology is recognized as a method that overestimates consumption.
The maximum dietary exposure of BCM-95® from these foods is 182.51 mg curcumin per
day. DolCas does not intend to use BCM-95® to intentionally impart color to food; any
coloring resulting from its use in food as an added nutrient will be unintentional.
In addition, DolCas also intends to incorporate BCM-95® at a level of 500 mg/serving for
use in medical foods. The medical food use is recommended to consist of up to 2 servings
per day. The medical food use is not intended to be long term therapy. The medical food
will only be used as necessary as directed by a physician; however the table below
assumes a two serving per day average use level.
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Table 10. Proposed Food Categories and Intended Use Levels for BCM-95®
USDA Mean Mean Grams

Mean Grams
Grams of x 2 grams
Use Level of curcumin
Food USDA Serving Food curcumin Reference
BCM 95® Consumed
Category Category Size (g) Consumed Consumed Number
(mg/serving) (All
(All (All
Individuals)
Individuals) Individuals)
Ref. 2, Table
Yogurt Yogurt 40 225 8 1.42 2.84 9.4,
p. 29
Nutrition Special
60 45 45 60 120 Ref. 3
bars category
Ref. 1,
Fluid milk
Appendix B
(not
Smoothie 40 244 182 29.84 59.67 (All
consumed
Individuals)
with cereal)
p. 240
Total 91.26 182.51
Reference 1: Foods Commonly Eaten in the United States Quantities Consumed Per Eating Occasion and in a Day, 1994-96 Helen Smiciklas-
Wright, Diane C. Mitchell, Sharon J. Mickle, Annetta J. Cook, Joseph D. Goldman. Available at:
http://www.ars.usda.gov/SP2UserFiles/Place/12355000/pdf/Portion.pdf (Accessed January 14, 2015).
Reference 2: DATA TABLES: Results from the USDA's 1994-96 Continuing Survey of Food Intakes by Individuals and 1994-96 Diet and Health
Knowledge Survey Table Set 10 Food Surveys Research Group, Beltsville Human Nutrition Research Center, Agricultural Research Service, U.S.
Department of Agriculture, 10300 Baltimore Ave., Bldg. 005, Rm 102, BARC-West, Beltsville, Maryland 20705-2350. Available
at: http://www.barc.usda.gov/bhnrc/foodsurvey/home.htm (Accessed January 14, 2015).
Reference 3: Based off of Kellogg’s Special K Nourish Bar Nutritional Information, Available at: http://www.specialk.com/en_us/products/nutrition
bars/dark-chocolate-nut-delight.html (Accessed January 14, 2015).
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IV. SELF-LIMITING LEVELS OF USE
This section is not applicable to this notification.
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V. COMMON USE OF BCM95® PRIOR TO 1958
Turmeric has at least 6,000 years of documented human consumption in Asia (Brouk,
1975). Curcuma appeared in the “Yao Xing Lun” of Chinese medicine in the Tang dynasty
(A.D. 618-907) and was included in the Compendium of Materia Medica in the Ming
dynasty (A.D. 1590) (Yue et al., 2010). Chinese medicine reports the use of the rhizome to
treat clots, bruises, and epilepsy. In Thailand, turmeric is used to treat cobra venom
(Bremness, 2002).
Turmeric is most extensively cultivated in India, followed by Bangladesh, China, Thailand,

Cambodia, Malaysia, Indonesia, and the Philippines. It is also cultivated on a small scale
in most tropical regions in Africa, America, and Pacific Ocean Islands. However, India is
the largest producer, consumer, and exporter of turmeric (Ravindran, 2007).
It should be noted that while there are references to a long time historical use of turmeric
and curcumin (as curcuma), these references are considered to be secondary references
and are not used for the basis of a GRAS conclusion but as corroborative information.
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VI. NARRATIVE- GRAS CONCULSION
A. GRAS Criteria
FDA defines “safe” or “safety” as it applies to food ingredients as:
“…reasonable certainty in the minds of competent scientists that the substance is not
harmful under the intended conditions of use. It is impossible in the present state of
scientific knowledge to establish with complete certainty the absolute harmlessness of
the use of any substance.”2
Amplification is provided in that the determination of safety is to include probable

consumption of the substance in question, the cumulative effect of the substance, and
appropriate safety factors. It is FDA’s operational definition of safety that serves as the
framework against which this evaluation is provided.
Furthermore, in discussing GRAS criteria, FDA notes that:
“…General recognition of safety requires common knowledge about the substance

throughout the scientific community knowledgeable about the safety of substances
directly or indirectly added to food.”
“General recognition of safety through experience based on common use in food

prior to January 1,1958, shall be based solely on food use of the substance prior
to January 1, 1958, and shall ordinarily be based upon generally available data
and information.”3
Practically speaking, the standard for establishing GRAS status is “reasonable certainty of
no harm under the intended conditions of use.” FDA discusses in more detail what is
meant by the requirement of general knowledge and acceptance of pertinent information
within the scientific community, i.e., the so-called “common knowledge element,” in terms
of the two following elements:4
 Data and information relied upon to establish safety must be generally available,
and this is most commonly established by utilizing published, peer-reviewed
scientific journals; and
 There must be a basis to conclude that there is consensus (but not unanimity)
among qualified scientists about the safety of the substance for its intended use,
and this is established by relying upon secondary scientific literature such as
published review articles, textbooks, or compendia, or by obtaining opinions of
2 See 21 CFR 170.3(i).

3 See 21 CFR 170.30(a).
4 See 62 FR 18938 (17 April 1997) http://www.gpo.gov/fdsys/pkg/FR-1997-04-17/pdf/97-9706.pdf.
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expert panels or opinions from authoritative bodies, such as the National Academy
of Sciences.
The apparent imprecision of the terms “appreciable,” “at the time,” and “reasonable
certainty” demonstrates that the FDA recognizes the impossibility of providing absolute
safety in this or any other area (Lu, 1988; Renwick, 1990; Rulis and Levitt, 2009).
B. Discussion of Safety of BCM-95®
Many published studies are available on various preparations of curcumin, including on

BCM-95® itself and similar preparations that contain turmerone.
1. JECFA Safety Review
There is a long review history of curcumin by JECFA. At their seventy-eighth meeting,

JECFA reviewed all other relevant studies and established a tentative ADI of 0-1 mg/kg bw
on the basis of chronic mouse study conducted by the National Toxicology Program (NTP,
1993) on turmeric oleoresin (curcumin content 79-85%). The key effect on liver weight in
mice was used to establish the tentative ADI based on a NOEL of 220 mg/kg bw, and a
200–fold safety factor was used to give the 0-1 mg/kg bw ADI. JECFA acknowledged the
lack of carcinogenic activity seen in the NTP studies and expressed a willingness to
recalculate the ADI after review of an adequately conducted animal study for reproductive
effects. Subsequently JECFA reviewed a reproductive study conducted in rats (Ganiger et
al., 2007). The only effects in this study were minor body weight differences in the F2
generation derived from mating of the F1 generation at the high dose of 850 - 1100 mg/kg
bw/day. The NOAEL was established as the mid-dose in this study of 250-320 mg/kg
bw/day, and the ADI was reestablished without a tentative designation as 0-3 mg/kg
bw/day based on the use of a 100-fold safety factor (WHO, 2004).
It should be noted that there are conflicting studies indicating that curcumin has antifertility
effects. Most notably in a study by Ghosh et al. (2011), anti-gonadotrophic effects were
observed including complete inhibition of ovulation in albino rats at both oral doses studied
(25 and 50 mg/kg bw/day). These results are surprising since in the more rigorous two
generation reproductive study conducted in rats by Ganinger et al. (2007) there was no
interference with reproduction at doses several fold higher.
a. Expert Panel Opinion
In reviewing the afore mentioned study by Ghosh et al., the Panel notes that there was an
absence of many experimental details and results in the publication by Ghosh et al.,
including the documentation of the strain and source of rats used and the results were
described in the narrative without any tabular or graphical presentation of the data. In
view of the documented consumption of curcumin in India of 1 gram/person/day or more
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(equivalent to 16 mg/kg bw/day) and the fact that India has one of the highest birth rates in
the world, the results of the Ghosh study do not seem credible. The Panel has agreed that
the results of the more rigorous study by Ganinger et al. that were reviewed by JECFA are
more comprehensive and indicate the lack of any antifertility effects at current levels of
exposure.
b. DolCas Opinion
DolCas also reviewed the JEFCA opinion and Ghosh et al. (2011) and Ganinger et al. (2007)
studies. DolCas concludes that the Ghosh study is lacking in scientific rigor and the resulting
data from the Ganinger study coupled with the opinion of both JEFCA and the independent
Expert Panel supports the conclusion for a lack of antifertility effects at the current levels of
dietary exposure.
2. Safety of the Combination of Turmerone with Curcumin
The safety of the proposed combination of turmerone with curcumin is supported by

several studies on BCM-95® which showed an absence of adverse effects. These studies
are summarized in a published article (Aggarwal et al., 2016) and include acute oral
toxicity studies in rats and mice and subchronic oral toxicity study in rats where the
NOAEL was 1000 mg/kg bw/day, the highest dose tested. In addition, a lack of
mutagenicity was seen in vitro in bacteria and a lack of clastogenicity was seen in vitro in
mammalian bone marrow cells. Further, there was a lack of effect in vivo in a mouse
micronucleus test.
DolCas finds the compilation of scientific literature on curcumin supports the conclusion of
Generally Recognized As Safe (GRAS).
C. Common Knowledge Elements Supporting GRAS Conclusion
The safety review of BCM-95® is primarily supported by a substantial number of publically

available studies in laboratory animals and human subjects that have been published in
the scientific literature or are otherwise publicly available.
Turmeric, turmeric extract and turmeric oleoresin have long been considered as GRAS by
FDA for use as a spice and a flavoring agent in foods. In addition, FDA considers turmeric
and turmeric oleoresin to be safe as a color additive for use in food. JECFA has reviewed
curcumin several times and has established an ADI of 0-3 mg/kg bw. EFSA confirmed the
safety of curcumin and endorsed the ADI established by JECFA (EFSA, 2010). In
addition is has been reported that Verdure Science, and Sabinsa have made self-affirmed
GRAS determinations for similar curcumin extracts. Many other reviews have been
conducted by several independent scientists, and they consider curcumin to be of low
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toxicity and well-tolerated by oral administration in humans at doses of 1 gram per person
per day or greater (Chattopadhyay, 2004; Sharma, 2005; Epstein et al., 2010).
DolCas, having reviewed the body of scientific knowledge thus concludes that the
common knowledge requirement needed for a valid GRAS conclusion has been fulfilled.
D. Panel Findings
The independent Expert Panel reviewed the complied scientific data, evaluating the
information in order to determine if a GRAS conclusion based on scientific procedures
could be made for BCM 95®. The Expert Panel was comprised of scientists qualified by
both training and experience.
1. Safety Discussion on BCM-95® By An Independent Panel Of Qualified Experts
“The Expert Panel notes that scientific literature on curcumin has been well reviewed by
several independent scientists and support exists for levels higher than 3 mg/kg bw/day as
safe for use in humans. Key points made by these reviews include:
 Epstein et al., (2010) suggested that oral doses up to 12 g/d are well tolerated in
human subjects based on the study by Lao et al., (2006).
 Chattopadhyay et al., (2004) pointed out that the average intake of turmeric by
Asians varies from 0.5 to 1.5 g/person/day without report of adverse effects. This
reviewer cites human trials to also indicate that curcumin has no apparent toxicity
when administered at doses of 1–8 g/day (Chainani-Wu, 2003) and 10 g/day
(Aggarwal et al., 2003).
 Sharma et al., (2005) cites a phase I human trial with 25 subjects using up to 8000
mg of curcumin per day for 3 months noting the absence of toxicity from curcumin
(Cheng et al., 2001), and five other human trials using 1125 – 2500 mg of curcumin
per day have also found it to be safe (Deodhar et al., 1980; Satoskar et al., 1986;
James, 1994; Lal et al., 1999; Lal et al., 2000).
The Expert Panel also agrees with the JECFA conclusion that there is no conclusive
evidence of carcinogenicity based on the state-of-the-art bioassays in rats and mice that
were conducted by the National Toxicology Program (NTP, 1993), while also noting the
lack of genotoxicity found in other assays.
The Expert Panel has reviewed the studies on turmerone and various preparations of
curcumin with turmerone and has not found any additional safety concerns. “
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2. Expert Panel Review of Manufacturing Process for Safety
“The Expert Panel has reviewed the manufacturing procedure and product specifications
for BCM-95®, noting that the manufacturing process does not introduce any harmful
ingredients or chemicals of concern. The specifications are rigorous and establish a good
basis for a food grade product. The Panel also finds that documentation from DolCas
indicates that the manufacturing is conducted in compliance with FDA Good
Manufacturing Practices (GMP) regulations. Long-term studies have shown that the
product is stable.
3. Panel Opinion
“The Expert Panel is of the opinion that there is a strong presumption of safety for BCM-
95®. The JECFA ADI of 3 mg per kg/bw per day for curcumin is based on a significant
number of toxicology and clinical studies on curcumin. FDA responded to GRN 460 for
curcumin with a “no questions” letter and had no objection to proposed uses that did result
in exposure that is greater than the JECFA ADI. DolCas has published toxicology studies
on their product (Aggarwal et al. 2016) which corroborate the toxicology and clinical
studies on curcumin that supported the JECFA ADI. The scientific literature does not
provide any evidence to expect and increased risk of allergy due to oral exposure to BCM-
95®.
Based on the chemical characterization of BCM-95® and a review of the published

literature on BCM-95® and other preparations of curcumin, the Expert Panel concludes
that consumption of BCM-95® at 3 mg/kg bw/day or 180 mg/person/day is generally
recognized as safe when consumed by the general population from the proposed uses in
conventional foods. In addition, the Expert Panel has reviewed the use of up to 1,000
mg/day in medical foods. The Panel notes that use in medical foods will be intermittent
and only when necessary to manage symptoms of certain patients as directed by a
physician. This medical supervision when viewed in concert with the fact that curcumin
consumption in India has been estimated at greater than 1,000 mg/person/day plus, as
well as the recognition of several well conducted clinical studies at 1,000 mg/person/day
without adverse effects, in the collective provide support for the safety of BCM-95® at this
dose.”
4. Common Knowledge Elements Supporting GRAS Conclusion
The convened Expert Panel reviewed the assembled scientific literature and also offered
their conclusion regarding the fulfillment of “common knowledge” requirement.
“The Expert Panel agrees that there is sufficient information in the literature that there
would be a consensus of experts that would conclude that BCM-95® is safe for the
proposed food uses.
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The Expert Panel believes that a consensus of scientists reviewing the above published
studies (Reference Section VI (C)) would conclude that BCM-95® is generally recognized
as safe for its intended use at 180 mg/person/day for the general population and for the
use in medical foods at levels of 1000 mg/person/day for intermittent use under medical
supervision. The Expert Panel agrees that there is sufficient information in the literature
that there would be a consensus of experts that would conclude that BCM-95® is safe for
the proposed used. Consequently, the common knowledge requirement needed for a
valid GRAS conclusion has been fulfilled.”
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5. Expert Panel Conclusions5
“The Dolcas curcumin product, referred to as BCM-95® that is produced in

accordance with FDA Good Manufacturing Practices requirements and
which complies with the food grade specifications depicted in Table 9 of
this safety evaluation is Generally Recognized As Safe when used as an
ingredient in smoothies, yogurt and nutritional bars at levels summarized in
Table 10, resulting in a maximum dietary level in the general adult
population of 3 mg/kg bw/day or 180 mg/person/day. In addition, the use of
up to 1,000 mg/person/day in medical foods on an intermittent basis as
directed by a physician is also Generally Recognized As Safe.”
“We have independently and collectively evaluated the above-referenced information and
offer this GRAS declaration based on scientific procedures in accordance with FDA’s
standard for food ingredient safety, i.e., reasonable certainty of no harm under the
intended conditions of use. “
June 29, 2016

(b) (6)
(b) (6)
Richard C. Kraska, Ph.D., DABT Robert S. McQuate, Ph.D.
(b) (6)
Kara Lewis, Ph.D.
5
The detailed educational and professional credentials for some of the individuals serving on the Expert Panel can be found on the GRAS
Associates website at www.gras-associates.com. Drs. Kraska and McQuate worked on GRAS and food additive safety issues within FDA’s GRAS
Review Branch earlier in their careers and subsequently continued working within this area in the private sector. Dr. Lewis has extensive
experience in preparing GRAS dossiers. All three panelists have extensive technical backgrounds in the evaluation of food ingredient safety. Each
individual has previously served on multiple GRAS Expert Panels. Dr. Kraska served as Chair of the Panel.
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E. Dolcas Biotech’s Conclusion of Generally Recognized As Safe for Notified

Substance, BCM 95®
DolCas has concluded that the notified substance, BCM 95® (also known as Biocurcumax™
and Biocurcumin™ and commonly referred to as curcumin) is GRAS and that the safety
standards, per 21 CFR Part 170.30 Subpart E, of reasonable certainty of no harm, based on
scientific procedures and common knowledge as described herein, are met. This conclusion
is based on the in-depth review of the collective generally available scientific data regarding
the safety of BCM 95® curcumin, common knowledge and general consensus among
qualified experts corroborated by the written GRAS conclusion of an independent Expert
Panel of qualified persons whom reviewed all publicly available referenced safety data.
We certify that this GRAS notification is complete and is a balanced representation of all data
available.
October 21, 2016

(b) (6)
K G Rao, President
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VII. SUPPORTING DATA FOR THE SAFETY ASSESSMENT ON BCM-95® &

CURCUMIN TO SUPPORT A GRAS CONSULSION
A. Safety Data on Curcumin
The publically available scientific literature on curcumin is expansive. Both the biological
activity and toxicity of multiple preparations of curcumin with different composition have
been evaluated. Examples of formulations of curcumin that have been investigated are
included in Table 11.
Table 11. Examples of Curcumin Preparations in Published Scientific Literature
Curcumin Preparation Composition Selected Citation(s)
88% total curcuminoids (curcumin,

demethoxycurcumin bisdesmethoxycurcumin)
®
BCM-95 (Arjuna Natural Sanmukhani et al.,
and volatile oils from rhizomes of Curcuma
Extracts) (2014)
longa L.L.
Mixture of three curcuminoids: curcumin (1a,

Commercially available
ca.70-75%), demethoxycurcumin (1b, ca. 15-
natural curcumin (obtained
20%), and bisdemethoxycurcumin (1c, ca. 5- Cuomo et al., (2011)
from extraction from turmeric)
10%)
Standardized mixture of natural curcuminoids

and lecithin in a 1:2 ratio, with 2 parts
microcrystalline cellulose (20% natural
curcuminoid mixture, 40%
phosphatidylcholine, and 40% Cuomo et al., (2011)
microcrystalline cellulose). Similar ratio of
curcuminoids as natural curcumin
16.89% curcuminoids, of which 93.82% was
curcumin with a ratio of curcumin to Epikuron
130 of 1:4. Epikuron 130 P is a “deoiled, Marczylo et al., (2007)
powdered soybean lecithin enriched with 30%
Curcumin Phospholipid phosphatidylcholine”.
®
Products (Meriva )
Natural curcuminoid mixture (20%),
phosphatidylcholine (40% and Belcaro et al., (2010)
microcrystalline cellulose (40%). Curcuminoid
mixture contained 75% curcumin, 15%
demethoxycurcumin, and 10%
bisdemethoxycurcumin.
Curcumin 13.02%; demethoxycurcumin Cucuzza et al., (2008)
®
Curcuvet 4.03%; bisdemethoxycurcumin 2.95%, total Farinacci et al., (2009
curcuminoids 20.0% + phospholipids 80%) a, b)
Cuomo et al., (2011)
Curcumin only, generally obtained by
Monomolecular curcumin
synthesis.
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Curcumin Preparation Composition Selected Citation(s)
Curcumin (synthesized + small amounts of

20% of desmethoxycurcumin and
®
Curcumin-C3 Complex Irving et al., (2013)
bisdemethoxycurcumin).
Huamn: Storka et al.,
® 400 mg lipoic acid plus 400 mg curcumin
Lipicur (2015), Di Pierro et al.,
phytosome (Meriva®) plus 4 mg piperine.
(2013)
Made from fenugreek (Trigonella
goenumgraecum) – derived soluble dietary
fiber made of galactose and mannose units,
delivers high levels of curcumin, 1 to 1.5 µM
for 6 to 8 hours after administration compared Liju et al., (2015)
Cucumagalactomannosides with 0.04 to 0.08 µM for less than 1 hour.
10% curcumin, 2% other curcuminoids such

® as demethoxycurcumin and Huma: Kanai et al.
Theracurmin
bisdemethoxycurcumin, 46% glycerin, 4% (2011, 2012, 2013)
(Liquid type, CR-011L) gum ghatti, and 38% water. Sasaki et al., (2011)
Human: Cox et al.,
Solid lipid curcumin particle, 400 ng contains
(2014)
approximately 60 mg curcumin, excipients,
®
Longvida Optimized and small amounts of other curcuminoids
Animal:
Curcumin present in turmeric extract.
Dadhaniya et al.,
(2011)
curcumin micronisate produced concentrated

powder form” technology* blending 25%
Curcumin Micronized Powder curcumin powder with 58.3% triacetin and Schiborr et al., (2014)
16.7% panodan (E472e.Solution is sprayed
onto silicon dioxide
Composed of 7% curcumin powder

Curcumin Liquid Micelles (equivalent to 6% curcumin) and 93% Tween- Schiborr et al., (2014)
80 (Kolb, Hedingen, Switzerland)
Curcumin loaded polymeric Preparation of hydrogel nanoparticles:

