Glucosamine Safety Assessment

Safety Assessment of Glucosamine Ingredients
as Used in Cosmetics
Status: Final Report for Panel Review

Release Date: May 23, 2022
Panel Meeting Date: June 16 – 17, 2022
The Expert Panel for Cosmetic Ingredient Safety members are: Chair, Wilma F. Bergfeld, M.D., F.A.C.P.; Donald V. Belsito,
M.D.; David E. Cohen, M.D.; Curtis D. Klaassen, Ph.D.; Daniel C. Liebler, Ph.D.; Allan E. Rettie, Ph.D.; David Ross, Ph.D.;
Ronald C. Shank, Ph.D.; Thomas J. Slaga, Ph.D.; Paul W. Snyder, D.V.M., Ph.D.; and Susan C. Tilton, Ph.D. Previous Panel
member involved in this assessment: Lisa A. Peterson, Ph.D. The Cosmetic Ingredient Review (CIR) Executive Director is
Bart Heldreth, Ph.D. This safety assessment was prepared by Priya Cherian, Senior Scientific Analyst/Writer.
© Cosmetic Ingredient Review

1620 L Street, NW, Suite 1200 ♢ Washington, DC 20036-4702 ♢ ph 202.331.0651 ♢ fax 202.331.0088 ♢
[email protected]
Distributed for Comment Only -- Do Not Cite or Quote
SAFETY ASSESSMENT FLOW CHART

INGREDIENT/FAMILY Glucosamine Ingredients ______________________________
MEETING ___June 2022 ___________________________________________________
Public Comment CIR Expert Panel Report Status
2020 Priority List

INGREDIENT
PRIORITY LIST
SLR
February 5, 2021
DRAFT REPORT
Draft Report December 2021
60-day public comment period
Table
Table IDA TR
IDA Notice IDA

December 10, 2021
DRAFT TENTATIVE
REPORT
Draft TR March 2022
Table
Table
Tentative Report Issue TR

March 11, 2022
Draft FR DRAFT FINAL REPORT

June 2022
60-day Public comment period
Table
Table Different Conclusion
Issue
PUBLISH Final Report FR
Commitment & Credibility since 1976
Memorandum
To: Expert Panel for Cosmetic Ingredient Safety Members and Liaisons
From: Priya Cherian, Senior Scientific Analyst/Writer, CIR
Date: May 23, 2022
Subject: Safety Assessment of Glucosamine Ingredients as Used in Cosmetics
Enclosed is the Draft Final Report of the Safety Assessment of Glucosamine Ingredients as Used in Cosmetics
(report_Glucosamine_062022). At the March 2022 meeting, the Expert Panel for Cosmetic Ingredient Safety (Panel)
issued a Tentative Report for public comment on these 4 ingredients, with the conclusion that Acetyl Glucosamine,
Glucosamine, Glucosamine HCl, and Glucosamine Sulfate ingredients are safe in cosmetics in the present practices of use
and concentration described in this safety assessment when formulated to be non-irritating.
Since the issuing of the Tentative Report, no new unpublished data were received. Comments on the Tentative Report that
were provided from Council (PCPCcomments_Glucosamine_062022), as well as CIR responses to these comments
(response-PCPCcomments_Glucosamine_062022) have been included in this packet. Changes to the language involving
the inhalation exposure boilerplate and use in airbrush delivery systems have been highlighted to aid the Panel’s review.
Also included in this packet are the report history (history_Glucosamine_062022), a data profile
(dataprofile_Glucosamine_062022), the search strategy (search_Glucosamine_062022), transcripts of previous meetings
(transcripts_Glucosamine_062022), 2022 FDA VCRP data (VCRP_Glucosamine_062022), and the flow chart
(flow_Glucosamine_062022).
The Panel should carefully consider the Abstract, Discussion, and Conclusion presented in this report. If these are
satisfactory, the Panel should issue a Final Report.
Memorandum
TO: Bart Heldreth, Ph.D.

Executive Director - Cosmetic Ingredient Review
FROM: Alexandra Kowcz, MS, MBA

Industry Liaison to the CIR Expert Panel
DATE: March 23, 2022
SUBJECT: Tentative Report: Safety Assessment of Glucosamine Ingredients as Used in

Cosmetics (release date March 11, 2022)
The Personal Care Products Council respectfully submits the following comments on the
tentative report, Safety Assessment of Glucosamine Ingredients as Used in Cosmetics.
Abstract – If the functions are included in the Abstract, please identify the ingredients associated
with the function. If the goal is to only state all the ingredients in the report once in the abstract,
perhaps the first two sentences of the Abstract should be revised to: “The Expert Panel for
Cosmetic Ingredient Safety (Panel) assessed the safety of Glucosamine and three related
ingredients. Two of the ingredients, Acetyl Glucosamine and Glucosamine Sulfate, are reported
to function in cosmetics as skin-conditioning agents, Glucosamine HCl is reported to function as
a pH adjustor, and the function of Glucosamine is not reported.”
Introduction – Please revise: “as well as the endpoints that Panel typically evaluates” (add “the”
before Panel)
Definition and Structure – If “Figure 1” is going to be included in the text, the Figure should be
labeled “Figure 1”.
Chemical Properties – Please revise: “Available information on the chemical properties of the
glucosamine ingredients are presented in Table 2” (either change “are” to “is”, or delete
“Available information on the”)
Method of Manufacture – “cellulose” is not an enzyme
Impurities, Glucosamine HCl – Stating the concentration of free-base glucosamine as purity is

misleading. Reference 8 also states that the Glucosamine HCl sourced from Aspergillus niger
meets USP specifications (>98%).
Cosmetic Use – A “table” (Table 4) is not necessary when only one ingredient has no uses
reported to the VCRP and PCPC concentration of use survey. If the non-used ingredient needs
to be part of a table, perhaps it could be added as a footnote to Table 3.
Dermal Penetration, In Vitro, Acetyl Glucosamine – If both 14C-labeled Acetyl Glucosamine and
14
C-labeled niacinamide were used, how did they distinguish the radioactivity from each
compound? If they only used one labeled compound at a time, the study summary should more
clearly state the protocol.
Chronic – Since there was only one concentration (5%) that was greater than 2.5%, rather than
stating “in animals dosed with concentrations of greater than 2.5%”, please state: “in animals
dosed with 5%”.
Anti-Carcinogenicity, In Vitro, Glucosamine – Units of mM should be called concentration

rather than dose.
Reduction of IgE-Mediated Hypersensitivity, Acetyl Glucosamine and Glucosamine HCl;

Summary – The description of the protocol (reference 50) indicated that histamine was measured
“in the plasma of the right ear”. The descriptions of the results of this study (both in the
Reduction of IgE-Mediated Hypersensitivity section and the Summary) indicate histamine was
measured “both in the ear and plasma”. If two measurements were made, they should both be
described in the protocol summary.
Dermal Irritation and Sensitization Studies – As part of the summary of sensitization studies,
please state the highest µg/cm2 dose tested (1000 µg/cm2) as presented in Table 6.
Epidemiological Studies – Please correct “associate” to “associated”
Summary – Please state the route of exposure used in the single dose Beagle dog study.
Discussion – It would be helpful to note that based on OECD 497, Defined Approaches to Skin
Sensitization, and the completed in chemico and in vitro assays, Acetyl Glucosamine is
considered a non-sensitizer. Please correct: “clinical sensitization data s at up to 2% Acetyl
Glucosamine”. (delete “s”)
Table 6, reference 54 – Please indicate the difference between the mg/cm2 dose (likely the
product dose) compared to the µg/cm2 dose (likely the Glucosamine HCl dose).
2
Glucosamine – June 2022 – Priya Cherian

Comment Submitter: Personal Care Products Council
Date of Submission: March 23. 2022
Comment Response/Action
Abstract – If the functions are included in the Abstract, please Addressed
identify the ingredients associated with the function. If the goal
is to only state all the ingredients in the report once in the
abstract, perhaps the first two sentences of the Abstract should
be revised to: “The Expert Panel for Cosmetic Ingredient Safety
(Panel) assessed the safety of Glucosamine and three related
ingredients. Two of the ingredients, Acetyl Glucosamine and
Glucosamine Sulfate, are reported to function in cosmetics as
skin-conditioning agents, Glucosamine HCl is reported to
function as a pH adjustor, and the function of Glucosamine is
not reported.”
Introduction – Please revise: “as well as the endpoints that Panel Addressed
typically evaluates” (add “the” before Panel)
Definition and Structure – If “Figure 1” is going to be included It is labeled as Figure 1.
in the text, the Figure should be labeled “Figure 1”
Chemical Properties – Please revise: “Available information on Addressed
the chemical properties of the glucosamine ingredients are
presented in Table 2” (either change “are” to “is”, or delete
“Available information on the”)
Method of Manufacture – “cellulose” is not an enzyme Addressed
Impurities, Glucosamine HCl – Stating the concentration of Addressed
free-base glucosamine as purity is misleading. Reference 8 also
states that the Glucosamine HCl sourced from Aspergillus niger
meets USP specifications (>98%).
Cosmetic Use – A “table” (Table 4) is not necessary when only This table was requested by a Panel member at the
one ingredient has no uses reported to the VCRP and PCPC March 2022 meeting.
concentration of use survey. If the non-used ingredient needs to
be part of a table, perhaps it could be added as a footnote to
Table 3.
Dermal Penetration, In Vitro, Acetyl Glucosamine – If both 14C- This was not addressed in the study; the protocol was
labeled Acetyl Glucosamine and 14C-labeled niacinamide were written as stated in the study text
used, how did they distinguish the radioactivity from each
compound? If they only used one labeled compound at a time,
the study summary should more clearly state the protocol
Chronic – Since there was only one concentration (5%) that was Addressed
greater than 2.5%, rather than stating “in animals dosed with
concentrations of greater than 2.5%”, please state: “in animals
dosed with 5%”.
Anti-Carcinogenicity, In Vitro, Glucosamine – Units of mM Addressed
should be called concentration rather than dose
Reduction of IgE-Mediated Hypersensitivity, Acetyl Addressed
Glucosamine and Glucosamine HCl; Summary – The
description of the protocol (reference 50) indicated that
histamine was measured “in the plasma of the right ear”. The
descriptions of the results of this study (both in the Reduction of
IgE-Mediated Hypersensitivity section and the Summary)
indicate histamine was measured “both in the ear and plasma”.
If two measurements were made, they should both be described
in the protocol summary
Dermal Irritation and Sensitization Studies – As part of the Irritation and sensitization text, when a table is
summary of sensitization studies, please state the highest provided, does not include dose, but does include
µg/cm2 dose tested (1000 µg/cm2 ) as presented in Table 6 concentration
Epidemiological Studies – Please correct “associate” to Addressed
“associated”
Summary – Please state the route of exposure used in the single Addressed
dose Beagle dog study
Discussion – It would be helpful to note that based on OECD The Panel should address whether or not they’d like
497, Defined Approaches to Skin Sensitization, and the this language included in the report.
completed in chemico and in vitro assays, Acetyl Glucosamine
is considered a non-sensitizer. Please correct: “clinical
sensitization data s at up to 2% Acetyl Glucosamine”. (delete
“s”)
Table 6, reference 54 – Please indicate the difference between Addressed
the mg/cm2 dose (likely the product dose) compared to the
µg/cm2 dose (likely the Glucosamine HCl dose)
History – Glucosamine Ingredients
February 2021
• SLR posted
• Comments on SLR received
• Concentration of use data received
• Data received:
o Repeat insult patch test; mask containing 0.005% Acetyl Glucosamine
o Human maximization assay; product containing 0.25% Glucosamine HCl
o Human maximization assay; product containing 0.01% Glucosamine
April 2021
• Data received
o Repeat insult patch test; leave-on product containing 0.005% Glucosamine HCl
December 2021
• Panel reviews Draft Report and issues an IDA; requests impurities data on Acetyl Glucosamine,
and irritation and sensitization data on all ingredients at the max use concentration of 5%
January 2022
• Unpublished data received from Council:

o HRIPT on liquid foundation containing 2% Acetyl Glucosamine
o 21-d cumulative irritation assay on eye cream containing 2% Acetyl Glucosamine
o In vitro ocular irritation assay on face serum with 2% Acetyl Glucosamine
• Updated 2022 FDA VCRP data received
o Increased uses for Acetyl Glucosamine and Glucosamine HCL
o Decreased uses for Glucosamine
o Still no uses reported for Glucosamine Sulfate
March 2022
• Panel reviews Draft Tentative Report

• Panel issues a safe as used conclusion for all 4 ingredients in report
• TR posted
• Council comments received on TR
June 2022
• Panel reviews Draft Final Report

Glucosamine Ingredients Profile – June 2022 – Writer, Priya Cherian
Repeated Dermal Dermal Ocular Clinical
Toxicokinetics Acute Tox DART Genotox Carci
Dose Tox Irritation Sensitization Irritation Studies
Dermal Penetration
Method of Mfg
Retrospective/
Reported Use
Case Reports
Phototoxicity
Multicenter
Impurities
Inhalation
Inhalation
In Vitro
In Vitro
In Vitro
In Vitro
Dermal
Dermal
Dermal
Dermal
Human
Human
In Vivo
Animal
Animal
Animal
ADME
log P
Oral
Oral
Oral
Oral
Acetyl Glucosamine x x x x x x x x x x x x
Glucosamine x x x x x x x x
Glucosamine HCL x x x x x x x x x x
Glucosamine Sulfate x x x x
* “X” indicates that data were available in a category for the ingredient
1
Glucosamine Ingredients
Ingredient CAS # PubMed FDA HPVIS NIOSH NTIS NTP FEMA EU ECHA ECETOC SIDS SCCS AICIS FAO WHO Web
Acetyl Glucosamine 10036-64-3; 72- yes yes no no no no no yes no no no no no no no yes
87-7; 7512-17-6
Glucosamine 3416-24-8 yes no no no no yes no yes no no no no no no no yes
Glucosamine HCL 66-84-2 yes no no no no yes no yes yes no no no no no no yes
Glucosamine Sulfate 29031-19-4 yes no no no no no no yes yes no no no no no no yes
Search Strategy
Search terms below were searched for in the websites listed above. If useful information was found, a “yes” is noted.
Search Terms
• INCI names
o Acetyl Glucosamine
o Glucosamine
o Glucosamine HCl
o Glucosamine Sulfate
 CAS numbers
o 10036-64-3
o 72-87-7
o 7512-17-6
o 3416-24-8
o 66-84-2
o 29031-19-4
 chemical/technical names  carcinogenicity

 metabolism  mutagenicity
 dermal  pigmentation
 inhalation  tyrosinase
 skin  melanogenesis
 toxicity  Ames
 drugs  Reproductive
 medicine  Teratogenicity
 irritation  Synthesis
 ocular
 eye
 sensitization
 allergy
 manufacture
 cancer

LINKS
Search Engines
 Pubmed (- http://www.ncbi.nlm.nih.gov/pubmed)
Pertinent Websites
 wINCI - http://webdictionary.personalcarecouncil.org
 FDA databases http://www.ecfr.gov/cgi-bin/ECFR?page=browse
 FDA search databases: http://www.fda.gov/ForIndustry/FDABasicsforIndustry/ucm234631.htm;,
 Substances Added to Food (formerly, EAFUS): https://www.fda.gov/food/food-additives-petitions/substances-
added-food-formerly-eafus
 GRAS listing: http://www.fda.gov/food/ingredientspackaginglabeling/gras/default.htm
 SCOGS database: http://www.fda.gov/food/ingredientspackaginglabeling/gras/scogs/ucm2006852.htm
 Indirect Food Additives: http://www.accessdata.fda.gov/scripts/fdcc/?set=IndirectAdditives
 Drug Approvals and Database: http://www.fda.gov/Drugs/InformationOnDrugs/default.htm
 FDA Orange Book: https://www.fda.gov/Drugs/InformationOnDrugs/ucm129662.htm
 (inactive ingredients approved for drugs: http://www.accessdata.fda.gov/scripts/cder/iig/
 HPVIS (EPA High-Production Volume Info Systems) - https://iaspub.epa.gov/oppthpv/public_search.html_page
 NIOSH (National Institute for Occupational Safety and Health) - http://www.cdc.gov/niosh/
 NTIS (National Technical Information Service) - http://www.ntis.gov/
o technical reports search page: https://ntrl.ntis.gov/NTRL/
 NTP (National Toxicology Program ) - http://ntp.niehs.nih.gov/
 Office of Dietary Supplements https://ods.od.nih.gov/
 FEMA (Flavor & Extract Manufacturers Association) GRAS: https://www.femaflavor.org/fema-gras
 EU CosIng database: http://ec.europa.eu/growth/tools-databases/cosing/
 ECHA (European Chemicals Agency – REACH dossiers) – http://echa.europa.eu/information-on-
chemicals;jsessionid=A978100B4E4CC39C78C93A851EB3E3C7.live1
 ECETOC (European Centre for Ecotoxicology and Toxicology of Chemicals) - http://www.ecetoc.org
 European Medicines Agency (EMA) - http://www.ema.europa.eu/ema/
 OECD SIDS (Organisation for Economic Co-operation and Development Screening Info Data Sets)-
http://webnet.oecd.org/hpv/ui/Search.aspx
 SCCS (Scientific Committee for Consumer Safety) opinions:
http://ec.europa.eu/health/scientific_committees/consumer_safety/opinions/index_en.htm
 AICIS (Australian Industrial Chemicals Introduction Scheme)- https://www.industrialchemicals.gov.au/
 International Programme on Chemical Safety http://www.inchem.org/

 FAO (Food and Agriculture Organization of the United Nations) - http://www.fao.org/food/food-safety-quality/scientific-
advice/jecfa/jecfa-additives/en/
 WHO (World Health Organization) technical reports - http://www.who.int/biologicals/technical_report_series/en/
 www.google.com - a general Google search should be performed for additional background information, to identify
references that are available, and for other general information
Glucosamine – CIR Expert Panel Meeting Transcripts
DECEMBER 2021 PANEL MEETING – INITIAL REVIEW/DRAFT REPORT
Belsito Team – December 6. 2021

DR. BELSITO: This is the first time we’re looking at the four ingredients in this report. And we received lots of data from
various sources. So what do we think here at this point?
DR. LIEBLER: My high level takeaway is include all the ingredients. Method of manufacture, composition and impurities
are okay for all. These are absorbed, but no significant toxicity. And if the sensitization data are okay, then safe as used.
We’ll deal with the pigmentation issue in the discussion.
DR. BELSITO: Yeah, so I had safe as used, but need to finesse the discussion. So do we need to deal with the DART issues?
Or is this dose effect? Because there were a whole bunch of different DART issues that sort of went back and forth. Paul,
you’re usually the person I go to for this.
DR. SNYDER: Yeah, I looked at those pretty carefully. I mean, those positive studies were oral in the diet and
intraperitoneal injections. And then there was an intrauterine 60-day sustained release pellet. So I just didn’t think they had
much relevance to the dermal.
DR. BELSITO: Okay. And would we need to put that in the discussion?
DR. SNYDER: We could. I mean, we could state that the repro effects were seen at levels that far exceeded what would be a
cosmetic use.
DR. BELSITO: Okay, so the dose that was used is irrelevant to cosmetics?
DR. SNYDER: Yeah.
DR. BELSITO: Okay. And, Dan, how were you going to deal with the pigment issue?
DR. LIEBLER: Well, I wanted to just bring that up. I think that we need to talk about it as a team. I'm trying to remember
now if the study, the human with acetylglucosamine at the bottom of PDF 22. Trying to get an idea -- okay, so 4 percent
niacinamide and 2 percent acetylglucosamine and this is for facial hyperpigmentation, obviously not a cosmetic use. But is
that a lot higher than our maximum use concentration of acetylglucosamine for a leave-on on skin? I'm scrolling down to the
use table. Acetylglucosamine, up to five percent leave-on dermal contact.
DR. BELSITO: Which is what it was in this product.
DR. LIEBLER: Yeah. Right. So this is one where I defer to you and David on the context in which somebody would be
using this for facial hyperpigmentation. Is that something that’s treated with acetylglucosamine? Is that relevant to a cosmetic
that would contain the same amount? In other words, if you’re not hyperpigmented, is this something that would cause a loss
of pigmentation in somebody who, you know, was not trying to deal with hyperpigmentation? I just didn’t have a good feel for
the clinical context here, and whether or not that impacts our evaluation in a cosmetic use context.
DR. BELSITO: Yeah, so -- but the effect is on tyrosinase, right? So it would effect normal, not just diseased. But, I mean, I
thought that we would deal with this simply by saying that effects on pigmentation are, you know, drug and not cosmetic and
not under our purview. And that manufacturers should be aware of this in designing cosmetic products, or whatever that
boilerplate is we’ve used for other ingredients. Because we don’t have an NOAEL for this.
DR. LIEBLER: Yeah.
DR. BELSITO: And also, as you point out, what we’re told is, it’s used up to 5 percent in a face product and this is the
concentration that caused the lightening. Or we don’t know that it’s the -- first of all, we don’t know if it’s the
acetylglucosamine that caused it, right?
DR. LIEBLER: Right.
DR. BELSITO: It just happened to be in the product.
DR. LIEBLER: I'm looking, but I'm not sure I see anywhere where there’s evidence that the glucosamine or
acetylglucosamine is a, biochemically, is a tyrosinase inhibitor.
DR. BELSITO: I thought I saw that someplace.
MR. GREMILLION: Could I, I'm sorry, this is Thomas, CFA, I just wanted to ask a clarifying question. When they say it
improved the appearance of facial hyperpigmentation, does that just mean it succeeded in having a lightening effect, so it’s
used as a skin lightener?
DR. BELSITO: Yes.
MR. GREMILLION: Okay.
DR. SNYDER: Don, on Page 22, under the Animal and Human, Acetylglucosamine.
DR. BELSITO: Yeah.
DR. SNYDER: Is that a misstatement? That third from last line of that first paragraph, “The degree of pigmentation at each
time point measured after the application of acetyl glucosamine was higher than the vehicle control group.” Should that -- was
that supposed to be the degree of depigmentation?
DR. BELSITO: Yeah, let me -- can I just answer Dan’s question first and then go back --
DR. SNYDER: Yeah, sorry, go ahead.
DR. BELSITO: -- because I'm in a separate page. Dan, the tyrosinase activity, that is in the references, Reference Number
44.
DR. LIEBLER: Oh. It wasn’t brought out in the report because I missed it.
DR. BELSITO: Right. “Disruption of tyrosinase glycosylation of N-acetylglucosamine and its depigmenting effect on guinea
pig skin and in human skin.” So that was the reference. Sorry, Paul, what PDF page are you on?
DR. SNYDER: Page 22. Under the Animal and Human, Acetylglucosamine.
DR. BELSITO: Yeah.
DR. SNYDER: The third from last. It says, “The degree of pigmentation at each time point measured after application of
acetylglucosamine was higher than the vehicle control group.”
DR. BELSITO: Yeah, I had that flagged. I think it should be hypopigmentation.
DR. SNYDER: Okay, because otherwise there’s no effect.
DR. BELSITO: Right, yeah.
MS. CHERIAN: It’s probably a mistake. I can fix that.
DR. SNYDER: Just verify that that’s correct.
MS. CHERIAN: I'm going to double-check the reference.
DR. BELSITO: Yeah. It would have to be hypopigmentation.
DR. LIEBLER: So I didn’t look at the reference that Don just cited, reference 44 on tyrosinase inhibition. If there are data
specifically that indicates that any of these glucosamines are inhibitors of tyrosinase, that should be brought into that section
under the pigmentation issues. I don’t know what it actually says in that paper that was cited. I haven't had a chance to look at
it, but maybe we need to bring that out and see what it actually says.
DR. BELSITO: Okay.
DR. LIEBLER: I think Thomas has his hand up.
MR. GREMILLION: Sorry, I just needed to lower that. Sorry.
DR. LIEBLER: Okay.
DR. BELSITO: So, in the next iteration, you want a deeper dive into Reference 44, Dan?
DR. LIEBLER: Yeah. I think we should just bring out -- either there’s no evidence in that paper specifically for tyrosinase
inhibition by acetylglucosamine or any glucosamines. If that’s the case, and Priya reads that and sees that, then I don’t think
we need to bring it in. But if there are data indicating tyrosinase inhibition, in other words a biochemical mechanism to link
these, then that’s need to be brought in. I'm comfortable certainly leaving that to Priya to read the paper and make that
judgement.
DR. BELSITO: Okay.
DR. LIEBLER: Or if she has a question, she can send it to me and get my take. Send me a copy of the paper and I can -- you
know, or even just the passage and I can look at it. I think, Priya, if you’re comfortable doing that, then please just go ahead
and look into that reference for us.
MS. CHERIAN: Great. I can do that. Thank you.
DR. BELSITO: Okay. Go ahead, Paul.
DR. SNYDER: So what is our interpretation of this lightening effect?
DR. BELSITO: That there are these reports and that we have to -- we’ll deal with them the way we’ve dealt with other
ingredients that have been reported to cause skin lightening. That that’s not a cosmetic effect and that manufacturers should be
aware of this in compounding cosmetic products.
DR. SNYDER: Okay, because there does appear to be an effect, in vitro and in vivo, so.
DR. BELSITO: Right, yeah.
DR. SNYDER: Okay. Okay.
DR. BELSITO: We don’t know that it’s from the glucosamine but, you know, there’s certainly enough of a flag there. But,
you know, we need to look at that boilerplate, Bart, because this I'm sure will pop up in the future and we should make sure
that the language is consistent.
DR. LIEBLER: Yeah, Paul, this is the reason I asked for Priya to look at that reference. Because if there’s biochemistry data
to indicate that the glucosamine can inhibit tyrosinase, then that provides a mechanistic basis for raising the concern with
respect to the glucosamine.
DR. SNYDER: Yeah, I mean, this was an unusual one where the in vitro data was dose dependent decrease in melanin
content, which kind of struck me at first. And then that with the in vivo data, so, okay.
DR. BELSITO: Right. Okay. Any other issues with the pigmentation effect? Okay.
DR. SNYDER: No, I think I misspoke, Don, I want to go back to that repro. So the repro there was, while there was
positive/negative, but the big one was that 60-day sustained release pellet in the intrauterine was negative. So that held a lot of
weight for me to not be worried about the other ones that had plus/minus effects.
DR. BELSITO: Okay. So, Priya, in the discussion that the concentrations causing these effects were greater than would be
expected from cosmetics and also the 60-day study gave us further assurance?
DR. SNYDER: Yeah.
DR. BELSITO: In the risk assessment, Priya -- this is PDF Page 25 -- I just thought that we needed to make clear that the
number in parenthesis is the margin of safety values. Because I wasn’t sure, until I read the Norwegian food safety report, that
that’s what those numbers refer to.
I was very confused where you say 10 percent glucosamine sulfate in a body lotion, open parenthesis, 35.0. I just didn’t know
what that 35.0 was. I mean, you have margin of safety MOS in parenthesis, but I thought you were just putting the acronym in
there. See what I mean?
MS. CHERIAN: I see what you mean.
DR. LIEBLER: You could simply just put, in the first one, MOS equals 35.0.
DR. BELSITO: Right.
DR. LIEBLER: And then the others will be obvious.
DR. BELSITO: Okay, and also, we don’t have that study per se in the report. We have a review from Anderson, et al. And,
interestingly, when I looked at that review, it’s not in their references. They cite this paper by Setnikar, et al. An article
entitled, “Antiarthritic effects of glucosamine sulfate study in animal models.” And it’s in a journal called
Arzneimittelforschung, which, I guess, translates to drug research and I couldn’t find it. So we don’t have any primary data on
this margin of safety and I'm not even sure what the supposed adverse event was. So, I was also proposing if we do keep it in -
- you know, what I mentioned -- but maybe deleting it completely. You know, there’s just -- this is just a review by Anderson,
and I don’t know where they came up with those numbers. And it really makes something that is part of normal human body
look toxic.
DR. SNYDER: Where you at, Don, what page?
DR. BELSITO: I'm on the risk assessment still.
DR. SNYDER: Okay.
DR. BELSITO: If you look at the reference for the risk assessment, which I did because I didn’t understand the numbers in
parenthesis. The reference is to an article by Anderson, et al, 2005. When you go to the Anderson article, it actually ends up
being a review. And it cites for these margin of safety numbers, an article by Setnikar, Pacini Revel, entitled, “Antiarthritic
effects of glucosamine sulfate studied in animal models.” And it’s from a journal Arzneimittelforschung, which I could not
find on Columbia.
And, so, I don’t know if that had the primary data for these endpoints, but I'm also not even sure what was the adverse event
that they were looking at to calculate margin of safety. Right? It says calculated the margin of safety values, for what
endpoint? So I really thought that that risk assessment should just go away and never even be mentioned. Comments?
DR. SNYDER: I don’t understand why the Norwegian Food Safety Authority would be studying body lotion, leg cream, and
face cream. I mean, the NOAEL came from a dog study, a repro -- oral dose study in dogs.
DR. BELSITO: Right.
MR. GREMILLION: Sorry, this is Thomas. Did CIR reach out to the study authors when --
MS. CHERIAN: Yes, I did try to obtain that reference and it was unobtainable.
DR. BELSITO: The Setnikar reference, is that what you’re referring to, Priya?
MS. CHERIAN: Yes.
DR. BELSITO: Yeah. I mean, I couldn’t get it either. And we have no primary data. And, yeah, so we know that the margin
of safety was obtained from a repeated oral dose toxicity assay performed in dogs, but what was the endpoint that they saw?
What was the effect? Was it weight loss, something trivial? We don’t even know.
DR. SNYDER: It had to be something deemed to be adverse so I'm less worried about that other than --
DR. BELSITO: It just seems that we’re quoting this and it’s just very sloppy referencing., total lack of any primary data.
And we’re not even sure what the adverse event was.
DR. LIEBLER: Well, we can't get that information, so we need to dump it. So I think we’ve settled that.
DR. SNYDER: It’s not going to impact our overall assessment.
DR. BELSITO: Okay. Then I would suggest we completely strike through that section. Is everyone comfortable with that?
DR. LIEBLER: Yep.
DR. KLAASSEN: Yes.
DR. SNYDER: I say more details or strike.
DR. BELSITO: Okay. Well, we’re not going to get more details. I tried and Priya tried.
DR. SNYDER: I also tried to retrieve it and couldn’t get it.
DR. BELSITO: Okay. More details or strike, Priya, I wouldn’t spend a lot of time because I spent way too much time.
MS. CHERIAN: Okay.
DR. BELSITO: So we dealt with the DART, pigmentation. So I think it’s safe as used and in the discussion we’ve already
talked about the DART issues. We’re going to try and get a boilerplate for the pigment issues. We’re going to strike through
the Norwegian margin of safety calculations in the absence of knowing anything about it. Is there anything else that needs to
go into the discussion? Or is anyone uncomfortable with the safe as used?
DR. LIEBLER: I'm fine with it. I think we’ve covered the points. I think Priya’s got the comments.
DR. SNYDER: I'm good.
MS. CHERIAN: I just have one comment. We have irritation and sensitization data, but we don’t have it at the max use
concentration of 5 percent. Is that okay?
DR. BELSITO: Yes.
MS. CHERIAN: Okay.
DR. BELSITO: I mean, there have been -- we have it and there are no clinical reports. There’s nothing about these that
concern me. I put with -- oh, we also, Priya? Yeah, this is it. So if you go to PDF Page 24, you have the data there, so there’s
a DPRA, there’s a Keratino-Sens and there’s an h-CLAT and they’re negative. So we got three out of three in vitros, and sort
of the rule of thumb is two out of three makes it a non-sensitizer. So we have the in vitro data to support that it’s not a
sensitizer and there’s a lack of clinical reports. So I'm not concerned.
MS. CHERIAN: Okay, thank you.
DR. BELSITO: In the case reports, I mean, with these asthma and that, I mean, we don’t even know what the excipients were
in those, so I didn’t make much of those and I didn’t think we needed to even discuss that. It does have some aerosol use,
we’re happy with the safe as used, or do we need the boilerplate about the data insufficient for aerosol use?
DR. SNYDER: I'm frantically trying to go to the table.
DR. BELSITO: Table is on PDF 30 and it’s deodorant underarm to 0.01 percent.
DR. SNYDER: Yeah, again, this is one where there’s a distinct absence of any toxicity through oral studies.
DR. BELSITO: Right.
DR. SNYDER: I think this is one we craft that way to say that, you know, the 0.01 percent would result in a low exposure
even in a deodorant spray, with a particle size distribution -- and put that in there that we know from our resource document.
And then say the absence of any systemic toxicity data or chemical characteristics of the -- chemical/physical characteristics of
the ingredient, there was no concern for inhalation.
DR. BELSITO: Okay, because we have absolutely zero inhalation data.
DR. SNYDER: Yeah, but this is glucosamine, I don’t --
DR. BELSITO: Yeah. I'm fine with it, I'm just pointing out. Okay. We’re going to, unless I hear otherwise, Priya, we’re
going with safe as used. We need to put in the discussion why we’re not asking for respiratory data. And a boilerplate on skin
lightening and delete the margin of safety unless you can get more supporting data. And the DART, again, the dose is
irrelevant and then the 60-day study. Anything else for the discussion?
DR. KLAASSEN: I think the fact that this is a dietary supplement also gives some degree of satisfaction that it’s not a
major problem.
DR. BELSITO: Yeah, I mean, it’s used by millions of people, right, including myself, so. But the FDA does not specifically
regulate dietary supplements, right?
DR. KLAASSEN: Right.
DR. BELSITO: They only -- and if there are consumer reports of adverse events.
DR. KLAASSEN: Right.
DR. BELSITO: Okay. So I'm not sure dietary supplement helps our argument in terms of any founded science, but --
DR. EISENMANN: One note that deodorant is a not spray. I think she would’ve indicated if it was a spray. I just looked it
up in my Use table.
DR. BELSITO: Okay. So then the spray use was just, it’s .07, but not deodorant. So deodorant, underarm, when you report
that, Carol, if it were a spray you’d put spray?
DR. EISENMANN: I would put spray and I have it listed deodorants, not spray, 0.01, on the table that I provided quite a
while ago.
DR. BELSITO: Okay. Okay, it’s not in table three, though. Maybe that would be helpful to put in deodorant, not spray?
Underarm; not spray? Okay. Anything else on these glucosamines? No? Priya, you have your marching orders?
MS. CHERIAN: I do.
DR. BELSITO: Okay, great. Okay, it’s 12:01, lunch time?
DR. SNYDER: Did we skip sugarcane, or did I fall asleep?
DR. BELSITO: You fell asleep.
DR. SNYDER: Okay.
DR. BELSITO: It was -- you went into hyperglycemic coma, Paul.
DR. SNYDER: I probably jumped ahead because there was nothing there.
DR. BELSITO: Yeah.
DR. SNYDER: It was no comments, safe as used, done.
DR. BELSITO: Yeah, exactly, that’s what happened.
DR. SNYDER: Okay.
DR. BELSITO: Okay. So we’ll see you all at 1:00?
DR. SNYDER: Yes, sir.
DR. BELSITO: Okay, enjoy your lunch.
DR. KLAASSEN: Bye.
Cohen Team – December 6, 2021
DR. COHEN: Okay. Next is glucosamine. And this is Priya’s. This is a draft report. It’s the first time we’re reviewing this,
and the safety assessment is for four derived ingredients. It’s used as a skin conditioning agent. We have frequency of use.
It’s in a number of leave-on products and some rinse-off products. We have max use for acetyl glucosamine in a lipstick at 2
percent, 2 percent in an eye lotion. And (audio skip 00:28:36) the recitation from just the review in the schedule.
DR. SHANK: Where is this again, please? Table 3?
DR. COHEN: Yeah. Table 3.
DR. SHANK: And your question is what?
DR. COHEN: That max use, is it 5 percent for acetyl glucosamine?
DR. PETERSON: That’s what the table says.
DR. COHEN: Yeah. Yeah. Okay.
DR. CHERIAN: It’s 5 percent.
DR. COHEN: It’s 5 percent. Okay. So, why don’t I open it up to the group for method of manufacturing and impurities.
There was some material there. Lisa, you want to just comment on what you felt we need?
DR. PETERSON: I guess I thought we needed impurities for acetyl glucosamine. That was the need from the chemistry
perspective. I had some questions about whether we needed to worry about nitrosamines. I mean, there’s not going to be any
stable nano compounds expected to be formed, but I saw we had put this in other compound statements. So I guess it’s not --
once I thought it through, I wasn’t concerned about it but I just thought it might be worth bringing up.
DR. COHEN: In what context would we bring it up?
DR. PETERSON: Just making sure it’s not in -- I think it’s the wrong issue for this compound because sometimes
nitrosamines can be formed depending on what the other ingredients are in the mixture, like if there’s nitrate, and there are
some other compounds we’re reviewing that the nitrosamines issue comes up to make sure that they’re not formulated in a way
that nitrosamines can be formed. I think this is a case where I’m overreacting because it’s a primary amine and any
nitrosamine would not be stable.
DR. SLAGA: Right.
DR. COHEN: Ron, what thought -- it looks like this gets in. When they put it on a knee, they were able to actually get it into
the synovial fluid from the surface. What are your thoughts on what we need on this since it’s our first time out?
DR. SHANK: I had two needs. For skin sensitization, the data we have are well below the maximum use concentrations, so
we need skin sensitization for these compounds at maximum use concentrations. The difference is quite large. Acetyl
glucosamine, we have data at 0.005. The maximum concentration is 5 percent. And for the glucosamine hydrochloride we
have it at 0.25 with the max use is 5. So, we need skin sensitization at the higher concentrations.
The other need I have is in report there’s a reference number 442N acetyl glucosamine suppressing melanogenesis. But there
are no details given. I went to the paper, all I could get was the abstract, that didn’t help. So I think we need to see the whole
paper and then (audio skip) intraperitoneal injection. So that would produce blood concentrations far greater than (audio skip).
And glucosamine penetrates the skin very slowly, so I think in the discussion we should mention that the DART data in the
report don’t reflect what would occur with cosmetic use. Those are the only comments I had on the report.
DR. COHEN: Tom.
DR. SLAGA: Yes, I had the same issue with the sensitization data. The rest of the data, it’s not an irritant, it’s not genotox.
It’s also an antimutagen and anticar- (audio skip), so I’m kind of safe with all of those aspects. So, I feel the sensitization data
is the only thing needed.
DR. COHEN: The irritation information that we have is -- at least in HRIPT is very low concentration. It’s several orders of
magnitude below max use, so maybe we just go out with irritation and sensitization at max use and see what we can get?
DR. SLAGA: Fine, yeah.
DR. SHANK: Yes.
DR. COHEN: And do we have a boilerplate or comments regarding pigmentation?
DR. SLAGA: No.
DR. SHANK: No.
DR. COHEN: Okay. Look, I have the issue of reducing hyperpigmentation as well.
DR. PETERSON: I thought we had in the past discussed that you could put that’s not a -- sorry, I have some trouble speaking
this morning.
DR. BERGFELD: It’s not a cosmetic effect.
DR. PETERSON: It’s not a cosmetic -- it’s not supposed to be a cosmetic effect. It would be considered a drug if it was a
skin whitener or something like that.
DR. SHANK: It would be a toxic -- it would be an adverse effect.
DR. COHEN: We would have it at least in the discussion, right?
DR. BERGFELD: Absolutely.
DR. SHANK: Yes.
DR. PETERSON: Yeah, I put that up there that there was an issue with skin lightening. I also had a question about the
reference that was raised by council. They said that it was considered unreliable, and I guess I was wondering what the data
were. Why was it considered unreliable, and if something’s considered unreliable, should we really include it in the report?
Because a piece of that data is not really -- it’s just additive to several other things where the data seems to be more reliable.
So, I was curious about why it was highlighted for being unreliable.
MS. CHERIAN: Do you know its reference?
DR. PETERSON: It is reference 20 -- look at council’s note. Reference 2, Table 4.
DR. SHANK: In the text of the report can you tell me what page --
DR. PETERSON: Oh, sure.
DR. SHANK: -- the data are presented?
DR. PETERSON: Table 4 is on PDF page 30.
DR. COHEN: I remember seeing that. I just can’t -- where was it about that reliability?
DR. PETERSON: It’s the last line of Table 4.
DR. COHEN: Last line Table 4. Okay.
DR. PETERSON: It’s under the dotted line. It’s one “Glucosamine HCL mice strain unspecified.” I mean, the data aren’t --
I guess it’s because it’s a glucosamine HCL but --
MS. CHERIAN: It was an ECHA study, so it was, I’m assuming, summarized data.
DR. PETERSON: Ah, and that’s why it’s not reliable?
MS. CHERIAN: I can doublecheck in the dossier and see why it was considered unreliable.
DR. PETERSON: She doesn’t really say -- I mean, the letter calling attention to it just says the reference is unreliable or the
study is unreliable.
MS. FIUME: Can someone from industry -- Jay, can you respond to the concerns for that citation, please?
DR. PETERSON: You are on mute, Jay.
DR. ANSELL: I’m sorry, I was just away for a second. Could you repeat the question?
MS. FIUME: Oh, sorry, in the comments it said in Table 4 the one reference from the ECHA dossier was not considered very
reliable (audio skip) considered unreliable.
DR. ANSELL: I don’t have that in my notes. Linda, do you have a --
Dr. KATZ: No, we don’t.
DR. SHANK: Since we don’t know why -- and I don’t think that table’s very important in evaluating the safety -- acute oral
LD50s and they’re huge. Grams per kilogram bodyweight, yeah. So I wouldn’t put too much time on it.
DR. PETERSON: I just thought it was interesting. It was highlighted as being unreliable.
DR. COHEN: Okay.
DR. SHANK: Why?
MS. CHERIAN: Sometimes ECHA data states in their summaries that they didn’t consider a study reliable because they
require certain factors like a certain number of animals or a certain strain or something like that, so it could’ve been that kind of
issue.
DR. PETERSON: Okay.
DR. COHEN: So, we’ll go out with an IDA on (audio skip) -- sensitization of (large audio skip 00:42:00).
Full Panel – December 7, 2021