Dandekar et al.,
nanoparticles of Eudragit combination of hydroxyl propyl methyl
(2010)
S100 cellulose and polyvinyl pyrrolidone.
Wet-milling technique with narrow particle
Curcumin nanoparticles Yin et al., (2013)
size distribution in the range of 2-40 nm
* Brunner, G., Applications of supercritical fluids. Ann. Rev. Chem. Biomol. Eng. 2010, 1, 321–342
B. Biological Activity of Curcumin
1. Gastrointestinal System
Turmeric increases mucin secretion in rabbits and may act as a gastroprotectant against
irritants (Lee et al., 2003). However, the ability of curcumin to protect against stomach
ulcers is in question. In guinea pigs, 50 and 20 mg curcumin/kg bw has been shown to
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protect the stomach from phenylbutazone and 5-hydroxytryptamine-induced ulcers,

respectively (Dasgupta et al., 1969, Sinha et al., 1974). However, 0.5% curcumin failed to
protect against histamine-induced ulcers (Bhatia et al., 1964). In a study that was
reviewed by JECFA in WHO Food Additive Series 17 (WHO, 1982), 50 mg/kg bw and 100
mg/kg bw curcumin produces ulcers in rats after daily administration for 6 days (Gupta et
al., 1980). A more recent study demonstrates the anti-ulcer activity of curcumin in rats at
doses in the range of 20-80 mg/kg bw given for 6 days. The protection against ulcers was
likely through decreased acid secretion and effects on other ulcerative effectors (Tuorkey
and Karolin, 2009).
In the intestine, curcumin enhances the activity of enzymes such as lipase, sucrase and
maltase (Platel and Srinivasan, 1996). Antiflatulent activity of curcumin was observed in
rats (Bhavani Shankar and Sreenivasa Murthy, 1979) and antispasmotic activity of sodium
curcuminate has been observed in isolated guinea pig ileum (Rao et al., 1982).
In the liver, increased bile production was observed in dogs by both curcumin and
essential oil of C. longa (Jentzsch et al., 1959; Ozaki and Liang, 1988). In rat hepatocytes,
curcumin and its analogs have shown protective activity against carbon tetrachloride
(CCl4), D-galactosamine, peroxide and ionophore-induced toxicity (Hikino, 1985; Song et
al., 2001; Kang et al., 2002). In the pancreas, curcumin also increases the enzyme activity
of pancreatic lipase, amylase, trypsin and chymotrypsin (Platel and Srinivasan, 2000).
2. Cardiovascular System
Evidence from available studies shows that curcumin attenuates the severity of damage
caused by myocardial infarction (Nirmala and Puvanakrishnan, 1996). Curcumin also
improves Ca2+-transport in the cardiac muscle, which could possibly aid pharmacological
intervention to correct defective Ca2+ homeostasis (Sumbilla et al., 2002). It has also been
shown that curcumin has significant hypocholesteremic effects in hypercholesteremic rats
(Patil and Srinivasan, 1971).
3. Nervous System
The antioxidant activity of curcumin and a manganese complex of curcumin results in the
protective action against vascular dementia (Vajragupta et al., 2003; Thiyagarajan and
Sharma, 2004).
4. Lipid Metabolism
In rat plasma, curcumin reduces low density lipoprotein (LDL), very low density lipoprotein
(VLDL), and total cholesterol in liver with an increase in alpha-tocopherol. This suggests
an in vivo interaction between curcumin and alpha-tocopherol to increase the
bioavailability of vitamin E and decrease cholesterol levels (Kamal-Eldin et al., 2000). The
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fatty acid content of serum after ethanol-induced liver damage is significantly decreased
by curcumin treatment (Akrishnan and Menon, 2001)
5. Anti-Inflammatory Activity
In rats and mice, curcumin is effective against carrageenan-induced edema (Ghatak and
Basu, 1972; Rao et al., 1982; Srivastava and Srimal, 1985; Brouet and Ohshima, 1995;
Srimal and Dhawan, 1985). In addition, the volatile oil of C. longa shows potent anti-
inflammatory effects (Yegnanarayan et al., 1976). In humans, curcumin administration
has resulted in relief from rheumatic symptoms (Deodhar et al., 1980). It has been found
that the anti-inflammatory effect of curcumin is mediated through inhibition of NFkB
(nuclear factor kappa-light-chain-enhancer of activated B cells) activation and the down
regulation of cyclooxygenase-2 and nitric oxide synthase through suppression of NFkB
activation (Surh et al., 2001). Curcumin also has been shown to aid wound healing in
diabetic mice (Sidhu et al., 1999).
6. Antioxidant Effects
Curcumin acts as a scavenger of free radicals (Ruby et al.; 1995, Subramanian et al.,
1994) and can protect hemoglobin from oxidation (Unnikrishnan and Rao, 1995). In vitro,
curcumin mediates inflammation by significantly inhibiting the generation of reactive
oxygen species (ROS) like superoxide anions, H2O2 and nitrite radical formation by
activated macrophages. Curcumin also lowers ROS in vivo (Joe and Lokesh, 1994) and
since ROS have been implicated in the development of various pathological conditions
(Bandyopadhyay et al., 1999, Halliwell, 1998, Halliwell and Gutteridge, 1990), curcumin
can control diseases through antioxidant activity.
In contrast, curcumin has also shown pro-oxidant activity. One study reported that
curcumin failed to prevent H2O2-induced single-strand DNA breaks, and also caused DNA
damage (Kelly et al., 2001). Curcumin has also been shown to cause oxidative damage of
rat hepatocytes and the human erythrocytes (Galati et al., 2002).
7. Anticarcinogenic Effects
Curcumin acts as a potent anticarcinogenic compound via various mechanisms. One

mechanism is the induction of apoptosis and inhibition of cell-cycle progression (Chen and
Huang, 1998). Curcumin also suppressed tumor growth through the inhibition of iNOS
(nitric oxide synthase) and COX-2 (cyclooxygenase-2) production (Brouet and Ohshima,
1995). However, curcumin affects distinct cell lines differently. Leukemia, breast, colon,
hepatocellular and ovarian carcinoma cells all undergo apoptosis in the presence of
curcumin. However, lung, prostate, kidney, cervix, melanoma cells and CNS malignancies
all show resistance to the cytotoxic effect of curcumin (Khar et al., 2001).
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8. Anticoagulant Activity
Curcumin demonstrates anticoagulant activity by inhibiting collagen and adrenaline-

induced platelet aggregation in vitro and in the rat thoracic aorta in vivo (Srivastava et al.,
1985).
9. Antifertility Activity
Turmeric extracts have a history of use as a folk medicine in India as an antifertility and
aborcifacient agent (Ghosh et al., 2011). Curcumin inhibits the motility of sperm in
humans (Rithaporn et al., 2003) and inhibits the growth of flank organs in the hamster
(Liao et al., 2001). In rats, the oral administration of turmeric rhizome extracts resulted in
a 100% antifertility effect at doses of 100 or 200 mg/kg bw (Garg, 1974). These same
authors did not find anti-ovulatory effects in rabbits at doses of up to 200 mg/kg bw of this
extract. As a result of their review of these studies, JECFA requested a multigeneration
reproduction/teratology study (WHO, 1982). The committee subsequently reviewed an
unpublished multigeneration reproductive study in rats (later published as Ganiger et al.
(2007). The results of this study were sufficient for The Committee to allocate an ADI of 0-
3 mg/kg bw for curcumin, based on the NOEL of 250-320 mg/kg bw per day in the
multigeneration study, and the application of a safety factor of 100 (WHO, 2004).
In a more recent study, the histopathological examination of ovaries in albino rats after
curcumin administration revealed that curcumin has an antiovulatory effect (Ghosh et al.,
2011). Two groups of six animals each received oral curcumin doses of either 25 mg/kg
bw or 50 mg/kg bw for 10 days. Animals were sacrificed and histopathological
examination of the ovaries and uteri were done. Vaginal smears were also observed in
treatment and control animals to determine the occurrence of ovulation during the oestrus
cycle. In the control group there were normal ovaries, uterus and oestrus cycle. In the
curcumin treated groups there was no evidence of ovulation and no features of ovulation
in the histopathological examination of the ovaries. The authors concluded that curcumin
appears to suppress the oestrus phase in rats.
In another study, the oral administration of curcumin did not affect fertility in mice (Naz,
2011). However, curcumin did reduce human and murine sperm motility and function in
vitro, and also reduced the in vivo fertility in female mice when administered intravaginally
(i.v.) and intraperitoneally (i.p.). The in vitro incubation of human and murine sperm with
curcumin caused a concentration-dependent decrease in sperm forward motility. Another
study was performed to determine the effect of curcumin on the in vivo fertility in female
mice. Ten to 500 µg of curcumin dissolved in DMSO was administered orally each night
before mating, and by the i.p. and i.v. routes. The oral administration of curcumin did not
affect fertility. The administration of curcumin via i.p. and i.v. caused a significant
reduction in fertility. The mice that were treated with curcumin were successfully mated
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again without any curcumin treatment, demonstrating that the contraceptive effect of
curcumin may be reversible.
The antifertility effect of an aqueous extract of Curcuma longa L. was investigated in the
male mouse (Mishra and Singh, 2009). Male Parkes mice were orally administered 600
mg Curcuma longa L. extract/kg bw/day for 56 and 84 days. Recovery studies were also
performed. Histological examination shows that the mice treated with the test article had
non-uniform degenerative changes in the seminiferous tubules including marked reduction
in diameter, loosening of germinal epithelium and mixing of spermatids of different stages
of spermatogenesis. The epididymis and seminal vesicle also showed histological
changes compared to control animals. In addition, the treatment had adverse effects on
motility, viability, morphology and number of spermatozoa. In treated animals, there were
also reductions in serum testosterone, fertility and litter size after mating. After 56 days of
treatment withdrawal, the above parameters were recovered to control levels.
The contraceptive effect of Curcuma longa L. extract in males was also demonstrated in
the albino rat (Ashok and Meenakshi, 2004). Rats were fed daily oral doses of C. longa
aqueous extract and 70% alcoholic extract for 60 days. In both of the treated groups,
reductions in sperm motility and density were observed. The authors concluded that C.
longa may have affected androgen synthesis by inhibiting the Leydig cell function or the
hypothalamus pituitary axis, which results in arrested spermatogenesis.
C. Metabolism of Curcumin
Standard curcumin exhibits minimal bioavailability due to poor absorption from the gut.
The major portion of ingested curcumin is excreted in an unmetabolized form in the feces
(Sharma et al., 2005). A small portion that is absorbed is converted into water-soluble
metabolites and is excreted. Therefore, the ability of standard curcumin to impart a
biological effect on target tissues is very limited (Antony et al., 2008).
An early study in rodents demonstrated that an oral dose of 1 g/kg bw of standard

curcumin resulted in the excretion of 75% of the dose in feces and a negligible amount in
the urine (Wahlstrom and Blennow, 1978). An intravenous study in rodents resulted in
large quantities of curcumin and tetrahydrocurcumin and hexahydrocurcumin metabolites
in the bile. After dosing, more than 50% was excreted in the bile within 5 hours
(Ravindranath and Chandrasekhara, 1981; Holder et al., 1978). A preclinical oral study in
rats showed that metabolic reduction of curcumin happens within minutes of
administration. Small amounts of curcumin were detected in the plasma of the rats with
higher levels of curcumin glucuronide and curcumin sulfate in the plasma (Ireson et al.,
2002). A study using 2% curcumin in the diet (equating to 1.2 g curcumin/kg bw) for 14
days showed that low nanomolar levels are detectable in the plasma, with concentrations
in the liver and mucosal tissue of the colon ranging from 0.1 to 1.8 nmol/g tissue.
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In humans, low systemic bioavailability was demonstrated in pilot and Phase I clinical trials
performed with standard curcumin. An explanation for the poor systemic availability when
administered orally may be efficient first-pass metabolism by the liver, leaving a limited
amount to be passed on to the rest of the system. However, some degree of intestinal
metabolism and absorption does occur as suggested by the detection of metabolites in the
plasma of patients consuming high daily doses of curcumin (Sharma et al., 2005). In a
pilot study where patients consumed 3.6 g of curcumin for 7 days prior to hepatic surgery,
only trace levels of metabolites were detected in the peripheral blood samples and liver
(Garcea et al., 2004). The authors of this pilot study concluded that the dose of oral
curcumin required to produce hepatic levels high enough to exert pharmacological activity
cannot be readily attained and such an approach of administering curcumin orally is
probably not feasible.
BCM-95® is a curcumin preparation with enhanced bioavailability from a unique blend of

curcuminoids and the essential oil of turmeric. The bioavailability of BCM-95® is 7-8 times
higher than for standard curcumin. Moreover, curcumin is retained in the blood for
significant levels---even at 8 hours post administration. This was demonstrated in a cross-
over study to evaluate the human oral bioavailability of BCM-95® (Antony et al., 2008).
Metabolism in the blood was analyzed 1, 2, 3, 4.5, 6 and 8 h after dosing with 4 x 500 mg
capsules of BCM-95® and compared with a similar dose of standard curcumin. It was also
compared to a curcumin-lecithin piperine preparation which has been used in other studies
and shown to provide enhanced bioavailability. Results showed that the absorption of
curcumin was faster from the BCM-95®, peaking in the first hour and reaching a maximum
at 4.5 h. After 8 h, some residual curcumin remained in the blood. The absorption of
standard curcumin was slower, peaking at 2 hours and disappearing after 4.5 hours. The
relative bioavailability of BCM-95® was about 6.93-fold compared to standard curcumin.
D. Toxicology Studies on (BCM-95®)
1. Acute Study
Swiss albino mice and Wistar albino rats (10 male and 10 females) were used for an acute
toxicity study (Aggarwal et al., 2016). BCM-95® was administered orally at the dose level
of 5,000 mg/kg bw and a group of five males and five females were administered vehicle
control. The animals were observed for a period of 14 days. No mortality or treatment
related toxic signs and symptoms were observed. The body weight gain between the
treated group and the control was not significantly different. At the end of the study,
necropsy did not reveal any pathologically significant abnormality. The LD 50,, maximum
tolerated dose, and minimal lethal dose of BCM-95® for rats and mice is >5,000 mg/kg bw.
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2. Subchronic Studies
A 90-day repeated dose oral toxicity study was performed in Wistar rats in accordance
with the guidelines OECD 408 (Aggarwal et al., 2016). Four groups of 20 animals (10
male and ten female) received via oral gavage either 0 (vehicle control), 100, 500 and
1000 mg/kg bw BCM-95® for 90 days. Two additional satellite groups of 10 rats (5 male
and 5 female) ---also designated as “satellite control” and “satellite high dose”, were
administered vehicle and 1000 mg/kg bw BCM-95®, respectively, for 90 days. After
terminal sacrifice of the test and control group animals, the satellite animals were kept
under observation for an additional 28 days to determine any delayed toxic effect. There
were no treatment related toxic signs in any of the BCM-95® treatment groups or high
dose satellite treatment group compared to the control group. The body weight gains of all
of the treatment groups and satellite dose animals were comparable to their control
counterparts. Feed consumption of the dose groups was also comparable to the control
animals. No variations were observed in the hematological parameters of any of the
treatment animals compared to controls. In addition, no differences in any of the
biochemical parameters between treatment and control animals were reported. No
differences were observed between treatment and control groups on the analysis of the
urine samples collected at the end of the experiment. For the animals sacrificed at day 90
and in the satellite animals observed for an additional 28 days, organ weights of the
treatment groups were comparable to the control group. There were no histopathological
differences between any of the treatment groups and their counterpart controls. The
NOAEL of BCM-95® is 1000 mg/kg bw in Wistar rats, the highest dose tested.
In an additional rat study, BCM-95® was administered to four groups of five female rats in
the diet at the levels of 0, 100, 250, and 750 mg/kg bw/day for 45 days (Aggarwal et al.,
2016). At the end of the study period, hematological, biochemical and histological
analyses were performed. No death or abnormality occurred in the control or treated
animals, and no adverse physical changes were observed. Clinical, hematological and
biochemical parameters in BCM-95®-treated animals were comparable to untreated
controls. There was no significant change in clotting time although an increase in total
leukocyte count was observed in treated animals. Serum total protein, albumin, globulin,
SGOT, SGPT and blood glucose were not affected although serum alkaline phosphatase
increased in rats receiving high doses of BCM-95®. While serum total cholesterol was
decreased, hepatic cholesterol and triglycerides were not affected in BCM-95®-treated
animals. These exposures of BCM-95® also did not produce any histological lesions in
liver.
3. Genotoxicity & Mutagenicity Studies on BCM-95®
In an Ames test (bacterial reverse mutation assay), BCM-95® was tested against the
Salmonella typhimurium strains TA-98, TA-100, TA-102, TA-1535 and TA-1537 with and
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without metabolic activation at the concentrations of 1000, 2000, 3000, 4000 and 5000
μg/plate (Aggarwal et al., 2016). The colony count in the test groups was not significantly
different from the negative control group. Adequate responses in the positive control
plates confirmed the sensitivity of the Salmonella strains. The test was negative for
mutagenicity in all the strains with and without metabolic activation.
A mammalian bone marrow chromosome aberration test was performed using BCM-95® in
albino Wistar rats (Aggarwal et al., 2016). A group of 20 rats (10 males and 10 females)
was administered BCM-95® orally at a single dose of 2000 mg/kg bw, and a negative
control group was administered vehicle only. A positive control group was administered
cyclophosphamide at a dose of 50 mg/kg bw intraperitoneally. Bone marrow was
processed at sacrifice, 18 and 24 hours after dosing. No evidence of structural or
chromosomal aberrations was observed at 2000 mg/kg bw BCM-95®. The total number of
aberrations in the treatment group was not significantly different than the control group. It
was concluded that BCM-95 ® had no clastogenic activity under the conditions of the study
up 2000 mg/kg bw.
A mammalian erythrocyte micronucleus test in mice was performed using BCM-95®

(Aggarwal et al., 2016). A total of 60 animals (30 males and 30 females) was distributed
into three main groups and orally administered either 2000 mg BCM-95®/kg bw, negative
vehicle control, or a positive control of cyclophosphamide. Bone marrow was processed
at the times of sacrifice which were 24 and 48 hours after dose administration. No
mortality or toxic signs were observed in any of the animals, nor were significant observed
changes found in the number of immature and mature erythrocytes or in the total number
of erythrocytes of treated male and female animals at the 2000 mg/kg bw treatment level
at 24 and 48 hours compared to the controls. In addition, there were no observable
effects in the micronuclei at 24 or 48 hours in the treatments groups compared to the
negative control. It was concluded that BCM-95® did not show any clastogenic potential in
the micronucleus test.
4. Other Studies in Animals on BCM-95®
The effect of 300 mg BCM-95®/kg bw was assessed by studying the markers of liver
function in a group of male Sprague-Dawley rats with carbon tetrachloride (CCl4)-induced
liver injury and alcohol-induced liver injury (Dolcas, unpublished study). CCl4-induced
hepatitis was produced in rats by administering a low dose of CCl4 for three months.
Alcohol-induced hepatitis was produced by administering alcohol to rats for three months.
One group of rats receiving CCl4 or alcohol for three months also received daily BCM-95®
in the feed. Liver injury was assessed by changes in parameters such as an increase in
serum enzymes, e.g., glutamic-oxaloacetic transaminase (GOT), glutamic-pyruvic
transaminase (GPT) and lactate dehydrogenase (LDH), a decrease in albumin-globulin
ratio, an increase in serum lipids such as cholesterol and triglyceride and an increase in
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serum bilirubin. BCM-95® appeared to have a protective effect against CCl4-induced liver
injury as evidenced by a decrease in the level of serum enzymes, increase in
albumin/globulin (A/G) ratio, decrease in serum cholesterol and triglyceride (TG), bilirubin
and urea. BCM-95® also appears to reduce steatosis as evidenced by a decrease in the
level of cholesterol and TG in the liver. It also appeared to have an antifibrotic effect as
evidenced by a decrease in the extent of accumulation of collagen in liver. Treatment with
BCM-95® appeared to offer a protective effect against alcoholic hepatitis based on the
observed reversal of changes in abnormal liver function tests such a serum transminases,
serum lipids and bilirubin. The extent of steatosis and fibrosis caused by alcohol appeared
to be less in rats receiving BCM-95®, indicating a protective effect against alcoholic
hepatitis. However, evaluation of biochemical parameters indicated that it offers only a
partial protective effect.
Leray et al. (2011) studied the effect of a blend of BCM-95® and citrus polyphenol-
supplemented diet on the inflammatory state in obese cats. Two groups of cats (n=8, 3
males, 5 females) were fed a diet supplemented with either citrus extracts (protein 34·3 %,
fat 15·4 %, starch 30·6 %, hesperidin (Natural Orange Extract; Exquim SA, Barcelona,
Spain) 0·05% and naringin (citroflavonoids soluble; Exquim SA) 0·1% diet) or with highly
bioavailable curcumin extract from C. longa (protein 34·2%, fat 16·5%, starch 28%, Bio-
Curcumin (BCM-95®, Frutarom, Londerzeel, Belgium) 0·09% diet), for two 8-week periods
in a crossover design. Many markers of inflammation were unaffected by either treatment,
except for a decreased concentration of plasma acute-phase protein (APP). The authors
concluded that hesperidin and naringin or BCM-95® have beneficial effects on the obesity-
related inflammatory state. No adverse effects were reported in any of the experimental
animals throughout the study period.
Sanmukhani, et al. (2011) conducted a study in rats and mice where they investigated the
antidepressant-like activity of BCM-95® and its combination with fluoxetine and
imipramine. Efficacy was evaluated by using the forced swimming test (FST) in glass jar
and the tail suspension test (TST) after acute (three doses) dosing in mice; and the forced
swimming test with activity wheel after chronic (14 days) dosing in rats. Locomotor activity
was also tested after acute dosing in mice. Both the acute model of FST and TST, and
the chronic model of FST with water wheel showed significant antidepressant-like activity
of curcumin in 100 mg/kg dose of BCM-95®compared with the vehicle control. The effect
of BCM-95® (100 mg/kg) was similar to that of fluoxetine and imipramine, but its addition to
fluoxetine and imipramine did not improve their antidepressant activity. BCM-95®
increased both the swimming and climbing behavior in FST. It was concluded that the
antidepressant-like activity could be due to an increase in serotonin, norepinephrine and
dopamine levels in the brain. No signs of neurotoxicity were observed in this study.
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E. Clinical Studies on BCM-95®
Several clinical studies have been conducted on BCM-95® that were designed to show
efficacy in maintaining health.
1. Joint Health
The safety and efficacy of BCM-95® and Boswellia serrat (Bospure®) extracts were
evaluated and compared with a selective COX-2 inhibitor in 28 healthy subjects
(Kizhakkedath et al., 2013). The BCM-95® formulation was administered twice a day at a
dose of 500 mg, and was more successful than the COX-2 inhibitor administration of 100
mg twice a day for joint health symptoms. The treatment was well-tolerated and no
adverse effects were observed in vital signs, hemogram, liver and renal function tests.
Chandran and Goel (2012) studied the safety and efficacy of BCM-95® in patients with
rheumatoid arthritis (RA). Forty-five (38 female, 7 male, mean age 47.88 years) patients
diagnosed with RA were divided into three groups receiving either 500 mg BCM-95® or
diclofenac sodium (50 mg) alone or in combination for 8 weeks. Patients in all treatment
groups showed significant changes in their Disease Activity Score (DAS). The group
receiving BCM-95® showed the highest improvement in DAS and American College of
Rheumatology (ACR) criteria for reduction in tenderness and swelling of joint scores.
Hematology, blood chemistry, C-reactive protein, antistreptolysin-O, rheumatoid factor,
and blood sugar were monitored bi-weekly for safety evaluation. There were no major
changes among groups in blood urea, serum creatinine, serum calcium, serum
phosphorus, total bilirubin, direct bilirubin, serum glutamic pyruvic transaminase (SGPT),
serum glutamic oxaloacetic transaminase (SGOT) and fetal bovine serum (FBS). The
adverse events associated with BCM-95® included mild fever and throat infection. The
authors concluded that BCM-95® was generally safe and well-tolerated in most subjects
when administered for a period of up to 8 weeks.
2. Urinary Health
Hejazi et al. (2013) reported the results of a pilot clinical trial using BCM-95® as a
radioprotector in patients with prostate cancer who had undergone radiation therapy.
Forty prostate cancer patients undergoing external beam radiotherapy (EBRT) were
randomly assigned to the BCM-95® group (3 g/day) or the placebo group for 20 weeks.
Quality of life was assessed by the Persian version of the European Organization for
Research and Treatment of Cancer prostate cancer-specific quality of life questionnaire
(QLQ-PR25). The change in urinary symptoms across the 20-week period differed
significantly between groups, and patients in the BCM-95® group experienced much milder
urinary symptoms compared with the placebo group. No group differences were observed
in any other domain of the QLQ-PR25. The authors conclude that curcumin can confer
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radioprotective effect in patients with prostate cancer who undergo radiation therapy
through reducing the severity of radiotherapy-related urinary symptoms.
3. Mood and Depression
Sanmukhani et al. (2014) reported the results of a randomized, observer masked clinical
study, with 3 parallel treatment arms to compare the efficacy and safety of BCM-95® with
the drug, fluoxetine, in patients with major depressive disorder (MDD). Sixty patients
diagnosed with MDD were randomized in a 1:1:1 ratio for a 6-week treatment with
fluoxetine (20 mg) or curcumin (1,000 mg) individually or in combination. Group I received
fluoxetine 20 mg/day in the morning, group II received BCM-95®1,000 mg/day, while group
III received fluoxetine 20 mg/day and BCM-95® 1,000 mg/day. Efficacy and safety were
evaluated after two, four and six weeks by measuring the response rate according to the
Hamilton Depression Rating Scale 17-item scale (HAM-D17). The secondary efficacy
measures were mean change in HAM-D17 score at two, four and six weeks; remission
rate according to HAM-D17 scale; response rate on the clinical global impression-
improvement (CGI-I) assessment scale; score on clinical global impression-severity of
illness (CGI-S) scale and global efficacy at the end of study. The proportion of
responders as measured by the HAM-D17 scale was higher in the combination group
(77.8%) than in either the fluoxetine (64.7%) or the BCM-95® (62.5%) groups; however,
these data were not statistically significant. The mean change in HAM-D17 score at the
end of six weeks was comparable in all three groups. The investigators’ opinion on global
efficacy was that there was no statistical difference in the 3 treatment groups---all 3 groups
showed “excellent” or “good” efficacy of the study medication.
An unpublished protocol for an intended double-blind, placebo-controlled clinical study (no

author) was provided. It will assess the antidepressant and anti-inflammatory effects of
BCM-95® (1000 mg/day) on 40-60 adults with mild to moderate depression. Changes in
depression, anxiety, and general health will be measured over an 8-week period. Levels
of cortisol, kynurenine pathway metabolites (measure of inflammation), and oxidative
stress markers will be assessed over time.
4. Cognitive Function
Baum et al. (2007) conducted a 6-month human trial on the effects of BCM-95® on blood
lipid profiles. Elderly patients (n=31, aged 50 or over with progressive memory decline)
were randomized to three oral, daily doses of BCM-95®: placebo, 1 g, or 4 g. Plasma
curcumin and metabolites were measured at 1 month. At baseline, 1 month, and 6
months, blood samples were taken after an overnight fast to measure serum lipid and
lipoprotein concentrations. To monitor safety, liver and kidney function parameters were
measured, including sodium, potassium, urea, creatinine, protein, albumin, bilirubin,
alkaline phosphatase, and alanine aminotransferase (ALT/GPT). Of these parameters,
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only ALT/GPT differed among groups, which may have been due to an elevated baseline
level of ALT/GPT in the 1 g/day dose group. At the end of the trial, mean ALT/GPT levels
were 16.8 in the placebo group, 24.6 in the 1 g/day group, and 16.5 for the 4 g/day dose
group. Therefore this change was not dose related. The plasma curcumin concentration
reached a mean of 490 nmol/L for the 4 g dose and 270 nmol/L for the 1 g dose.
Triacylglycerol, total cholesterol, LDL and HDL cholesterol levels were not affected by
BCM-95® consumption at either dose. However, a positive and significant correlation
between the concentrations of plasma curcumin and serum cholesterol was found.
Adverse effects from BCM-95® consumption at 1 g or 4 g doses were mild, and included a
case of dizziness, and increased delusions, constipation, and diarrhea. There were fewer
adverse events reported at the 4 g dose than the 1 g dose. The results of the study
suggest that daily administration of BCM-95® at a dose of 4 g/day for 6 months did not
reveal any significant safety concerns.
5. Chemoprotection
Shakibaei et al. (2014) described an in vitro study regarding curcumin’s role in enhancing
chemosensitization. Current therapies for the treatment of colorectal cancer (CRC) mainly
comprise 5-Fluorouracil-based (5-FU) chemotherapies. Previous studies have shown that
combined treatment of curcumin with 5-FU induces more significant cytotoxicity in DNA
mismatch repair (MMR)-deficient colorectal cancer (CRC) monolayer cultures compared to
the agent individually. High density 3D cultures of CRC cell lines and their corresponding
isogenic 5-FU-chemoresistant derivative clones were treated with 5-FU either without or
with curcumin in time- and dose-dependent assays. Pre-treatment with curcumin
significantly enhanced the effect of 5-FU on HCT116R and HCR116+ch3R cells, in
contrast to 5-FU alone. Curcumin and/or 5-FU strongly affected MMR-deficient CRC cells
in high density cultures, however, MMR-proficient CRC cells were more sensitive.
Curcumin also exhibited the ability to effectively suppress cancer stem cell (CSC) pools as
evidenced by a decreased number of CSC marker positive cells.
Goel and Aggarwal, (2010), in a review paper, outlined curcumin’s role as a chemo
resensitizer and protector. The paper provides a review of the literature while addressing
curcumin’s effect as a chemosensitizer in a large number of cancers including breast, colon,
pancreas, gastric, liver, and prostate. Similar studies have also revealed that this agent can
sensitize a variety of tumors to gamma radiation. The mechanism believed to be
responsible for these effects is the downregulation of various growth regulatory pathways
and specific genetic targets including genes for NF-κB, STAT3, COX2, Akt, antiapoptotic
proteins, growth factor receptors, and multidrug-resistance proteins. Research also
supports curcumin’s effect in protecting normal organs from chemotherapy and
radiotherapy-induced toxicity through its ability to induce the activation of NRF2 and induce
the expression of antioxidant enzymes.
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An unpublished protocol by C. R. Becerra addresses an ongoing colon cancer study at

Baylor University for terminally ill patients (Becerra, 2013). The primary objective of the
study is to confirm the clinical safety and to determine the maximum tolerable dose for
curcumin. Secondary objectives are to test curcumin’s chemo resistant clinical efficacy in
combination with 5-FU and to retrospectively determine DNA methylation status of
peripheral blood circulating tumor cells (CTC) pre-and post-curcumin treatment using
archived blood from clinical responders and non-responders.
6. Studies in Progress
Clinical trials using BCM-95® are ongoing, and a search of the U.S. National Institutes of
Health site ClinicalTrials.gov2 yielded 5 current clinical studies using BCM-95®. These
studies are summarized in Table 12.
Table 12. Current Clinical Studies Using BCM-95® (from ClinicalTrials.gov)
Number of
Condition Dose Duration Design/Adverse Effects Study Status
Subjects
42 months
500 mg Study to evaluate the efficacy,
(18
BCM-95® safety, and tolerability of BCM
months of
(oral dose) 95 in patients with relapsing
enrollment Phase 2,
Multiple Sclerosis 2x/day with 80 multiple sclerosis by examining
s, 24 Ongoing
subcutaneou the difference between the
month
s Interferon proportion of subjects with active
treatment
Beta 1a T2 lesions assessed by MRI.
period)
Study the effects of BCM-95
(Curamed) in osteoarthritis
500 mg 67
compared to Curamin (500 Not yet open
BCM-95® 12 osteoarthritis
Osteoarthritis mg, 3x/day) or Placebo. The for participant
(Curamed) weeks patients in
effects will be measured by recruitment
3x/day each group
degree of joint pain and
physical performance.
BCM-95®
administer
ed by
ingested
mouth
rinse.
There will
To determine how safe
be 3 12-15 Phase 1,
4-6 curcumin is and how well it
Mucocitis participant chemotherapy Phase 2, not
weeks works to treat mucocitis in
at each of patients yet recruiting
chemotherapy patients.
4 does
levels
(0.33g, 1g,
2g, 3g)
per rinse,
three
times daily
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Number of
Condition Dose Duration Design/Adverse Effects Study Status
Subjects
Study to determine recurrence
500 mg
6 600 males of prostate cancer by Phase 2,
Prostate Cancer BCM-95®
months (Estimated) measuring serum prostate Recruiting
2x/day
specific antigen.
Study to determine the
radioprotective effects of
BCM-95T in prostate cancer
using magnetic resonance
3g spectroscopy (MRS 1 week
7-8 40 males Unknown
Radioprotection BCM-95®/ before radiation therapy and 3
weeks (Estimated)
day months after radiotherapy
completion. Also prostate
specific antigen (PSA)
rebound will be compared
after 1 year.
F. Toxicology Studies on Other Sources of Curcumin
1. Acute Study
The single-dose oral administration of 5 g curcumin/kg bw in rats did not result in any toxic
effects (Wahlstrom and Blennow, 1978). In addition, oral toxicity studies using 2.5 g
turmeric/kg bw or 300 mg/kg bw of an alcohol extracts of turmeric in guinea pigs, rats, and
monkeys did not result in any toxicity (Shankar et al., 1980). The reported acute LD50 of
curcumin oil in rats exceeds 5 g/kg and the acute oral LD50 of curcumin is greater than 2
g/kg (Opdyke and Letizia, 1983; Srimal and Dhawan, 1973).
Dadhaniya et al. (2011) performed acute and subchronic safety assessments of Longvida®
(curcumin) in rats and mice. The oral LD50 in both rats and mice was found to be greater
than 2000 mg/kg bw/day. In the subchronic toxicity study, the NOAEL for Longvida ® was
determined to be 720 mg/kg bw/day, the highest dose tested.
2. Short-Term Study
Short-term safety studies of curcumin in animals have been well-reviewed (Chianani-wu,

2003). Rats that were fed 1.8 g/kg bw/day for 90 days showed no adverse effects, as was
the case with monkeys fed 0.8 mg/kg bw/day for 90 days (Majeed et al., 1995).
However, curcumin from turmeric has shown to cause hepatotoxicity in mice and in rats at
high doses. A study in female Wister rats and Swiss mice fed 0%, 0.01, 0.1, 0.2, 1%, or
5% turmeric and 0%, 0.05%, and 0.25% ethanolic turmeric extract in the diet for 14 and
another group of mice and rats was fed 0 or 5% turmeric extract for 90 days. Mice were
more susceptible to the hepatotoxic effects of the extracts than rats. Histological effects
(focal necrosis or focal necrosis with regeneration) were observed after consumption of
5% turmeric extract for 14 days in the diets of mice. These effects were also occasionally
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observed for lower doses of turmeric extract and for both doses of ethanolic turmeric
extract. In the 90-day study, mice showed significant reductions in body weight gain and
significant increases in absolute and relative liver weight after consuming 5% turmeric in
the diet. These effects were not observed in mice after 14 days, with the exception of a
reduction in the relative liver weight for the 0.05% ETE group. The rats that were fed 5%
turmeric for 90 days showed a reduction in body weight gain, significant decrease in liver
weight (absolute only), and hepatotoxicity. The authors note that these changes have
been observed at extremely high doses of turmeric, about 200-5,000 times the ADI of 0-
2.5 mg/kg allocated by the JECFA. The authors also explain that human consumption for
adults generally falls in the range of 0.2-0.6 g/person/day, and the toxic doses observed in
these studies are at least 50 times higher than this and should not raise any alarm for
human consumption (Deshpande et al., 1998).
Hepatoxicity was seen in another study where mice were fed whole turmeric at levels of
0.2%, 1%, or 5% or ethanolic turmeric extract (0.05% or 0.25%) for 14 days.
Histopathological examination showed coagulative necrosis in the liver accompanied by a
zone of regenerating hepatic parenchymal cells. The ultrastructural changes seen in liver
parenchymal cells were non-specific reactions to injury. The authors concluded that mice
seem to be a susceptible species for turmeric induced toxicity (Kandarkar et al., 1998).
3. Genotoxicity & Mutagenicity Studies
Curcumin exhibits both pro- and antimutagenic effects. It has been shown to reduce the
number of aberrant cells in a chromosomal aberration assay in Wistar rats at 100 and 200
mg/kg bw (Shukla et al., 2002). Turmeric also prevents mutation effects of the powerful
mutagen urethane (el Hamss et al., 1999). On the other hand, curcumin and turmeric
have been shown to enhance gamma-radiation-induced chromosome aberration in the
Chinese hamster ovary (Araujo et al., 1999). It also has been shown to not protect against
hexavalent chromium-induced DNA strand break, and chromium and curcumin together
have been shown to cause DNA breaks in human lymphocytes and gastric mucosal cells
(Blasiak et al., 1999).
4. Reproductive Study
Ganiger et al. (2007) performed the final toxicology study on curcumin that was reviewed
by the JECFA at the 61st meeting in 2003 (originally reviewed by JECFA as a 2002
unpublished report and subsequently published by Ganiger in 2007). The study assessed
the two-generational reproductive toxicity of oral curcumin in Wistar rats. Three groups of
rats were fed diets containing curcumin at concentrations of 1,500, 3,000 and 10,000 ppm.
No adverse toxicological effects were observed in the parental animals. There was no
effect of curcumin on reproductive parameters and the only effect on offspring was a small
reduction in pre-weaning body weight gain in the F2 pups at the highest dose level. The
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mean body weights of the F2 offspring were significantly decreased on postnatal days 1
and 7 at the intermediate dose, and on postnatal days 7, 14 and 21 at the highest dose.
This trend was dose-related, but the effect was small, with average body weights being
greater than 90% that of the control pups, and the changes were reported to be within the
data for historical controls. There were no other effects on general health, body weight,
pup survival and fertility in either generation. The effects at the intermediate dose were
considered to be incidental; therefore, the dose of 250–320 mg/kg bw/day for the F1
generation was the NOEL. The authors concluded that the NOEL for reproductive toxicity
of curcumin fed in the diet for two generations was 10,000 ppm, which is equivalent to 847
and 959 mg/kg bw/day for male rats and 1043 and 1076 for females for F 0 and F1
generations, respectively. However, JECFA (2003) concluded that body weight reduction
in F2 pups at the highest dose prevented it from being regarded as a no adverse effect
level. Therefore, the ADI for curcumin was changed to 0-3 mg/kg bw based on the intake
of 250 - 320 mg/kg bw in the mid-dose group.
5. Human Studies
Many human studies using curcumin have been well reviewed in the literature (Chainani-
Wu, 2003; Epstein et al., 2010) and have shown evidence of the safety of curcumin. As
described in Sharma et al. (2005), Cheng et al. (2001) observed no toxic effects of
curcumin when administered at a dose of up to 8,000 mg/day. In addition, five other
clinical studies administered doses of curcumin ranging from 1,125 to 2,500 mg per day
and noted the safety of curcumin (Deodhar et al., 1980; Satoskar et al, 1986; James,
1996; Lal et al., 1999; Lal et al., 2000). In addition, Arggarwal et al. (2003) reported there
was no apparent toxicity of curcumin at a dose of 10,000 mg/day. Curcumin remains a
topic of active research, and other clinical studies have been published following the
issuance of the Chainani-Wu and Epstein reviews. The studies are summarized in 0.
G. Studies Conducted by National Toxicology Program on Curcumin
The studies conducted by NTP were reviewed by the NTP evaluation process, and it was
concluded that the evidence for carcinogenicity in mice and rats was equivocal (NTP,
1993).
In a 13-week study, groups of 10 male and 10 female rats were fed diets containing 0,
1,000, 5,000, 10,000, 25,000 or 50,000 ppm turmeric oleoresin. These dietary levels of
turmeric oleoresin were estimated to deliver about 50, 250, 480, 1,300 or 2,600 mg/kg bw
to males and 60, 300, 550, 1,450, or 2,800 mg/kg bw to females, respectively. In males
receiving 50,000 ppm, the final mean body weight was lower than that of the controls.
Feed consumption in all groups was similar to the controls. The absolute liver weights of
female rats and the relative liver weights in male rats receiving 5,000, 10,000, 25,000 and
50,000 ppm were significantly greater than the controls. No significant differences were
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found in clinical or hematologic chemistry, and urinalysis parameters. In males and

females receiving the 50,000 ppm dose, hyperplasia of the mucosal epithelium was
observed in the cecum and colon. Clinical findings in treated animals included stained fur
and discolored feces and urine.
In a 13-week mouse study, groups of 10 male and 10 female B6C3F mice were fed 0,
turmeric oleoresin were estimated to deliver average daily doses of 50, 250, 480, 1,33 or
2,600 mg/kg bw to males and 60,0300,0550, 1,450 or 2,800 mg/kg bw in females,
respectively. In males receiving 50,000 ppm, the rinal mean body weight was lowere than
that of the controls. Feed consumption in all groups was similar to the controls. . The
absolute liver weights of female rats and the relative liver weights of male rats recieing
5,000, 10,000, 25,000 or 50,000 ppm dose, hyperplasia of the mucosal epithelium was
observed in the cecum and colon.
In a 13-week mouse study, grops of 10 male and 10 female B6C3F mice were fed 0,
turmeric oleoresin were estimated to deliver average daily doses of 150, 750, 1,700,
3,850, 7,700 mg/kg bw to males and 200, 1,000, 1,800, 4,700 or 9,300 mg/kg bw in
females, respectively. Thefeed consumption, final mean body weight gains, and final mean
body weights were the same in treated groups as in controls. The absolute and relative
liver weights of male mice recieivng 5,000 ppm and male and female mice that recieved
10,00, 25,00 and 50,000 ppm of turmeric oleoresin were significantly greater than the
controls. There were no significant changes compare to controls in hematologic and
clinical chemistry or urinalysis parameteres, nor were treatment-related histopathologic
lesions observed. Clinical finds in treatment animals included stained fur and discoloration
in the feces in rine.
In the 2-year NTP studies, groups of 60 male and 60 female B6C3F1 mice and F344/N
rats received doses of 0, 2,000, 10,000 or 50,000 ppm turmeric oleoresin in the feed. Up
to ten animals from each group were reserved for a 15-month interim examination. There
were no differences in survival and feed consumption in rats or mice between the treated
groups and the control group throughout the study. The estimated average daily turmeric
consumption values in rats were 80, 460, or 2,000 mg/kg bw in males and 90, 440, or
2,400 mg/kg bw in females. In rats, there were no clinical findings that were related to
toxicity. Male rats receiving 50,000 ppm had increased incidences of ulcers, hyperplasia,
and hyperkeratosis of the forestomach and cecum. In addition, male and female rats
receiving 50,000 ppm and male rats receiving 10,000 ppm had increased sinus ectasia of
the mesenteric lymph node. In female treated rats, there were significant increases in
clitoral gland adenoma in all dose groups, but, due to the similar incidence in all dose
groups, there was a lack of correlation to dose. The investigators concluded that under
the conditions of the 2-year feeding studies there was no evidence of carcinogenic activity
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of turmeric oleoresin in male F344/N rats at any dose level. NTP concluded that there
was equivocal evidence of carcinogenic activity of turmeric oleoresin in female rats based
on the increase in clitoral gland adenoma.
In mice, the estimated average daily turmeric consumption values were 220, 520 or 6,000
mg/kg bw for males and 320, 1,620 or 8,400 mg/kg bw for females. Alkaline phosphatase
values in males and females mice receiving 10,000 and 50,000 ppm turmeric were
significantly higher than the controls. There were no other significant differences in
hematologic or clinical chemistry in either males or females. At the 15-month interim
evaluation, the absolute and relative liver weights of male and female mice in the 10,000
and 50,000 ppm dose groups were significantly greater than the controls, and
hepatocellular neoplasms occurred in several treatment male and female mice but not in
controls. At the end of the 2-year study, there were significantly increased hepatocellular
adenomas in males and females receiving 2,000 or 50,000 ppm. The incidences of
hepatocellular adenoma and carcinoma in all exposed groups of male mice exceeded the
range for neoplasms in historical control male mice. In the small intestine, three male
mice that received 2,000 ppm turmeric and three male mice that received 10,000 ppm
turmeric had carcinomas of the small intestine, while no carcinomas were observed in the
control or 50,000 ppm groups. Since there was no dose-response trend, the investigators
were unsure if the neoplasms were treatment-related. In the forestomach and pituitary
gland, the incidence of lesions was well within the range for the historical control mouse.
The investigators concluded that in B6C3F1 mice, there was equivocal evidence of
carcinogenic activity of tumeric oleoresin in males based on an increased incidence of
hepatocellular adenoma at the 10,000 ppm level and the occurrence of carcinomas of the
small intestine in the 2,000 and 10,000 ppm groups. NTP concluded that there was
equivocal evidence of carcinogenic activity in female mice due to an increased incidence
of hepatocellular adenoma in the 10,000 ppm group.
H. JECFA Review of Curcumin & Turmeric
Turmeric oleoresin, the product of solvent extraction of turmeric containing <90% of total
coloring matter (curcuminoids), and curcumin were evaluated by JECFA at its 13th, 18th,
22nd, 24th, 26th, 30th, 35th, 39th, 44th, 51st and 57th meetings (WHO 1970, 1974, 1978,
1980, 1982, 1987, 1990, 1992, 1995, 2000, and 2002). The latest review at its 61st
meeting (WHO, 2004) established an ADI of 0-3 mg/kg bw based on an updated
reproductive study in rats (subsequently published as Ganiger et al., 2007). JECFA
assigned a no observed effect level (NOEL) of 250 - 300 mg/kg based on this study. The
highest doses tested (847 and 959 mg/kg bw/day for male rats and 1043 and 1076 for
females in the F0 and F1 generations, respectively) in this study were used to determine
the NOEL by the authors, however, JECFA concluded that body weight reduction in F2
pups at the highest dose prevented it from being regarded as a NOAEL. The ADI of 0-3
mg/kg bw was obtained by applying a 100-fold safety factor for extrapolation from animals
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to humans. The test material in this study consisted of 80% curcumin or diferuloylmethane
(1, 7-bis(4-hydroxy-3-methoxyphenyl) hepta-1,6-diene-3, 5-dione) and 99% total
curcuminoids. At the 61st meeting, JECFA reviewed two new clinical studies (Sharma et
al., 2001; Cheng et al., 2001) but concluded that these clinical studies had little relevance
to setting an ADI. Therefore, the previous ADI of 0-3 mg/kg bw was left unchanged.
In previous meetings, JECFA reviewed all other relevant studies which resulted in a
tentative ADI of 0-1 mg/kg bw on the basis of chronic mouse and rat studies that were
conducted by the National Toxicology Program (NTP, 1993) on turmeric oleoresin
(curcumin content 79-85%). The key effect on liver weight in mice was used to establish
the tentative ADI based on a NOEL of 220 mg/kg bw, and a 200–fold safety factor was
used to give the 0-1 mg/kg bw ADI. JECFA expressed a willingness to recalculate the ADI
after review of an adequately conducted animal study for reproductive effects (WHO,
1996).
JECFA closely examined the tumor incidence in the mouse and rat chronic study, along
with studies on the mutagenic and other genotoxic activity of turmeric oleoresin and
curcumin. JECFA concluded that the increased incidence in liver and clitoral gland tumors
seen in some dose groups was not dose related and that there was no evidence that
curcumin was genotoxic.
I. Safety Studies on Desmethoxycurcumin
Currently, no traditional toxicology studies are available on desmethosycurcumin in the