DR. COHEN: So this is a draft report for glucosamine, and this is the first time we’re reviewing this. This safety assessment
has four derived ingredients which are used as skin conditioning agents. The frequency of use is reported, and we have max
use of glucosamine up to 5 percent. And it may be used in lipstick formulations and eye lotions. Our motion is for an IDA
asking for impurities for acetyl glucosamine, irritation and sensitization at max use for acetyl glucosamine.
DR. BERGFELD: Don?
DR. BELSITO: We have it safe as used.
DR. COHEN: That’s why we do it this way, I guess.
DR. BELSITO: So, Dan, you want to comment on the manufacturing?
DR. LIEBLER: Let’s see. So your IDA was impurities for acetyl glucosamine?
DR. COHEN: Yes.
DR. LIEBLER: Okay. Yeah. It’s not listed.
DR. BELSITO: We have a method of manufacturing. You can’t get anything from that?
DR. LIEBLER: It doesn’t provide a strict purity specification.
DR. BELSITO: But is there anything in what’s used to manufacture that you’d be concerned about?
DR. LIEBLER: There’s either a chemical modification of purified glucosamine or a production from a plant source. And
first time we’re seeing this; right?
DR. BERGFELD: Right.
DR. COHEN: Yes.
DR. LIEBLER: Yeah. Okay. Let’s just go ahead and I’ll support the IDA. We can triangulate if necessary depending on
what information we get.
DR. BERGFELD: Anyone else want to make a comment? Don, are you seconding it now?
DR. SNYDER: Well, Don, you said on the sensitization for this that you used the logic of the adverse outcomes pathway. It
had two of three of the in vitro are negative and no clinical reports of sensitization or irritation. So that cleared the sensitization
even though it wasn’t at the max concentration of use.
DR. BELSITO: Right. So I’m just back to looking at --
DR. COHEN: Our human sensitization data is more than an order of magnitude off from max use.
DR. BELSITO: Yeah. But, again, David, we now have three of three in vitro tests, all of them predicting no sensitization.
We have a DPRA. We have a Keratinosense and we have the h-CLAT. So, you know, it’s totally predicted to be non-
sensitizing, and we have acetyl glucosamine and HRIPT. Now, granted, it’s not at max concentration of use, non-sensitizing. I
just didn’t feel we needed the data. Particularly, we have completely negative in vitro data that is accepted methodology for
determining in vitro sensitizing capabilities. And we have no clinical reports.
DR. COHEN: Yeah. I don’t want to rely this early on the absence of data as being an indication of its safety.
DR. BELSITO: We don’t have absence of data. We have three --
DR. COHEN: Well, no, there’s no clinical reports.
DR. BELSITO: We have three of three in vitro tests which are accepted methodologies for assessing sensitization.
DR. COHEN: We have one in vitro test for irritation; right? And certainly these HRIPTs might uncover some irritancy
and/or sensitization at higher concentrations.
DR. BELSITO: We have an in vitro test of a neat material that was nonirritating in reconstructed human epidermis with
OECD guidelines, and we have three OECD guideline in vitro sensitization test which cover three aspects of the adverse
outcome pathway for sensitization that we can study in vitro and that are accepted.
DR. COHEN: So, Don, I guess it’s really more a question and advice on your part is if we’re relying that heavily on the in
vitro and you’re seeing no signs of sensitization in these in vitro irritation/sensitization, then why are we doing the human
ones? And if we still want that as a corroboration, by that logic we can have people doing HRIPTs at one part per million
getting a negative result and then saying okay, we have two in vitro, and we have a negative human; and that’s it.
DR. BELSITO: Well, I mean, first of all, maybe you weren’t part of the panel when we got the in vitro presentations, and
certainly Dan and I are privy to the fact that, you know, we’re using these in vitro tests for fragrances all the time. Europe has
banned animal testing for cosmetic use, and they also feel that it’s unethical to do HRIPTs, which have now been rephrased by
the fragrance industry as not HRIPT but confirmation of no induction of sensitization.
So we as a cosmetic ingredient review panel need to begin stepping up to accepting and understanding the in vitro studies that
are done for sensitization because as materials come in where we need this data, we cannot ask for animal data. If it’s out
there, we can certainly use it, but we cannot ask for new animal data.
DR. LIEBLER: So, David, I’m the not the dermatologist obviously, but I’m the other person who’s on the RIFM panel. And
I’ve been kind of watching how this dynamic has developed about what data are accepted to clear this sensitization endpoint on
both panels. And on the CIR panel we have frequently usually had HRIPT data to clear the sensitization endpoint at
concentration of use, and we usually haven’t cleared ingredients that didn’t meet that standard. On the other hand, on the
RIFM side, we’ve been making increasingly heavy uses of the in vitro tests, the DPRA, the Keratinosense and the h-CLAT are
kind of the trio that get used. Thanks for the slide there, Bart.
This is just from a presentation that we had. We have used those on the RIFM side to make a decision about the sensitization
risk, and so this is the first time that I can recall on a CIR review where we’ve been presented with this situation where we’ve
at least -- Don has suggested that I think this clears the sensitization endpoint -- first time that I can recall. And this is the
logic. And I think it’s changing for reasons in the RIFM panel because that’s an international panel. It’s dealing with not only
the data situation in the U.S. but the data situation worldwide and particularly in the EU where we’re going to -- we have less
and less access to HRIPT data to clear fragrance materials.
So that’s just my observation of what the dynamic is, and it’s finally hitting us square in the face on the CIR panel with this
ingredient -- with these ingredients.
DR. COHEN: Well, thank you. It makes me feel better that this is the first time it’s coming up like that here. I’d love to hear
that presentation and maybe other members of our team would as well because I wasn’t here for it. I understand the evolution
of these in vitro tests, but we’re still presented with human data that’s pretty far off. We’re early on in the stage of this report,
and I think I’d still stick with our IDA for now.
DR. LIEBLER: I can support that for the reasons that we just discussed, and I would also ask Bart if Don Bjerke’s
presentation was recorded?
DR. HELDRETH: Yes, it was.
DR. LIEBLER: I’m wondering if that could be made available webinar-style to members of the Panel to dial up and listen to
on a cold winter’s night over the holiday break to at least have a chance to listen to it, anybody who didn’t hear Don’s
presentation when he made it. That was just the last couple of years, I guess.
DR. BERGFELD: It would be nice to have printed that slide as well sent to us.
DR. HELDRETH: I’ll have a look into it.
MS. KOWCZ: And, Bart, this is Alex. We can also ask Don if he’d be opened to actually presenting it because I think it’s
always better to have in person because we can ask questions as they come up. Just a suggestion from the industry, from
PCPC.
DR. HELDRETH: Yeah. I like that a lot. For those of you who haven’t met Don Bjerke, he’s a fantastic presenter and really
knows his stuff, so I think that would be great if we could ask Don to come back.
MS. KOWCZ: That presentation was actually 2016 from the slide that you’ve shown.
DR. LIEBLER: Oh, man. Time flies.
MS. KOWCZ: Most of us were not here.
DR. BERGFELD: I suspect things have changed a little bit too.
MS. KOWCZ: Just a recommendation, Bart, if you’d like to take us up on it.
DR. LIEBLER: I support the IDA that David’s asking for with the understanding that this is an area where there are shifting
criteria. We’re really seeing it on the RIFM side, and I think that’s why Don is -- Don’s not just arbitrarily saying these three
in vitro tests clear it for us. But I think we need to reckon with this, and perhaps as a process that needs to take place and be
evaluated on the CIR panel as well.
DR. BERGFELD: Well, it sounds like everyone agrees to that, and Bart’s going to facilitate it. So may we move on?
DR. LIEBLER: Don, are you agreeing to that? The ask for sensitization data?
DR. BELSITO: I mean, I don’t think we need it, but it’s early in the process. I think the other team is uncomfortable with the
in vitro because they’re not familiar with it, so I’m fine. I’ll just go on record saying if we don’t get it, I will go back and
support the safety as I just suggested.
DR. BERGFELD: So are you going to second the motion of the IDA?
DR. BELSITO: Yes.
DR. BERGFELD: And we assume that we will before the next meeting be able to review the presentation by Dr. Don --
MS. KOWCZ: Bjerke
DR. BERGFELD: Bjerke. Okay. And maybe some of it in print form as well could be sent to us.
DR. LIEBLER: Yes.
DR. BELSITO: Wilma, can I just interject totally off topic? Are we going to be discussing the Women’s Voice of the Earth
submission on MCI/MI?
DR. BERGFELD: WE don’t have that on the agenda, so I’ll leave that up to Bart to discuss. I know we discussed it in our
team meeting.
DR. BELSITO: Yeah. So -- go ahead, Bart.
DR. HELDRETH: Yeah. I was just going to say the letter from Women’s Voices for the Earth came in after we created the
initial panel material, so there was no way to go back in time and put it back on the agenda. But the panel is welcome to
discuss any items that come in, so if you want to interject it, that’s just fine.
DR. COHEN: Should be do it in other items?
DR. BERGFELD: Yes, we could do it under other items.
DR. BELSITO: We also need a presentation on the QRA for MI because it was my recommendation that we bring that back
to the panel, and I think that that is very relevant to the concerns voiced by WVE that we decided to go with the QRA approach
as opposed to an outright ban as Europe did. So I don’t know if we’re going to be discussing it, but that would be another good
presentation.
DR. BERGFELD: So let’s assume that that will also occur. Okay, Bart?
DR. HELDRETH: Yes. I will ask for both.
DR. BERGFELD: Good. All right. I’m going to call the question on the glucosamine and the IDA and the listed needs. We
understand that in between we’re going to get this information on the in vitro testing for assessment of sensitization. So all
those opposing? Abstaining? Unanimously approved. So now moving on to our next ingredient, Dr. Belsito on ginger,
another botanical.
MARCH 2022 MEETING – SECOND REVIEW/DRAFT TENTATIVE REPORT
Belsito Team – March 7, 2022

Dr. Donald Belsito
OK. Anything else on these acrylamide acrylate copolymers? So, we're keeping the conclusion as is, we're going to make in the
discussion, and it's also in the respiratory boilerplate. OK.
Any other points that anyone needed to make on this documents? And will incorporating the wave three comments from the
Council. OK. So, we're going to move on to glucosamine.
Let me say please. And so we are pretty much already I think have this wrapped up. There was wave three comments that we
can get to in a moment. So basically we were willing to go with safe as used the last iteration because we were believers in the
in vitro data. But the other team, had some issues.
The one issue that did come up with the HR IPT was some very mild cumulative irritation and dermal eye cream. I guess it was
2%. Acetyl glucosamine and it was included. So I didn't know whether we had to say, particularly since there's an eye cream
use up to 5% formulated to be non-sensitizing with these.
Dr. Paul Snyder

I had the same question, Don.
Dr. Donald Belsito

Yeah. I mean, I'd be more comfortable saying or not non sensitizing, non-irritant safe is used when formulated to be non-
irritating.
Dr. Paul Snyder

I agree.
Dr. Dan Liebler

So I had one comment on the discussion of the draft discussion on PDF page 34. The third paragraph, which is, mostly about
skin lightening. And I think it's fine up until the last sentence. And then that last sentence was really about another topic which
is about the
Dr. Donald Belsito

Yeah.
Dr. Dan Liebler

negative and in chemico in vitro irritation and sensitization, data provided on asked to glucosamine. I think that that belongs in
its own paragraph, even if it's just a one sentence, but it's a separate topic.
Dr. Donald Belsito

OK. So, you want that moved.
Dr. Dan Liebler

Just carriage return right before it.
Dr. Donald Belsito

The last sentence to a separate paragraph.
Dr. Dan Liebler

Yeah. And I don't know if there needs to be any further discussion at that point in that sentence about the negative in chemical
invitro data.
Dr. Donald Belsito

Yeah, I mean. Actually, that was probably in the discussion before we had them. The actual HRIPT.
Dr. Dan Liebler

Yeah, if we got the HRIPTS, maybe we don't even need to that sentence at all.
Dr. Donald Belsito

I think we can just delete it.
Dr. Dan Liebler

OK.
Monice Fiume (CIR)

So would that be deleted and then be replaced by the boilerplate language we use if it's going to be safe when nonirritating, the
language that would normally be brought in?
Dr. Donald Belsito

Yeah. So we're going to delete that last sentence, since we also have human data now and just discuss the irritation that was
seen during in induction patching in the HRIPT. There's a reason why. OK, so safe as used when formulated to be non-
irritating. Get rid of that last sentence in the discussion or that that last sentence in the third paragraph of the discussion and
substitute it with something to the effect that it made HRIPT study ever 2% formulation. Evidence of irritation was seen during
the induction phase is, given the use at 5% or night cream formulated? However, we usually put it, advise to take caution for
irritation or whatever, I don't know.
Dr. Dan Liebler
I agree.
Dr. Donald Belsito

Then we need to look at Wave 3 Council comments for a second. Yes.
Dr. Dan Liebler

Sure. Aside from incorporating the HRIPT into discussion. Or the lat it looks like all the editorial except for the last point. The
new HRIPT studies should be mentioned in the discussion.
Dr. Donald Belsito

Yeah.
Dr. Dan Liebler

Like if it's sufficient, we don't need to mention it the discussion.
Dr. Donald Belsito

We're only to the extent that with the 2% there was irritation seen during the induction, which is the reason why we're
formulating to be non-irritating.
Dr. Dan Liebler

OK, so we've dealt with that.
Dr. Donald Belsito

Yeah. Any other comments on Glucosamine's? OK, let's see if we can get quacktolacktones done here. I'm saying this. There is
also a wave 3 on these. OK, so. We're looking at the fact, in September 2021, we issued an IDA for this group, and we asked
for method of manufacturing data for Blucher, world lactone and glucoheptonate impurities data for four of them, irritation and
sensitization data at maxim concentration of use. Who's got an HRIPT and 106 subjects, 15% Gluconolactone was received. It
was nonirritating and non sensitizing, and that is basically what we got. So based upon that where are we with this documents?
I thought we could go with Gluconolactone as safe as used ride bono lactone needs impurities and all the others needed
manufacturing impurities. Assuming we keep them, given the lack of function in cosmetics. Then there were those three that
didn't have a function anyway, that that was my thought. After looking at this so I'll open it up to the team.
Dr. Paul Snyder

I agree with the split conclusion.
Dr. Dan Liebler

Me too.
Dr. Paul Snyder

Almost there in less than.
Dr. Dan Liebler

No, I agree with you that you're you. I agree with Don and Paul completely with what Don just said and those are my
comments on the report to.
Dr. Donald Belsito

So. Do we review ingredients that are in the dictionary without any reported function?
Monice Fiume (CIR)

We do because I mean, that does happen occasionally. Usually not this often, but we don't always know. The function.
Dr. Donald Belsito

OK. I mean we can keep them in their report. They'll just be insufficient data. OK. Then then just to go through it
gluconolactone safe is used right? Bundle lactone needs impurities, and all the others need manufacturing impurities and would
and we're keeping them in their report.
Dr. Dan Liebler

Right.
Dr. Paul Snyder

So Don or so down on page 17. Should we put an asterisk by those where there's where there's no reported function?
Dr. Donald Belsito

OK, hold on, Paul. I was just doing some 17. That we could, I mean that would be nice.
Dr. Paul Snyder

I think that would help link back to the into to our conclusion.
Monice Fiume (CIR)

So I'm going to do a Bart impersonation here where the functions are not always informative or correct when they're provided.
So I know Bart usually hasn't issue with relying on function for determining safety. I mean, it's the panel's prerogative to have
it marked if you want. Buty yeah, I just know that that is an issue that Bart often has concern over is the functions in what
they're listed as.
Dr. Donald Belsito

OK. I mean then we don't need to star them. It's not a big deal. We're still saying they're inefficient. They are insufficient for
manufacturing impurities.
Monice Fiume (CIR)

So it's the panel's prerogative, but I just know I've heard Bart on this many times.
Dr. Donald Belsito

I'm OK either way, I just raised it because I thought one of the reasons for grouping was chemical similarity in a similar
function, and since we don't have function, how can you say the function is similar, but I I'm OK keeping them in and in two
years, you know wiping out other cosmetic ingredients that safety is not supported by, you know, just so we can go through
this dictionary.
Jay Ansell (PCPC)

You know, to that point though, but we have often included members of the family, that have no reported uses, with the
proviso that were it to be used, it would be used consistent with the application and concentrations included within the report.
So.
Dr. Donald Belsito

That's true. I gotcha.
Dr. Curtis Klaassen
I thought I read in the minutes from the other. Come from the other committee that Bart had said that they were thinking about
a change in that. That you know, if there weren't no uses, maybe they we wouldn't include anymore. Does anybody know
anything about that?
Jay Ansell (PCPC)

I don't know specifically what Bart was a referring to, but our position is that the inclusion within a family should not be driven
on weather the material is used or not but that the data is reliable from each ingredient to support all of the other ingredients .
And I see Don raised his hand.
Donald Bjerke (P&G)

Yeah, the science and Support Committee issued a recommendation not to review ingredients that have no reported uses as a
potential gain and efficiency. And the response we got back was yes, we hear you. Thank you. But we're going to continue to
do it, which is perfectly fine.
Dr. Curtis Klaassen

OK, let's clarify.
Dr. Dan Liebler

Yeah.
Monice Fiume (CIR)

I think I'd like to take it one step further in conversations about this with Bart is that if in ingredient has no views. And doesn't
have any data that can support itself or other ingredients in the report. Then, as the priority list is being built, the tendency
would be not to include those in the grouping because it doesn't provide any information either safety wise or use wise. So that
is one thought right now.
Jay Ansell (PCPC)

Right. And that would be our position as well is that for efficiencies that the parent compound. Be identified because of its use.
And those other materials would only be included if they provide data which is reliable for assessing of the of the parent
compound.
Monice Fiume (CIR)

But then I'd also like to ask Dan for input, being that you know you are involved in the groupings as the Subcommittee on the
for the for the panel, what are your thoughts on it?
Dr. Dan Liebler

Well. We include ingredients if we're asked to include them basically that's the overriding. Yeah, that's the way. I mean, there's
no committee anymore. It's just me and I know it.
Monice Fiume (CIR)

It’s a committee of 1.
Dr. Dan Liebler

And I don't really even get asked about that unless we're looking at priorities generally. I think that right now my understanding
is that we're asked to include anything that's reasonably related that's in the dictionary. And so, we air on the side of inclusion
and we typically, I mean I, I quickly see at the priority stage whether there are uses or functions and we just include them, and
that, of course, leaves us with a bunch of insufficient’ s in many, in many cases. And then we waste a lot of time going through
the insufficient process. I guess I'm. I mean, we can tolerate that it does cause spin our wheels with insufficiencies on the other
hand, if we don't go through the insufficient process, we don't. I don't think we, we vacuum up the available data that we need
it just it takes one or two or sometimes three iterations that we report to arrive at the fact that we just aren't getting data on a
particular ingredient, then we have to say insufficient. So, if we want to air on the side of inclusion of the possible ingredients,
gathering the relevant data on the broadest, you know, number of dictionaries listed ingredients that are in a family. I think
we're kind of stuck with our current process.
Dr. Donald Belsito

Yeah. And I mean, I think at some point we need to. Addressed the fact that by having these ingredients in the dictionary, even
though they're not used, we put ourselves up to public comment that there are X number of thousands of things being used in
cosmetics. And you know why I have not been looked at for safety. So you know, I mean. Yeah, there's an advantage to
looking at materials that we can group into a group and then saying the data is not sufficient usually because we don't have
manufacturing or impurities. Because otherwise we're reading across for a lot of the other tox endpoints so. I can see the
benefit of including them just you know, for. For transparency and for the public awareness that you know, I mean. Keep
hammering back that you have this dictionary is. You know, just a wish list and many of the things listed there aren't even
being used.
Dr. Dan Liebler

Or made.
Dr. Donald Belsito

Yeah. OK. Any. So, then we have the wave three comments, any that really were just all editorial and I think can be included
in?
Dr. Dan Liebler

I have. Yeah. One that was, I just want to comment on the second point definition and structure about how gluconolactone is
involved in the glucose 6 phosphate dehydrogenase deficiency, I thought.
Dr. Donald Belsito

Uh huh.
Dr. Dan Liebler

That point in the report is PDF 18 under at the very top of the page, and it just says Gluconolactone is also involved in the
metabolic disorder called G6 PD dehydrogenase deficiency pathway. I think at that point is not really relevant to our
assessment and that that sentence could be just deleted from the report and that was what I recommended, and that then
obviates the Council comment.
Dr. Donald Belsito

Yeah. So that we're striking that out.
Dr. Dan Liebler

Yeah. And I struck it out on my copy of the report.
Dr. Donald Belsito

I just did as well, and I guess that will pop up in my comment section that I deleted something and we can discuss it tomorrow
to make sure the other team is happy with it.
Dr. Dan Liebler

Right.
Dr. Donald Belsito

So the draft discussion on these, we need the inhalation boilerplate conclusion, I've already given you. Animation boilerplates.
Yeah, but data is otherwise sufficient for econolacktone, but for cagonolacktone we need impurities and for the others we need
manufacturing impurities.
Dr. Dan Liebler

Agree.
Dr. Donald Belsito

Anything else to go on the discussion other than the inhalation boilerplate and our lack of manufacturing impurities on the
materials were not clearing.
Dr. Dan Liebler

Nope.
Dr. Donald Belsito

Paul, Curt.
Dr. Paul Snyder

No, I think you s marized it perfectly. I had one comment. So, when he's mentioned that there was going to be maybe an effort
to update the VCRP. Data how it's collected, or something wasn't that is it correct to Monice?
Monice Fiume (CIR)

Not how it's correct collected, how it's presented in the.
Dr. Paul Snyder

That was presented. So I was wondering if in the end when we do put the table together, what if we had an asterisk by those
that had no reported uses and that has had asterisk at the bottom said if they if they were to be used it would be within the
context of the use table with regards to the types of uses and the other concentrations or something. Would that be useful or not
because that just.
Dr. Donald Belsito

Well, we have that now. Usually there's a table that follows the table with a concentration of use is in the number that lists the
ones where there is no current use and say if they were to be used, the expectation is yaddayaddayadda.
Dr. Paul Snyder

OK.
Monice Fiume (CIR)

This script and we actually it's actually split so if there's an insufficient conclusion and there's no reported use that has a
different, it takes it further, but right if things are found. The whole family is determined safe. We do add that astrisk saying
that it's assumed that they're being used at the same. The same manners as the other reported in the in the table.
Dr. Dan Liebler

And that's after the conclusion.
Monice Fiume (CIR)

That's in the conclusion, yes.
Dr. Dan Liebler
Right, it's supposed to be in that little table at the end. Yeah. So that's where I'd split.
Dr. Paul Snyder

Well, the only reason I'm saying is that in this report, it's kind of different cause. On page 25 we have Table 3 which is only
lists frequency and concentration use for only one of the ingredients. We looked at, it doesn’t have a table that says no uses.
Monice Fiume (CIR)

It's indicated on PDF page 18. The four ingredients that are not in use.
Dr. Paul Snyder

Yeah, I understanding the narrative it does, but usually we don't. We usually include an all the ingredients in the table, the
VCRP table.
Monice Fiume (CIR)

Often we. Not in the table. Well, if we have ingredients that have no use according to VCRP and the industry survey,
sometimes will include those in a second table which is just the listing. It all depends on the number of uses and if it's easier to
present it as a second table or just present it in text. If you would like to always see that in an additional table, we could do that,
but it's not in the use table. It's a separate listing.
Dr. Dan Liebler

Monice don't we typically have a footnote to the frequency of use table that lists the ingredients that have no reported uses.
Dr. Donald Belsito

We typically have a separate table.
Monice Fiume (CIR)

No, no reported means per category for the category that's in that table that the frequency in concentration of use table only
include ingredients that have uses.
Dr. Dan Liebler

Right, but we for ingredients that have no uses and therefore no use data. It seems inefficient to have a full table for those. I
thought that we had a listing typically right after the frequency of use table. For the ones that do have uses. I thought it used to
be like a footnote there. In this case it would be a footnote after Table 3.
Monice Fiume (CIR)

Not usually if anything table four would say these have no reported use is according to the VCRP and Council survey and we
would list them there.
Dr. Dan Liebler

OK. Well, I mean we can do that, and I think that's kind of what Paul was getting at.
Monice Fiume (CIR)

Yeah, yeah. And I think in most cases we do. I have. My guess is that because only one ingredient was in use that they were
just listed in the text of the report. But we can add that listing in as a table four.
Dr. Donald Belsito

Yeah, I had added in it just you know it follows our usual pattern.
Dr. Dan Liebler

Is that which talking about Paul?
Dr. Paul Snyder

Yeah, I mean it, it just struck me that there was just that we have this elaborate conclusion with insufficient data
announcement, but then we don't have any, there's no data there in that table, so.
Dr. Donald Belsito

OK.
Dr. Paul Snyder

Yeah. Yeah. I just think it's just we just need to be consistent in how we do it.
Dr. Donald Belsito

OK.
Monice Fiume (CIR)

So can I ask because we’ve done this several different ways and we've gotten comments back from the Council. So, we've
included that table, which is the listing of those with no uses according to FDA and industry when it's been as little as one or
two ingredients and will receive comments that say why do you have this in here? It's only one or two ingredients listed. So can
I take it as you would like to see it pretty much all the time, just so it's clear.
Dr. Donald Belsito

Yeah.
Monice Fiume (CIR)

OK.
Dr. Dan Liebler

Yep.
Monice Fiume (CIR)

Thanks.
Dr. Paul Snyder

Yeah, I do. I'm very relying on the table, so make sure that the table matches the narrative. I usually kind of verify that when
I'm reading a report, but again, it's something you can discuss if you're going to talk about the VCRP had also can talk a little
bit about how to tabulate it for presentation of the panel, and maybe there can propose a couple different looks if there's some
new way to do it, there might be more beneficial for us.
Monice Fiume (CIR)

OK, I will be working on that for June. So, I'll see what I can come up with to make it as efficient as possible for the panel
members.
Dr. Donald Belsito
Thank you. So, It’s 12:02pm, anything more on the glycolockdowns before we break for lunch? And come back with our
discussion on what to do with yeast.
Dr. Dan Liebler

Nothing else for me.
Dr. Donald Belsito

OK.
Dr. Paul Snyder

Nothing for me.
Dr. Donald Belsito

So we'll regroup at 1:00 o'clock.
Cohen Team – March 7, 2022
Dr. David Cohen
Were all aligned. OK so. Chromide safe. OK, got it. And I guess we've all been waiting for this conversation. Glucosamine. I'm
just pulling it up. OK, so, in December we issued an IDA for glucosamine and, we requested impurities data on acetyl
glucosamine and irritation at sensitization on all the ingredients at max use. So we received HRIPT on 2% acetyl glucosamine
below the max use. We received 21 day cumulative irritancy assay. Although I must say I couldn't read the results of that in the
report, they would just it look like the PDF was broken up, I just couldn't read it and we have some in vitro ocular data. I
thought the wave three edits we're good. And I thought the HRIPT on the 2%, did it have some irritant signal there during the
inductions? And last we could talk about the pigmentation again? But ah, I'll open it up for discussion because, the question is,
are we going to use the in silico and in vitro data as a surrogate for HRIPT for max use? Are we there? And I know it's going to
be something tomorrow, so. I need the training guys. I need you to. What are we going to do with this? Wilma, you're on mute?
Dr. Ron Shank

Well. We have sufficient. Irritation that sensitization data for Assateague glucosamine. And I think that can be used to read
across to the others. But we'll see what the chemists have to say.
Dr. Thomas Slaga

Yeah, I have safe as used.
Dr. Wilma Bergfeld

Why wouldn't you use the specialized testing that was just presented to us? Just because it's an update, it's an upgrade. And put
it into the document.
Dr. Ron Shank

Including yes.
Dr. Wilma Bergfeld

If that can't be, if that can be shared.
Dr. David Cohen

I think we can include it. I think we should include it that the real question is are, you know.
Dr. Wilma Bergfeld

Right.
Dr. David Cohen

Ron and Tom comments about the we have. We're using a read across for the HRIPT and we're giving it a safe issues because
of that, not because of the in vitro data. Right? And I guess the challenges you're saying, why not? Why? What if we didn't
have that read across which you use it and I don't know how convincing I think it's really important information and its
substantive but it's not in lieu of. To me, human HRIPT data, because you know you, you know, Wilma, if they went to publish
this and they didn't have 5% on the acetyl glucosamine, that did be no way to corroborate that there, right. And even if they
didn't have temper it with 10%, that's the way kind of looked at it.
Dr. Wilma Bergfeld

Well, that's the problem it there's a need for growing information understanding of these new testing mechanisms. But yeah, I
agree with you. I think you have to keep the human with the other. I just think about this at this point in time, they have to run
parallel.
Dr. David Cohen

Yeah. Or one of the constituents.
Dr. Ron Shank

I agree.
Dr. David Cohen

Comes in at max use, the others are corroborated with that in vitro data. I just, I didn't think the presentation got to the point
where I say I don't need HRIPT data anymore.
Dr. Ron Shank

But now we are you need the human data. On several examples. Not just one. To show that the old process of risk assessment,
using all of this in chemical, in silico data, all these models, accurately predicts the human. That has to be validated with
human data. Once that's established, clearly across the board.
Dr. Thomas Slaga

Right.
Dr. Ron Shank

Then eventually you could not rely on human data, but until you have a very large base or all of them.
Dr. Thomas Slaga

The base.
Dr. Ron Shank

Risk assessment models have been confirmed. Correct. Positive, correct, negative. By human data you have to have the human
data.
Dr. Thomas Slaga

Right.
Dr. David Cohen

I'm Circling back around Ron because we have human data on 2% and max uses 5%.
Priya Cherian (CIR)
Dr. Cohen, if you're uncomfortable with the irritation data, but you're OK with the remaining data, you can issue as safe as
used inclusion on when formulated to be not irritating.
Dr. David Cohen

Yeah. No, I know that's the sort of the fail safe. But the question still comes back to Ron, I sort of. Accepted the statement
about the read across, but acetyl glucosamine HRIPT is at 2% and it's max uses at 5%. And that's where the rub comes back. So
could you just check on it? Could you just comment on that? And I and or check on it and I see Carol has her hand up.
Dr. Ron Shank

OK.
Carol Eisenmann (PCPC)

Well, I just.
Dr. Ron Shank

Well, it's a matter of concentration difference, I agree. But now you have this rather extensive risk assessment analysis which
we heard this morning. Which will predict Acid steel glucosamine is not as sensitizer period. So you haven't confirmed at 2%,
do you really need to go out and ask for 5%? And I think that's up to, the dermatologists because you have the great experience
on that.
Dr. Wilma Bergfeld

You have a higher patient study at 20%.
Dr. David Cohen

Well. Say that again.
Dr. Wilma Bergfeld

I think you have an eye irritation study at 20%. And it wasn't it was not irritating, but it was not irritating. Yeah, well, at least
you have that at a higher present.
Dr. Ron Shank

Yeah, that's irritation.
Dr. David Cohen

Carol, you were going to make a comment.