scientific literature. A search of the literature using the Toxicology Data Network Database
(TOXNET) on December, 2015 using the search term “Desmethoxycurcumin” yielded 8
results. One study indicated that desmethoxycurcumin and curcumin have time and
concentration-dependent protective effects against DNA damage (Subramanian et al.,
1994) and another examined the systemic bioavailability of curcumin (Marczylo et al.
2007). The other studies were less relevant including studies about dyes and
pigmentation efficacy (Jentzsch et al., 1970; Racz et al., 1972). Other studies mentioned
desmethoxycurcumin only as a component of curcumin and its efficacy in chemoprotective
effects (Epelbaum et al., 2010) and anti-inflammatory effects (Jacob et al., 2007). The
other two articles described preparation on curcumin niosomes and effects of curcumin on
mosquitoes
J. Safety Studies on Bisdesmethoxycurcumin
No traditional toxicology studies on bisdesmethoxycurcumin surfaced in searching the

scientific literature. A search of the literature using the Toxicology Data Network Database
(TOXNET) on December 2015 using the search term “bisdesmethoxycurcumin” yielded 7
results. These 7 studies were identical to the studies listed above for
dexmethoxycurcumin.
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K. Other Studies on Turmerone
Nishiyama et al. (2005) investigated the effects of turmeric extracts on blood glucose
levels in type 2 diabetic mice. These turmeric extracts were obtained by ethanol extraction
(E-ext) to yield both, curcuminoids and sesquiterpenoids (including turmerones), hexane
extraction (H-ext) to yield sesquiterpenoids, and ethanol extraction from hexane-extraction
residue (HE-ext) to yield curcuminoids. The control group was fed a basal diet, while the
other groups were fed a diet containing 0.1 or 0.5 g of H-ext or HE-ext/100 g of diet or 0.2
or 1.0 g of E-ext/100 g of diet for 4 weeks. Although blood glucose levels in the control
group significantly increased (P < 0.01) after 4 weeks, feeding of 0.2 or 1.0 g of E-ext, 0.5
g of H-ext, and 0.5 g of HE-ext/100 g of diet suppressed the significant increase in blood
glucose levels. Furthermore, E-ext stimulated human adipocyte differentiation, and these
turmeric extracts had human peroxisome proliferator-activated receptor-gamma (PPAR-
gamma) ligand-binding activity in a GAL4-PPAR-gamma chimera assay. Also, curcumin,
demethoxycurcumin, bisdemethoxycurcumin, and Ar-turmerone had PPAR-gamma ligand-
binding activity. PPAR-γ is a member of the nuclear receptor family of transcription
factors, a large group of proteins that mediate ligand-dependent transcriptional activation
and transrepression. PPAR-γ is highly expressed in adipose tissue and plays a crucial
role in adipocyte differentiation. It is also expressed in a variety of other tissue and cell
types where it plays key roles in the regulation of metabolism and inflammation. Induction
of PPARγ activity by curcuminoids and the turmerones could be one of the mechanisms
through which these compounds exert their anti-diabetic action. There were no adverse
effects reported in any of the animals.
Liju et al. (2011) found that oral administration of turmeric oil (Ar-turmerone 61.8%, curlone
12.5%, ar-curcumene 6.1%) for one month to mice significantly increased superoxide
dismutase, glutathione, and glutathione reductase enzyme levels in blood and glutathione-
S-transferase and superoxide dismutase enzymes in liver. Turmeric oil showed significant
reduction in paw thickness in carrageenan, dextran-induced acute inflammation, and
formalin-induced chronic inflammation. No adverse effects were reported by the authors.
Several in vitro studies have been performed to demonstrate the efficacy of turmerone and
to show that the combination of curcumin and turmerone could result in better
bioavailability than curcumin alone. Lantz et al. (2005) reported that a combination of
curcuminoids and turmeric oils produce a better anti-inflammatory effect than that
produced by curcuminoids alone in HL-60 cells exposed to proinflammatory mediators.
Similarly, Yue et al. (2012) found that a turmeric extract including curcumin and
turmerones were transported in Caco-2 cells more readily than curcumin alone. Caco-2
cell monolayers are widely used as an in vitro model to study drug permeability because
these cells are similar to the absorptive cells in the human intestine. Another study by Yue
et al. (2010) demonstrated that turmeric extracts (including curcuminoids and volatile oil)
had chemopreventive/antitumor properties in human breast cancer cell lines.
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L. Allergenicity
A case report described the development of contact dermatitis on the hands and forearms
in response to contact with food coloring in a 58-year-old woman who worked in a pasta
factory Kieć-Swierczyńska and Krecisz (1998). When a patch test was conducted, a
positive reaction to curcumin and curcuma was observed.
In another case report, a 54-year-old woman had a positive reaction to tetrahydrocurcumin

(1% pet.), an ingredient of Avon age block cream (Avon Cosmetics Ltd. Northampton, UK),
but had a negative reaction to the other constituents of the product (Lamb and Wilkinson,
2003).
A 53-year-old woman experience recurrent facial and eyelid swelling and a red scaly rash
when she used Avon age block cream (Avon Cosmetics Ltd. Northampton, UK)
(Thompson and Tan, 2006). When ingredients of the cream were tested individually, she
showed a positive reaction only to tetrahydrocurcumin (1% pet.).
Fischer and Anger (2004) two cases of contact dermatitis that developed in one man 53-
year-old man and one 56-year old woman after their skin was clean with yellow
chlorhexidine solution. Patch testing showed that they were allergic to curcumin.
Liddle et al. (2006) described a case of contact urticaria following exposure to curcumin in
a 44-year-old woman. They also described a case of a 20-year-old woman with no known
history of contact urticaria or sensitivity to curcumin who was administered a prick test and
developed a wheal at the site of application.
A study conducted by Futrell and Rietchel (1993) investigated the incidence of contact
allergy to 12 spices found in traditional foods of New Orleans in individuals with suspected
contact dermatitis. Study participants were 19 men and 36 women aged 2 to 76 years. The
study participants were subjected to patch tests for turmeric, curry, cumin seed, ginger,
nutmeg, oregano, cinnamon, sweet basil, cayenne pepper, coriander, clove, and sage.
When two concentrations of curry, cumin seed, and turmeric were tested, the numbers of
study participants who had positive reactions were 0, 1, and 0, respectively. There were 3,
3, and 2, positive reactions, respectively, in response to 25% concentration of curry, cumin
seed, and turmeric.
A case of allergic dermatitis was described for a 31-year-old woman with a history of
erythema on the dorsal surface of her hands for the previous year (Hata, 1997). The
woman applied topical ointments including “Chuu-ou-kou” to the eruptions, but the lesions
worsened. The woman had a positive response to the active ingredient, Curcuma longa
L.at 2.5% (the amount in “Chuu-ou-kou”), 1.25%, and 0.25% pet. Although the essential
oil, which includes turmerone, dihydroturmerone, zingiberene, d-α-phellandrone, and
cinerol, produced a negative result, curcumin gave a positive result at 1%, 0.5%, and 0.1%
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pet. A control study in which 30 individuals were treated with Curcuma longa L.(2.5%,
1.25%, and 0.25%), curcumin (1% pet.), curry powder (25% pet.), dried ginger (kankyo,
25% pet.), and vanilla essence 10% pet. showed no positive responses.
In summary, incidences of individuals who have experienced contact dermatitis or urticaria

in response to dermal exposure to curcumin have been reported in the literature; however,
no basis exists on which to expect a tendency for development of allergic responses to
curcumin in foods.
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Appendix A Flow Chart Of Manufacturing Process For BCM-95®
PROCESS FLOWCHART: BCM – 95® CG
RAW MATERIAL
STORAGE
POWDERING UNIT
PUMP
EXTRACTOR ETHYL ACETATE

STORAGE TANK
EXTRACTORS:
(TAKE ABOUT 4
STAGE I SOLVENT PORTION WASHINGS DISCHARGE
WASTE AFTER
RECOVERING SOLVENT)
FILTER
MISCELLA STORAGE DISTILLED ETHYL ACETATE

TANK FOR REUSE
RISING FILM CONDENSER

EVAPORATOR
30 – 40% CONCENTRATION
STRIPPER CONDENSER
OLEORESIN 60%( +5)

CONCENTRATION
CHILLING UPTO 0O
Page 75 of 125
DolCas Biotech, LLC
CRUDE CRYSTALS FILTRATE

90% CURCUMINOIDS
RECRYSTALLIZATION
(ETHYL ACETATE)
VACCUM DRYING AND MILLING
CPE – 028 IN PROCESS

(CURCUMINOIDS 98%)
ANALYSIS
STAGE II MIXED WITH BIOENHANCER

AGITATE FOR 4 HRS.
VACUUM DRYING, POWDERING

AND SIEVING
STERILIZED
FINISHED PRODUCT
ANALYSIS AND
FINISHED PRODUCT
(BCM– 95CG)
RELEASE
Page 76 of 125
EVAPORATION AND
SOLVENT RECOVERY
DolCas Biotech, LLC
Appendix B Certificates Of Analysis For Five Production Batches Of

BCM-95®
Page 77 of 125
DolCas Biotech, LLC
r:. ~.~..=-~~-,1,
l
~
~
~
, 9 Lenei Road, landing, NJ 07850
Ph· 973
347 1958
- fax·
973-347-0433 Product Name:
Botanical Name:
Plant Port Used:
BCM-95° (Bio-Curcumin" )
Curcuma tonga
Rhizome
Product Code:
lot Number:
Dote of Manufacturing: September 2016
~i
i
j.•
:; Country of Origin: India Retest Date: September 2019 ~
I- ~!~t~~!~!~ON
Color
~~s~CIFICATION
Orange red
~~ZT METHOD
Visual
~~!~i~~s
Complies
1
.g
i
~
5
Appearance
Flavor
Odor
Analytical Assay
Powder
Characteristic
Characteristic
Visual
Organoleptic
Organoleptic
complies
Complies
Complies
1~
~
~
i
Herb Extract Ratio 25:1 In House Specification Complies ~
Solubility (in Acetone) Soluble IP Complies ft
' (in water) Insoluble IP Complies ~
~ Moisture NMT 2% USP <921> 0.50% 1
~
li. Extraction Solvent 100% Ethyl Acetate In House Specification Complies ~
l Particle Size 100% thru 30 mesh USP <786> Complies
Allergens None detected Elisa Complies
~., Tap Density (g/ ml) NLT 0.60 USP <616> 0..77
~ Bulk Density (g/ml) NlT 0.39 USP <616> 0 53
ij Pesticide Residue Complies with USP USP <561> complies
~ Excipients None In House Specification Complies
~;\ Carriers None In House Specification Complies
~ Residual Solvents
I Benzene
Carbon Tetrachloride
As per USP
As per USP
US P<467>
USP <467>
Complies
Complies
I~ 1,2-Dichloroethane
1,1-Dichloroethene
1,1,1-Trichloroethane
Ethyl Acetate
As per USP
Asper USP
As per USP
As per USP
USP <467>
USP<467>
USP <467>
USP <467>
Complies
Complies
Complies
Complies
Ethanol As per USP USP <467> Complies
~ Acetone As per USP USP <467> Complies
i Trace Metals
Total Heavy Metals
Arsenic
NMT 10 ppm
NMT 1 ppm
ICP-MS 0.268S ppm
I
ICP-MS 0.0716 ppm
Cadmium NMT 1 ppm ICP-MS 0.028S ppm
lead NMT O.S ppm ICP-MS 0.1684 ppm
Mercury NMT 1 ppm ICP-MS BDL*
(*BDL: As -0.02 ppb, Pb- 0.015 ppb, Hg- 0.02 ppb)
Microbiological Assay
Total Plate Count NMT 1,000 cfu/g AOAC, BAM 30 cfu/ g
Yeast & Mold NMT 100 cfu/g AOAC, BAM Not Detected
Salmonella Absent/ 25g AOAC, BAM Complies
E. coli Absent/ lOg AOAC, BAM Complies
Staphylococcus aureus Absent/ lOg AOAC, BAM Complies
Pseudomonas aeruginosa Absent/ lOg AOAC,BAM Complies
Aflatoxin Absent AOAC, BAM Complies
Coliforms Absent/ lOg AOAC, BAM Complies
(**Microbial assay- detection limit -10 cfu/g)
Assay for Actives

Volatile compounds of Turmeric Present UV-Vis Complies
Total Curcuminoids Complex: NLT 95% HPlC 97.50%
Consisting of Curcumln, Desmethoxy Curcumln, 8/s-Desmethoxy Curcumin and Volatile Oils of Turmeric Rhizome
m
Total Curcumlnoids NLT86% HPLC 90.28%
m Curcumin NLT65% HPLC 71.63%
m
11 BCM-95~ & Blo-Curcumin• are registered trademarks of Dolcas Biotech llC
~~ • Material is NON-ETO and NON-Irradiated
~~ • GMO Free
~ • Store In a cool, dry place and away from direct sunl (b) (6) . 'I
m • Shelf life: Retest 3 vears from date of manufacturin I 1/
~ Approved By: Date: /J/,~t/t .
l ..-::::::_::::.:~:::::::::::::::::~m:::::-.~.-::::~::=... _.)
Page 78 of 125
DolCas Biotech, LLC
Dolcas Biotech LLC CERTIFICATE OF ANAlYSIS

9 Lenel Road, Landings, NJ 07850
Ph: 973-347-1958 Fax: 973-347-0433
Product Name: BCM-95• (Bio-Curcumin• ) Product Code: (b) (4)
Botanical Name: Curcuma longa Lot Number: (b) (4)
Plant Part Used: Rhizome Date of Manufacturing: January 2016
Country of Origin: India Retest Date: January 2019
DESCRIPTION SPECIFICATION TEST METHOD RESUlTS

Identification Pass TLC Complies
Color Orange red Visual Complies
Appearance Powder Visual Complies
Flavor Characteristic Organoleptic Complies
Odor Characteristic Organoleptic Complies
Ana/'{_tical Assa '{_

Herb Extract Ratio 25:1 In House Specification Complies
Solubility (in Acetone) Soluble IP Complies
(in water) Insoluble IP Complies
Moisture NMT2% USP <921> 0.6%
Extraction Solvent 100% Ethyl Acetate In House Specification Complies
Particle Size 100% thru 30 mesh USP <786> Complies
Tap Density (glml) NLT 0.60 USP <616> 0.73
Bulk Density (glml) NLT 0.39 USP <616> 0.48
Pesticide Residue Complies with USP USP <561> Complies
Excipients None In House Specification Complies
Carriers None In House Specification Complies
Residual Solvents
Benzene As per USP USP <467> Complies
Carbon Tetrachloride As per USP USP <467> Complies
1,2-Dichloroethane As per USP USP <467> Complies
1,1-Dichloroethene As per USP USP <467> Complies
1,1,1-Trichloroethane As per USP USP <467> Complies
Ethyl Acetate As per USP USP <467> Complies
Acetone As per USP USP <467> Complies
Trace Metals
Total Heavy Metals NMT 10 ppm ICP-MS 0 .1784 ppm
Arsenic NMT 1 ppm ICP-MS 'BDL
Lead NMT 0.5 ppm ICP-MS 0.1427 ppm
Mercury NMT 1 ppm ICP-MS 0.0357 ppm
(•BDL: As-0.02 ppb, Pb-0.015 ppb, Hg-0.02 ppb)
Microbiological Assa y
Total Plate Count NMT 1,000 cfulg AOAC, BAM 20 cfulg
Yeast & Mold NMT 100 cfulg AOAC, BAM 20 cfulg
Salmonella Absent I 25g AOAC, BAM Complies
E. Coli Absent I lOg AOAC, BAM Complies
Staphylococcus au reus Absent I lOg AOAC, BAM Complies
Pseudomonas aeruginosa Absent I lOg AOAC, BAM Complies
Coliforms Absent I l Og AOAC, BAM Complies
( ..Microbial assay- detection limit - 10 cfulg)
Assay for Actives

Total Curcuminoids Complex: NLT 95% HPLC 97.3 1%
Consisting of Curcumin, Desmethoxy Curcumin, Bis-Desmethoxy Curcumin and Volatile Oils of Turmeric Rhizome
Total Curcuminoids NLT 86% HPLC 90.31%

Curcumin NLT 65% HPLC 71.63%
BCM-95° & Bio-Curcumin° are registered trademarks of Dolcas Biot ech LLC
• Material is NON-ETO and NON-Irradiated
• GMO Free
• Store in a cool, dry place and away from direc
• Shelf Life: Retest 3 years from date of manuf (b) (6)
Date: ---'-h
-+,i
.L. ,~
. fc. L. o>"---
The above analytical information is analyzed and certified by Arjuna Naturals Extracts Ltd STAR KOSHER CERTIFIED
Page 79 of 125
DolCas Biotech, LLC
Dolcas Biotech LLC

9 lenel Road, landings, NJ 07850
CERTIFICATE OF ANALYSIS
Ph: 973-347-1958 fax: 973-347-0433
Product Name: BCM-95° (Bio-Curcumin•) Product Code: (b) (4)
Botanical Name: Curcuma Iongo lot Numbe r: (b) (4)
Plant Part Used: Rhizome Date of Manufacturing: April 2016
Country of Origin: India Retest Date: April2019
DESCRIPTION SPECIFICATION TEST METHOD RESULTS

Analy_tica/ Assay_
Herb Extract Ratio 25:1 In House Specification Complies
Particle Size 100% t hru 30 mesh USP <786> Complies
Tap Density (g/ml) NLT0.60 USP <616> 0.83
Bulk Density (glml) NLT 0.39 USP <616> 0.58
Residual Solvents
Carbon Tetrachloride As per USP USP <467> Complies
1, 1-Dichloroethene As per USP USP <467> Complies
1,1, 1-Trichloroethane As per USP USP <467> Complies
Trace Metals
Total Heavy Metals NMT 10 ppm ICP-MS 0.4451 ppm
Arsenic NMTl ppm ICP-MS 0.0096 ppm
Lead NMTO.S ppm ICP-MS 0.4355 ppm
Mercury NMTl ppm ICP-MS BDL'
(•BDL: As- 0.02 ppb, Pb- 0.015 ppb, Hg - 0.02 ppb)
Microbiological Assay_
Total Plate Count NMT 1,000 cfulg AOAC, BAM 20 cfulg
Yeast & Mold NMT 100 cfulg AOAC, BAM Not detected..
E. coli Absent I lOg AOAC, BAM Complies
Staphylococcus aureus Absent I lOg AOAC, BAM Complies
Pseudomonas aeruginosa Absent I lOg AOAC, BAM Complies
Coliforms Absent I lOg AOAC, BAM Complies
(.. Microbial assay- detection limit - 10 cfulg)
Assay for Actives

Total Curcuminoids Complex: NLT 95% HPLC 96.56%
Consisting of Curcumin, Desmethoxy Curcumin, Bis-Desmethoxy Curcumin and Volatile Oils of Turmeric Rhizome

BCM-95• & Bio-Curcumin• are registered trademarks of Dolcas Biotech LLC

' Material is NON-ETO and NON-Irradiated
• GMO Free
• Store in a cool, dry place and away from direct su
*Shelf life: Retest 3 years from date of manufact (b) (6)
The above analytical information is analyzed and certified by Arjuno Naturals Extracts Ltd STAR KOSHER CERTI FIED
Page 80 of 125
DolCas Biotech, LLC
Dolcas Biotech LLC CERTIFICATE OF ANALYSIS

9 Lenel Road, Landmgs, NJ 07850
Ph: 973-347-1958 Fax: 973-347-0433
www.dolcas-b•otech.com
Product Name: BCM-95° (Bio-Curcumin°) Product Code:
(b) (4)
Botanical Name: Curcuma Iongo lot Number: (b) (4)
Plant Part Used: Rhizome Date of Manufacturing: June 2016
Country of Origin: India Retest Date: June 2019

Appearance Powder Visua' Complies
Flavor Characteristic OrganoleptiC Complies
Odor Characteristic Organoleptic Compl1es
Analr.ticol Assor.
Herb Extract Ratio 25:1 In House SpecifiCation Complies
Particle Size 100% thru 30 mesh USP <786> Complies
Tap Density (g/ml) NLTO.GD USP <616> 0.80
Bulk Density (g/ml) NLT 0.39 USP <616> 0.56
Residual Solvents
Carbon Tetrachlonde As per USP USP <467> Complies
1,1-Dichloroethene As per USP USP <467> Complies
1,1,1-Trichloroethane As per USP USP <467> Complies
Trace Metals
Arsenic NMT 1 ppm ICP-MS 0.0415 ppm
Lead NMTO.S ppm ICP-MS 0.1827 ppm
(' BDL: As- 0.02 ppb, Pb- 0.015 ppb, Hg- 0.02 ppb)
Microbiological Assor.
Total Plate Count NMT 1,000 cfu/g AOAC, BAM 20 cfulg
Yeast & Mold NMT 100 cfu/g AOAC, BAM Not detected
E. coli Absent I lOg AOAC, BAM Complies
Staphylococcus aureus Absent I lOg AOAC, BAM Complies
Pseudomonas aerugmosa Absent I lOg AOAC, BAM Complies
Coliforms Absent I lOg AOAC, BAM Complies
( • • Microbial assay- detection limit -10 cfulg)
Assay for Actives

Volatile compounds of Turmenc Present UV-V1s Complies
Total CurcuminoidsComplex: NLT95% HPLC 96.75%
Consisting of Curcumln, Desmethoxy Curcumin, Bis-Desmethoxy Curcumln and Volatile Oils of Turmeric Rhizome

BCM-95° & Bio-Curcumin• are registered trademarks of Dolcas Biotech LLC

'GMO Free
'Store in a cool, dry place and away from direct sunlight.
• Shelf Life: Retest 3 years from date of manufac (b) (6)
Date: tj1~
Page 81 of 125
DolCas Biotech, LLC
Dolcas Biotech LLC CERTIFICATE OF ANALYSIS

9lenel Road, Landing, NJ 07850
Ph: 973-347-1958 Fax: 973-347-0433
BCM-95 ~
www.dolc:as-biotec.h.c.om
Product Name: (Bio-Curcumin$) Product Code:
(b) (4)
Botanical Name: Curcuma Iongo Lot Number:
(b) (4)
Plant Part Used: Rhizome Date of Manufacturing: August 2016
Country of Origin: India Retest Date: August 2019

Anal~tical Assa~
Herb Extract Ratio 25:1 In House Specificat ion Complies
Moisture NMT 2% USP <921> 0.5%
Extraction Solvent 100% Ethyl Acetate In House Specificat ion Complies
Residual Solvents As per USP USP <467> Residual Solvents
Particle Size 100% t hru 30 mesh USP <786> Complies
Tap Density (g/ml) NLT 0.60 USP <616> 0.77
Bulk Density (g/ ml) NLT 0.39 USP <616> 0.53
Pesticide Residue Complies w ith USP USP <561> Com plies
Excipients None In House Specifi cat ion Complies
Carriers None In House Specifi cat ion Complies
Trace M etals
Arsenic NMT 1 ppm ICP-MS 0.1038
Lead NMT 0.5 ppm ICP-MS 0.3553 ppm
Cadmium NMT 1 ppm ICP-MS Complies
(*BDL: As - 0.02 ppb, Pb- 0.015 ppb, Hg- 0.02 ppb)
Microbiological Assay
Total Plate Count NMT 1,000 cfu/g AOAC, BAM 30 cfu/g
Yeast & Mold NMT 100 cfu/ g AOAC, BAM Not detected
Salmonella Absent/ 2Sg AOAC, BAM Complies
E. coli Absent / lOg AOAC, BAM Complies
Staphylococcus i3ureus Absent / lOg AOAC, BAM Complies
Pseudomonas aeruginosa Absent / lOg AOAC, BAM Complies
Afiatoxin Absent AOAC, BAM Complies
Coliforms Absent/ lOg AOAC, BAM Complies
(..Microbial assay- detection limit- 10 cfu/ g)
Assay for Actives

Total Curcuminoids Complex: NLT95% HPLC 96.64%
Consisting of Curcumin, Desmethoxy Curcumin, Bis-Desmethoxy Curcumin ond Volatile Oils of Turmeric Rhizome
Total Curcuminaids NLT 86% HPLC 90.80%

BCM-95• & 8io-Curcumin8 are registered trademarks of Dolcas Biotech LLC

• GMO Free
• Sto re in a cool, dry place and away from direct sunlight.
• Shelf Life: Retest 3 vears from date of manufacturino.
• This material is manufactured without the use of any harmful solvents. (e.g., Benzene, Carbon Tet rachloride,
1,2-Dichloroethane, 1,1-Dichloroethene, 1,1,-Trichloroethane)
By:----- --
(b) (6)
Approved
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Appendix C JECFA Specifications For Curcumin
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nJRIVERIC OLEORESIN
Prepared at the 35th JECFA (1989), published in FNP 49 (1990) and in
FNP 52 (1992). Metals and arsenic specifications revised at the 59th
JECFA (2002). A terrporary AD/ established at the 30th JECFA (1986) was
not maintained at the 35th JECFA (1989)
DEFINITION Obtained by solvent extraction of turmeric (CUrcuma longa L.). Only the
foil owing solvents may be used in the extraction: acetone. di chloromethane,
1,2-di chlo ro ethane. methanol. etha noI. i sopropa noI and light petroleum
(hexanes)
The selection of a turmeric ole ore sin of a particular camp osition is based on
the intended use in food . In generaI, all turmeric ol eoresi ns contain
colouring matter and most contain flavouring matter but some oleore sins
are processed to remove aromatic campo unds. Commercia I products
include oleoresins (per se) and formulations in which oleo resin is diluted in
carrier solvents and which may contain emuIsifi ers and antioxidants.
Purified extracts of turmeric containing more than 90% total co louring matter
are subject to sp ecifi cations for "Cu ncumin".
Turmeric Oleoresins are sold on the basis of "colour value" or "curcumin
content", which gene rally means the total content of the cu ncumin aid
substances (I) curcumin, (II) demethoxycurcumin and (Ill) bis
demethoxycurcumin.
Chemica I names The principle co louring camp onents are:

I. 1,7-Bis(4-hydroxy-3-meth oxyph enyl)h epta-1 ,6-di ene- 3,5-di one
II . 1-(4-Hydroxyphenyl)- 7-(4-hydroxy-3-meth oxyph enyl)-he pta-1 ,6-die ne-
3,5-dione
Ill . 1,7-bis(4-hydroxyphenyl)hepta-1 ,6-diene-3, 5-dione
Chemica I formula Chemical formula

I. C21H2o~
II. C2oH 1s05
Ill. C19H 1s04
Structural fo rmu Ia
I. R1 = R2 = -OCH3
II . R1 = -OCH3, R2 = H
= =
Ill. R1 R2 H
Formula weight I. 368.39

II. 338.39
Ill. 308.39
Assay Content of total colouring matter (curcuminoid content) not less than
declared.
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DESCRIPTION Turmeric Oleoresins, per se, are deep brownish-orange viscous oily fluids,
pasty semisolids or hard amorphous solids containing 37-55% curcuminoids
and up to 25% volatile oil. Diluted turmeric oleoresin formulations are,
generally yellow solutions containing 6-15% curcuminoids and nil to 10%
volatile oil.
FUNCTIONAL USES Colour, flavouring agent
CHARACTERISTICS
IDENTIFICATION
Solubility (Vol. 4) Insoluble in water
Colour in ethanol The ethanol-soluble fraction of the sample is characterized by its pure
yellow colour and light green fluorescence; if this ethanol extract is added to
concentrated sulfuric acid, a deep crimson is produced.
Boric acid test Treat an aqueous or dilute ethanolic suspension of the sample with
hydrochloric acid until a slightly orange colour begins to appear. Divide
mixture into 2 parts and add some boric acid powder or crystals to one
portion. Marked reddening will be quickly apparent, best seen by
comparison with the portion to which the boric acid has not been added.
The test may also be made by dipping pieces of filter paper into an
ethanolic suspension of the sample, drying at 100°, and then moistening
with a weak solution of boric acid to which a few drops of hydrochloric acid
have been added. On drying, a cherry red colour will develop.
PURITY
Residual solvents (Vol. 4) Acetone : Not more than 30 mg/kg

Methanol: Not more than 50 mg/kg
Ethanol: Not more than 50 mg/kg
Isopropanol: Not more than 50 mg/kg
Dichloromethane and 1 ,2-dichloroethane: Not more than 30 mg/kg, singly or
in combination
Light petroleum (hexanes): Not more than 25 mg/kg
Arsenic (Vol. 4) Not more than 3 mg/kg
Lead (Vol. 4) Not more than 2 mg/kg

Determine using an atomic absorption technique appropriate to the
specified level. The selection of sample size and method of sample
preparation may be based on the principles of the method described in
Volume 4, "Instrumental Methods."
METHOD OF Method I
ASSAY
Standard Preparation
Transfer about 250 mg of purified curcumin, accurately weighed, into a 100-
ml volumetric flask, and record the weight as W, in mg. Dissolve in acetone,
dilute to volume with acetone, and mix. Pipet a 1-ml portion of this solution
into a second 100-ml volumetric flask, dilute to volume with acetone, and
Page 85 of 125
DolCas Biotech, LLC
mix. Finally, pipet a 5-ml portion of the last solution into a 50-ml volumetric
flask, dilute to volume with acetone, and mix.
Sample Preparation
Transfer an accurately weighed amount of the sample, equivale ntto about
250 mg of curcumi n, into a 100-ml val umetric flask, and record the weight
as w, in mg. Dissolve in acetone, dilute to volume with acetone, and mix.
Pipet a 1-ml portion of this sol uti on into a second 100-ml volumetric flask,
dilute to volume with acetone, and mix. Finally, pipet a 5-ml portion of the
Iast sol uti on into a 5 0-ml volumetric flask, dilute to volume with acetone, and
mix.
Procedure
Determine the absorbance of each solution in 1-cm cells at the wave Iength
of maximum absorption at about421 nmwith a suitable spectrophotometer,
using acetone as the blank.
Calculate the percentage of curcumin in the sample by the formula:
W Au
lOOx-x-
w As
V\ohere
Au = the absorba nee of the Sample Preparation
As = the absorbance of the standard preparation.
(NOTE: The absorbance readings should be made as soon as possible
after the solutions are prep ared to avoid colour loss).
Method II
Accurately weigh (W) about 0 .1 g of the sample in a 100-ml beaker. Add 50
ml of ethanol and extract the co lour by vigorously stirring. Filter the sol uti on
into a 200-ml val umetric flask. Make up to volume with eth anal.
Take an ali quat of the colour sol uti on and dilute with additional ethanol
according to the estimated colouring matters content as follows:
Colourina matter confen Dilution fado

Less than 20% 20
Between 20 and 40% 50
More than 40% 100
Determine the absorbance (A) at 425 nm in a 1-cm cell.

Calculate the total colouring matters content of the sample by the formula:
Ax lOOOOxD
Wx 1607
where
D = 0 A, 1 and 2 for dilution factors of 20, 50, and 1DO, respectively .
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Appendix D Accelerated And Long-Term Stability Report For BCM-95®
ACCELERATED STABILITY STUDY:. BIO-CURCUM~ (BCM 95CG~
Bio-Curcumin~ (BCM -95Co!} isastandardized extract ofcurcuminoids with not less than 95%total curcuminoid
complex.
Effect of temperature on the Curcuminoidcontent Arrhenius plot for detecting drug stability at room
at elevated temperature temperature
(/)
100 _. .. f/fc 5
lJ Ill
ii 75 ~:Jcc
~
t: ~4
~ 50 X3
:::(
~
::l Ol2
0 25 0
0~
0 0
0 1 2 3 4 5 0 2000 4000 6000 8000 10000 12000
Time,IY-5. lime, secords
I
Report
Based on the accelerated stability study, the shelf life of the Bio •curcumi~ (BCM 95 C~) is 3 years and 5months with
respect to its curcuminoid content.
Reference:
Physical Pharmacy by Alfred ~artio; 4~tioo
Publisher : Lippincott Williams &Wilkins
AwoltersKluwerwmpaoy.
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DolCas Biotech, LLC
LONG TERM STABILITY DATA: 810-CURCUMIN®(BCM-95CG®)

(ReferenceICHGuideline)
Bio-Curcumin~ (BCM -95C~) isastandardized extract ofcurcuminoidswith not less than 95%total curcuminoid
complex.
The Proposed Stability Specificationsare :
Tests Acceptance Criteria Analytical Procedure
Colour &Appearance OrangeRedPowder Visual
Moisture NMT 2% USP<616>
Assay NLT95%Total Curcuminoid HPLC

Complex
Mjcrobial Assay
Total PlateCount <1000cfu/g AOAC,BAM
Yeast &Mould <100cfu/g AOAC,BAM
E-coli AbsenUlOg AOAC,BAM
Salmonella AbsenU25g AOAC,BAM
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DolCas Biotech, LLC
The Acceptance limits for these attributes remain the same as those used to confinn the quality of thefinished product on
batch release.
StudyConductedOn:-2/1/2006
DurationOfStudy :-3Years
Stability Protocol
Strength Container/Oosure Conditions Sample Times Batches
1Kgx15 HM-HDPE Temperature 0,3,6,9,12,18,24,30,36 (b)

(4)
(b) (4)
30°C(t/-2) and months
Humidity 65%(t/-
2)
1Kgx15 HM-HDPE Temperature 0,3,6,9,12,18,24,30,36 (b) (4)

Humidity 65%(+I-
2)
1Kgx15 HM-HDPE Temperature 0,3,6,9,12,18,24,30,36 (b) (4)

Humidity 65%(t/-
2)
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DolCas Biotech, LLC
(b) (4)
Parameters Month: 0 Month: 3 Month:6 Month : 9 Month: 12 Month:l8 Month: 24 Month:30 Month:36
Colour & Orange Orange Orange Red Orange Red Orange Red Orange Red Orange Red Orange Red Orange Red
Appearance Red Red Powder Powder Powder Powder Powder Powder Powder
Powder Powder
Moisture 0.2% 0.2% 0.2% 0.2% 0.2% 0.2% 0.2% 0.3% 0.3%
Curcumino 95.5% 95.4% 95.4% 95.4% 95.4% 95.4% 95.4% 95.3% 95.3%
dcomplex
Total plate 40Cfu/G 50 Cfu/G 50Gu!G 50Gu!G 50 Cfu/G 50Cfu/G 60Gu!G 60 Cfu/G 60Cfu/G
count
Yeastand Not Not Not Not Not Not Not Not Not
Mould detected detected detected detected detected detected detected detected detected
E-coli Negative Negative Negative Negative Negative Negative Negative Negative Negative
Salmonella Negative Negative Negative Negative Negative Negative Negative Negative Negative
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DolCas Biotech, LLC
(b) (4)
Parameters Month: 0 Month:3 Month:6 Month: 9 Month: 12 Month:l8 Month: 24 Month:30 Month:36
Colour& Orange Orange Orange Red

Appearance Red Red Powder Orange Red Orange Red Orange Red Orange Red Orange Red Orange Red
Powder Powder Powder Powder Powder Powder Powder Powder
Moisture 0.3% 0.3% 0.3% 0.3% 0.3% 0.3% 0.4% 0.4% 0.4%
Curcumino 95.7% 95.7% 95.7% 95.6% 95.6% 95.6% 95.5% 95.5% 95.4%
dcomplex
Totalplate 50 Cfu/G 50 Cfu/G 50 Cfu/G 60Cfu/G 60 Cfu/G 60Cfu/G 70 Cfu/G 70 Cfu/G 70 Cfu/G
count
Yeast and Not Not Not Not Not Not Not Not Not
Page 91 of 125
DolCas Biotech, LLC
(b) (3) (B)
Parameters Month: 0 Month:3 Month:6 Month: 9 Month:12 Month:18 Month: 24 Month: 30 Month:36
Colour& Orange Orange Orange Red

Appearance Red Red Powder Orange Red Orange Red Orange Red Orange Red Orange Red Orange Red
Powder Powder Powder Powder Powder Powder Powder Powder
Moisture 0.2% 0.2% 0.2% 0.2% 0.2% 0.3% 0.3% 0.3% 0.3%
Curcumino 95.6% 95.6% 95.6% 95.6% 95.5% 95.5% 95.5% 95.4% 95.4%
dcomplex
Totalplate 40 Cfu/G 40 Cfu/G 40 Cfu/G 40 Cfu/G 50 Cfu/G 60 Cfu/G 60Cfu!G 60 Cfu/G 60Cfu!G
count
Yeast and Not Not Not Not Not Not Not Not Not
Page 92 of 125
DolCas Biotech, LLC
Graphical Representation Of Long Term Stability Data
Bio~urcumin {BCM-95CG)
..
r::
98 . . - - - - - - - - - - - - - - ,
Ill
E 97.5
0
u
~ 97
Q.
E
0 96.5
(.)
'C
0 96
-Er:: . .
~ 95.5 ,...,· ·· ~··
- · ~'
- · ...- '· i·
• •
··· ····l· ··· · •
... ··:.~· · · ·--s
::l
0 95 r-~~-r-r~~~~~-r~
0 3 6 9 12 15 18 21 24 27 30 33 36 39
Month
I ~BCM9ii:G RD·II -BCM9ii:GRD·12 ... , ... BCM9i:GRD·O I
Based on thelong-term stability study at Temperature 30°C(+1·2) and Humidity 65 %(+1·2), Bio·curcumin®
(BCM 95CG®)is found to be stable up to 3years ofstudy period.
Reference:·
ICH Q1A(R2)Stability Testing of New DrugSubstances andProducts.
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DolCas Biotech, LLC
Appendix E Elevated Temperature Stability Report

(Temperatures: 400C, 500C, 600C)
STABILITY DATA: BIOCURCUMI~ BCM-95 CG
Scope oftheStudv:
To check the thermalstability of total curcumoidsand Ar-turmerone content(w.r.t volatile oil) of the Biocurcumin®BCM-
95 CG
Product Description
Biocurcumin®BCM-95 CG isastandardized with 95% total curcuminoid +volatilecomponentsof turmeric.
ConditionsfortheStudy
For the study the 100 gms of sample istaken inside aglass bottle. Sample iskept in~de water bath setat 30°C,through the
time ofthestudy. Simillarly sample isalso kept at 40°C,50°C,&60°C
Sampling pattern
Biocurcumin®BCM-95CG is placed in the water bath. It isplanned totake sampleatdifferent hours0,2,4,6,12, and24
for the analysisofTotal curcuminoid content , Moisture and Ar-turmerone (w.r.t volatile oil)
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DolCas Biotech, LLC
The Proposed Stability Specifications are:
Tests Acceptance Criteria Analytical Procedure

Colour &Appearance Yellowishorange red powder Visual
Total Curcuminoid+Volatile NLT95% HPLC
componets
Ar-turmerone(w.r.t Volatileoil) NLT45% GC
The Acceptance limits for these attributes remain the same as those used to confinn the quality of the finished product on
batch release.
Stability At 30°C
Parameters Hour- 0 Hour -2 Hour-4 Hour -6 Hour-12 Hour -24
Colour &Appearance Orange Red Orange Red OrangeRed Orange Red Orange Red Orange Red
Total Curcuntinoid +
Volatilecomponets 95.9% 95.8% 95.8% 95.7% 95.7% 95.7%
Ar-turmerone(w.r.t Volatile
oil) 46.1% 46.1% 46.1% 46.1% 46.1% 46.1%
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Stability At 40°C
Parameters Hour- 0 Hour -2 Hour -4 Hour -6 Hour -12 Hour -24
Colour &Ap~arance Orange Red Orange Red Orange Red Orange Red Orange Red Orange Red
Powder Powder Powder Powder Powder Powder
Total Curcuminoid +
oil) 46.1% 46.1% 46.1% 46.1% 46.1% 46.1%
Stabiii tv At sooc
Parameters Hour- 0 Hour -2 Hour -4 Hour -6 Hour -12 Hour -24
Colour &Ap~arance Orange Red Orange Red Orange Red Orange Red Orange Red Orange Red
Total Curcuminoid +
oil) 46.1% 46.1% 46.1% 46.05% 46.05% 46.05%
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DolCas Biotech, LLC
Report Stabilitv At 60°C
Parameters Hour -0 Hour -2 Hour -4 Hour -6 Hour -12 Hour -24
Colour &Appearance OrangeRed Orange Red Orange Red Orange Red Orange Red Orange Red
Total Curcuntinoid +
Ar-turmerone (w.r.t Volatile
oil) 46.1% 46.1% 46.0% 46.0% 46.0% 46.0%
Effect of Temperatue on tTotal curcuminoids + volatile components of