A couple things. First are the in vitro assays being, they were completely negative. They work very clearly negative, not you
know questionable. They were clearly negatives. And these are always OECD, I mean it they have gone through a lot of review
things don't get into OECD guidelines without a lot of review. This isn't just Procter & Gamble or are company *(inaudible)
very rigorous review.
Dr. Thomas Slaga

OK. All of that.

So I you know I get your point, but I in this case, these were very negative studies. I mean, at glucosamine is immaterial in our
body, so it be hard to think that it's a sensitizer.
Dr. David Cohen

Well, I mean there are a number of endogenous chemicals that people become sensitized to. You know estrogens,
progesterone, cortisol, different chemicals than this but, at the disposition of this report is going to change the way the panels
do their work. I mean it's really important. And I think if I had heard in that presentation using these models that max use
concentration and 2X max use concentration corroborated the data. I would say yeah. You've built the clinical bridge from the
in vitro data and I'm not moved by this. Of course I'm moved by it, but that that final step was not taken. That's just the problem
I have with it. We don't have 5%, we don't have 10% suggesting, yeah, this in vitro bridge demonstrated that this model does
work. I don't even have that. I don't have any of that. I have very convincing models that suggest this would not predict
sensitization, but there's no human data suggesting that thats true.
Dr. Ron Shank

Well. 2%. Was negative. That would tend to support no sensitization. But I agree you're going 2 1/2 times at concentration if
that's what you want. I think we should ask for it.
Dr. David Cohen

I really don't want to just dig my heels in for the sake of it is so this is not going to be the last time we see in vitro data in the
absence of human data. And are we going to be OK with it? I don't mean I, I guess with sounding very, I'm sounding very
philosophical at this. Today, because there's a.
Dr. Thomas Slaga

It's very important bring this up tomorrow. The difference of two to 5% to, you know, see what?
Dr. Wilma Bergfeld

That's a big difference. Almost twice.
Dr. Thomas Slaga

It's just.
Dr. David Cohen

Dons presenting this tomorrow and it'll come in from our last conversation, as safe as used.
Dr. Thomas Slaga

Yeah.
Dr. David Cohen

Because that's how it happened last time and we asked. I think we asked for more information and then? So I'll bring it up
because we don't have to. We don't have to come up with the conclusion first.
Dr. Wilma Bergfeld

Could I ask a question? They talk about the glucosamine being a dietary supplement. And frequently it, combined with
chondroitin sulfate and this is also approved by the FDA for debulking agent? So it would seem to me that in those particular
practices that would be at higher concentrations and ingested.
Dr. David Cohen

Yeah. Yeah. One last comment they may maybe Wilma you could comment this discussion about it's it changes in pigment.
Dr. Wilma Bergfeld

Yes.
Dr. David Cohen

Right, OK. And I completely get that pigment changes are a drug effect, right?
Dr. Wilma Bergfeld

Right.
Dr. David Cohen

But there's a discussion about its inhibition of torosidis activity.
Dr. Wilma Bergfeld

Right.
Dr. David Cohen

And there's discussion of it being effective in changing pigment at 2%, which is 2 1/2 times lower than the max. Use
concentration. So I might suggest that, pigmentary changes are a side effect when they're not the intended effect, and it.
Dr. Wilma Bergfeld

Yes, but it's also mixed in that study with four percent nicotinamide.
Dr. David Cohen

Yeah.
Dr. Wilma Bergfeld

Which is also a bleaching agent.
Dr. David Cohen

Right. But then the further data on its Physiology with suggest it does have an impact on tyrosinase and it really did reduce
melanin content rather considerable way. So rather than.
Dr. Wilma Bergfeld

Right, right.
Dr. David Cohen

In the, you know, punting and saying well, changes in pigment is a drug effect, and that's not what we're looking at. But if
someone who had type 345 skin is putting on 2 1/2 times the concentration of where we're seeing an effect had, maybe they
don't want to lighten their skin. Is this going to be an adverse effect of it?
Dr. Wilma Bergfeld

Yes.
Dr. David Cohen

So we handle that in the discussion or is this a problem?
Dr. Wilma Bergfeld

Yes. Well, I think in US going the discussion that's my opinion and we have to decide how we are going to dumb it down if
that's what we want to do.
Dr. Thomas Slaga

Sure.
Dr. Wilma Bergfeld

Because it will be in formulation and some of the effects will be somewhat neutralize. However, in this particular product,
which is a treatment product. It's a drug and the two products are both depigmenting.
Dr. David Cohen

Right. It had to, you know it, it had to do a little bit with the same thing we're talking about with sensitization. It's at a much
lower concentration than what we're reporting is max use here.
Dr. Wilma Bergfeld

Right, right.
Dr. Ron Shank

Yeah.
Dr. David Cohen

I think its hard to have it both ways. When you say, the physiology reduces melanin production, using it as a threptic works,
but where not dealing with threptics.
Dr. Wilma Bergfeld

I think it's a problem. I think it's a problem and thank you for bringing it up. The we've had some other similar agents that we
have said it cannot be a depigmenting agent.
Dr. Ron Shank

Right.
Dr. David Cohen

So how did you conclude with those?
Dr. Wilma Bergfeld

We put those in the discussion, did we ever put them into that? Bart, did we ever put him into the conclusion? Think they were
mainly discussion points? The depigmenting effects. I can't hear you. Some of the quinones, other quinones that we've handled.
Dr. Bart Heldreth

So even with something like kojic acid where you know that's huge skin lightener we handle in the discussion, I think I think
the approach is that you know when we have something that we know it's going to be a sensitizer we know that the formulators
can create a product that's not sensitizing, you know, they can formulate to be non-sensitizing. Ultimately, I think maybe you
know the formulators can make sure they use the low enough concentration for or other conditions when they're formulating a
product on skin so that it doesn't have that effect now because that's a drug effect it doesn't usually go into work conclusion or
I'm sorry, yeah, into our conclusion. So I mean, if you wanted to put some stronger language in the discussion saying, hey, you
formulators, you know, be really careful because, you know, you're right on the edge here of causing what could be considered
a very negative effect? You know that that's the panel's prerogative.
Dr. Wilma Bergfeld

Well, I think what David is saying is it our testing is at 2% nonsense teising, but it's also 2% in the depigmenting agent. So
there is no concentration difference. It would be it strictly on the formulations as you indicated, and I did also.
Dr. David Cohen

And max uses 5%.
Dr. Wilma Bergfeld

Earlier. Yeah.
Dr. David Cohen

Max uses 5% on face and neck products.
Dr. Wilma Bergfeld

Maybe we should go out and say is that right? Is it that high? Because sometimes when they've redone these voluntary
contributions of concentration, they've actually gone down. When they reviewed it.
Dr. Bart Heldreth

Yes. We could ask Carol that to the double check, make it sure the concentration isn't wrong.
Dr. Wilma Bergfeld

Yeah. Well, I guess that the bottom line is it should not have a depigmenting effect that has to go into the into the discussion no
matter what.
Dr. Bart Heldreth

Right.
Dr. Wilma Bergfeld

I'd like to address the safety Ron of the Dietary Supplement and the debulking agents. Those are almost like food they're being
ingested. By many, many people.
Dr. Ron Shank

Yes. How? What's your question?
Dr. Wilma Bergfeld

Well we excuse those particular ingredients that have food or foods or grass.
Dr. Ron Shank

Yes.
Dr. Wilma Bergfeld

Now these are not in that category, but they are ingested.
Dr. Ron Shank

Yes.
Dr. Wilma Bergfeld

And they're interested in for, like good amounts it because of the products they're in dietary supplements, and in debulking
agents of pills.
Dr. Ron Shank
Yes.
Dr. Wilma Bergfeld

What we can't consider those food, but do they have the same sort of caveat that because it's ingested and there's no toxic effect
that it wouldn't be handled the same way. Or if you have enough systemic types, I guess in this one.
Dr. Ron Shank

They're not foods.
Dr. Wilma Bergfeld

Yeah, that's it.
Dr. Ron Shank

I think they're classified as dietary supplements.
Dr. Wilma Bergfeld

Right.
Dr. Ron Shank

Mostly to control joint.
Dr. Wilma Bergfeld

Yes.
Dr. Ron Shank

Physiology. And there, there is little evidence to support that the oral administration of the glucosamine, chondroitin sulfate has
any harmful effects. Whether they, whether it's effective in preventing joint effects, is questionable.
Dr. Ron Shank

But whether they have harmful effects isn't, but that's oral administration. Not dermal. Not topical.
Dr. Wilma Bergfeld

Right.
Dr. Ron Shank

So when you put it on the skin, it might be quite different.
Dr. Wilma Bergfeld

I'm not talking about the depending ability, just about the systemic tox if you ingest a supplement, and it's widely used, it must
be safe.
Dr. Ron Shank

Yes. And I think it is approved by FDA.
Dr. Wilma Bergfeld

Yeah.
Dr. Ron Shank

As a supplement.
Dr. Wilma Bergfeld

So it would support systemic toxicity, lack of systemic toxicity.
Dr. Ron Shank

Yes, yes it would.
Dr. Wilma Bergfeld

That's the point, OK?
Dr. Ron Shank

Yeah, I don't think there's this systemic tox.
Full Panel – March 8, 2022
Dr. Don Belsito
So, glucosamine. At the last meeting, the Cohen team didn't quite like the in vitro data and they wanted to see some in vivo
data and also get a further handle on the in vitro studies that were used to assess this. And Don Bjerke did a marvelous job
yesterday, going over that. And also, we were supplied with HRIPT data that more than covered the risk of the current
exposure. However, in the process of looking at that data, it appears that there was some irritation in the HRIPT studies with
macular erythema being seen during the induction. So, my team thought we could go ahead with a safe as used when
formulating to be non-irritating?
Dr. David Cohen

So I don't want to 2nd that motion yet. So, could we have more discussion?
Dr. Don Belsito

Sure.
Dr. Wilma Bergfeld

Sure.
Dr. David Cohen

Yeah. So Don, thanks, for we picked up the same thing in that eye cream with several patients having erythema, and I think
that irritation provision is good. And, our team really enjoyed the conversation and lecture yesterday about the in vitro models.
The question still came up in our conversation quite a bit is that there's a great discussion of the methodology of the in vitro
models and the reasoning for it, and it is certainly steeped in science; but, what we didn't see is a bridge from that in vitro data
to in vivo data. And I think, under normal circumstances, we would take a novel model and we would compare it directly to the
predicate comparator that's considered the gold standard. And for me, the gold standard is the HRIPT. In this situation, so you
would say we have several models that have predictive value and we believe that there's no data, there's no suggestion of risk.
And here is the HRIPT data in max use and maybe above max use to say that that bridge is drawn. But what we have is, we
have human data at 2 1/2 times lower a dose than max use. So, I'm not sure that we bridged it.
Dr. Don Belsito

Well actually Don re-crunched the numbers and we're actually above the cumulative exposure, is that correct? Don, if I read
your email quickly this morning?
Dr. Donald Bjerke

Yes, just a few comments come in and I did some more homework last night and have a true appreciation for the volume of
information that the Expert Panel deals with. So, what I reported yesterday, I reported two HRIPTs and two human
maximization tests when in fact there was a third HRIPT that was done at two percent acetyl glucosamine in a liquid
foundation. And as I look at the dose per unit area that was applied on that patch, it's it amounts to 1000 micrograms per
centimeters squared. So, in fact, that data supports a sevenfold increase over the maximum consumer application. So, 5%
glucosamine in a leave on face cream amounts to 136 micrograms per centimeter squared. And as we all know, when we're
doing a quantitative risk assessment, it's dose per unit area that that makes the difference. So, in fact, we do have informatory.
Dr. Ron Shank

That's right.
Dr. Donald Bjerke

Data confirm it or HRIPT data which supports the conclusion of a non-sensitizer, if we just looked at the in vitro and in
chemico and in silico data alone. One other comment, if I may, Dr. Slaga reached out and had actually a very good question as
well and that was what was used as the reference data set for the validation of the OECD 497, which defined approaches and in
fact there were 196 ingredients that were used in the validation data set and so that was I think 166 or in the local lymph node
assay database. And I forget what the number was for the human database, but that information can be found in the OECD
497th guidance document and I forwarded that to Dr.Slaga.
Dr. David Cohen

Well, yeah, so that would be a whole discussion on the CIR Panel using these predictive models, but it in the acetyl
glucosamine instance, we didn't have that. And I did see the email this morning and I'm not sure if I equate a dose per unit area
and a patch test and then equalize a total exposure over an entire face; because, then we could dilute a 10X and put it on a
whole trunk, and we know that the risk of sensitization is very much related to the concentration at that unit area dose. Right,
so in the HRIPT was 2%. Right. And so you're saying that dose per unit area is the 1000 micrograms per centimeter squared
and the face one is equivalent to that over a larger period. I'm not sure I get that because you're putting a certain dose, but
you're spreading it out, which has much lower risk of sensitization elicitation.
Dr. Donald Bjerke

Yes, I completely understand your concern and let me send you a link, it was in regulatory toxicology and pharmacology. I
think in 2008 they had an entire issue that was devoted to contact dermatitis. And in there there's a couple key references. They
talk about the evidence behind why dose per unit area is more appropriate. So let me send you that information and see if that
helps kind of explain where we're coming from.
Dr. David Cohen

Right. But in the email, you know, you took the 2% HRIPT, which is in a patch test, right? And somehow equated it to the
consumer exposure and that as another bridge. I just right, we just address that I can't build that bridge. But, I get the science.
Dr. Don Belsito

A lot of this comes is being driven actually by industry and particularly in the fragrance industry. So, there is what's called the
Creme RIFM Model and it has wonderful data on habits and practices of use of cosmetics. And that's all part of the sort of the
cumulative dose exposure to a various chemical, particularly fragrance which is used in a variety of different cosmetic product
so that that information is really been honed for. And PCPC has been doing it for a long time to looking at habits and practices
and exposures. I think there's pretty good data on it. It's not just something we usually look at, but those per unit area is the way
to go. The other comment that I would make is that, you're going to have to get comfortable with in vitro testing because as
Don alluded to this yesterday, Europe does not like testing in humans either. They are very much against it and actually as a
result of that, they fragrance industry has no longer calls these HRIPT's. They're called confirmation of no induction level in
humans, CNIH. To stress the fact that they have good data to suggest that the level that they're testing will not cause
sensitization.
Dr. David Cohen

Well, that's exactly the point, Don. I completely agree with that. The I think these in vitro and in silico models are getting us
away from animal testing which, everyone’s moving away from, but still there's a confirmatory human study, at least early, at
least for now, right? So, when you're calling the safe as used now based on this data, it would be. I'm doing this, not very long,
a year and a half or so, this would be the first time I'd see that happen.
Dr. Wilma Bergfeld

It is the first time.
Dr. David Cohen

Yeah. And I don't see the bridge built yet.
(inaudible)
Dr. Don Belsito

Right. We have absolutely nothing to suggest that these are sensitizers. We have three out of three in vitro tests that are
negative. We have a number of human tests, it's all clean. I mean, it's glucosamine.
Dr. David Cohen

Yeah, Don, I don't want you to think I have an issue with glucosamine and it's an issue on the process. I have one other point
that I wanted to bring up on it and it's the skin lightning issue which was discussed at the last meeting. But you know this pretty
compelling data that there is a therapeutic effect at 2% and I understand the visceral response.
Dr. Don Belsito

I understand.
Dr. David Cohen

That's a drug effect or a pharmacological effect, that would not be in our purview. There's also biologic data in this report
suggesting inhibition of tyrosinase too, with a consequential reduction in melanin production and a melanoma cell line. So, my
point is that at 2% it's doing that in in vivo at 1%. It's doing that in vitro and our max uses 5% and I'd suggest that skin
lightning would be an adverse effect, not a pharmacological effect at. It's something we really need to think about.
Dr. Don Belsito

It's considered a pharmacological effect, the way we've always dealt with cosmetics, anything that changes biology or function
of the skin is considered drug and not in our purview and should not occur as a result of a cosmetic that's in our discussion, I
believe.
Dr. David Cohen

Yes. So you know we, we should have something, you know it must not have a depigmenting effect.
Dr. Don Belsito

I think that's discussion is.
Dr. David Cohen

Right. Yeah, yeah.
Dr. Wilma Bergfeld

I think it is too.
Dr. David Cohen

Yeah, it is. Can I throwback to our group for their thoughts on it?
Dr. Wilma Bergfeld

OK.
Dr. David Cohen

After this discussion.
Dr. Wilma Bergfeld

What? What can you specifically ask them? What you want them to respond to?
Dr. Don Belsito

Well, my conclusion as safe as used when formulated to be non-irritating was the conclusion.
Dr. David Cohen

Ron.
Dr. Ron Shank

I saw Nothing in the database to suggest it's a sensitizer. All of the work presented yesterday.
I am sensitive to the fact that the HRIPT test was it at only 2% and it's used at 5% maximum, so I left it up to a battle between
the dermatologists. If I have to, I hate to split myself in half. For a long time, we have asked for a sensitization data at the
maximum concentration used in cosmetics. But this one particular time, we have now a lot of in vivo, in chemico, in silico
data. New kinds of risk assessment, processes that seemed to strongly support that it is not going to be a sensitizer.
Dr. David Cohen

Dr. Thomas Slaga. Dr. Ron Shank
So who do I support? We have one more dermatologist. On the Panel. Yeah. Maybe we could get that dermatologist to
comment.
Dr. Wilma Bergfeld

Are you talking about?
Dr. David Cohen

What? This is not, by the way, I'm not suggesting that I won't support Don’s motion. I just wanted to have a little bit more of a
discussion about it and discussed the concerns about the clinical bridge. So, Ron, you're not in an irreconcilable place right
now. And I don't want you to think that we're splitting the baby here, that there were not.
Dr. Ron Shank

OK.
Dr. Thomas Slaga -

Is there a way to get around or the 5% in the discussion to why we're not considering that, is there a way that we can?
Dr. Don Belsito

Because the in vitro.
Dr. Thomas Slaga -

After thinking over, emphasize why we're saying that 2% is okay and that the 5% is, you know we can deal with it.
Dr. Don Belsito

Well, the presentation demonstrated three out of three tests. You know that if you look at the AOP, you know the three aspects
of the AOP, protein binding, keratinocyte activation, dendritic cell activation, there are no signals there at all. I think we can
use that in vitro data to support our conclusion.
Dr. Paul Snyder

It's not just also the in vitro data. We have no clinical case reports and so there's nothing to support it. So as much as I enjoyed
hearing Ron Squirm, I wish you would let it go on just a little bit longer.
Dr. Don Belsito

Right.
Dr. Thomas Slaga -

Yeah.
Dr. Paul Snyder

I think we're, I think we're applying what Don educated us with yesterday that it doesn't meet. There's two out of those three
categories that it doesn't mean. And so even though we don't have maximum concentrations like that's why our team was OK
with the 2%.
Dr. Don Belsito

Don, you have your hand up.
Dr. Thomas Slaga -

Yeah, let's make sure that's emphasized in a discussion.
Dr. Don Belsito

Yeah.
Dr. Donald Bjerke

Yeah. So, one additional point or a couple of additional points. So, one is you know think about if we had a local lymph node
assay that was negative in all likelihood, we probably wouldn't follow that up with an additional HRIPT. So, if you go back to
that validation table and look at the predictive nature of the of those defined approaches that are just as good as having a local
lymph node assay.
Donald Bjerke (P&G)

So that that may be one other way of looking at it. And then it also like to reinforce what doctor Belsito just said and that is if
you look at the DPR A, you know, 1% depletion basically means no depletion. And if you look at the keratocytes and you look
at the maximum doses that were tested, did not have any signal whatsoever. So, this one is as clean as we can get.
Dr. Wilma Bergfeld

I think that this description of all these new tests would go in a paragraph into the document and then be referred to in the
discussion as you explain this. I, as a dermatologist, I am responding to the dose per unit because in all the patch testing that
we've done, we've not considered that we've taken at face value the concentration. And that would make us rethink in the future
all the patch testing in the actual dosing and risk assessment.
Dr. Don Belsito

Well, Wilma, actually, if you apply the correct amount to the patch test, that's how they calculate those per unit area. If you're
applying the correct amount that you're supposed to be applying, then you we are consistently coming with a dose per unit area
that should be approximately the same. It's not, I don't think anyone is it.
Dr. Wilma Bergfeld

Yeah.
Dr. Don Belsito

You know the pet. allergens a little bit more different, difficult than they liquid allergens, which you can pipette out 25 mics,
but I think we're pretty consistent with patch testing except when we increase or decrease the concentration, the allergen. Then
of course we're changing those per unit area. So, I think patch testing, we've never talked about those per unit area. With each
test we get a spring in there.
Dr. Wilma Bergfeld

Never. Never.
Dr. David Cohen

Well, Don, it came up when the true test was being developed that it was a consistent dose per unit area in the commercial true
test platform, but you're right. Our chambers are of limited size and that you know the amount going on is reasonably
consistent.
Dr. Wilma Bergfeld

Alright.
Dr. David Cohen

So. We could add and I also picked up on the irritant signals there so. I'll second the Motion.
Dr. Wilma Bergfeld

I think with that Don, do have a question or comment to make again?
Donald Bjerke (P&G)

Yeah, just a quick comment. So, one thing we also have to recognize is that those patch studies typically exaggerate the dose
because of the semi occlusive or occlusive nature of the patch.
Donald Bjerke (P&G)

So that should be considered as well. And the other thing as far as dose per unit area, if you look at how we assessed the
preservatives, that's all based on dose per unit area when we do the quantitative risk assessment for preservatives.
Dr. David Cohen

But.
Donald Bjerke (P&G)

So we have actually been using that approach.
Dr. David Cohen

Well, the patch test is intended to exaggerate, right? Because number one, it's a small area of application. It's on the back,
whereas we're plying these products on the face and eyelids. It's, it's meant to uncloak those that may respond because they're
also not putting it on 300 times a year on the back, like someone putting it on their face. So, it's a balancing act for sure.
Dr. Wilma Bergfeld

OK, well, I'm going to close this discussion. Then we have a Motion. It's been seconded. I'm going to call the question all those
who oppose? Abstain? We have unanimous approval unless there's another comment. Yeah. Anything? Yeah. OK.
Priya Cherian (CIR)

I'm OK, but are we bringing in any specific discussion material?
Dr. Wilma Bergfeld

Don.
Priya Cherian (CIR)

About the enter data.
Dr. Don Belsito

Well, I think that. Yeah, you should have pretty much captured it that we're going to discuss the fact that although we don't
have an HRIPT at concentration of use or there are no signals either in the in vitro studies or, in the literature? and that in the hi
ET there was some evidence of irritation. And bring the induction phase, and therefore we feel that, you know, that could be a
concern in formulators need to be aware of that. Otherwise the data is really very clear. I mean the usual respiratory boilerplate.
Priya Cherian (CIR)

OK, got it.
Dr. Wilma Bergfeld

K.
Safety Assessment of Glucosamine Ingredients

as Used in Cosmetics
Status: Final Report for Panel Review

Release Date: May 23, 2022
Panel Meeting Date: June 16 – 17, 2022
The Expert Panel for Cosmetic Ingredient Safety members are: Chair, Wilma F. Bergfeld, M.D., F.A.C.P.; Donald V. Belsito,
M.D.; David E. Cohen, M.D.; Curtis D. Klaassen, Ph.D.; Daniel C. Liebler, Ph.D.; Allan E. Rettie, Ph.D.; David Ross, Ph.D.;
Ronald C. Shank, Ph.D.; Thomas J. Slaga, Ph.D.; Paul W. Snyder, D.V.M., Ph.D.; and Susan C. Tilton, Ph.D. Previous Panel
member involved in this assessment: Lisa A. Peterson, Ph.D. The Cosmetic Ingredient Review (CIR) Executive Director is
Bart Heldreth, Ph.D. This safety assessment was prepared by Priya Cherian, Senior Scientific Analyst/Writer.
© Cosmetic Ingredient Review

1620 L Street, NW, Suite 1200 ♢ Washington, DC 20036-4702 ♢ ph 202.331.0651 ♢ fax 202.331.0088 ♢
[email protected]
ABBREVIATIONS
AUCss area under the curve; extent of exposure
BAL bronchoalveolar lavage
BCOP bovine corneal opacity and permeability
BUN blood urea nitrogen
Cmax peak serum concentration
Css peak concentration
CAS Chemical Abstracts Service
CI confidence interval
CIR Cosmetic Ingredient Review
Council Personal Care Products Council
CPSC Consumer Product Safety Commission
DART Developmental and Reproductive Toxicity
Dictionary International Cosmetic Ingredient Dictionary and Handbook
DNFB dinitrofluorobenzene
DPRA Direct Peptide Reactivity Assay
ECHA European Chemicals Agency
ET50 Effective time causing 50% reduction in tissue viability
FDA Food and Drug Administration
FITC fluorescein isothiocyanate
FW formula weight
GFR glomerular filtration rate
h-CLAT human cell line activation test
HPLC high performance liquid chromatography
HR hazard ratio
HRIPT human repeated insult patch test
IC50 half maximal inhibitory concentration
IgE immunoglobulin E
IGF-1 insulin-like growth factor 1
IL interleukin
Kow n-octanol/water partition coefficient
LC-MS/MS liquid chromatography-tandem mass spectrometry
LD50 median lethal dose
ME microemulsion
MnNCE micronucleated normochromatic erythrocytes
MnPCE micronucleated polychromatic erythrocytes
MoS margin of safety
MW molecular weight
MTT 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide
NCE normochromatic erythrocytes
NOAEL no-observable-adverse-effect-level
NR not reported
OECD Organisation for Economic Cooperation and Development
OVA ovalbumin
Panel Expert Panel for Cosmetic Ingredient Safety
PCE polychromatic erythrocytes
PBS phosphate-buffered saline
SBP systolic blood pressure
SHR spontaneously hypertensive rats
SLS sodium lauryl sulfate
SIAscopyTM noncontact spectrophotometric intracutaneous analysis
SIDS screening information dataset
SPF sun protection factor
T1/2 elimination half life
TG test guidelines
THP-1 human monocytic cell line
Tmax time to reach serum concentration
US United States
UV ultraviolet
VCRP Voluntary Cosmetic Registration Program
ABSTRACT
The Expert Panel for Cosmetic Ingredient Safety (Panel) assessed the safety of Acetyl Glucosamine, Glucosamine,
Glucosamine HCl, and Glucosamine Sulfate. Two of the ingredients, Acetyl Glucosamine and Glucosamine Sulfate, are
reported to function in cosmetics as skin-conditioning agents, Glucosamine HCl is reported to function as a pH adjustor, and
the function of Glucosamine in cosmetics is not reported. The Panel reviewed the available data and concluded that these
glucosamine ingredients are safe in cosmetics in the present practices of use and concentration described in this safety
assessment when formulated to be non-irritating.
INTRODUCTION
This assessment reviews the safety of the following 4 ingredients as used in cosmetic formulations:
Acetyl Glucosamine Glucosamine HCl
Glucosamine Glucosamine Sulfate
According to the web-based International Cosmetic Ingredient Dictionary and Handbook (wINCI; Dictionary), Acetyl
Glucosamine and Glucosamine Sulfate are reported to function in cosmetics as skin-conditioning agents – miscellaneous,
Glucosamine HCl is reported to function as a pH adjuster, and the function of Glucosamine is not reported (Table 1).1 These
glucosamine ingredients are being reviewed together due to structural similarities, sharing an aminomonosaccharide core
group in common.
This safety assessment includes relevant published and unpublished data that are available for each endpoint that is
evaluated. Published data are identified by conducting an exhaustive search of the world’s literature. A listing of the search
engines and websites that are used and the sources that are typically explored, as well as the endpoints that the Panel typically
evaluates, is provided on the Cosmetic Ingredient Review (CIR) website (https://www.cir-
safety.org/supplementaldoc/preliminary-search-engines-and-websites; https://www.cir-safety.org/supplementaldoc/cir-report-
format-outline).
Some of the data included in this safety assessment were found on the European Chemicals Agency (ECHA) website.2,3
Please note that the ECHA website provides summaries of information generated by industry, and it is those summary data
that are reported in this safety assessment when ECHA is cited. Some types of data were found but not included, as no
relevance to cosmetic use could be surmised (e.g., studies on the efficacy of Glucosamine for the treatment of arthritis).
CHEMISTRY
Definition and Structure
The definitions and structures of the ingredients included in this review are provided in Table 1. All of these ingredients
share the ubiquitous aminomonosaccharide, Glucosamine (CAS No. 3416-24-8; Figure 1), as the core structure. Structurally,
Glucosamine is modified glucose with an amine group replacing the hydroxyl group found on carbon two (C2).4
Glucosamine and its salt forms, i.e., Glucosamine HCl (CAS No. 66-84-2) and Glucosamine Sulfate (CAS No. 29031-19-4),
are metabolized to Acetyl Glucosamine (CAS Nos. 10036-64-3, 72-87-7, 7512-17-6) via the hexosamine pathway.5
Figure 1. Glucosamine
Chemical Properties
Glucosamine HCl (formula weight (FW) = 215.63 g/mol; log Kow = -1.91) and Glucosamine Sulfate (FW = 277.25
g/mol) are charged, highly polar, and water-soluble salts.5 The acetylated glucosamine metabolite, Acetyl Glucosamine (MW
= 222.21 g/mol; log Kow = -2.2), is less polar and neutral. Available information on the chemical properties of the
glucosamine ingredients is presented in Table 2.
Method of Manufacture
The methods described below are general to the processing of commercial forms of glucosamine ingredients. It is
unknown if they apply to cosmetic ingredient manufacturing.
Acetyl Glucosamine
Acetyl Glucosamine may be prepared using chitin as a substrate via chemical, enzymatic, and biotransformation
methods.6 Chemical production of Acetyl Glucosamine involves the chemical degradation or dissolving of chitin with a
strong acid, such as hydrochloric acid. Another method of chemical production of Acetyl Glucosamine involves the
acetylation of Glucosamine using pyridine as a solvent, in the presence of tributylamine and acetic anhydride. In addition,
enzymatic hydrolysis may be performed to produce Acetyl Glucosamine. Several of these enzymes include derivatives of
Trichoderma viride, Aspergillus niger, Carica papaya L., and Aeronomium. Examples of substances that degrade chitin
include cellulose, lysozyme, papain, and lipase. Production of Acetyl Glucosamine via biotransformation involves the
degradation of chitin using whole microbes (e.g., Aeromonas caviae, Chitinibacter tainanensis). Genetically modified
microorganisms (e.g., Escherichia coli) may also be used to produce Acetyl Glucosamine, using glucose as a substrate.
Glucosamine, Glucosamine HCl, and Glucosamine Sulfate
Commercial forms of Glucosamine are prepared mainly from the hydrolysis of chitin, which is the main component of
shells from crustaceans (crab, lobster, and shrimp).7 The produced Glucosamine can then be transformed into Glucosamine
Sulfate or Glucosamine HCl. Glucosamine Sulfate is typically stabilized by co-crystallization or co-precipitation with
sodium chloride. Commercial forms of Glucosamine can also be prepared from the hydrolysis of chitin with Aspergillus
niger biomass.8 In order to derive Glucosamine HCl, the hydrolysate is acidulated with hydrochloric acid for several hours at
100 °C. The product is then filtered to remove solid impurities. Crystals are separated and purified by centrifugation and
washing with water.
Impurities
Acetyl Glucosamine
Impurities following chemical and enzymatic synthesis of β-N-Acetyl Glucosamine were evaluated via high resolution
mass spectrometry, nuclear magnetic resonance spectroscopy, and liquid chromatograph-tandem mass spectrometry.9 The
impurities α-N,6-diacetylglucosamine and α-N-acetylglucosamine were observed to be present. β-N-Acetyl Glucosamine
prepared via chemical and enzymatic methods contained a concentration of 146 ± 0.15 and 10.90 ± 0.02 µg/kg α-N,6-
diacetylglucosamine, respectively. Quantification of α-N-acetylglucosamine was not performed, as the recovery value was
too low.
Glucosamine HCl
The United States Pharmacopeia states that Glucosamine HCl must have a minimum of 98% purity and contain ≤ 3
ppm arsenic and ≤ 0.001 % heavy metals.10 These purity specifications also pertain to Glucosamine HCl derived from
Aspergillus niger.8
Natural Occurrence
Glucosamine is a monosaccharide that is synthesized from glucose by the hexosamine biosynthetic pathway in nearly
all types of human body cells.11 This natural compound is a constituent of mucosal secretions, skin, tendons, ligaments, and
cartilage.7 In mammals, Acetyl Glucosamine may be found as a component of glycoproteins, proteoglycans,
glycosaminoglycans, and other connective tissue building blocks.6 Acetyl Glucosamine may also be found in human milk at
levels of 600 - 1500 mg/ml. Acetyl Glucosamine is the monomeric unit of chitin, which is found in arachnids, most fungal
cell walls, insect exoskeletons, the shells of crustaceans, and parts of invertebrates. It may also be present as an extracellular
polymer of some microbes.
USE
Cosmetic
The safety of the cosmetic ingredients addressed in this assessment is evaluated based on data received from the US
Food and Drug Administration (FDA) and the cosmetics industry on the expected use of these ingredients in cosmetics, and
does not cover their use in airbrush delivery systems. Data are submitted by the cosmetic industry via the FDA’s Voluntary
Cosmetic Registration Program (VCRP) database (frequency of use) and in response to a survey conducted by the Personal
Care Products Council (Council) (maximum use concentrations). The data are provided by cosmetic product categories,
based on 21CFR Part 720. For most cosmetic product categories, 21CFR Part 720 does not indicate type of application and,
therefore, airbrush application is not considered. Airbrush delivery systems are within the purview of the US Consumer
Product Safety Commission (CPSC), while ingredients, as used in airbrush delivery systems, are within the jurisdiction of the
FDA. Airbrush delivery system use for cosmetic application has not been evaluated by the CPSC, nor has the use of
cosmetic ingredients in airbrush technology been evaluated by the FDA. Moreover, no consumer habits and practices data or
particle size data are publicly available to evaluate the exposure associated with this use type, thereby preempting the ability
to evaluate risk or safety. Therefore, airbrush application of cosmetic products is not assessed by the Panel.
According to 2022 VCRP survey data, Acetyl Glucosamine is reported to be used in 198 formulations (185 leave-on
formulations and 13 rinse-off formulations; Table 3), and Glucosamine HCl is reported to be used in 77 formulations (64
leave-on formulations and 13 rinse-off formulations).12 Glucosamine is reported to be used in 2 leave-on formulations. The
results of the concentration of use survey reported by the Council in 2020 indicate Acetyl Glucosamine also has the highest
concentration of use in a leave-on formulation; it is used at up to 5% in face and neck products (not spray).13 Glucosamine
Sulfate is not reported to be in use according to 2022 VCRP and 2020 concentration of use data, as indicated in Table 4.
Incidental ingestion of Acetyl Glucosamine may occur, as it is used in lipstick formulations at concentrations up to 2%.
In addition, Acetyl Glucosamine and Glucosamine HCl are used in formulations applied near the eye; for example, Acetyl
Glucosamine is reported to be used at concentrations up to 2% in eye lotions.
Some of these glucosamine ingredients are used in formulations that could possibly be inhaled. For example, Acetyl
Glucosamine is reported to be used at 0.1% in pump hair sprays and at up to 0.07% in face powders. In practice, as stated in
the Panel’s respiratory exposure resource document (https://www.cir-safety.org/cir-findings), most droplets/particles
incidentally inhaled from cosmetic sprays would be deposited in the nasopharyngeal and tracheobronchial regions and would
not be respirable (i.e., they would not enter the lungs) to any appreciable amount. Conservative estimates of inhalation
exposures to respirable particles during the use of loose powder cosmetic products are 400-fold to 1000-fold less than
protective regulatory and guidance limits for inert airborne respirable particles in the workplace.
Additionally, although products containing some of these ingredients may be marketed for use with airbrush delivery
systems, this information is not available from the VCRP or the Council survey. Without information regarding the
frequency and concentrations of use of these ingredients (and without consumer habits and practices data or particle size data
related to this use technology), the data are insufficient to evaluate the exposure resulting from cosmetics applied via airbrush
delivery systems.
All of the glucosamine ingredients named in the report are not restricted from use in any way under the rules governing
cosmetic products in the European Union.14
Non-Cosmetic
In the US, Glucosamine (up to 1500 mg/d) and its metabolites are not classified as drugs, but as dietary supplements,
under the US FDA Dietary Supplement Health and Education Act of 1994.5,15 Acetyl Glucosamine and Glucosamine salts
(Glucosamine Sulfate and Glucosamine HCl) are commercially available as dietary supplements, and are commonly
administered in conjunction with chondroitin sulfate. According to 21 CFR 216.23, N-acetyl-D-glucosamine [Acetyl
Glucosamine] is a bulk drug substance that may be used to compound topical drug products, in accordance with section 502A
of the Federal Food, Drug, and Cosmetic Act.
In most European countries, Glucosamine is marketed as both a medicinal product and a food supplement.7 In France,
Glucosamine (in the form of the sulfate or HCl salt) is used in orally-ingested medicinal products as the only active
ingredient (up to 1250 mg/d). In veterinary medicine, Glucosamine HCl is commonly used for treating osteoarthritis in
dogs.16
TOXICOKINETIC STUDIES
Dermal Penetration
In Vitro
Acetyl Glucosamine
The skin penetration of 14C-N-Acetyl-D-Glucosamine was evaluated in split-thickness Caucasian cadaver skin.17 The
skin was cut and mounted in standard Franz-type diffusion cells (exposed skin surface area of 0.79 cm2) maintained at 34 °C.
The receptors were filled with phosphate-buffered saline (PBS) incorporating 1% polysorbate-20 and 0.02% sodium azide,
and skin was allowed to equilibrate for 2 h. Aliquots of the test formulations were spiked with 14C-niacinamide and assayed
for total radiolabel in triplicate. Approximately 5 µl of the test formulations (2% Acetyl Glucosamine alone in an unknown
vehicle, or a combination of 4% niacinamide and 2% Acetyl Glucosamine with an unknown vehicle) was applied to the cells
using a positive displacement pipette (n = 8). The receptor solution was collected and replaced at 2, 4, and 6 h (termination)
of study. Solutions were assayed for total radiolabel via liquid scintillation. Approximately 7% of the applied dose
permeated the skin when the test substance containing Acetyl Glucosamine alone was applied. Approximately 6.5% of the
applied dose permeated the skin when the test substance containing both Acetyl Glucosamine and niacinamide was applied.
The test substances were found to readily penetrate into and through human skin.
Glucosamine HCl
Using a saturated aqueous solution of Glucosamine HCl, in vitro permeation studies were performed on human
epidermal membranes prepared by a heat separation method and mounted in Franz-type diffusion cells with a diffusional area
of 2.15 ± 0.1 cm2.18 Studies were performed over a 48 h period by loading donor compartments with 2 ml of the
Glucosamine HCl solution of each diffusion cell (n = 5), and evaluating receptor solutions for permeation. Glucosamine HCl
permeated through the skin with a flux of 1.497 ± 0.42 µg cm2/h, a permeability coefficient of 5.66 ± 1.6 x 10-6 cm/h, and a
lag time of 10.9 ± 4.6 h.
The transdermal penetration of 5% Glucosamine HCl in different vehicles (aqueous, oil-in-water cream, liposomal
suspension, liposomal gel, cubic liquid crystalline bulk phase) was evaluated in the dorsal skin of Sprague-Dawley rats
mounted in Franz diffusion cells (diffusional surface area of 2.14 cm3).19 Epidermal sides of the skin were exposed to the
various formulations of Glucosamine HCl (100 mg). Aliquots (0.5 ml) were withdrawn from the receptor compartment over
a period of 12 h and evaluated for Glucosamine HCl via high-performance-liquid-chromatography (HPLC). The steady state
flux of the drug through the skin for the aqueous solution, cream, liposomal suspension, liposomal gel, and cubic phase was
calculated to be 56.89 ± 23.76, 58.24 ± 29.46, 57.61 ± 26.72, 57.27 ± 4.35, and 248.89 ± 64.57 µg/h/cm2, respectively.
According to study authors, the reason for the enhanced permeation of Glucosamine HCl caused by the cubic phase was
likely due to the structural similarity between the cubic phase and biomembrane.
Glucosamine Sulfate
Skin permeation of Glucosamine Sulfate was evaluated in Sprague-Dawley full-thickness rat skin.20 Freshly excised rat
skin was mounted between the donor and receptor cell (area of diffusion was 2.14 cm2). Donor cells, facing the stratum
corneum surface, contained 5% Glucosamine Sulfate aqueous solution (3 ml). Receptor cells, which faced the dermis side,
were filled with normal saline solution (12 ml). At predetermined time intervals, 0.5 mL of the receptor solution was
withdrawn and refilled with the same volume of fresh receptor solution. Samples were analyzed by HPLC. The skin
permeation rate (amount recovered in receptor fluid) was determined to be 13.27 µg/cm2/h.
Human
Glucosamine Sulfate
The penetration of a 10% Glucosamine Sulfate cream into the synovial fluid of patients with knee osteoarthritis (134
subjects/group) was evalauted.21 For treated groups, cream (2 g) was placed on the knee, for 1-3 h, followed by synovial
fluid collection. A control group was not subjected to any treatment, but their synovial fluid was collected. Synovial fluid
from both treated and control groups was evaluated for Glucosamine concentrations via HPLC. The mean Glucosamine
concentrations in treated and control patients were 100.56 ng/ml and 17.83 ng/ml, respectively (p < 0.0001).
Absorption, Distribution, Metabolism, and Excretion (ADME)
Animal
Oral
Glucosamine HCl
A pharmacokinetic analysis was performed via liquid chromatography-tandem mass spectrometry (LC-MS/MS) in 4
female Beagle dogs.22 Animals were given a single oral dose of a dietary supplement containing 450 mg Glucosamine HCl.
Blood samples from dogs were collected and analyzed 0, 1, 2, 4, 6, 8, 12, and 24 h post-administration. Glucosamine was
detected up to 8 h post-dose, with a time to reach serum concentration (Tmax) of 2 h and a peak serum concentration (Cmax) of
9.69 µg/ml. The elimination half-life (t1/2) of Glucosamine after administration of the test substance was approximately 35
min.
Glucosamine HCl and Glucosamine Sulfate
Blood levels, tissue distribution, and excretion patterns of radioactivity were studied in Sprague-Dawley rats (44 rats/
sex) after oral administration of [14C]Glucosamine HCl diluted with unlabeled Glucosamine Sulfate (dose not reported).23
Plasma, urine, feces, blood, and organs/tissues were evaluated for radiolabel concentrations. At 1 - 2 h after administration,
Glucosamine radioactivity was bound to or incorporated into plasma proteins. After peaking at 2 - 4 h, radioactivity declined
from plasma at a slower rate (t1/2 = 46 h). Approximately half of the radioactivity was excreted as [14C]carbon dioxide, and
40% of the radioactivity was excreted in the urine. Only 2% of the administered dose was excreted in feces. Radioactivity
analysis in tissues and organs revealed that the [14C] from the labeled Glucosamine quickly entered into all tissues, included
cartilage, reaching a maximum at 8 h.
Human
Oral
Glucosamine HCl
Glucosamine HCl bioavailability from two different orally-administered formulations was evaluated in healthy adult
males (9/group) under fasting conditions.24 A single dose of Glucosamine HCl was administered to the volunteers via a
dispersible tablet (240 mg Glucosamine HCl/tablet) or capsule (240 mg Glucosamine HCl/capsule). Subjects received either
2 Glucosamine HCl tablets or capsules with 250 ml water. Blood samples were collected before test substance
administration, and at various intervals up to 12 h after administration. Plasma Glucosamine concentration was evaluated via
the LC-MS/MS method. The mean Cmax, Tmax, and T1/2 values were reported to be 907.1 ng/ml, 3.03 h, and 1.10 h,
respectively, for the dispersible tablet formulation. For the capsule formulation, mean Cmax, Tmax, and T1/2 values were
reported to be 944.40 ng/ml, 3.30 h, and 1.50 h, respectively.
Glucosamine HCl and Glucosamine Sulfate
The pharmacokinetics of Glucosamine after oral administration of crystalline Glucosamine Sulfate and Glucosamine
HCl were evaluated in 12 healthy volunteers (5 male and 7 female).25 Volunteers received once-daily, oral administrations of
crystalline Glucosamine Sulfate soluble powder at a dose of 1500 mg, or Glucosamine HCl capsules at a dose of 500 mg, for
3 consecutive days, alone, or in combination with chondroitin sulfate (400 mg). Glucosamine was determined at steady state
in plasma collected up to 48 h after the last dose by a validated LC-MS/MS method. After Glucosamine Sulfate
administration, peak concentrations (Css, max) and extent of exposure (AUCss) averaged 9.1 ± 6.3 µM and 76.5 ± 23.0 µM/h,
respectively. Significantly lower plasma concentrations (p ≤ 0.005) were determined after the administration of Glucosamine
HCl alone (Css, max and AUCss averaged 4.5 ± 1.8 µM and 21.4 ± 7.6 µM/h, respectively), or in combination with chondroitin
sulfate (Css, max and AUCss averaged 3.3 ± 1.0 µM and 13.8 ± 5.4 µM/h, respectively).
TOXICOLOGICAL STUDIES
Acute Toxicity Studies
Oral
Details regarding the acute oral toxicity studies summarized below can be found in Table 5.
The reported median lethal dose (LD50) values for Glucosamine were higher than the doses tested ( > 15,000 mg/kg in
mice and > 8000 mg/kg in rats and rabbits).26 According to an ECHA dossier, the acute oral LD50 for Glucosamine HCl was
reported to be 15,000 mg/kg bw in mice.2
Short-Term Toxicity Studies
Oral
Glucosamine HCl
The effect of oral Glucosamine was evaluated in male Sprague-Dawley and male spontaneously hypertensive rats
(SHR; 8 rats/strain/group).27 Four groups of both rat strains received either no treatment (control), Glucosamine (0.5%),
chondroitin sulfate (0.4%), or a combination of both, for 9 wk, via diet. A concentration of 0.5% or 0.4% of Glucosamine
and chondroitin sulfate roughly calculates to 1500 and 1200 mg/d, respectively. Systolic blood pressure (SBP) and body
weight were evaluated weekly. Hematological and histological evaluations were performed. No statistically significant
differences in body weight were observed in any of the four dietary groups. SBP of both strains consuming the two
ingredients alone and in combination was statistically significantly lower than the SBP in control animals. No statistically
significant histological differences were found in the hearts, kidneys, or livers among the treated and control groups. In
Sprague-Dawley rats, there were no relevant trends in blood chemistries among the four groups, however BUN levels were
significantly lower (p < 0.03) in the control group compared to the other three groups. In SHR, no hematological differences
between groups were observed.
Subchronic Toxicity Studies
Animal
Oral
Acetyl Glucosamine
Acetyl Glucosamine was fed to F344 rats (10 rats/sex/group) via pelleted diets containing 0, 0.625, 1.25, 2.5 or 5%
Acetyl Glucosamine for 13 wk.28 Clinical signs, food intake, hematology, serum biochemistry, and histopathology were
evaluated in all animals. All animals survived until the end of the experiment. A slight, non-significant increase in body
weights was observed in males receiving 0.625, 1.25, and 2.5% Acetyl Glucosamine from wk 4 until the end of the
experiment. Statistically significant elevation of weight gain was observed in males receiving 0.625, 1.25 and 2.5% Acetyl
Glucosamine at the terminal sacrifice, which resulted in decreased relative weights in many organs. However, no obvious
indications of toxicity were observed in any of the parameters evaluated. The no-observed-adverse-effect-level (NOAEL)
was determined to be > 5%.
Human
Oral
Acetyl Glucosamine
The effect of orally ingested Acetyl Glucosamine was evaluated in healthy adult humans.29 Safety assessments were
performed via physical parameters, hematology, blood biochemistry, and urinalysis. The test supplement contained green tea
extract powder and either 500 (n = 22) or 1000 (n = 22) mg of Acetyl Glucosamine. The placebo supplement contained
green tea extract powder without Acetyl Glucosamine (n = 24). All subjects were instructed to take the supplements,
dissolved in a cup of water, once a day for 16 wk. A total of 66 adverse events occurred in 12, 10, and 9 subjects receiving
placebo, 500 mg/d Acetyl Glucosamine, and 1000 mg/d Acetyl Glucosamine, respectively, and there was no significant
difference in the frequency among the 3 groups. Relatively frequent adverse symptoms included cold symptoms, gastric
distress, and pain. These effects were generally mild. Routine physical and cardiovascular characteristics, hematology, and
blood chemistry, did not show any significant abnormalities in all three groups.
Glucosamine HCl
A 16-wk, randomized, double-blind, placebo-controlled crossover trial of a combination of Glucosamine HCl (1500
mg/d), chondroitin sulfate (1200 mg/d), and manganese ascorbate (228 mg/d) was conducted in degenerative joint disease
patients.30 Thirty-four male patients were randomized and given either the test substance (a tablet containing a combination
of Glucosamine HCl, chondroitin sulfate, and manganese ascorbate), or a placebo for 8 wk. For an additional 8-wk period,
the patients crossed over to the regimen not followed previously. Patients were asked to complete a survey of symptoms
consistent with toxicity and to return cards for fecal occult blood testing at the end of each protocol phase. No patients
reported symptoms requiring termination of study, and symptom frequency on medication was similar to that at baseline.
Vital signs, occult blood testing, and hematologic parameters were similar among the placebo and medicated groups.
Chronic Toxicity Studies
Oral
Acetyl Glucosamine
The chronic toxicity potential of Acetyl Glucosamine was evaluated in F344 rats (10 rats/sex/group).31 Acetyl
Glucosamine was administered via the diet at levels of 0, 1.25, 2.5 or 5%, for 52 wk. Clinical effects, mortality, hematology,
serum biochemistry, and histopathology were evaluated. After gross examination, the brain, heart, lungs, liver, spleen,
adrenals, kidneys, and testes were weighed. No toxic effects were observed in any parameter evaluated; however, slight
suppression of body weight gain was observed in animals dosed with 5%. This effect appeared to be due to a slight reduction
of caloric intake with the high concentration of test compound.
DEVELOPMENTAL AND REPRODUCTIVE TOXICITY STUDIES