Biocurcumax BCM 95 CG
97.00% . , . . . - - - - - - - - - - - - - - - - - - - - - - - - - - .
(I) "
:s ......f
-o ·c
~
()
96.50%+ - - - - - - - - - - - - - - - - - - - - - - - - - - - 1
~~
0 ..
i) :J
'(5 I-
I: ...
·- 0
E 0
:J ..
() 1:
.. (I)
96.00% IL
~- -
- · - --~~
. "1-:t--~~--t-t-
.... .......
.' ....... -·I'· .... -~=~---
...... ..-
:-:·:·':".......~"''"~"·-
· --.~~1
:J 1: 95.50% + - - - - - - - - - - - - - - - - - - - - - - - - - - - 1
() 0
- c.
SE
1- 8 95.00% +----.--------.-------,------,------;------!
0 5 10 15 20 25 30
I-t-- 30'C --t-- 40'C ... , ... 50'C ---.- 60~ I Time (1-tlur)
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DolCas Biotech, LLC
Effect of Temperatue on Ar- turmerone content of Biocurcumax BCM 95 CG
47.00%
~ ......
~ ~
~ ......
- 0
g·c 46.60%
+~
VI I.
"0
·o
j
t-
t: ...
46.20%
~--.a::::·· . ...---·I· ..·:::-.::: . . .·::..:. .. . ·I
·- 0
E VI
j .. 45.80%
0 t:
I. ~
j t:
0 0 45.40%
- c.
!0 E
0
t- 0
45.00%
0 5 10 15 20 25 30
l-t--30'C _._ 4o'C ••, •• socc GO'C I Time (Hour)
Result:
Based onthe stabilitystudyat different temperatures, Biocurcumin®BCM-95 CG is found to be stableat

elevated temperatures
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DolCas Biotech, LLC
Appendix F Human Studies on Other Curcumin Preparations
Lao et al. (2006) performed a dose escalation study to determine the maximum tolerated
dose and safety of a single dose of uniformly milled curcumin extract (C3 Complex™,
Sabinsa Corporation) in humans. The test preparation contained a minimum 95%
concentration of three curcuminoids: curcumin, bisdemethoxycurcumin, and
demethoxycurcumin. Twenty-four healthy subjects were administered escalating doses of
the extract from 500 to 12,000 mg. No curcumin was detected in the serum of subjects
administered 500, 1,000, 2,000, 4,000, 6,000 or 8,000 mg. Two subjects administered
10,000 or 12,000 had low levels of curcumin in serum. Seven subjects experienced minimal
toxicity that did not appear to be dose-related. Adverse effects included diarrhea, headache,
rash, and yellow stool. No other adverse events were reported, and the authors concluded
that the tolerance of curcumin in single doses up to 12,000 mg is excellent.
Other human clinical studies using oral curcumin have not reported any major signs of
toxicity. In patients with rheumatoid arthritis in India, the administration of 1.2 to 2.1 g of oral
curcumin daily did not produce any major adverse effects (Deodhar et al., 1980). In a high-
dose oral curcumin study in Taiwan, up to 12 g of curcumin were administered daily for 3
months in patients with pre-invasive malignant or high risk pre-malignant conditions. No
resulting toxicity was reported in this study with daily administration up to 8 g. The 12 g/day
dose was not acceptable to the patients due to the bulky volume of the tablets (Cheng et al.,
2001). Curcumin was well-tolerated in a clinical study in the UK at all dose levels up to 3.6 g
daily for 4 months in patients with advanced colorectal cancer. However, two types of
gastrointestinal adverse events were reported by patients. One patient consuming 0.45 g
daily developed diarrhea one month into the study and one patient consuming 3.6 g daily
developed diarrhea four months into the study. Another patient consuming 0.9 g curcumin
daily experienced nausea. In blood tests, a rise in serum alkaline phosphatase level was
observed in four patients, and serum lactate dehydrogenase increased to more than 150% of
pre-treatment values in three patients. The authors concluded that these effects may be
more related to the progression of disease rather than treatment (Sharma et al., 2004).
Joshi et al. (2003) conducted a 3-month clinical trial to study the safety and tolerance of
turmeric oil in humans. Volunteers were administered 0.6 mL of turmeric oil three times a
day in capsule form for 1 month and 1 mL in 2 divided doses for 2 months. The composition
of turmeric oil was as follows: 59% Turmerone and Ar-Turmerone, 25% zingiberene, 1%
cineole, 15 d-phellandrene, 0.6% d-sabinene, and 0.5% borneol. There were no acute
tolerability side effects on day one, and there was no effect of turmeric oil on weight, blood
pressure, clinical, hematological, renal or hepatic toxicity at 1 month and 3 months. One
volunteer had an allergic skin reaction to the turmeric oil preparation and another volunteer
had reversible hypertriglyceridemia. No other adverse reactions were observed.
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Das et al. (2010) evaluated the efficacy of turmeric and turmeric oil in patients with oral
submucous fibrosis (OSMF), a chronic disease of the oral mucosa with a high incidence of
malignancy. Forty-eight patients who were clinically and histopathologically confirmed as
having OSMF were divided into three groups. Group 1 received 1 g curcumin in capsules,
group II received 600 mg turmeric oil (from a dropper) and group III received control
multinal (1 g) tablets daily for three months. After the treatment period and follow-up,
there was a significant improvement in clinical signs and symptoms of patients treated with
curcumin and turmeric oil compared to the control. There were also positive changes in
the histological examination of treatment groups, including a reduction in inflammatory
cells. All of the patients tolerated the treatment and there were no allergic or adverse
effects from the treatment.
Table 13. Summary of Select Curcumin Studies
Study Study Dosage and study Preparation Duration Key Observations OSL
Population design Description (days) Considerations
Deodhar et 18 patients double-blind 1200 mg/day Two weeks Only a mild improvement Small dose and
al., (1980) with crossover Curcuma longa (14 days) in symptoms was evident short duration
rheumatoid L.in 3 divided
arthritis doses
Srimal and Individuals 1,500 mg/day 4 weeks No adverse effects

Dhawan with curcumin
(1985) osteoarthritis
Satoskar et 40 patients 1,200 mg/day Not specified 5 days Curcumin resulted in a Small study
al. (1986) who had curcumin (n=13) significant reduction in
recently had tenderness at site, cord
surgery for Placebo (n=13), edema, cord tenderness,
inguinal phenylbutazone, and pain at the operation
hernia (n=14) site compared with
baseline. Placebo only
Randomized, improved pain at site and
double-blind, cord tenderness
placebo-controlled,
parallel group
Thamlikitkul 116 2,000 mg curcumin 8 capsules /day 7 days The curcuma group had
et al. (1989) individuals (n=39) Curcuma significantly more study
with domestica Val participants with a
dyspepsia Placebo (n=41) (250 mg dried favorable outcome than
syndrome rhizome powder, the placebo group.
Flatulence(n=36) containing 0.2 mL
of volatile oil and Frequency of side effects
randomized, double- was not different for the
24 mg total
blind, placebo- three groups. Side effects
curcuminoids)
controlled, were mild and self-
multicenter study limiting.
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Soni and 10 healthy 500 mg/day 98% pure 7 days Curcumin decreased Small study
Kuttan (1992) men and curcumin curcumin serum peroxides and
women (Bombay Oil serum cholesterol,
Single group study Industries, Ltd., increased HDL
Angamali) cholesterol, no effect on
serum triglycerides or
body weight. No toxic
effects such as nausea,
vomiting, headaches, or
unusual bowel
movements observed
Kositchaiwat 60 patients 750 mg dried Curcuma longa Six weeks (42 Complete ulcer healing Variation in ulcer
et al. (1993) with gastric Curcuma longa L.in L.rhizome cut into days); patients was observed in 33.3 % size
ulcer, 18-80 capsules split over small pieces and with ulcer of patients, 51.9 %
years old three doses in one dried then improvement patients had improved
day (250 mg/dose) crushed into during study ulcers. After 12 weeks,
powder for continued for 70.6 % patience had
randomized, encapsulation an additional complete ulcer healing.
controlled six weeks.
James (1996) 40 individuals 625 mg, 4 times per 56 days Well-tolerated

with HIV day
Hastak et al. 32 individuals 3,000 mg/day Turmeric oil and 3 months The product reduced the Small study
(1997) with oral turmeric extract turmeric oleoresin number of micronuclei in
submucous (n=10) were prepared by oral submucous fibrosis
fibrosis Kancor Flavours patients. It also educed
600 mg turmeric and Extracts the number of
oleoresin/day in Limited (Kochin, micronuclei that were
3,000 mg of Kerala, India) and induced by
turmeric extract alcohol turmeric benzo[a]pyrene.
(n=13) extract
600 mg turmeric oil

+ 3,000 mg of
turmeric extract /day
(n=16)
Random, parallel
group study
Ramirez 30 healthy 20 mg/day curcumin 2 tablets/day each 60 days Curcumin extract reduced Small study,
Boscá et al. volunteers extract containing 10 mg high levels of placebo, no
(1997) if a hydroalcoholic peroxidation of HDL and control group
LDL in individuals with
extract of
high baseline levels of
Curcuma longa these substances.
Non-controlled trial L.(A.S.A.C. Liver biochemistry
Pharmaceutical parameters were all in
International) the normal rang. No toxic
effects reported including
nausea, diarrhea, or
constipation
Page 101 of 125
DolCas Biotech, LLC
Rasyid and 12 healthy 20 mg curcumin Curcumin (Merck 2 days at least Curcumin increased Small study
Lelo (1998) individuals Schudschardt) one week gallbladder contraction
apart compared with placebo
Randomized,
double- blind,
placebo-controlled,
crossover study
Van Dau et 130 patients 6 g Curcuma longa Curcuma longa Eight weeks Turmeric did not offer an Potentially
al. (1998) with duodenal L.in tablets per day L.rhizome cut into (56 days) improvement to ulcer inadequate
ulcer small pieces and healing over placebo dosage
dried then
crushed into
double-blind, two powder for
center study compression into Authors stated that the
tablets majority of the symptoms
were related to ulcer
disease and that
Curcuma longa L.and the
placebo were both well-
tolerated
Lal et al. 32 men and 1,125 mg/day 375 mg curcumin 12 weeks, Efficacy of curcumin is Small study, no
(1999) women with curcumin (n=18) administered 3 evaluations at comparable to that of placebo control
chronic times/day as 2-week corticosteroid therapy, group
anterior Curcumin+antituber gelatin capsules. intervals the standard treatment
uveitis cular treatment >95% pure and lacks side effects of
(n=14) curcumin isolated corticosteroids. There
Non-controlled from rhizomes of was no recurrence of
study C. longa symptoms observed. No
side effects
Heng et al. 40 individuals 1% curcumin gel Reduction in PhK activity,

(2000) with psoriasis keratin transferrin
receptor expression,
parakeratosis, and
10 individuals with density of epidermal
psoriasis CD8+T cells
Lal et al. 5 individuals 1,125 mg/day 6 to 22 months 4 of the 5 individuals who

(2000) with idiopathic curcumin completed the study had
orbital a complete recovery,
pseudotumors
No recurrence of
symptoms at follow up.
No side effects were
reported
Page 102 of 125

DolCas Biotech, LLC
Ramirez 8 healthy 20 mg/day curcumin 2 tablets/day 15 days Curcumin treatment Small group, no
Boscá et al. individuals containing a significantly reduced placebo control
(2000a) with hydroalcoholic fibrinogen levels
abnormally extract of C. longa
high levels of Non-controlled trial (A.S.A.S
plasma Pharmaceutical
fibrinogen International, No side effects including
A.I.E., Alicante nausea, diarrhea or
Spain) constipation were
reported.
Ramirez 12 healthy 20 mg/day curcumin 2 tablets/day 1 month (30 Curcumin treatment was Small study, no
Boscá et al. men with high containing a days) associated with a placebo, no
(2000b) LDL-C values hydroalcoholic reduction in LDL-C and control group
(>150 mg/dl) extract of C. longa apo B and an increase in
Non-controlled trial (A.S.A.S HDL-C and apo A.
Pharmaceutical
International, No side effects including
A.I.E., Alicante nausea, diarrhea or
Spain) constipation were
reported.
Cheng et al. 25 study Phase I clinical trial 3 months Some individuals

(2001) participants developed frank
who had 500, 1,000, 2,000, malignancies.
undergone 4,000, 8,000 and
surgery for 12,000 mg/day Some beneficial effects of
bladder curcumin curcumin were observed.
cancer, had Curcumin is not toxic to
arsenic humans at a dose of up
Bowen’s to 8,000 mg/day. The
disease of the 12,000 mg/day dose was
skin, uterine not acceptable because
cervical of bulkiness.
intraepithelial
neoplasm,
oral
leukoplakia,
intestinal
metaplasia of
stomach
Prucksunand 45 individuals 5 600 mg/day Turmeric 12 weeks for By week 12, 19 of 25

et al. (2001) with turmeric prepared from ulcer patients individuals with ulcers
suspected crude powder of and 4 weeks were healed. There were
peptic ulcer dried rhizome of for non-ulcer no changes in
Curcuma longa patients hematological
Phase II clinical trial L.Linn measurements and liver
and renal function.
Page 103 of 125

DolCas Biotech, LLC
Sharma et al. 15 individuals 440, 880, 1320, Capsules Up to 4 5 individuals had stable
(2001b) with advanced 1760, and 2,200 contained 20 mg months disease after 2 to 4
colorectal mg/day Curcuma curcuminoids (18 months of treatment.
cancer extract mg curcumin and Consumption of curcumin
refractory to 2 mg is safe up to a 2,200
chemotherapy desmethoxycurcu Treated lasted mg/day or 180 mg/d
min) in 200 mg until disease curcumin.
essential oils progression or
from Curcuma withdrawal Nausea in 1,320 mg dose
spp (Phytopharm from the study and diarrhea in in 880 mg
plc. dose and 1 at 2,200 mg
(Godmanchester, dose, but authors stated
UK) curucmi well-tolerated
and no dose-limiting
toxicity
Joshi et al. 9 healthy 0.6 mL turmeric oil Gelatin capsules 12 weeks There were no effects of
(2003) volunteers 3 times a day for containing turmeric oil on weight,
one month, then 1 turmeric oil blood pressure,
mL in 3 divided symptoms or safety
doses for 2 months. parameters. One subject
dropped out due to
allergic skin rash, which
disappeared after
discontinuation of
turmeric oil.
Bundy et al. 166 72 mg (1 tablet) or Cynara™ 8 weeks Curcumin treatment

(2004) individuals 144 mg (2 tablets) Turmeric, significantly reduced IBS
with self- of curcumin extract Lichtwater by 53% for the 72 mg/day
reported Pharma (UK) Ltd., dose group and 60% for
irritable bowel Marlow, UK the 144 mg/day dose
syndrome group.
(IBS) for at uncontrolled,
least 3 randomized, Adverse effects included
months partially blinded pilot flatulence and dry mouth.
study The authors reported no
major side effects of
curcumin treatment
Sharma et al. 15 patients Dependent on dose C3 Curcuminoid 4 months Systemic activity and
(2004) with advanced level, patients capsules(Sabinsa compliance trial. A daily
colorectal consumed 1, 2, 4, or CorpNJ). Each dose of 3.6 g curcumin
was advocated for Phase
cancer 8 capsules capsule contained
II evaluation.
(containing 450, 500 mg
900, 1800, or 3600 curcuminoids
mg of curcumin) (450 mg curcumin
once daily 40 mg of
desmethoxy
curcumin, 10 mg
of bisdesmethoxy
curcumin)
Page 104 of 125

DolCas Biotech, LLC
Durgaprasad 20 individuals 500 mg/day 500 mg/day 6 weeks Significant reduction in

et al. (2005) with tropical curcumin curcumin +5 red blood cell levels of
pancreatitis mg/day piperine malonyldialdehyde and
increase in red blood cell
GSH levels.
Holt et al. 5 individuals 550 mg, 2-3 60 days Reduced proctitis

(2005) with ulcerative times/day for 60 symptoms symptoms and
proctitis days need to take medication
in 4 of 5 study
participants
5 individuals
with Crohn’s
Disease 360 mg curcumin 30 days 100% reduction in CDAII
3x/day scores.
and 4 times/day
60 days
Shoskes et 45 cadaveric 480 mg curcumin + Each tablet of 1 month Oxy-Q improved renal
al. (2005) kidney 20 mg quercetin Oxy-Q contained function.
recipients 480 mg curcumin
+ 20 mg quercetin
960 mg curcumin Well-tolerated with

+40 mg quercetin minimal side effects.
Cruz-Correa 5 individuals 1,440 mg/day 3 doses of Oxy mean of 6 Side effects were limited
et al. (2006) with familial curcumin and 40 Q/day (480 mg month (3 to 9 and no laboratory
adenomatous mg/day quercetin curcumin + 20 mg months) anomalies were noted
polyps quercetin 3
times/day)
Lao et al. 24 healthy 500, 1000, 2000, Standardized Single dose at Seven subjects Single dose
(2006) adults 4000, 8000, 10000, powdered extract each dose experienced minimal
12000 mg curcumin (C3 Complex, level toxicity (yellow stool,
in escalating doses Sabinsa headache) that was not
Corporation), dose-related. High single
Containing: doses of curcumin were
curcumin between well-tolerated.
70% and 80%,
demethoxycurcu
min between 15%
and 25%, and
bisdemethoxycurc
umin between
2.5% and 6.5%
Page 105 of 125

DolCas Biotech, LLC
Hanai et al. 89 patients 2 g curcumin/day 2 x 1g doses of 6 months (180 Fewer relapses; 2 g, large sample
(2006) with quiescent curcumin/day days) improved clinical activity size, long
ulcerative index. duration
colitis Curcumin
randomized, prepared by API
placebo controlled, Co, Ltd (Gifu,
multicenter, double- Japan) contained Mild, transient side-
blind 50% curcumin, effects such as
42.5% abdominal bloating that
microcrystalline may not have been due
cellulose, 7.5% to curcumin.
malitol and the
composition of the
placebo was 25%
microcrystalline
cellulose, 29.6%
dextrin, 10%
cornstarch, 35%
malitol, 0.15%
FD&C Yellow No.
5, 0.04% FD & C
Yellow No. 6, and
caramel color
Ng et al. 1,010 non- Curry consumption Curry Age 63-90 Better Mini-Mental State
(2006) demented years Never or Examination scores
elderly Asian rarely,
subjects occasionally or
(epidemiologic often
al study)
Chainani-Wu 33 patients 2 g/day Curcumim C3 7 weeks (49 No difference between 2 g, small

et al. (2007) with oral Complex days) treatment group and sample size,
lichen planus (Sabinsa Corp, control. Study was ended short duration;
Piscataway, NJ) after first interim analysis.
randomized, double-
blind Containing:
curcumin between
70% and 80%, Dose was well-tolerated
demethoxycurcu
min between 15%
and 25%, and
bisdemethoxycurc
umin between
2.5% and 6.5%
Page 106 of 125

DolCas Biotech, LLC
36 adults with 1 g or 4 g/day Packets of 6 months (180 No effect on Up to 4 g, small

progressive curcumin curcumin were days) triacylglycerols, total LDL sample size but
Baum et al. decline in preparation provided by and HDL cholesterol; long duration.
(2007) memory and Kancor Flavors, positive significant Given the lack of
cognitive Kerala India, and correlation of serum adverse effects
function curcumin cholesterol to plasma in studies using
randomized, double- capsules were curcumin this dose, this
blind provided by study is choses
Arjuna Natural as basis for the
Extracts, Kerala, OSL for
India No severe adverse supplemental
events observed. curcumin.
Di Mario et al. 25 individuals Twice daily Curcumin 7 days Significant reduction in

(2007) with H. pylori treatment with a overall symptom severity
infections and combination of 30 (P<0.001) and serum
functional mg curcumin, 100 pepsinogen I (P=0.02)
dyspepsia mg bovine and serum pepsinogen II
lactoferrin, 600 mg (P≤0.001). No significant
N-acetylcysteine, effect on IgG and gastrin
and 20 mg 17.
pantoprazole
Johnson and 12 individuals 450, 1800, or 3,600 Curcumin 7 days Only the 3,600 mg
Muktar who were mg of curcumin/day curcumin dose was at the
(2007) scheduled to level of detection.
undergo Phase I clinical trial Increased M1G adducts
surgery possibly due to surgery.
Dhillon et al. 21 patients 8 g/day curcumin 1 g caplets from 8 weeks Two study participants
(2008) with advanced Sabinsa, each showed clinical effects.
pancreatic Non-randomized, containing 1 g Blood tests and renal and
cancer open label, phase II curcuminoids hepatic function tests
trial (900 mg were conducted.
Original n=25 curcumin, 80 mg Curcumin was well-
desmethoxycurcu tolerated, no toxicity
min, and 20 mg occurred
bisdesmethoxycur
cumin)
Kurd et al. 8 Patients 4.5 g/day Capsules 16 weeks Dose was well-tolerated Low subject
(2008) with chronic curcuminoid C3 contained 95% and safe in psoriasis number
psoriasis Complex curcuminoids patients. Low response
vulgaris (Sabinsa Corp., rate to the curcumin
Piscataway, NJ) treatment. Adverse
events reported for 10/12
Phase II, single- study participants. Mild
arm, single-dose, adverse events
non-controlled considered likely related
to curcumin treatment:GI
upset/ heat
Page 107 of 125

DolCas Biotech, LLC
intolerance/flashes.
Antony et al. 11 healthy 4x500 mg BCM BCM-95 Single dose to Short-term Bioavailability
(2008) volunteers 95™ in one group, (Biocurcumax™. determine of BCM-95™ was 6.37
control curcumin in Arjuna Natural bioavailability relative to that of a
second group Extracts). Control curcumin-lecithin-piperine
curcumin combination. No adverse
capsules (Life events were reported.
Extension, USA)
Usharani et 72 diabetic 300 mg/day NCB-02 NCB-02 8 weeks (56 Favorable effect on 600 mg, large
al. (2008) patients described as an days) endothelial dysfunction. sample size,
encapsulated short duration.
preparation of The authors stated that
randomized, standardized no serious adverse
parallel-group curcuminoids events were reported.
Baum et al. 34 probable or 1 g or 4 g/day Curcumin 6 months (180 Curcumin increased Up to 4 g, small
(2008) possible curcumin capsules (Arjuna days) vitamin E, but had not sample size but
Alzheimer’s preparation Natural Extracts, effect on Amyloidβ 40. No long duration.
disease (AD) Kerala, India) and change in sodium, Supports OSL
patients curcumin packets potassium, urea, selected above.
for combining with creatinine, protein,
randomized, food (Kancor albumin, bilirubin, alkaline
placebo-controlled, Flavours, Kerala, phosphatase, and alanine
double-blind India) aminotransferase
(ALT)/glutamic-pyruvic
transaminase between
baseline and 6 months.
Number of adverse
events: 4g curcumin=2,
1g curcumin=6, 0 g
curcumin, =7. No severe
adverse events observed.
Golombick et 26 patients 4,000 mg/day oral C3 curcuminoids 3 months Curcumin reduced the
al. (2009) with curcumin from alley finger paraprotein load in
Monoclonal turmeric, each individuals with a
Gammopathy tablet including paraprotein level of
of Undefined 1,000 mg >20g/l
Significance, curcuminoids,
which can (900 mg
Single blind,
precede curcumin, 80 mg
randomized,
multiple desmethoxycurcu
crossover, pilot
myeloma min, and 20 mg of
study
bisdesmethoxycur
cumin
Page 108 of 125

DolCas Biotech, LLC
Deepa Das et 48 patients 1 g curcumin/day or Not well-specified 3 months Significant improvement Small study
al. (2010) with oral turmeric oil in clinical signs and number
submucous containing 600 mg symptoms in patients
fibrosis curcumin treated with curcumin and
turmeric oil. Treatment
was well-tolerated.
placebo-controlled
Epelbaum et 17 individuals 8,000 mg/day C3 Curcuminoids Median Median time to tumor

al. (2010) with advanced curcumin Complex® as two duration= 2 progression=2.5 months,
pancreatic 4,000 mg weeks range=1-12 months;
cancer doses/day median survival time =5
(Sabinsa Corp, months, range 1-24
Open label, phase, Piscataway, NJ) months
II clinical trial and1,000 mg/m2 Administered
gemcitabine via until death, 7 patients had GI toxicity-
i.v. for 3 of 4 disease abdominal fullness and
weeks. progression, pain, mild hematological
toxicity toxicity (neutropenia and
cytopenia, n=2)
Gota et al. Healthy 650 mg Longvida™ Longvida™ Single dose Good tolerability
(2010) individuals Optimized Curcumin Optimized
and Curcumin (130 to
individuals 195 mg curcumin)
with late stage
osteosarcoma
Koosirirat et 36 chronic 700 mg turmeric Each tablet Six weeks (47 Curcumin alone had little Only single dose
al. (2010) gastritis tablet 3 times per contained 40 mg days) effect on H. pylori turmeric used
patients day (2100 mg/day) curcumin infection in gastritis
patients in comparison to
patients receiving
standard therapy
(Omeprazole, Amoxicillin,
and Metronidazole)
Agarwal et al. 50 patients 500 mg capsule Curcumin 3 weeks post Lower mean pain and
(2011) following curcumin every 6 h supplied by surgery fatigue scores
laparoscopic Indsaff Inc. (India)
cholecystecto Randomized,
my double-blind,
prospective Patients able to decrease
analgesics and increased
pain relief.
Page 109 of 125

DolCas Biotech, LLC
Carroll et al. 44 smokers Stage 1: 2 g 98.0 curcumin 30 days No significant changes in

(2011) with 8 or more curcumin once daily, powder, Sabinsa PGE2 or 5
Abnormal n=20 subjects corp, East hydroxyeicosatetraenoic
Crypt Foci on Windsor, NJ acid following curcumi
screening Stage 2: 4g (16 consumption.
colonoscopy capsules), n=20
subjects Neither dose of curcumin
resulted in a clinically
Nonrandomized, significant elevation in
open label, Phase liver function
IIa clinical trial measurements
Curcumin was well-

tolerated.
Kanai et al. Patients with 8 g/day curcumin Sabinsa Dose-limiting None of the surviving
(2011) advanced toxicity patients had a complete
pancreatic Corporation or partial response, 5 had
cancer (Piscataway, NJ, stable disease (28%).
USA) in
microbead form. None of the study
C3 complex) participants withdrew due
consisted of to intolerability of
curcumin. No cumulative
Curcumin (73%), toxicity of curcumin was
demethoxycurcu observed. Authors stated
min (22%), and that combined therapy
bisdemethoxycurc with curcumin and
umin (4%). gemcitabine is safe and
well-tolerated.
Golombick et 19 patients 4,000 mg/day Each C3 25 treated Curcumin was associated

al. (2012) with MGUS curcumin curcuminoid with 4,000 mg with a reduction in serum
and 17 granule stick pack for 3 months creatinine, free light –
patients with (Sabinsa chain ratio and difference
smouldering Corporation, in clonal and nonclonal
multiple 8,000 mg/day Piscataway, NJ) light chain and involved
myeloma curcumin contained 3600 18 treated with free light chain. There
mg of curcumin, 8 mg for 3 was also a reduction in a
320 mg of months after 3 marker of bone
desmethoxycurcu months of resorption.
Randomized, treatment with
double blind, min, and 80 mg of
bisdesmethoxycur 4,000 mg
placebo controlled Curcumin
crossover study cumin.
Page 110 of 125

DolCas Biotech, LLC
Kanai et al. 6 healthy 150 mg Theracumin Theracurmin Single oral One report of grade I
(2012) individuals and (Theravalues doses two diarrhea, but not other
Corporation, weeks apart toxic effects were
210 mg Tokyo, Japan), observed
Theracurmin 105 curcumin, 2%
other
curcuminoids,
such as
demethoxycurcu
min, and
bisdemethoxycurc
umin, 46%
glycerin, 4% gum
ghatti, and 38%
water.
Ringman et 30 patients 0, 2 g or 4 g/day Curcumin 24 weeks (68 No clinical or biochemical Up to 4 g, small
al. (2012) with mild or curcumin (n=12/dose days) benefit sample size, and
moderate preparation group) as Tolerability parameters relatively long
probable AD Curcumin C3 monitored including duration. Safety
Complex® hematocrit, glucose parameters
(open label levels, lipid profile, monitored and
randomized, double- study chemistry panel, TSH. No no serious
blind extended to 48 significant changes out of adverse effects
weeks) normal range observed.
No serious adverse Supports OSL
effects observed. Minor selected above.
GI complaints, but not
statistically significant
compared to placebo.
Chainani-Wu 20 patients 6 g/day (n=10) Curcumin C3 12 days Improvement in signs and 6 g/day, small
et al. (2012) with oral complex in 3 symptoms of oral lichen sample size
lichen planus divided doses planus. Safety parameters
(Sabinsa monitored (blood counts;
randomized, double- Corporation), liver enzymes; C-reactive
blind Piscataway, NJ protein; and interleukin-6
level); no significant
difference in blood counts
and liver enzymes between
groups. Curcumin was
well-tolerated with no
significant difference in
adverse events between
groups, including diarrhea,
constipation, abdominal
pain, heartburn, or nausea,
(P=0.33) or change in liver
enzymes (AST, ALT, and
alkaline phosphatase),
P=0.16.
Page 111 of 125

DolCas Biotech, LLC
Pinsornak 38 individuals 1 g/day curcumin Curcumin 3 months (120 Looked atperfomance on 1 g, small
and with primary manufactured by days) the Knee injury and sample size;
Niempoog knee the Govt. Osteoarthritis Outcome moderate
(2012) osteoarthritis Pharmaceutical Score and the pain visual duration ”High
corporation of analog score. No clinical number of
Thailand benefit dropouts
Double blind
Curcumin was Renal function
randomized
administered with deterioration (2/37) and
prospective trial
75 mg/day facial swelling (1/37) in
diclofenac the control group and
1/36 hair falling out in the
experimental group.
Chuengsama 240 1.5 g/day curcumin Curcumin 9 months (270 Prevented T2DM 1.5 g, large
rn et al. prediabetic preparation consumed as 6 days) development. Improved sample size,
(2012) patients, 237 capsules/day, β cell function; higher long duration.
allocated to each containing adiponectin., increased
groups 250 mg curcumin HOMA-β, reduced C
Randomized, manufactured by peptide compared with
double-blind, the Government placebo, no effect on
placebo-controlled Pharmaceutical proinsulin/insulin ratio.
trial Organization of No significant difference
Thailand and between groups was
made from an observed for AST, ALT,
ethanol extract of creatinine, and BMD,
the ground there were no signs of
rhizomes of C. edema.
longa Linn No significant adverse
events occurred. There
was reports of itching
(n=1), constipation (n=2),
and vertigo (n=1) in the
curcumin group.
Golombick et 36 patients 4 g/daycurcumin 4g “C3” 3 months (90 Decreased free-light Smal number of
al. (2012) with followed by open curcuminoid days) chain ration, reduced study
monoclonal label extension at 8 granule stick difference between clonal participants and
gammopathy g/day packs from and nonclonal light short duration
of Sabinsa Option for change. Decreased bone
undetermined Placebo containing Corporation open label resorption marker.
significance no curcumin (Psicataway, NJ) extension for a
and each containing further 3 Serum creatinine were
smoldering 4,000 mg months more reduced I the 4g
multiple curcuminoids curcumin dose group and
randomized, double-
myeloma (3,600 mg serum parathyroid
blind placebo-
curcumin, 320 mg hormone was reduced b
controlled,
desmethoxycurcu 19.8% (P=0002),which
crossover study
min, and 80 mg of the authors stated
bisdesmethoxycur warrants further study..
cumin
Page 112 of 125

DolCas Biotech, LLC
Panahi et al. 96 male 1 g/curcumin 4 weeks (28 Improved antioxidant 1 g; large sample
(2012a) patients with Curcumin C3 days) status, reduced pruritis size, short
sulphur- Complex® severity, greater duration
mustard capsules improvement in QoL.
induced randomized, double- containing 500
pruritus, 80 blind, placebo- mg curcuminoids Six dropouts in the
completed the controlled, two- and 5 mg curcumin group due to
study center trial Bioperine® (Sami gastrointestinal side
Labs Limited) effect (n=3), fear of side
effects (n=1), inability to
return to the clinic due to
distances (n=1), and
unknown reason (n=1).
10 dropouts in placebo
group due to no
treatment response or
worsening symptoms
(n=7), gastrointestinal
side effects (n=2), and
inability to return to the
clinic (n=1).
Panahi et al. 96 male 1 g/curcumin Curcumin C3 4 weeks (28 Greater reductions in 1 g; large sample
(2012b) patients with Complex® days) serum IL-8 and hs-CRP size, short
sulphur- capsules (Sami for the curcumin group duration
mustard Labs Limited) compared with the
induced randomized, double- placebo (P<0.001),
pruritus, 80 blind, placebo- significant reduction in
completed the controlled, two- serum CGRP for the
study center trial curcumin group (P<
0.001), but not the
placebo group, and no
effect on serum IL-6.
Significant correlations
between changes in
calcitonin-related gene
peptide (CGRP) and IL-6
(P = 0.011) and between
Dermatology Life Quality
Index (DLQI) and IL-8 (P
= 0.026) for the curcumin
group. Changes in serum
IL-8 concentrations were
identified as significant
predictors of DLQI scores
(P= 0.026).
Six dropouts in the

curcumin group due to
Page 113 of 125

DolCas Biotech, LLC
gastrointestinal side
effect (n=3), fear of side
effects (n=1), inability to
return to the clinic due to
distances (n=1), and
unknown reason (n=1).
10 dropouts in placebo
group due to no
treatment response or
worsening symptoms
(n=7), gastrointestinal
side effects (n=2), and
inability to return to the
clinic (n=1).
Chandran 45 patients 500 mg curcumin or Curcumin was in 8 weeks The curcumin group Short-term trial
and Goel with 50 mg diclofenac the form of BCM- showed the highest
(2012) Rheumatoid sodium (50 mg) or 95 (Arjuna Natural degree in the
Arthritis (RA) the combination Extracts, India) improvement of RA
randomized, single- symtpoms with minimal
blinded adverse events.
DiSilvestro et 38 healthy 400 mg/day Longvida® 4 weeks (28 Lowering of plasma 400 mg,
al. (2012) subjects curcumin Optimized days) triglyceride values, relatively small
preparation (80 mg Curcumin salivary amylase levels, sample size,
curcumin, with plasma beta amyloid short duration
vegetable stearic protein concentrations argue against
acid dextrin, plasma sICAM readings, the use of this
hydroxypropylmehyl plasma alanine amino study for
cellulose transferase activities; identification of
(vegetarian raising of salivary radical an OSL
capsule), soy scavenging capacities,
lecithin, ascorbyl plasma catalase activities
palmitate, and plasma nitric oxide;
silicon dioxide) increased plasma
myeloperoxidase without
increased c-reactive
protein levels.
placebo-controlled
No adverse events
reported.
Volak et al. 8 healthy 8 g curcuminoids 4 g curcuminoids+ 2 days No clinically significant

(2012) individuals and 48 mg 24 mg piperine effect on CYP3A.
piperine/day. Other administered CYP2C9, or paracetamol
treatments were orally 2 times/day conjugation enzymes.
midazolam,
flurbiprofen, and (Sabinsa The authors did not
paracetamol, or Corporation, mention adverse effects.
matched placebo. Piscataway, NJ)
Randomized,
Page 114 of 125

DolCas Biotech, LLC
placebo-controlled,
crossover study
Irving et al. Individuals 2.35 g/day 5 x 470 mg 14 days Curcumin was present in
(2013) who were capsules, the mucosa for up to 40
planning to Curcumin C3 hours after it was
undergo Complex® administered.
endoscopic (Sabinsa
biopsy or Corporation, 13 adverse events were
colonic Utah) with 470 mg reported, but they were
resection curcumin C3 not serious.
complex
comprising 80%
curcumin and
20%
desmethoxycurcu
min and
bisdesmethoxycur
cumin
Irving et al Individuals 2.35 g/day 5x 470 mg 14 days Curcumin was present in

(2013) who were capsules, the mucosa for up to 40
planning to Crucumin C3 hourse after it was
undergo Complex® administered. 13 adverse
endoscopic (Sabinsa events were reported ,
biopsy or Corporation, but they were not serious.
colonic Utah) with 470 mg
resection curcumin C3
complex
comprising 80%
curcumin and
20%
desmethoxycurcu
min and
bisdesmethoxycur
cumin
Kanai et al. 16 individuals Theracurmin 2 g Theracurmin® Curcumin Maximum plasma levels

(2013) with and 4 g containing (liquid type, CR consumed were 324 ng/mL, for the
pancreatic or 200 mg curcumin 011L):10% daily orally 200 mg curcumin dose
biliary tract (n=10) and 400 mg curcumin, 2% along with and 440 ng/mL for the
cancer curcumin (n=6), other gemcitabine 400 mg curcumin dose.
respectively curcuminoids, therapy
including No unexpected adverse
demethoxycurcu events. 3 study
min and participants continued to
bisdemethycurcu consume Theracurmin®
min, 46% for 9 months without
glycerin, 4% gum adverse events
ghatti (primarily attributable to
polysaccharides) Theracurmin®.
Page 115 of 125

DolCas Biotech, LLC
and 38% water
Kizhakkedath 28 individuals 350 mg Curcuma BCM-95® 12 weeks No adverse effects on

(2013) with longa L.extract containing 70% vital signs, hemogram
osteoarthritis (BCM-95®) curcumin, 17% liver and kidney function
of the knee demethoxycurcu tests.
joint min, 3.5%
bisdemethoxycurc The treatment was safe,
umin and 7/5% was not associated with
turmeric essential dose-related toxicity or
oils and 150 mg adverse effects, and was
Boswellia serrate well-tolerated.
extract containing
75% boswellic
acids and 10%
AKBA (both
Arjuna Natural
Extracts, Aluva,
Kerala, India)
Klickovic et 10 healthy 12 g curcumin 12 capsules Single dose Curcumin was not

al. (2013) men with containing detected in plasma
different Curcumin C3 before or after
(GT)n length Complex® administration of
polymorphism Open label, powder Curcumin C3 Complex®.
s in promoter uncontrolled, Phase Curcumin does not affect
region of I, pilot study HO-1 mRNA or protein
hemo level in peripheral blood
oxygenase monuclear cells.
HO-1 gene Complete blood counts,
blood, dialysate, and
urine chemistry were
measured. No clinically
relevant safety effects of
administration of
Curcumin C3 Complex®.
Morimoto et 24 healthy 30 mg/100 mL Theracurmin® Single doses Theracurmin had a higher
al. (2013) individuals (Theravalues to study absorption efficiency that
Single dose, double- Corporation) pharmacokinet other.
blind, 4-way ics No adverse effects of any
crossover study curcumin drink.
Sahebkar et 30 obese 1 g/day Two doses/day of 30 days Reduced oxidative stress 1 g; small
al. (2013) individuals 0.5 g Curcumin parameters pro-oxidant sample size;
C3® Complex antioxidant balance short duration.
(P=0.044). No significant
with 5 mg
randomized, double- effect on weight, BMI,
bioperine®, (Sami antiHsp27, or anti-oxLDL.
blind crossover Labs, Ltd. The investigators did not
Bangalore, India) mention adverse effects
in this study.
Page 116 of 125

DolCas Biotech, LLC
Ryan et al. 30 breast 6 g/day curcumin Curcumin C3® 4-7 weeks (28 Reduced severity 6 g, small
(2013) cancer complex (Sabinsa 49 days) radiation dermatitis sample size,
patients with Corporation short duration.
radiation (Payson, Utah). Lack of clinically
dermatitis randomized, double- At least 95% relevant safety
blind, placebo- curcuminoids No significant adverse outcome
controlled (390 mg events observed measures argue
curcumin, 75 mg against this
desmethoxycurcu study for
min, 12.5 mg identification of
bisdemethoxycurc an OSL
umin) and
excipients
2 g curcumin 3
times/day
Kim et al. 60 subjects 3 g/day fermented Fermented 12 weeks (84 Reduction in ALT levels 2.37 g curcumin,
(2013) with mild to turmeric (0.79 turmeric powder days) AST levels modest sample
moderately mg/curcumin/g),final size; modest
elevated n=26 There were no observed duration;
alanine severe adverse events or supports the
transaminase abnormalities observed OSL selected
(ALT) levels on blood glucose, total above.
between 40 Or placebo (final protein, albumin, blood
IU/L and 200 n=22) urea nitrogen (BUN), and
IU/L creatinine levels.
randomized, double- Authors concluded that

blind, placebo- fermented turmeric
controlled powder at the doses
administered is safe and
generally well-tolerated.
Sugawara et 45 sedentary, 150 mg/day 6 capsules/day, 8 weeks (56 Aortic systolic blood 150 mg/day.
al. (2012) postmenopau curcumin each containing days) pressure and heart rate- Small sample
sal women Curcumin (n=11) 25 mg highly corrected aortic AP and size; short
Curcumin+exercise absorptive the central arterial duration.
(n=12)
Placebo (n=11) curcumin augmentation index (AIx)
Placebo+exercise dispersed with decreased when
(n=11) colloidal curcumin combined with
nanoparticles exercise intervention, but
Randomized, (Theracurumin, did not change with
double-blind, Theravalues, exercise or curcumin
placebo-controlled,
Tokyo, Japan) alone.
parallel design study
The authors stated that
no adverse effects of
curcumin ingestion
reported.
Page 117 of 125

DolCas Biotech, LLC
100 300 mg/day Each curcumin 3 months (90 Decreased fasting blood 300 mg; large
obese/diabetic curcuminoids capsule included days) glucose, HbA1c, insulin sample; short
Na et al. patients 36.06% curcumin, resistance index, serum duration.
(2013) 18.85% total free fatty acids,
demethoxycurcu triglyercides; increase in
randomized, double- min, and 42.58% lipoprotein lipase.
blind, placebo- bisdemethoxycurc
controlled umin and two 150 There were significant
mg capsules were effects of curcuminoids
taken each day on blood biochemical
(Hebei Food measures and liver
Additive Co., enzyme markers.
Shijiazhuang, The authors did not
Hebei, China). mention any adverse
effects in this study.
Mohammadi 30 obese 1 g/day curcumin C3 Complex® 30 days Reduced serum 1 g, small

et al. (2013) patients capsules (Sami triglycerides. No sample size,
Labs, Ltd., changes in total short duration.
Bangalore, India) cholesterol, LDL-C, or argue against
randomized, double- HDL-C, or serum hs- the use of this
blind crossover
CRP. study for
identification of
Monitored anthropometric an OSL
parameters, lipid profiles
Each tablet and CRP
contained 500mg
curcuminoids + 5
mg Bioperine.
Two tablet Adverse events after
consumed/day curcumin consumption
were constipation (n=2),
diuresis (n=2), and
elevated volume and
duration menstrual blood
loss (n=1). Individuals in
the placebo groups
reported constipation
(n=1), and feeling bloated
(n=3)
Bergman et 40 patients 500 mg/day 500 mg/day 5 weeks (35 No difference between Up to 500 mg.
al. (2013) with first curcumin curcumin days) curcumin and placebo Small sample
episode of (Curcumin Forte treatments in size; short
depression Balance, Extracts improvement of duration; argue
H. Plant, symptoms of depression. against the use
Randomized, Ra’anana, Israel) of this study for
double-blind, identification of
placebo-controlled The authors reported that an OSL
clinical study participants did not
complain of any adverse
Page 118 of 125