Oral
Glucosamine
The effects of premating Glucosamine supplementation via drinking water on Sprague-Dawley rat litter homogeneity,
uterine receptivity, and maternal hormones levels, were evaluated.32 Female rats (29 animals/group) were given either
normal drinking water, or drinking water supplemented with 0.5 mM Glucosamine, from 6 to 8 wk old. After a 2-wk
administration, the rats were mated. Ovaries, uteri, implantation sites, pup birth weight, maternal placental efficiency, and
plasma of dams were evaluated. Variation of within-litter birth weight in the Glucosamine-treated group was 5.55%, a
significantly lower variation than that of the control group (8.17%). Birth weights and absolute and relative ovary weights
were statistically significantly greater in the Glucosamine-treated group compared to the control group (p < 0.05). In the
Glucosamine-treated group, there were more successfully implanted blastocysts (13.38 ± 0.63 and 15.75 ± 0.59 in the control
and treated group, respectively), with more uniform distribution along the two uterine horns compared with the control group.
Maternal progesterone, estradiol, and insulin-like growth factor 1 (IGF-1) concentrations on day 19.5 of pregnancy were
significantly increased in treated rats, while insulin and total cholesterol levels were significantly decreased compared with
control rats.
Intraperitoneal
Glucosamine
The effects of pre-conception Glucosamine administration on reproductive outcomes was evaluated in 8-wk-old and 16-
wk-old adult female C57B1/6 mice (24 mice/group).33 Animals were given either 0, 20 mg/kg Glucosamine per day (in
phosphate-buffered saline (PBS))), via intraperitoneal injection, for 3 d. Mice that received no Glucosamine treatment during
the feeding period received injections of PBS only. On day 3, females were mated with a male, and mating success was
determined. On day 4, animals were once again treated with Glucosamine (same dose as previously given). For
successfully-mated females, this was the final injection; females that did not mate were re-introduced to males and given
daily injections until mating was successful (for a maximum of 4 nights). On day 18 of gestation, animals were killed,
examined, and all fetal parameters were assessed. The total number of implantations (p < 0.0001) and viable fetuses (p <
0.0001) was lowest in the 8-wk-old, Glucosamine-treated group. The number of implantations and viable fetuses among the
16-wk-old Glucosamine-treated mice and control mice did not differ significantly. Fetal weight was reduced by
Glucosamine treatment in 16-wk-old mice (p < 0.05), whereas the same treatment did not affect 8-wk old mice. Glucosamine
also reduced fetal length in pups derived from 16-wk-old Glucosamine-treated mice (p < 0.05). In addition, a significantly
higher number of abnormal fetuses was present in litters of 16-wk-old Glucosamine-treated mice, compared with all other
groups (p < 0.05).
Intrauterine
Glucosamine
The effects of intrauterine Glucosamine were evaluated in female ICR mice (3 mice/group).34 A hysterectomy of one
uterine horn was performed according to standard surgical procedures. A 60-d sustained-release Glucosamine pellet (15,
150, or 1500 µg) or placebo pellet was implanted into the top of the remaining uterine horn. Females recovered
independently for 10 d, and then mated with ICR male mice. The number of pups/litter was recorded until two litters after
the 60-d pellet release period. After hysterectomy and implantation of placebo pellets, litters were approximately half the
size that they were before surgery (5.6 and 12.7 pups/litter, respectively). Mice that received Glucosamine pellets delivered
significantly fewer live pups/litter over a 60-d pellet active period than those that received placebo pellets (15 µg
Glucosamine, 2.75 ± 0.73 pups/litter; 150 µg Glucosamine, 2.13 ± 0.85 pups/litter; 1500 µg Glucosamine, 0.25 ± 0.25
pups/litter; placebo, 5.61 ± 0.66 pups). The gross morphological appearance of the pups from placebo and Glucosamine-
treated mice were normal post-birth. Serum glucosamine levels were similar among placebo and treated groups. After the
60-d pellet release period, there was no statistically significant difference in litter sizes delivered by Glucosamine-treated and
placebo-treated mice, except at the highest dose level.
GENOTOXICITY STUDIES
In Vitro
Acetyl Glucosamine
An Ames assay was performed according to Organization for Economic Co-Operation and Development test guideline
(OECD TG) 471.3 Salmonella typhimurium strains TA 1537, TA 1535, TA 98, TA 100, and TA 102 were exposed to Acetyl
Glucosamine at concentrations of 156.25, 312.5, 625, 1250, 2500, and 5000 µg/plate, with and without metabolic activation.
Plates were maintained in triplicate, and the number of revertant colonies were recorded after the 48-h incubation period.
The test substance was non-mutagenic to any strain of S. typhimurium when tested under specified experimental conditions.
Glucosamine HCl
The potential genotoxicity of Glucosamine HCl derived from Aspergillus niger was evaluated in an Ames assay.8 The
tester strains (S. typhimurium TA 98, TA 100, TA 1535, and TA 1537, and E.coli WP2 uvrA) were exposed to Glucosamine
HCl at concentrations of 100, 333, 1000, 3300, and 5000 µg/plate, with and without metabolic activation. The test substance
was considered to be non-mutagenic.
In Vivo
Glucosamine HCl
An in vivo micronucleus assay was performed in accordance with OECD TG 474.8 Mice (number of animals and strain
not reported) were dosed with Aspergillus niger-derived Glucosamine HCl mixed with water, via gavage. The test substance
was administered in doses of 500, 1000, or 2000 mg/kg bw. There was no statistically significant increase in micronucleated
polychromatic erythrocytes (PCE) or decrease in the ratios of polychromatic PCEs and normochromatic erythrocytes (NCE)
at any dose level. The test substance was considered to be non-toxic to bone marrow.
ANTI-GENOTOXICITY STUDIES
In Vitro
Acetyl Glucosamine and Glucosamine
The anti-genotoxic effect of Glucosamine and Acetyl Glucosamine in human peripheral lymphocytes exposed to
oxidative stress was evaluated.35 Lymphocytes were treated with Acetyl Glucosamine or Glucosamine at concentrations of 0,
2.5, 5, 10, 20, or 50 mM. Cells were also treated with 25 µM hydrogen peroxide to induce DNA damage. Control cells were
treated with the vehicle (PBS) and hydrogen peroxide. Cells were analyzed and data were presented as % DNA in tail.
Acetyl Glucosamine only indicated a slight DNA protection at a concentration of 50 mM (p < 0.01). Glucosamine, at all
concentrations, showed a significant protective activity (p < 0.001) against hydrogen peroxide-induced DNA damage.
In Vivo
Glucosamine
The chemoprotective ability of Glucosamine against cisplatin-induced genotoxicity was evaluated in rat bone marrow
cells.36 Male Wistar rats (5/group) were fed diets containing either 75 or 150 mg/kg Glucosamine, for 7 consecutive d. On
the 7th d, 1 h after Glucosamine treatment, a single intraperitoneal dose of cisplatin (5 mg/kg) was administered. Three
control groups were used, a normal control group (oral PBS treatment and injection with saline), a Glucosamine control
group (oral 150 mg/kg Glucosamine treatment and injection of PBS), and a cisplatin control group (oral PBS treatment and
injection of cisplatin). All animals were killed 24-h post-treatment with cisplatin, and rat bone marrow cells were collected.
For each experimental group, a total of 5000 PCE and corresponding NCE were scored to determine the number of
micronucleated polychromatic erythrocytes (MnPCE) and micronucleated normochromatic erythrocytes (MnNCE).
Pretreatment with 75 and 150 mg/kg Glucosamine prior to cisplatin injection significantly reduced the frequency of MnPCE
and MnNCE (p < 0.05). Treatment with Glucosamine also prevented the fall in the PCE/(PCE + NCE) ratio as compared
with the cisplatin control group (p < 0.001). The test substance was considered to be an effective chemoprotector against
cisplatin-induced DNA damage.
CARCINOGENICITY STUDIES
Acetyl Glucosamine
The carcinogenic potential of Acetyl Glucosamine was evaluated in F344 rats (50 rats/sex/group).31 Animals were
given Acetyl Glucosamine in the diet at levels of 0, 2.5, or 5%, for 104 wk. Many tumors were found in males and females
in all groups; however, all tumors observed were well-known to occur spontaneously in F344 rats. No significant intergroup
differences in tumor frequency or histological types were apparent. Additionally, the number of neoplastic lesions observed
in animals was similar among control and treated groups. The test substance was considered to be non-carcinogenic.
ANTI-CARCINOGENICITY STUDIES
In Vitro
Glucosamine
The anti-proliferative potential of Glucosamine in human renal cancer cell lines (786-O and caki-1) was studied via an
3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide (MTT) and annexin V-fluorescein isothiocyanate (FITC)
assay.37 To evaluate cell proliferation, renal cancer cells were treated with either 0, 1, 5, or 10 mM Glucosamine, and
incubated. After incubation, MTT solution was added, cells were again incubated, followed by addition of dimethyl
sulfoxide and the evaluation of optical density. Glucosamine inhibited the proliferation of renal cancer cells in a
concentration-dependent manner (p < 0.05) as compared with the control group. In order to evaluate cell apoptosis, cancer
cells were serum-starved for 24 h, and treated with various concentrations of Glucosamine (0, 1, 5, or 10 mM) for 24 h. Cells
were then collected and washed twice with PBS. Then, cells were re-suspended, stained with FITC-annexin V/PI and
analyzed by flow cytometry. The apoptosis rate of both cell lines was up-regulated by the high concentration of Glucosamine
(10 mM), but down-regulated by low concentrations of Glucosamine (1 and 5 mM), as compared with the control groups.
Acetyl Glucosamine, Glucosamine, and Glucosamine HCl
The growth inhibitory effects of Glucosamine, Glucosamine HCl, and Acetyl Glucosamine on human hematoma
SMMC-721 cells were evaluated in vitro.38 Tumor cells were cultured in a growth medium supplemented with 15% bovine
calf serum, 100 U/ml penicillin, and 100 U/ml streptomycin at 37° C, seeded in 96-well plates, and incubated for 24 h. After
incubation, cells were treated with Glucosamine, Glucosamine HCl, or Acetyl Glucosamine (10 - 1000 µg/ml), and again
incubated for 24 – 120 h. Untreated cells were used as controls. Results measured by an MTT assay showed that
Glucosamine HCl and Glucosamine caused a concentration-dependent reduction in hepatoma cell growth. In addition,
human hepatoma cells treated with Glucosamine HCl resulted in the induction of apoptosis as assayed qualitatively by
agarose gel electrophoresis. Acetyl Glucosamine did not inhibit the proliferation of SMMC-7721 cells.
Animal
Glucosamine HCl
Sarcoma 180 tumor ascites cells were subcutaneously inoculated (0.2 ml/mouse) into 8-wk-old Kunming male mice
(number of animals not stated).38 Mice were divided and given an oral dose of either saline (control group) or Glucosamine
HCl dissolved in saline (125, 250, or 500 mg/kg/d). The method of oral administration was not stated. Administrations
occurred once daily for 10 d. The tumor was allowed to grow on mice for 10 d before it was removed from the animal and
evaluated. The anti-tumor activity of Glucosamine HCl was expressed as an inhibition ratio calculated as [(average tumor
weight of control – average tumor weight of treated group)/average tumor weight of control] x 100%. Glucosamine HCl, at
the intermediate dose (250 mg/kg/d), had the highest inhibition ratio (34.02%) on sarcoma 180 tumor growth. Inhibition
ratios at the 125 and 500 mg/kg/d dose levels were reported to be 27.84 and 29.33%, respectively.
OTHER RELEVANT STUDIES

Effects on Pigmentation
The following studies are included in this report as they may be relevant to concerns regarding depigmentation, skin
whitening, and anti-melanogenesis.
In Vitro
Acetyl Glucosamine
The effect of Acetyl Glucosamine on melanin production was evaluated in an in vitro assay using reconstituted human
tanned epidermis.39 Skin cultures were placed in 6-well tissue culture plates containing 2 ml/well of a growth medium.
Administrations of either Acetyl Glucosamine (1, 3, or 5% in water) or water alone (30 µl) were applied topically, for 10 d.
Culture medium and treatment was replenished daily. Skin equivalent cell cultures treated topically with 1, 3, or 5% Acetyl
Glucosamine produced dose-dependent decreases in melanin content. According to the study authors, Acetyl Glucosamine
can inhibit the enzymatic glycosylation of tyrosinase, resulting in pigmentation effects. In addition, pigmentation effects
following Acetyl Glucosamine exposure may occur due to its effect on the expression of several pigmentation-relevant genes.
The anti-melanogenic effect of an Acetyl Glucosamine-loaded microemulsion was evaluated in B16 melanoma cells.40
The microemulsion contained 1% Acetyl Glucosamine, 9% water, and 10% propylene glycol, 20% palm oil, and 60% of a
surfactant mixture. A control solution was prepared using the same components as the test microemulsion, excluding Acetyl
Glucosamine. In addition, an aqueous solution containing 1% Acetyl Glucosamine was also evaluated (untreated B16 cells
used for control). B16 cells were first plated with 1 µmol/l of α-melanin stimulating hormone for 3 d, followed by incubation
with microemulsions, at a 1:2000 dilution, for 24 h. Melanin content in B16 melanoma cells decreased by 21% and 44%
after treatment with the microemulsion and the microemulsion control, respectively. Slight melanin reduction was noted in
B16 cells treated with the aqueous Acetyl Glucosamine solution (7% reduction), compared to the untreated control.
Animal and Human
Acetyl Glucosamine
The whitening effect of Acetyl Glucosamine in skin was examined in humans (number of subjects not specified) and
brown guinea pigs (strain and number of animals not specified) that were subjected to ultraviolet (UV; wavelength not
provided)-induced pigmentation.41 The 5% Acetyl Glucosamine (information regarding solution not provided) was applied
to the dorsal skin of brown guinea pigs and the inner side of human forearm skin for 8 wk, twice a day. In humans, a visual
reduction in hyperpigmentation was observed 2 wk after treatment with the Acetyl Glucosamine solution, compared to the
vehicle-treated group, and a strong decrease in visible pigmentation was observed after 8 wk of Acetyl Glucosamine
treatment. The degree of hypopigmentation at each time point measured after the application of Acetyl Glucosamine was
higher than the vehicle control group. In guinea pigs, biopsy specimens were obtained from both the treated and control
groups 4 wk after topical application. Acetyl Glucosamine-treated skin had decreased levels of melanin without affecting the
number of melanocytes, compared to vehicle-treated skin.
Human
Acetyl Glucosamine
The reduction of facial hyperpigmentation after use of a moisturizer containing Acetyl Glucosamine and niacinamide
was evaluated in a 10-wk, randomized, double-blind, vehicle-controlled trial.42 During a 2-wk preconditioning period, the
test subjects (101 women/group) used the same commercial facial cleanser, nighttime moisturizer, and daytime moisturizing
lotion. After the 2-wk period, subjects used a daily regimen of either a morning sun protection factor (SPF) 15 sunscreen
moisturizing lotion and evening moisturizing cream containing 4% niacinamide and 2% Acetyl Glucosamine, or the SPF 15
lotion and cream vehicles. Product-induced changes in apparent pigmentation were assessed by capturing digital
photographic images of the women after 0, 4, 6, and 8 wk of product use. Images were evaluated by algorithm-based
computer image analysis for colored spot area fraction, by expert visual grading, and by chromophore-specific image analysis
based on noncontact spectrophotometric intracutaneous analysis (SIAscopyTM) for melanin spot area fraction, and melanin
chromophore evenness. By all parameters measured, the Acetyl Glucosamine and niacinamide formulation regimen caused a
more pronounced decrease in detectable areas of facial spots and the appearance of pigmentation, compared to those that used
the control formulation (p < 0.05).
A similar study, from Japan, was performed in healthy women (n = 25 women/group).17 Volunteers were instructed to
apply a formulation (0.3 g) containing either the placebo control or 2% Acetyl Glucosamine, on the side of the face, twice
daily, for 8 wk. Digital images of each side of the face of all subjects were captured at baseline, and at week 4 and 8.
Topical 2% Acetyl Glucosamine was effective in improving the appearance of facial hyperpigmentation based on computer
image analysis, with an overall directional (p = 0.089) spot area fraction change across the entire study.
Forty-five Caucasian women (Fitzpatrick skin types I, II, and III), aged 40 - 65 yr, with moderate skin texture and the
presence of at least mild to moderate-severe hyperpigmentation on the décolletage, were used in this study.43 Volunteers
were instructed to apply a neck cream containing 8% Acetyl Glucosamine and 4% triethyl citrate, each day, for 16 wk. Skin
pigmentation and texture were graded using a 0 – 5 scale with half-point increments. Irritation/tolerability parameters
(dryness, itching, stinging/burning) were measured at week 0, 8, 12, and 16 using a 0 - 3 scale (none, mild, moderate, severe).
Colorimetric measurements were also made at week 0, 8, and 16. A significant reduction of skin pigmentation was observed
at each time point (p < 0.001). After 16 wk, skin pigmentation was reduced by 23%. Chromameter measurements revealed
significant improvement at week 8 and 16 in brightness (p < 0.001) and erythema (p < 0.05). The test cream was well-
tolerated with no signs of irritation. One subject experienced an adverse event of contact dermatitis on two separate
occasions. No other adverse events were reported.
Reduction of IgE-Mediated Hypersensitivity
The following studies are included in this report as they may be helpful in addressing cosmetic safety concerns
regarding immunoglobulin E (IgE)-mediated hypersensitivity.
Glucosamine
The effect of Glucosamine on ovalbumin (OVA)-induced atopic dermatitis was evaluated in female BALB/c mice (5
mice/group).44 Approximately 1.5 ml of OVA and 3 ml of aluminum hydroxide gel were mixed, and 150 µl of the mixture
was intraperitoneally injected into mice 3 times a week, for 3 wk. After the first week of OVA injection, mice were
epicutaneously sensitized with OVA patches (1 cm x 1 cm patch containing 50 µl OVA). Patches were applied 3 times a
week, for 2 wk. After atopic dermatitis was induced, mice were given 100 µl Glucosamine injections at concentrations of 1
mg/10 µl, 1 mg/5 µl, and 1 mg/2.5 µl. After a week of Glucosamine administration, 3 OVA patches were again attached
during the next week. In addition, two control groups were used. One group received a PBS injection without OVA
induction, and a second group received a PBS injection with OVA induction. Clinical dermatitis scores decreased with
increasing Glucosamine dose (p < 0.001). Concentrations of tissue interleukin (IL)-13 and IL-17 decreased after
Glucosamine administration (each group: p = 0.002 and p < 0.001, respectively), but the concentrations of tissue IL-4 did not
show differences across groups. Serum IgE levels tended to be lower after Glucosamine administration (p = 0.004).
The anti-allergic effect of Glucosamine in female BALB/c mice with allergic rhinitis and asthma was studied.11 Mice
(8/group) were given an OVA intraperitoneal/intranasal challenge to induce allergic asthma and rhinitis. Thirty min prior to
sensitization induction, animals were administered Glucosamine treatment, via intraperitoneal injection, at concentrations of
either 1 or 5%. A negative control group received an intranasal/intraperitoneal challenge using sterile saline, and did not
receive Glucosamine treatment. A positive control group received an OVA intranasal/intraperitoneal challenge, and no
treatment with Glucosamine. Serum total and OVA-specific IgE, cytokine titers, and the number of inflammatory cells in
bronchoalveolar lavage (BAL) fluid were evaluated. A histopathologic examination of the lung and nasal cavity was also
performed. OVA-specific IgE and eosinophils in BAL fluid were significantly decreased after 5% Glucosamine treatment
compared with the positive control group (P < 0.05). In addition, significant improvement of inflammation was apparent in
groups treated with 1 and 5% Glucosamine when compared to the positive control group.
Acetyl Glucosamine and Glucosamine HCl
The anti-allergic effect of orally ingested Acetyl Glucosamine and Glucosamine HCl was evaluated in female BALB/c
mice (3 animals/group).45 The dorsal skin of each mouse was shaved and 100 µL 0.5% dinitrofluorobenzene (DNFB) in
acetone-soybean oil was applied to induce sensitization. After induction, Acetyl Glucosamine or Glucosamine HCl (0.1 or 1
mg/mouse) was administered orally, once per day, for 6 d. The method of oral administration was not specified. One h after
the final administration, both right and left ears were challenged with 20 µl 0.5% DNFB in acetone-soybean oil. The
thickness of the right ear was measured with a dial thickness gauge 0, 6, and 24 h after DNFB challenge. In addition, the
amount of histamine in the plasma of the right ear was measured. Oral administration of Acetyl Glucosamine or
Glucosamine HCl significantly inhibited DNFB-induced ear swelling in mice at both 6 h and 24 h after DNFB challenge (P <
0.05), and reduced the concentration of histamine in both the ear and plasma of DNFB-treated mice (P < 0.05).
Effect of Oral Administration on Atopic Dermatitis
Glucosamine
The effect of orally-administered Glucosamine in the treatment of atopic dermatitis was evaluated in a placebo-
controlled, double-blind, clinical trial. 46 Patients with atopic dermatitis received either a combination of 2 mg/kg
cyclosporine and 25 mg/kg Glucosamine (n = 16; Group A), or a combination of 2 mg/kg cyclosporine and placebo (n = 17;
Group B), for 8 wk. Among the 16 patients receiving Glucosamine treatment, 15 patients reported clinical improvement of
atopic dermatitis symptoms. Clinical improvement was noted in 10 of 17 patients treated with the placebo. Among the 19
intention-to-treat patients in each group, three from group A and 4 from group B experienced adverse effects, with abdominal
pain being the common adverse effect.
DERMAL IRRITATION AND SENSITIZATION STUDIES

Details regarding the irritation and sensitization studies summarized below can be found in Table 6.
No irritation was noted in an vitro reconstructed human epidermis assay performed using Acetyl Glucosamine (99.42%
purity).3 Multiple in chemico/in vitro sensitization assays (direct peptide reactivity assay (DPRA), KeratinoSensTM assay,
human cell line activation test (h-CLAT)) performed using Acetyl Glucosamine yielded negative results.3 Very mild
cumulative irritation was noted in a 21-d cumulative patch human dermal irritation using an eye cream containing 2% Acetyl
Glucosamine (12 subjects; occlusive conditions).47 HRIPTs performed using a mask containing 0.005% Acetyl Glucosamine
(108 subjects), a liquid foundation containing 2% Acetyl Glucosamine (105 subjects), and a leave-on product containing
0.005% Glucosamine HCl (51 subjects) yielded negative results.48-50 Similarly, no sensitization was noted in maximization
assays performed, each in 25 subjects, using a product containing 0.01% Glucosamine and a product containing 0.25%
Glucosamine HCl.51,52
OCULAR IRRITATION STUDIES

In Vitro
Acetyl Glucosamine
An EpiOcularTM 3-[4,5,-dimethylthiazol-2-yl]-2,5-diphenyltetrazolium bromide (MTT) conversion assay was performed
to determine the ocular irritation potential of a face serum containing 2% Acetyl Glucosamine.53 Stratified human
keratinocytes were exposed to the neat test article for 8, 16, 20, and 24 h. The effective time (ET50) at which the test
substance caused a 50% reduction in tissue viability was 17.2 h. The ET50 of the positive control was 16.3 min.
A bovine corneal opacity and permeability (BCOP) test assay was performed according to OECD TG 437.3 Bovine
corneas (3/group) were treated with either 750 µl of a saline solution containing 20% Acetyl Glucosamine, 750 µl of saline
alone (negative control), or 750 µl of a saline solution containing 20% imidazole (positive control). Corneas were exposed
for 4 h ± 5 min at 32 ± 1 °C. The mean in vitro irritancy scores for the test substance, negative control, and positive control
were 0.42, 0.70, and 105.42, respectively.
CLINICAL STUDIES
Lack of Hypersensitivity to Shrimp-Derived Glucosamine
Glucosamine
The tolerability of shrimp-derived Glucosamine was evaluated in shrimp-allergic individuals.54 Subjects with a history
of shrimp allergy were recruited and tested for both shrimp reactivity and shrimp-specific IgE by an ImmunoCAPTM assay.
Fifteen individuals with a positive skin prick test to shrimp and an ImmunoCAPTM class level of two or greater were selected
for a double-blind placebo-controlled food challenge using Glucosamine-chondroitin tablets containing 1500 mg of
synthetically-produced (control) or shrimp-derived Glucosamine. Immediate and delayed reactions (up to 24 h post-
challenge) were evaluated via a questionnaire. All subjects tolerated the 1500 mg Glucosamine administration from the
shrimp-derived and synthetic sources, without any incidences of hypersensitivity.
Case Reports
Glucosamine
A 52-yr-old with a history of long-standing intermittent asthma complained of exacerbation of underlying asthma.55
Exacerbation was characterized by shortness of breath and wheezing. Inhaled albuterol was not sufficient to extinguish or
diminish symptoms. Aside from osteoarthritis of the knees and hips, mild stage 1 hypertension, and obesity, the patient was
in reasonably stable health. During the course of 3 wk, the patient’s condition waxed and waned despite an increased
albuterol dose. The patient mentioned that her symptoms began after beginning a Glucosamine-chondroitin sulfate
preparation 3 times per day for arthritis treatment. This preparation contained 500 mg Glucosamine and 400 mg chondroitin
sulfate. Within 24 h of discontinuing Glucosamine and chondroitin treatment, the patient’s asthma symptoms completely
subsided.
A 67-yr-old male with type-2 diabetes was given oral antidiabetic medication (500 mg metformin, twice daily).56 The
patient had also been previously taking angiotensin-converting-enzyme inhibitors for hypertension for 5 yr, and Glucosamine
(1200 mg), once daily, for 3 yr, to relieve osteoarthritic knee pain. Fourteen yr after starting the diabetic medication, the
patient was referred to a nephrology consultant due to non-proteinuric renal insufficiency and a reduction of the glomerular
filtration rate GFR), from 86 to 46 ml/min, within 3 mo. A kidney biopsy revealed non-inflammatory, 40 – 50% fibrosis of
the renal cortex associated with acute tubular necrosis. The etiological investigation was negative apart from the daily
ingestion of 1200 mg Glucosamine. After stopping Glucosamine for 3 wk, GFR increased from 47.5 to 60 ml/min.
Reintroduction of Glucosamine resulted in loss of kidney function after 3 wk, with GFR reduced from 60 to 53 ml/min.
Glucosamine Sulfate
A 76-yr-old woman with arterial hypertension and osteoarthritis was referred for evaluation after an episode of urticaria
after drug intake.57 The patient was prescribed Glucosamine Sulfate for osteoarthritis, and suffered from erythematous
lesions and facial swelling within several hours after Glucosamine Sulfate intake. The following day, 5 min after a new dose,
the patient developed tongue, facial, and throat swelling with facial erythema. She was treated in the emergency department
with antihistamines and corticosteroids. Symptoms resolved within 4 h. After a washout period, a skin prick test and
intradermal test with Glucosamine Sulfate was performed. The skin prick test yielded negative results, however, the
intradermal test (concentration of 1.5 mg/ml) yielded positive results with a papule of 35 mm2. The intradermal test in 10
healthy volunteers was negative.
EPIDEMIOLOGICAL STUDIES
Cancer Endpoints
Glucosamine
The association between Glucosamine use and colorectal cancer risk was examined among 113,067 volunteers in the
Cancer Prevention Study II Nutrition Cohort.58 Those with a history of colorectal cancer prior to 2001, those with
inflammatory conditions, and those without sufficient information to determine exposure category for the Glucosamine
variable, were excluded from this study. Participants were first asked about Glucosamine intake in 2001 (baseline). Those
who reported current use were then asked to report this frequency and duration of use. At baseline, 10.7% of participants
(12,060), reported current Glucosamine use on ≥ 4 d/wk for ≤ 2 yr, and 5.6% of participants (6729), reported current use on
≥ 4 d/wk for ≥ 3 yr. Glucosamine intake was surveyed and updated every 2 yr until 2011. Current use of Glucosamine,
modeled using a time-varying exposure, was associated with a lower risk of colon cancer (hazard ratio (HR): 0.83, 95%
confidence interval (CI): 0.71 - 0.97), compared to those who reported no ingestion of Glucosamine. This reduction in risk,
however, was only observed for shorter duration use of Glucosamine (HR: 0.68, 95%, CI: 0.52 - 0.87), rather than the longer
duration of use (HR: 0.99, 95% CI: 0.76 - 1.29).
Similarly, the association between lung cancer and Glucosamine was evaluated in 76,904 volunteers with no prior
history of lung cancer.59 The participants were queried on their use of Glucosamine from the years 2000 - 2010. Low use
participants were considered to be volunteers who ingested Glucosamine < 4 d/wk or < 3 yr, and high use was considered to
be ingestion of Glucosamine for ≥ 4 d/wk and ≥ 3 yr. Compared to non-use, use of Glucosamine was associated with a 20%
reduction in lung cancer risk (HR: 0.80, 95% CI: 0.65 - 0.99) after multivariable adjustment. High 10-yr use of Glucosamine
(HR: 0.77, 95% CI: 0.56 – 1.05; P-trend = 0.04) was associated with a linear 23% reduction in lung cancer risk. A large
proportion of volunteers who reported Glucosamine use also used chondroitin. When the analysis of Glucosamine was
restricted to non-users of chondroitin (Glucosamine-only) an inverse association with lung cancer was apparent (HR: 0.84,
95% CI: 0.61 – 1.17), and high 10-yr use of Glucosamine alone was associated with a 61% reduction in lung cancer risk (HR
0.39, 95% CI: 0.17- 0.86).
RISK ASSESSMENT
Glucosamine Sulfate
The Norwegian Food Safety Authority calculated margin of safety (MoS) values for the use of 10% Glucosamine
Sulfate in a body lotion (35.0), leg cream (99.0), and face cream (178.0), and from overall exposure from cosmetics (29.2).60
These values were calculated assuming 100% dermal absorption, a NOAEL value of 430 mg/kg/d (obtained from a repeated
oral dose toxicity assay performed in dogs with a bioavailability of 20%), and a calculated relative daily exposure of 123.20,
43.50, and 24.13 mg/kg bw/d for the body lotion, leg cream, and face cream, respectively. According to this assessment,
maximum use levels were reported to be 18, 10, and 3.5% in face, leg and body lotion, respectively.
SUMMARY
The safety of Acetyl Glucosamine, Glucosamine, Glucosamine HCl, and Glucosamine Sulfate as used in cosmetics is
reviewed in this assessment. According to the Dictionary, Acetyl Glucosamine and Glucosamine Sulfate are reported to
function in cosmetics as skin-conditioning agents – miscellaneous, and Glucosamine HCl is reported to function as a pH
adjuster. The function of Glucosamine is not reported
According to 2022 VCRP survey data, Acetyl Glucosamine, Glucosamine HCl, and Glucosamine are reported to be
used in 198, 77, and 2 formulations, respectively. The results of the concentration of use survey conducted by Council
indicate that Acetyl Glucosamine has the highest concentration of use in a leave-on formulation; it is used at up to 5% in face
and neck products (not spray). Glucosamine Sulfate is not reported to be in use.
The skin penetration of Acetyl Glucosamine was evaluated in split-thickness Caucasian cadaver skin. Approximately
7% of the applied test substance (which contained 2% Acetyl Glucosamine) permeated the skin after 6 h. An in vitro
permeation assay was also performed with Glucosamine HCl in human epidermal membranes. Over a 48-h period,
Glucosamine HCl permeated through the skin with a flux of 1.497 ± 0.42 µg/cm2/h, a permeability coefficient of 5.66 ± 1.6 x
10-6 cm/h, and a lag time of 10.9 ± 4.6 h. The dermal penetration of 5% Glucosamine HCl in different vehicles was evaluated
in rat skin. Transdermal flux of Glucosamine HCl was greatest in the cubic liquid crystalline formulation (248.89 ± 64.57
µg/h/cm2). The skin permeation rate of Glucosamine Sulfate was determined to be 13.27 µg/cm2/h when evaluated in
Sprague-Dawley full-thickness rat skin. The amount of Glucosamine in synovial fluid was measured in osteoarthritis patients
following an application of 10% Glucosamine Sulfate cream. A mean Glucosamine concentration of 100.56 ng/ml was
observed in the synovial fluid of treated patients.
Female Beagle dogs were given a single oral dose of 450 mg Glucosamine HCl, and a pharmacokinetic analysis was
performed. Glucosamine was detected in the blood up to 8 h post-dose, with a Tmax of 2 h and a Cmax of 9.69 µg/ml.
[14C]Glucosamine HCl diluted with unlabeled Glucosamine Sulfate was given to Sprague-Dawley rats to examine excretion
patterns of radioactivity. Radioactivity analysis in tissues and organs revealed that the [14C] from the labeled Glucosamine
quickly entered into all tissues, included cartilage, reaching a maximum at 8 h. Bioavailability was also evaluated in humans.
Healthy adult males, under fasting conditions, were given a single oral dose of 480 mg Glucosamine HCl in a dispersible
tablet or capsule form. The mean Cmax, Tmax, and T1/2 values were reported to be 907.1 ng/ml, 3.03 h, and 1.10 h,
respectively, for the dispersible tablet form, and 944.40 ng/ml, 3.30 h, and 1.50 h, respectively, for the capsule form. The
pharmacokinetics of Glucosamine after a single oral administration of Glucosamine Sulfate and Glucosamine HCl were
evaluated in 12 healthy volunteers. Glucosamine was determined at steady state in plasma collected up to 48 h after the last
dose by a validated LC-MS/MS method. After Glucosamine Sulfate administration, peak concentrations and extent of
exposure averaged 9.1 ± 6.3 µM and 76.5 ± 23.0 µM/h, respectively. Significantly lower plasma concentrations (p ≤ 0.005)
were determined after the administration of Glucosamine HCl.
The reported LD50 values for Glucosamine were higher than the doses tested ( > 15,000 mg/kg in mice and > 8000
mg/kg in rats and rabbits). According to an ECHA dossier, the acute oral LD50 for Glucosamine HCl was reported to be
15,000 mg/kg bw in mice. In a 9-wk study, Glucosamine (0.5%) was fed to male Sprague-Dawley and SHR rats. The
systolic blood pressure in treated rats was statistically significantly lower than control animals. No statistically significant
histological differences were found in the hearts, kidneys, and livers, among the treated and control groups. Acetyl
Glucosamine (up to 5%) was fed to F344 rats for 13 wk. No obvious indications of toxicity were observed in any of the
parameters evaluated. The NOAEL was determined to be > 5%. The effect of orally-ingested Acetyl Glucosamine (1000 mg)
was evaluated in healthy adults. Volunteers ingested the dissolved Acetyl Glucosamine in water, once a day, for 16 wk. A
control group received green tea extract powder. Routine physical and cardiovascular characteristics, hematology, and blood
chemistry, did not show any significant abnormalities between control and treated groups. The potential toxic effects of a
tablet containing Glucosamine HCl (1500 mg/d), chondroitin sulfate (1200 mg/d), and manganese ascorbate (228 mg/d) in
degenerative disease patients was evaluated in a 16-wk crossover study. No patients reported symptoms requiring
termination of study, and symptom frequency on medication was similar to that at baseline. Vital signs, occult blood testing,
and hematologic parameters were similar among the placebo and medicated groups. The chronic toxicity potential of Acetyl
Glucosamine (up to 5%) given in the diet for 52 wk was evaluated in F344 rats. No toxic effects were observed in any
parameter evaluated, however, slight suppression of body weight gain was observed in animals dosed with 5%.
The effects of premating Glucosamine supplementation via drinking water on Sprague-Dawley rat litter homogeneity,
uterine receptivity, and maternal hormones levels were evaluated. Female rats were given 0.5 mM Glucosamine via drinking
water for 2 wk, and then mated. Birth weights and absolute and relative ovary weights were statistically significantly greater
in the Glucosamine-treated group compared to the control group (p < 0.05). Maternal progesterone, estradiol, and IGF-1
concentrations on day 19.5 of pregnancy were significantly increased in treated rats, while insulin and total cholesterol levels
were significantly decreased compared with control rats. The reproductive effects of intraperitoneal injections of
Glucosamine (0 and 20 mg/kg) was evaluated in 8-wk old and 16-wk old adult female mice. Fetal weight and length were
reduced in Glucosamine-treated 16-wk old mice, compared to control animals. In addition, a significantly higher number of
abnormal fetuses was present in litters of 16-wk old Glucosamine-treated mice compared with all other groups (p < 0.05).
The effects of intrauterine Glucosamine (up to 1500 µg) were evaluated in female ICR mice. Ten d after implantation of the
Glucosamine pellet, mice were mated. Mice that received Glucosamine pellets delivered significantly fewer live pups/litter
over a 60-d pellet active period than those that received placebo pellets. However, after the 60-d pellet active period, there
was no statistically significant difference in litter sizes delivered by Glucosamine-treated and placebo-treated mice, except at
the highest dose level.
Acetyl Glucosamine (up to 5000 µg/plate) was considered to be non-mutagenic in an Ames assay using S. typhimurium
strains TA 1537, TA 1535, TA 98, TA 100, and TA 102, with and without metabolic activation. Similarly, an Ames assay
was performed on Glucosamine HCl derived from Aspergillus niger. Tester strains (S. typhimurium and E. coli WP2 uvrA)
were exposed to up to 5000 µg/plate of the test substance, with and without metabolic activation. No mutagenicity was
observed. In an in vivo micronucleus assay, mice (strain not reported) were administered Aspergillus niger-derived
Glucosamine HCl (up to 2000 mg/kg bw) in water, via gavage. There was no statistically significant decrease in the ratios of
PCE and NCE at any dose level.
In an in vitro anti-genotoxicity assay, human peripheral lymphocytes were exposed to Glucosamine or Acetyl
Glucosamine at concentrations up to 50 mM. DNA damage was induced with hydrogen peroxide. Glucosamine, at all
concentrations, showed a significant protective activity (p < 0.001) against hydrogen peroxide-induced DNA damage. Acetyl
Glucosamine only indicated a slight DNA protection at the highest test concentration. The chemoprotective ability of
Glucosamine (diets containing up to 150 mg/kg Glucosamine; 7 d exposure) against cisplatin-induced genotoxicity was
evaluated in male Wistar rats. The test substance was considered to be an effective chemoprotector against cisplatin-induced
DNA damage.
The carcinogenic potential of Acetyl Glucosamine (up to 5% in the diet; 104-wk treatment) was evaluated in F344 rats.
The test substance was considered to be non-carcinogenic. The anti-proliferative potential of Glucosamine (10 mM) was
evaluated in human renal cancer cell lines (786-O and caki-1) via an MTT and FITC-annexin V/PI assay. The apoptosis rate
of both cell lines was up-regulated by the high concentration of Glucosamine (10 mM), but down-regulated by low
concentrations of Glucosamine (1 and 5 mM), as compared with the control groups. The growth inhibitory effects of
Glucosamine, Glucosamine HCl, and Acetyl Glucosamine on human hematoma SMMC-721 cells was evaluated in vitro.
Tumor cells were exposed to Glucosamine, Glucosamine HCl, or Acetyl Glucosamine, at concentrations of up to 1000 µg/ml.
Results measured by an MTT assay showed that Glucosamine HCl and Glucosamine caused a concentration-dependent
reduction in hepatoma cell growth. In an animal anti-carcinogenicity assay, Kunming male mice were inoculated with
sarcoma 180 tumor cells. Mice were orally treated for 10 d with up to 500 mg/kg Glucosamine HCl dissolved in saline.
Glucosamine HCl, at the intermediate dose (250 mg/kg/d), had the highest inhibition ratio (34.02%) on sarcoma 180 tumor
growth.
The effect of Acetyl Glucosamine on melanin production was evaluated in an in vitro assay. Reconstituted human
tanned epidermis cells were exposed to up to 5% Acetyl Glucosamine in water for 10 d. Dose-dependent decreases in
melanin content were observed. The whitening effect of Acetyl Glucosamine (5%) was evaluated in human and brown
guinea pig skin subjected to UV-induced pigmentation. A visual reduction in hyperpigmentation was observed 2 wk after
treatment with the Acetyl Glucosamine solution, in humans, compared to the vehicle-treated group. Acetyl Glucosamine-
treated guinea pig skin had decreased levels of melanin without affecting the number of melanocytes, compared to vehicle-
treated skin. Anti-melanogenic activity was evaluated using an Acetyl Glucosamine-loaded microemulsion and an aqueous
solution containing 1% Acetyl Glucosamine in B16 melanoma cells. Melanin content decreased by 22% and 7%, after
treatment with the microemulsion and the aqueous solution, respectively.
The reduction of facial hyperpigmentation after topical treatment on Acetyl Glucosamine was evaluated in a 10-wk trial.
Volunteers (101 women/group) were instructed to apply a facial lotion containing 4% niacinamide and 2% Acetyl
Glucosamine twice a day for 8 wk. A control group applied the lotion vehicle without 4% and 2% Acetyl Glucosamine. By
all parameters measured, the niacinamide and Acetyl Glucosamine formulation regimen caused a significant reduction in the
detectable area of facial spots and appearance of pigmentation compared to the controls (p < 0.05). In a similar study, from
Japan, healthy women (n = 25 women/group) were instructed to apply a facial lotion containing 2% Acetyl Glucosamine on
the side of the face, twice daily, for 8 wk. A control group applied the vehicle lotion that did not contain Acetyl
Glucosamine. Topical 2% Acetyl Glucosamine reduced the appearance of facial hyperpigmentation, with an overall
directional (p = 0.089) spot area fraction change across the entire study.
The effects of a neck cream formulation containing 8% Acetyl Glucosamine was evaluated in 45 Caucasian women.
Applications of the cream occurred once a day, for 16 wk. The test cream was well-tolerated with no signs of irritation. One
subject experienced an adverse event of contact dermatitis on two separate occasions. No other adverse events were reported.
The effect of Glucosamine injections (concentrations up to 1 mg/2.5 µl) on OVA-induced atopic dermatitis was
evaluated in female BALB/c mice. Clinical dermatitis scores decreased with increasing Glucosamine dose (p < 0.001).
Concentrations of tissue IL-13 and IL-17 decreased after Glucosamine administration (each group: p = 0.002 and p < 0.001,
respectively), but the concentrations of tissue IL-4 did not show differences across groups. The anti-allergic effect of
Glucosamine (concentrations up to 5%) in female BALB/c mice with allergic rhinitis was evaluated. OVA-specific IgE and
eosinophils in BAL fluid were significantly decreased after 5% oral Glucosamine treatment compared with the positive
control group. In addition, significant improvement of inflammation was apparent in groups treated with Glucosamine when
compared to the positive control group. The anti-allergic effects of orally-ingested Acetyl Glucosamine and Glucosamine
HCl (up to 1 mg/mouse; 6 d treatment) was also evaluated in BALB/c mice with DNFB-induced skin sensitization. Oral
administration of Acetyl Glucosamine or Glucosamine HCl significantly inhibited DNFB-induced ear swelling in mice at
both 6 h and 24 h after DNFB challenge (p < 0.05), and reduced the concentration of histamine in the ear plasma of DNFB-
treated mice (p < 0.05). In vivo sensitization assays performed on humans using various test substances (a mask containing
0.005% Acetyl Glucosamine, a product containing 0.01% Glucosamine, a leave-on product containing 0.005% Glucosamine
HCl, and a product containing 0.25% Glucosamine HCl) yielded negative results.
The effect of orally-administered Glucosamine (25 mg/kg) in the treatment of atopic dermatitis was evaluated in an
8-wk, placebo-controlled, double-blind, clinical trial. Among the 16 patients receiving Glucosamine treatment, 15 patients
reported clinical improvement of atopic dermatitis symptoms. Three Glucosamine-treated patients reported adverse effects,
with abdominal pain being the most common adverse effect.
Potential skin irritation of Acetyl Glucosamine was evaluated in an in vitro assay using 3 reconstructed human
epidermis samples. Reduction of cell viability was similar in the negative control and treated groups; therefore, the substance
was considered to be non-irritating. Acetyl Glucosamine was predicted to be non-sensitizing in a DPRA, KeratinoSensTM
assay, and h-CLAT. Very mild cumulative irritation was observed in a 21-d cumulative patch irritation assay performed
using an eye cream containing 2% Acetyl Glucosamine (12 subjects). HRIPTs performed using a mask containing 0.005%
Acetyl Glucosamine (108 subjects), a liquid foundation containing 2% Acetyl Glucosamine (105 subjects), and a leave-on
product containing 0.005% Glucosamine HCl (51 subjects) yielded negative results. Similarly, no sensitization was in
maximization assays performed, each in 25 subjects, using a product containing 0.01% Glucosamine and a product
containing 0.25% Glucosamine HCl.
In vitro ocular irritation assays were performed using a face serum containing 2% Acetyl Glucosamine and a saline
solution containing 20% Acetyl Glucosamine. Neither test substance was considered to be irritating when compared to
positive controls.
The tolerability of orally-ingested, shrimp-derived Glucosamine was evaluated in 15 shrimp-allergic individuals.
Subjects were given either 1500 mg of synthetically-derived or shrimp-derived Glucosamine. All subjects tolerated the 1500
mg Glucosamine administration from the shrimp-derived and synthetic sources, without any incidences of hypersensitivity.
A 52-yr old complained of exacerbation of underlying asthma after beginning treatment with a Glucosamine-
chondroitin sulfate preparation containing 500 mg Glucosamine. Within 24 h of discontinuing Glucosamine and chondroitin
treatment, the patient’s asthma symptoms completely resolved.
A 67-yr-old male with type-2 diabetes was referred to a nephrology consultant due to non-proteinuric renal
insufficiency and a reduction in GFR supposedly due to Glucosamine intake for the past 3 yr. After stopping Glucosamine
for 3 wk, GFR increased from 47.5 to 60 ml/min. A 76-yr-old woman with arterial hypertension and osteoarthritis was
referred for evaluation after an episode of urticaria after Glucosamine Sulfate intake. After treatment with antihistamines and
corticosteroids, symptoms resolved within 4 h.
The association between Glucosamine use and colorectal cancer risk was examined among 113,067 volunteers.
Participants were asked to log their Glucosamine intake from 2001 - 2011. Current use of Glucosamine, modeled using a
time-varying exposure, was associated with a lower risk of colon cancer, for those using Glucosamine for a short duration
(HR: 0.68, 95% CI: 0.52 - 0.87). Similarly, the association between lung cancer and Glucosamine was evaluated in 76,904
volunteers with no prior history of lung cancer. The participants were queried on their use of Glucosamine from the years
2000 - 2010. Compared to non-use, use of Glucosamine was associated with a 20% reduction in lung cancer risk (HR: 0.80,
95% CI: 0.65 - 0.99) after multivariable adjustment.
The Norwegian Food Safety Authority calculated MoS values for the use of 10% Glucosamine Sulfate in a body lotion,
leg cream, face cream, and from overall exposure from cosmetics. The MoS for each of these formulation types were 35.0,
99.0, 178.0, and 29.2, respectively.
DISCUSSION
This assessment reviews the safety of Acetyl Glucosamine, Glucosamine, Glucosamine HCl, and Glucosamine Sulfate
as used in cosmetic formulations. The Panel concluded that these ingredients are safe in the present practices of use and
concentration as described in this safety assessment, when formulated to be non-irritating.
The Panel noted the mild cumulative irritation that was observed during the 21-d cumulative irritation patch test
performed on 12 subjects using an eye lotion containing 2% Acetyl Glucosamine. Because this irritation was observed at a
concentration of 2%, and the maximum concentration of use for Acetyl Glucosamine in cosmetics is reported to be 5%, the
Panel was concerned that the potential exists for dermal irritation with the use of products formulated using glucosamine
ingredients. Therefore, the Panel specified that products containing glucosamine ingredients must be formulated to be non-
irritating.
In addition, the Panel considered the lack of human sensitization data at the maximum use concentration of 5%.
However, the available in chemico/in vitro sensitization data (i.e., DPRA, KeratinoSens™ assay, and h-CLAT, all performed
using Acetyl Glucosamine (99.42% purity)), clinical sensitization data at up to 2% Acetyl Glucosamine, and a lack of case
reports, as well as the Panel’s clinical experience with these ingredients, mitigated any concern.
Reproductive effects were observed in mice and rats following oral ingestion and intraperitoneal injections of
Glucosamine. The Panel determined that these effects would not be relevant to cosmetic exposure as administration in these
studies resulted in a much higher systemic concentration of Glucosamine than would be expected with cosmetic use. The
systemic safety of these ingredients is further supported by their use as dietary supplements/debulking agents, and available
systemic toxicity data.
In addition, data included in this report indicate that Acetyl Glucosamine may have a skin lightening effect. The Panel
noted that skin lightening is considered a drug effect, and should not occur during the use of cosmetic products. Because of
that caveat, the Panel’s knowledge of the mechanism of action (i.e., inhibition of tyrosinase activity resulting in reduced
melanin synthesis), and clinical experience, concern for this effect in cosmetics was mitigated. Nevertheless, cosmetic
formulators should only use this ingredient in products in a manner that does not cause depigmentation.
The Panel discussed the fact that some of these ingredients are used in formulations that could result in incidental
inhalation (e.g., Acetyl Glucosamine is used at up to 0.1% in pump hair sprays). Inhalation toxicity data were not available;
however, the oral toxicity data that were available did not report adverse effects. Furthermore, droplets/particles deposited in
the nasopharyngeal or tracheobronchial regions of the respiratory tract present no toxicological concerns based on the
chemical and biological properties of these ingredients. Coupled with the small actual exposure in the breathing zone and the
low concentrations at which these ingredients are used (or expected to be used) in potentially inhaled products, and a lack of
systemic toxicity, the available information indicates that incidental inhalation would not be a significant route of exposure
that might lead to local respiratory or systemic effects. As indicated in the respiratory exposure resource document and in the
Cosmetic Use section of this report, airbrush application of cosmetic products is not assessed by the Panel. A detailed
discussion and summary of the Panel’s approach to evaluating incidental inhalation exposures to ingredients in cosmetic
products is available at https://www.cir-safety.org/cir-findings.
CONCLUSION
The Expert Panel for Cosmetic Ingredient Safety concluded that of Acetyl Glucosamine, Glucosamine, Glucosamine
HCl, and Glucosamine Sulfate* are safe in cosmetics in the present practices of use and concentration described in this safety
assessment when formulated to be non-irritating.
* Not reported to be in current use. Were this ingredient not in current use to be used in the future, the expectation is
that it would be used in product categories and at concentrations comparable to others in this group.
TABLES
Table 1. Definitions, structures, and functions of glucosamine ingredients.1, CIR Staff