DolCas Biotech, LLC
effects.
80 500 mg curcumin 60 days A consistent

Belcaro et al. chemotheraph preparation (100 mg improvement of the side-
(2013) y and 80 curcumin) effect profile from both
radiotherapy chemo- and radiotherapy
patients Placebo-controlled was observed in the
trial treatment group.
No adverse events
reported
Elad et al. Children Dose was 10 to 30 Curcumall 21 days No oral adverse events Small study,
(2013) undergoing drops per day, (Tumron Health reported. One individual study design
doxorubicin tailored to body Products, developed stomach change from
containing weight (rinse was Jerusalem, Israel) upset. placebo
chemotherapy twice/day) controlled study
95% curcumin to one analagous
C3, turmeric and to a case series,
ginger, dissolved The authors stated that no control group,
Study design with glycerin and curcumin mouthwash study completer
comparable to a 0.4% alcohol was safe and well- had lowere
case series tolerated mucositis scores
than normally
seen in the
literature
Mazzolani 12 patients 240 mg Norflo tablets 12-month Small patient

and Togni with curcumin/day (EyePharma Co., follow-up After 12 months, no eyes population
(2013) chorioretinopa Italy) containing study showed further reduction
thy Meriva® (Indena, in visual acuity, 39%
Milan, Italy) showed stabilization, and
61% showed statistically
significant improvement.
Test material was well-
tolerated
Abidi et al. 70 individuals 1 g/day curcumin + CUR-500 (0.5 g 30 days Curcumin reduced airway
(2014) with mild-to standard asthma Cap Curcumin) obstruction as shown by
moderate therapy (Formonide twice/day (M/s improved FEV1 values.
bronchial Resicaps BD Indsaff and Chark
German Remedies)
asthma Intl. Private Ltd,
Standard asthma O/s Pahari Gate,
therapy Batala, Punjab)
Open label,
No clinically significant
randomized, single
adverse events
center study
Page 119 of 125

DolCas Biotech, LLC
Ganjali et al. 37 subjects 1 g/day curcumin 4 weeks (30 Serum IL-1β, IL-4 and 1 g. small
(2014) with BMI > 30 plus piperine C3 Complex days) VEGF reduced. sample size;
Formula (Sami short duration;
Labs Ltd., No effects on IL-1α, IL-2,
lack of control of
Bangalore, India) IL-6, IL-8, IL-10,
interferon γ (IFNγ), diet, argue
randomized, double- which contains against the use
epidermal growth factor
blind crossover curcumin, of this study for
(EGF), monocyte
demethoxycurcu chemoattractant protein-1 identification of
minand MCP-1, and TNF-α an OSL
bisdemethoxycurc
umin No adverse effects
reported.
Chuengsama 240 patients 1,500 mg/day 6 capsules/day 6 months (180 Curcumin significantly
rn et al. with Type 2 curcumin divided each capsule with days) lowered artherogenic risk
(2014) diabetes into two doses 250 mg curcumin. parameters in diabetic
patients, such as a
Dried rhizomes reduction in pulse-wave
ground into velocity, increased serum
randomized, double- powder and adiponectin, decreased
blind, placebo- ethanol extracted. leptin, and reduced
controlled study Total curcuminoid HOMA-IR, triglyceride
content was and uric acid and
between 75-85%; abdominal obesity .
made by the
Govt/
Pharmaceutical Minor symptoms reported
Organization of including hot flash (n=1),
Thailand constipation (n=12), and
nausea (n=1) in the
curcumin group and hot
flash, constipation,
vertigo, and itching in the
placebo group (n=1
each). Level of ALT
significantly lower than
placebo group (P=0.026),
no significant difference
in systolic/diastolic blood
pressure, creatinine, and
AST between groups, no
development of new Cad
or edema
Authors stated that

curcumin was well-
tolerated with few
adverse effects.
Page 120 of 125

DolCas Biotech, LLC
Belcaro et al. 124 patients 500 mg Curcumin Curcumin 4 months Patients experienced Lack of
(2014) with Phospholipids /day Phospholipids improved outcomes with randomization
osteoarthritis with glucosamine (Meriva®), Meriva® combined with
of the knee glucosamine
20 healthy Curcumin Curcumin 4 days total: Subjects reported less Up to 500 mg.
Drobnic et al, males to test Phospholipids, 1 Phospholipids Supplementati pain in the lower limb Short duration;
(2014) the effects of g/day Meriva®, Indena, on was after exercise compared argue against
curcumin on (corresponding to initiated 48 to placebo. Markers of the use of this
Milan, Italy
muscle damage and
delayed onset 400 mg hours prior to inflammation were lower study for
muscle curcumin/day) a downhill in curcumin group. identification of
soreness after running test an OSL
exercise. and continued
for 24 hours
randomized, after test
placebo-controlled,
single-blind pilot trial
Cox et al. 60 healthy 400 mg curcumin Longvida® 4 weeks (28 Improved working Short duration;
(2014) adults (60-85) preparation (80 mg Optimized days) memory, alertness and argue against
curcumin), n=30 Curcumin, is mood; reduced total and the use of this
curcumin in a LDL cholesterol study for
solid lipid identification of
formulation an OSL
Placebo, n=30
No effect on
hematological safety
measures. Well- tolerated
randomized, double-
blind, parallel-
groups
Hejazi et al. 40 prostate 3 g/day curcumin 6 capsules 9 weeks (63 Improved urinary Up to 3 g,
(2014) cancer preparation containing days) symptoms. relatively long
patients randomized, double BCM-95® duration, but
undergoing blinded, placebo- (Biocurcumin), Adverse effects not diseased nature
external beam controlled Arjuna Natural reported. Exclusion of population,
radiotherapy Extracts, Ltd. criteria included adverse relatively small
with hormone (n=20) effects to curcumin. sample size, lack
ablation of clinically
Contained 440 relevant safety
mg curcuminoids outcome
(347 mg measures argue
curcumin, 84 mg against use of
desmethoxycurcu this study for
min, and 9 mg identification of
bisdesmethoxycur an OSL.
cumin)
Placebo (n=20)
Page 121 of 125

DolCas Biotech, LLC
Kuptniratsaik 331 primary 1,500 mg/day C. Two capsules 4 weeks Similar effectiveness of
ul et al. knee domestica extracts after meals, three curcumin extract and
(2014) osteoarthritis (final n=171 study times per day for ibroprofen for treatment
patients who participants, 11 lost 4 weeks. The of knee osteoarthritis.
met the to follow up) curcumin
American 1,200 mg/day treatment was Similar adverse effects
Rheumatism ibuprofen (final prepared from for the curcumin and the
Association n=160 study dried ground placebo groups, but
criteria for participants, 14 lost rhizomes of C. curcumin group had
osteoarthritis, to follow up) domestica made significantly fewer GI
had a pain multicenter double- into a powder and effects.
rating of ≥5 blind, randomized extracted with
out of 10, and controlled trial ethanol from
were age 50 which oleoresin
years or older was removed.
Nakagawa et 41 patients Curcumin Theracurmin (180 8 weeks (56 Improvement in knee 0.4 g, moderate
al. (2014) with preparation (180 mg mg curcumin), 6 days) pain; sample size and
osteoarthritis curcumin) capsules/day moderate
One report of sensation duration; lack of
randomized, double- of tachycardia and clinically relevant
blind, prospective hypertension on day 50; safety outcome
one report of redness of measures argue
the tongue on day 5; No against use of
serious adverse events this study for
were observed. identification of
an OSL
Panahi et al. 80 patients 900 mg curcumin 8 weeks (56 Improvement in QOL; 0.9 g, moderate
(2014a) with solid preparation (180 days) reductions in sample size and
tumors mg/day curcumin) inflammatory markers. moderate
randomized Mild GI effects reported in duration; lack of
double-blind curcumin group clinically relevant
safety outcome
measures argue
against use of
this study for
identification of
an OSL
Panahi et al. 87 patients 900 mg curcumin 8 weeks (56 Greater elevation in the
(2014b) with solid preparation (180 days) activities of SOD and
tumors mg/day curcumin) CAT, and concentrations
of GSH; significantly
randomized reduced serum TBARS;
double-blind QoL scores improved.
Adverse events were not
reported. Exclusion
criteria included adverse
effects to curcumin.
Panahi et al. 89 patients 1.5g/day, 500 C3® complex 4 weeks Improved spirometric
(2014c) with chronic mg/day three capsules parameters curcuminoids
pulmonary times/day (SamiLabs Ltd. had a greater effect than
complications Bangalore, India) placebo in improving
from sulphur randomized, double- FEV1/FVC (p=0.002),
mustard blind , placebo- inflammatory mediators,
intoxication controlled IL-6, TNFα, TGFβ, hs-
CRP, CGRP, MCP-1 (all
P<0.001), IL8 (P=0.035)
and substance P
Page 122 of 125

DolCas Biotech, LLC
(P=0.016).
Authors describe as
being safe and well-
tolerated. No report of
severe adverse evemnts
resulting from medication
in study. In curcumin
group abdominal pain,
and constipation (n=4),
headache (2), unpleasant
aroma (n=3), and large
size of capsules (n=1).
Panahi et al. 40 patients 1.5 g/day curcumin 6 weeks (42 Reductions in pain 1.5 g/day; small
(2014d) with knee randomized, double- days) indices sample size;
osteoarthritis blind No adverse effects short duration.
observed
Pajardi et al. 180 patients 1000mg Axin C (Agave 6 months total Treatment was effective Combination
(2014) with carpal curcumin/day split Farmaceutici srl, (3 months in reducing pre and post- product tested
tunnel into 2 doses and as Prato, Italy) oral before surgery symptoms. only
syndrome part of a combination of surgery, 3 Treatment was well-
scheduled for combination alpha-lipoic acid, months post- tolerated.
surgery product, Axin C curcumin surgery)
phytosome, and
B-group vitamins
Rahimnia et 40 individuals 1,500 mg/day C3 3 divided doses of 6 weeks No significant difference
al. (2014) with mild-to Complex®, Sami C3 Complex® between groups for
moderate Labs Ltd. Each capsule serum IL-4, IL-6, hs-CRP.
degree Bangalore, India contained 500 mg TNF- α, TGF-β and
osteoarthritis Randomized, curcuminoids and erythrocyte sedimentation
double-blind 5 mg/bioperine rate
placebo-controlled (n=19, original
trial n=27)
Matched placebo
(n=21, original n=)
Lopresti et al. 56 individuals 1000 mg/day Curcumin as 8 weeks (56 Improved several mood- No significant
(2014) with major curcumin as BCM-95® (Arjuna days) related symptoms as difference
depressive BCM-95®, n=28 Natural Extracts, measured by the IDS between groups
disorder Placebo (cellulose), India) containing totoal (P=0.026) and in adverse
n=28 Randomized, 88% total IDSm (P=0.020) and in effects.
placebo-controlled curcuminoids STAlt anxiety scores for
double blinded weeks 4-8 in the
curcumin group. Authors
reported greater efficacy
in a subgroup with
atypical depression.
Adverse events were
described as minor and
one person in curcumin
group withdrew because
of adverse events. This
individual had previously
complained of stomach
bloating and pain.
Therewere not significant
differences in adverse
events between the
placbo and curcumin
groups.
Page 123 of 125
DolCas Biotech, LLC
Lopresti et al. 47 individuals 1000 mg/day Curcumin as 8 weeks (56 Elevated levels of plasma Small sample
(2015) with major curcumin as BCM BCM-95 (Arjuna days) endothelin-1 and leptin in size, No adverse
depressive 95, final n=22 Naturals Extracts, individuals who were effects
disorder Placebo (cellulose), India) containing treated with curcumin discussed.
N=25 randomized 88% total were associated with a
Randomized double curcuminoids greater decrease in he
blinded, placebo- Inventory of Depressive
controlled Symptomatology
(IDSSR30)
score. Placebo was
associated with reduction
in aldosterone and
cortisol
(P<0.05 for both)
Curcumin treatment was
associated with increased
substance P (P<0.001),
and urinary
thromboxaneB2
(P<0.05). There was
no association between
biomarker changes and
treatment outcome
Sanmukhani 51 individuals 1,000 mg/day BCM- Two times/day, 6 weeks No significant difference No placebo
et al(2014) with major 95 (2x500 mg BCM 500 mg capsule between groups in group few study
depressive 95) (BCM-95™, number of responders participants
disorder Randomized Arjuna Natural
observe-blinded Extracts,
with 3 parallel Kochi, Kerala,
treatment arms India). Each
containing total
curcuminoids
88% (curcumin,
bisdemethoxycur
cumin,
demethoxycurcu
min) and volatile
oils 7% from
rhizomes of C.
longa Linn
Schiborr et al. 23 healthy 500 mg 410 mg curcumin, Single dose No significant differences
(2014) individuals curcuminoids with 80 mg in serum concentrations
demethoxycurcu of Tot-C, LDL-C, HDL-C,
Single-blind, min and 10 mg TAG, and liver and
randomized, bisdemethoxycurc kidney function markers
crossover study umin as native between treatment
powder (Jupiter groups. All values were
Leys, Cochin, all in the normal ranges.
Kerala State,
India), micronized
powder with 25%
by wt curcumin
powder (RAPS
gmBH and Co.
KG, Kulmbach
Germany), or
liquid micelles
with 17.2%
curcumin powder,
Page 124 of 125

DolCas Biotech, LLC
Yang et al. 65 patients 1890 mg/day Capsules 12 weeks (84 Lipid lowering effect. Small sample
(2014) with metabolic curcumin contained 630 mg days) size
syndrome extract/day curcumin extract Mild diarrhea, nausea in
(3 doses of 630 mg (95% two individuals who were
curcumin extract) curcuminoids) treated with curcumin.
Randomized, with curcumin, The test material was
double-blind, demethoxycurcu well-tolerated
placebo-controlled min, and
bisdemethoxycurc
umin and other
constituents
Bayet-Robert 9 patients with Curcumin doses: No details 7 consecutive Multiple adverse events
et al. (2015) advanced and 500 mg/day (n=1), provided days/dose occurred. Dose limiting
metastatic 1,000 mg/day (n=1), toxicities included one
breast cancer 2,000 mg/day (n=1), grade 3 diarrhea at 6,000
4,000 (n=2), 6,000 mg/day, and at 8,000
mg/day (n=4), and mg/day, one grade IV
8,000 mg/day (n=5) neutropenia and one
grade III diarrhea.
Docetaxel (100
mg/m2 administered The authors set a
as 1 h.i.v. recommended dose for
infusionevery 3 Phase II trials of 6,000
weeks on day 1 for mg/d
6 cycles)
Phase 1 dose
escalation trial
Maccio et al. One patient 4 g/day curcumin Multi-targeted 1 year After one year of Single patient
(2015) with treatment treatment, all case
Myelofibrosis containing oral L myelofibrosis symptoms
carnitine 2 g/d, were in remission
celecoxib 100
mg/d, curcumin
(Meriva®, Indena,
Milan, Italy) 4 g/d,
lactoferrin 0.2 g/d,
and
subcutaneous re
combinant human
EPO (rHuEPO)-a
30000 UI/w
Storka et al. Healthy men Intravenous Synthetic Single dose Plasma curcumin and Small study
(2015) and women administration of 10, curcumin tetrahydrocurcumin
20, 40, 80, 120, synthesized by increase with increasing
180, 240, 320, and Sami Labs, Ltd. dose.
400 mg/m2 Lipicur™ Bangalore, India
(liposomal Authors said that
curcumin) liposomal curcumin was
(n=24) well-tolerated but
Placebo (n=26) observed transient red
Randomized, blood cell echinocyte and
double-blind increased mean cellular
placebo-controlled, volume of red blood cells
dose escalation,
phase I clinical trial
Page 125 of 125

Bonnette, Richard
From: Bonnette, Richard

Sent: Tuesday, January 03, 2017 8:09AM
To: 'cheryld@dolcas-biotech.com'
Subject: FW: your submission to the FDA GRAS notification program for curcumin
Hello Cheryl,
I have the submission on my desk. I had previously tried by email and voicemail (unsuccessfully) to reach KG Rao in
November, who was listed as the contact for the submission. There is a missing administrative component that is
preventing it's filing. I've forwarded the email for your information below. Once I receive the statements, the submission
will then move forward.
Regards,
Richard
From: Bonnette, Richard

Sent: Thursday, November 03, 2016 9:58AM
To: 'grao@dolcas-biotech.com'
Subject: your submission to the FDA GRAS notification program for curcumin
Dear Mr. Rao,

We received your submission dated Oct.25, 2016 regarding GRAS uses of curcumin. As part of a pre-filing review, it was
noted that the submission is missing a required component that will prevent its filing. It seems the submission is missing
a required statement described in Subpart E of Part 170. Particularly the certification statement from 170.225(c)(9). As
described in 170.225(c)(1), please also note that you're submitting a GRAS notice in accordance with Subpart E of Part
170. You may provide these statements as a separate letter and provide it either via email to me or in hardcopy to my
attention at our address below. After receiving the information, I'll append it to the submission and it will then be able
to be processed further.
Regards,
Richard
Richard E. Bonnette, M.S.

Consumer Safety Officer
Division of Biotechnology and GRAS Notice Review
Office of Food Additive Safety
U.S. FDA, Center for Food Safety and Applied Nutrition
(240)402-1235
Richard.Bonnette@fda.hhs.gov
Mailing address:
5001 Campus Drive, HF5-255
College Park, MD 20740
1
9 Lenel Road
I Landing, NJ 07850
W·CAPs· (877) 252.4326
Your \OUICI' for 100\lt
\tqttari.tn liquid <.tp~ult\
Richard E. Bonnette, M.S. JAN 5 2017

Consumer Safety Officer
Division of Biotechnology and GRAS Notice Review FOOD ~cib~~~~AFETY
Office of Food Additive Safety
U.S. FDA, Center for Food Safety and Applied Nutrition
RE: Certification Statement per 170.225(c)(9)
DoiCas Biotech is submitting a GRAS notice in accordance with Subpart E of Part 170, FDA GRAS
Notification.
DoiCas Biotech certifies that, to the best of our knowledge, our GRAS notice is a complete,
representative, and balanced submission that includes unfavorable information, as well as favorable
information, known to us and pertinent to the evaluation of the safety and GRAS status of the use of the
substance, BCM-95® curcumin complex (also known as BiocurcumaxrM and BiocurcuminrM).
DoiCas has concluded that the notified substance, BCM 95® (also known as BiocurcumaxTM and
BiocurcuminrM and commonly referred to as curcumin) is GRAS and that the safety standards, per 21 CFR
Part 170.30 Subpart E, of reasonable certainty of no harm, based on scientific procedures and common
knowledge as described herein, are met. This conclusion is based on the in-depth review of the
collective generally available scientific data regarding the safety of BCM 95® curcumin, common
knowledge and general consensus among qualified experts corroborated by the written GRAS
conclusion of an independent Expert Panel of qualified persons whom reviewed all publicly available
referenced safety data.
We certify that this GRAS notification is complete and is a balanced representation of all data available.
(b) (6)
KG Rao, President
DoiCas Biotech, LLC
9 Lenel Rd.
Landing, NJ 07850
SUBMISSION END

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GRAS Notice (GRN) No.

GENERALLY RECOGNIZED AS SAFE

PART I – INTRODUCTORY INFORMATION ABOUT THE SUBMISSION

PART II – INFORMATION ABOUT THE NOTIFIER

Name of Contact Person Position

Company (if applicable)

Mailing Address (number and street)

City State or Province Zip Code/Postal Code Country

Name of Contact Person Position

Mailing Address (number and street)

City State or Province Zip Code/Postal Code Country

Telephone Number Fax Number E-Mail Address

FORM FDA 3667 (5/16) Page 1 of 5

PART IV – INTENDED USE

FORM FDA 3667 (5/16) Page 2 of 5

1. Information about the Identity of the Substance

3 Biocurcumax™ and Biocurcumin™

FORM FDA 3667 (5/16) Page 3 of 5

PART VII – SIGNATURE

1. The undersigned is informing FDA that DolCas Biotech, LLC

has concluded that the intended use(s) of BCM 95 (curcumin)

9 Lenel Road, Landing, NJ 07850

(GRAS Affirmation Petition No.)

3. Signature of Responsible Official, Printed Name and Title Date (mm/dd/yyyy)

FORM FDA 3667 (5/16) Page 4 of 5

Attachment Folder Location (select from menu)

Summary of Safety Data And Food usage conditions For

Appendix A - Flow chart of manufacturing Process for BCM 95 75

Appendix B - Certificates of Analysis for Five Production Batches

Appendix C - JECFA Specifications for Curcumin 83

Appendix D - Accelerated and Long-Term Stability Report for

Appendix E - Elevated Temperature Stability Report 94

Appendix F - Human Studies on Other Curcumin Preparations 99

FORM FDA 3667 (5/16) Page 5 of 5

Food and Drug Administration

Attention: Dr. Paulette Gaynor

Dear Dr. Gaynor,

We look forward to your feedback.

(b) (6) J~"'

DoiCas Biotech, LLC

Enclosure: GRAS Notification for DoiCas Biotech, LLC- BCM-95® (Curcumin)

DolCas Biotech, LLC

DolCas Biotech, LLC

DolCas Biotech, LLC

APPENDIX F HUMAN STUDIES ON OTHER CURCUMIN PREPARATIONS ...............................................99

Table 1. Turmeric Use Levels Set Forth by Health Canada ................................................................................................................. 9

I. GRAS EXEMPTION CLAIM

A. Claim of Exemption From Requirement for Premarket Approval

B. Name & Address of Notifier

DolCas Biotech, LLC

Person Responsible for the Notification:

C. Common Name & Identity of Notified Food Substance

The common or usual name of BCM-95® is curcumin.

1 See 62 FR 18938 (17 April 1997) which is accessible at http://www.gpo.gov/fdsys/pkg/FR-1997-04-17/pdf/97-9706.pdf.

D. Conditions of Intended Use in Food

E. Basis for GRAS Conclusion

DolCas has undertaken a comprehensive GRAS evaluation of its product, BCM-95®.

The safety/toxicity studies, consumption/exposure information, and other related

3. FDA GRAS Regulatory Framework

4. Regulatory Background for Curcumin