Ingredient Definition Function
Acetyl Glucosamine Acetyl Glucosamine is the organic compound that conforms to the Skin-Conditioning Agents –
(10036-64-3; 72-87-7; 7512-17-6) structure: Miscellaneous
Glucosamine (3416-24-8) Glucosamine is the organic compound that conforms to the structure: Not Reported
Glucosamine HCl (66-84-2) Glucosamine HCl is the amine salt that conforms to the structure: pH Adjusters
Glucosamine Sulfate (29031-19-4) Glucosamine Sulfate is the amine salt that conforms to the structure: Skin-Conditioning Agents –
Miscellaneous
Table 2. Chemical properties

Property Value Reference
Acetyl Glucosamine
Physical Form Solid 3
Color White 3
Molecular Weight (g/mol) 221.21 3
Density (g/ml @ 20 ºC) 1.234 3
Vapor pressure (mmHg @ 20 ºC) 0.06 3
Melting Point (ºC) 162.7 3
Water Solubility (g/l @ 20 ºC) 256.8 3
log Kow (@ 23.7 ºC) -2.2 3
Glucosamine
Molecular Weight (g/mol) 179.17 61
Vapor pressure (mmHg @ 25ºC) 0.0000000902 62
Melting Point (ºC) 88 61
Water Solubility (g/L) 551 61
log Kow -4.2 62
Disassociation constants (pKa) 7.58 63

Table 2. Chemical properties

Property Value Reference
Glucosamine HCl
Physical Form Crystalline 64
Formula Weight (g/mol) 215.63 65
Color Off-White 64
Odor Odorless 2
Specific Gravity (@ 38 ºC) 1.42 64
Melting Point (ºC) 190 - 194 64
Water Solubility Soluble 2
log Kow -1.91 18
Disassociation constant (pKa) (@ 37 ºC) 7.75 18
Glucosamine Sulfate
Color Off-White 66
Formula Weight (g/mol) 277.25 66
Density(g/ml) 1.56 67
Boiling Point (ºC) 449.9 67
Water Solubility (g/l) Freely soluble 67
Disassociation constants (pKa) 12.51 (estimated) 68
Table 3. Frequency (2022)12 and concentration (2020)13 of use

# of Uses Max Conc of Use (%) # of Uses Max Conc of Use (%) # of Uses Max Conc of Use (%)
Acetyl Glucosamine Glucosamine Glucosamine HCl
Totals* 198 0.001 – 5 2 0.04 77 0.0001 – 5
Duration of Use
Leave-On 185 0.002 – 5 2 0.04 64 0.0001 – 0.9
Rinse-Off 13 0.001 – 5 NR NR 13 0.07 – 5
5Diluted for (Bath) Use NR NR NR NR NR NR
Exposure Type
Eye Area 12 0.2 – 2 NR NR 6 0.0001 – 0.2
Incidental Ingestion 3 0.002 – 2 NR NR NR NR
Incidental Inhalation-Spray 75a; 72b 0.1; 0.005 – 0.07b 1a NR 20a; 30b NR
Incidental Inhalation-Powder 75a 0.07; 0.12 – 5c 1a 0.04c 20a 0.0006 – 0.38c
Dermal Contact 194 0.01 – 5 1 0.04 67 0.0001 – 5
Deodorant (underarm NR 0.01 NR NR NR NR
Hair - Non-Coloring 1 0.001 – 0.55 1 NR 10 0.55
Hair-Coloring NR 0.01 NR NR NR NR
Nail NR NR NR NR NR NR
Mucous Membrane 4 0.002 – 2 NR NR NR NR
Baby Products NR NR NR NR NR NR
*Because each ingredient may be used in cosmetics with multiple exposure types, the sum of all exposure types may not equal the sum of total uses.
a
Not specified whether a spray or a powder, but it is possible the use can be as a spray or a powder, therefore the information is captured in both categories
b
It is possible these products are sprays, but it is not specified whether the reported uses are sprays.
c
It is possible these products are powders, but it is not specified whether the reported uses are powders
NR – not reported
Table 4. Ingredient not reported to be in use according to 2022 FDA VCRP and 2020 concentration of use data12,13
Glucosamine Sulfate
Table 5. Acute oral toxicity studies

Ingredient Animals No. /group Dose/Route of Administration LD50/Results Reference
Glucosamine Mice (strain unspecified) NR 5000 mg/kg; gavage LD50 > 5000 mg/kg 26
Glucosamine CD-1 Mice NR 8000 mg/kg; gavage LD50 > 8000 mg/kg 26
Glucosamine Mice (strain unspecified) NR 15,000 mg/kg; gavage LD50 > 15,000 mg/kg 26
Glucosamine Sprague-Dawley Rat NR 8000 mg/kg; gavage LD50 > 8000 mg/kg; no adverse effects reported 26
Glucosamine Rabbit (strain unspecified) NR 8000 mg/kg; gavage LD50 > 8000 mg/kg 26
Glucosamine HCl Mice (strain unspecified) NR 15,000 mg/kg (method of oral LD50 = 15,000 mg/kg 2
administration not specified)

NR = Not reported
Table 6. Dermal irritation and sensitization studies

Ingredient Test Article Concentration/Dose Test Population Procedure Results Reference
IRRITATION
In Vitro
Acetyl Glucosamine Acetyl Glucosamine tested neat; 16 mg 3 reconstructed human epidermis; OECD TG 439; Non-irritating 3
(99.42% purity) positive control: 5% sodium dodecyl sulfate; negative

control: PBS; 42 min incubation
Human
Acetyl Glucosamine Eye cream containing 2% tested neat; 0.2 g 12 21-d cumulative patch test; patches removed and re- Average irritation score of 0.34/4; very mild 47
Acetyl Glucosamine applied each day for 21 days (excluding weekends); cumulative irritation
occlusive conditions
SENSITIZATION
In Chemico/In Vitro
Acetyl Glucosamine Acetyl Glucosamine tested neat NR DPRA; OECD TG 442C; test material exposed to Non-sensitizing; mean percent depletion of 3
(99.42% purity) model synthetic peptides containing cysteine and cysteine and lysine was 1%
lysine; mean percent depletion of cysteine and lysine
calculated
Acetyl Glucosamine Acetyl Glucosamine 0.98 to 2000 µM 3 KeratinoSensTM assay; OECD TG 442D; human Non-sensitizing; IC50 = > 2000 µM 3
(99.42% purity) epidermal keratinocytes exposed to test substance;

cells analyzed for luciferase activity after 48 ± 2 h
incubation period
Acetyl Glucosamine Acetyl Glucosamine 1395 - 5000 µg/ml NR h-CLAT; OECD TG 442E; THP-1 cells incubated with Non-sensitizing; cell viability > 50% at all 3
(99.42% purity) test substance for 24 h and analyzed via flow tested concentrations
cytometry
Human
Acetyl Glucosamine Mask containing 0.005% tested neat; 108 HRIPT; occlusive conditions Non-sensitizing 48,69
Acetyl Glucosamine 2cm x 2 cm; est.

exposure under patch =
2.5 µg/cm2
Acetyl Glucosamine Liquid foundation containing tested neat; 105 HRIPT; occlusive conditions Non-sensitizing 50,69
2% Acetyl Glucosamine 2 cm x 2 cm; est.

exposure under patch =
1000 µg/cm2
Glucosamine Leave-on product containing tested neat; 51 HRIPT; occlusive conditions Non-irritating and non-sensitizing 49,69
0.005% Glucosamine HCl 25-38 mg/cm2 (product

dose); est. exposure
under patch = 1.25 –
1.90 µg/cm2
(Glucosamine HCl
dose)
Glucosamine Product containing 0.01% tested neat; 25 Maximization assay; induction phase – 0.25% SLS for Non-sensitizing 51,69
Glucosamine 2 cm x 2 cm; est. 24 h; subjects then exposed to the test substance for
exposure under patch = 48-72 h (5 total induction applications); 10-d rest
1.25 µg/cm2 period; challenge phase – 5% SLS for 1 h; subject then
exposed to test material for 48 h; all patches under
occlusive conditions; sites evaluated 15 min, 30 min,
and 24 h after patch-removal
Glucosamine HCl Product containing 0.25% tested neat; 0.05 g; est. 25 Maximization assay performed according to the same Non-sensitizing 52,69
Glucosamine HCl exposure under patch = procedures as above; occlusive conditions

55.6 µg/cm2
DPRA = direct peptide reactivity assay; h-CLAT = human cell line activation test; HRIPT = human repeated insult patch test; IC50 = half maximal inhibitory concentration; OECD TG = Organisation for Economic
Cooperation and Development test guidelines; PBS = phosphate-buffered saline; SLS = sodium lauryl sulfate; THP-1 = human monocytic cell line
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2022 FDA VCRP data – Glucosamine ingredients Priya Cherian
Acetyl Glucosamine
Eye Lotion 8
Other Eye Makeup Preparations 4
Tonics, Dressings, and Other Hair Grooming
Aids 1
Lipstick 3
Makeup Bases 3
Makeup Fixatives 2
Other Makeup Preparations 3
Other Personal Cleanliness Products 1
Cleansing 9
Face and Neck (exc shave) 58
Body and Hand (exc shave) 17
Moisturizing 57
Night 8
Paste Masks (mud packs) 3
Skin Fresheners 6
Other Skin Care Preps 15
Total: 198
Glucosamine
Tonics, Dressings, and

Other Hair Grooming Aids 1
Total: 2
Glucosamine HCL
Eye Lotion 4
Other Eye Makeup Preparations 2
Hair Conditioner 3
Shampoos (non-coloring) 2
Tonics, Dressings, and Other Hair Grooming
Aids 2
Other Hair Preparations 3
Foundations 1
Makeup Bases 2
Shaving Cream 1
Other Shaving Preparation Products 1
Cleansing 3
2022 FDA VCRP data – Glucosamine ingredients Priya Cherian
Moisturizing 26
Night 2
Paste Masks (mud packs) 3
Other Skin Care Preps 2
Total: 77
Glucosamine Sulfate
Total: 0

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Safety Assessment of Glucosamine Ingredients

Status: Final Report for Panel Review

© Cosmetic Ingredient Review

SAFETY ASSESSMENT FLOW CHART

MEETING ___June 2022 ___________________________________________________

Public Comment CIR Expert Panel Report Status

2020 Priority List

IDA Notice IDA

Tentative Report Issue TR

Draft FR DRAFT FINAL REPORT

Table Different Conclusion

Commitment & Credibility since 1976

TO: Bart Heldreth, Ph.D.

FROM: Alexandra Kowcz, MS, MBA

DATE: March 23, 2022

SUBJECT: Tentative Report: Safety Assessment of Glucosamine Ingredients as Used in

Method of Manufacture – “cellulose” is not an enzyme

Impurities, Glucosamine HCl – Stating the concentration of free-base glucosamine as purity is

Anti-Carcinogenicity, In Vitro, Glucosamine – Units of mM should be called concentration

Reduction of IgE-Mediated Hypersensitivity, Acetyl Glucosamine and Glucosamine HCl;

Epidemiological Studies – Please correct “associate” to “associated”

Glucosamine – June 2022 – Priya Cherian

History – Glucosamine Ingredients

• Unpublished data received from Council:

• Panel reviews Draft Tentative Report

• Panel reviews Draft Final Report

Glucosamine HCL 66-84-2 yes no no no no yes no yes yes no no no no no no yes

Glucosamine Sulfate 29031-19-4 yes no no no no no no yes yes no no no no no no yes

 chemical/technical names  carcinogenicity

 International Programme on Chemical Safety http://www.inchem.org/

DECEMBER 2021 PANEL MEETING – INITIAL REVIEW/DRAFT REPORT

Belsito Team – December 6. 2021

Full Panel – December 7, 2021

MARCH 2022 MEETING – SECOND REVIEW/DRAFT TENTATIVE REPORT

Belsito Team – March 7, 2022

Dr. Paul Snyder

Dr. Donald Belsito

Dr. Paul Snyder

Dr. Dan Liebler

Dr. Donald Belsito

Dr. Dan Liebler

Dr. Donald Belsito

Dr. Dan Liebler

Dr. Donald Belsito

Dr. Dan Liebler

Dr. Donald Belsito

Dr. Dan Liebler

Dr. Donald Belsito

Dr. Dan Liebler

Monice Fiume (CIR)

Dr. Donald Belsito

Dr. Donald Belsito

Dr. Dan Liebler

Dr. Donald Belsito

Dr. Dan Liebler

Dr. Donald Belsito

Dr. Dan Liebler

Dr. Donald Belsito

Dr. Paul Snyder

Dr. Dan Liebler

MEETING _June 2022 _________________________________________________