Safety Assessment of Hexamethylene Diisocyanate … · Safety Assessment of Hexamethylene...

Safety Assessment of Hexamethylene Diisocyanate (HDI) Polymers

as Used in Cosmetics

Status: Draft Tentative Report for Panel Review Release Date: November 20, 2015 Panel Meeting Date: December 14-15, 2015

The 2015 Cosmetic Ingredient Review Expert Panel members are: Chair, Wilma F. Bergfeld, M.D., F.A.C.P.; Donald V. Belsito, M.D.; Ronald A. Hill, Ph.D.; Curtis D. Klaassen, Ph.D.; Daniel C. Liebler, Ph.D.; James G. Marks, Jr., M.D.; Ronald C. Shank, Ph.D.; Thomas J. Slaga, Ph.D.; and Paul W. Snyder, D.V.M., Ph.D. The CIR Director is Lillian J. Gill, D.P.A. This report was prepared by Lillian C. Becker, Scientific Analyst/Writer.

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Commitment & Credibility since 1976

MEMORANDUM

To: CIR Expert Panel and Liaisons

From: Lillian C. Becker, M.S. Scientific Analyst and Writer

Date:

November 20, 2015

Subject: Hexamethylene Diisocyanate (HDI) Polymers As Used In Cosmetics

Attached is the draft tentative report of hexamethylene diisocyanate (HDI) polymers as used in cosmetics. [HDIply092015rep] Each ingredient in this report consists of copolymers synthesized, in part, from the monomer HDI; these ingredients are grouped together because they are all copolymers containing a common diisocyanate monomer.

At the September, 2015 meeting, the Panel issued an Insufficient Data Announcement with the following data needs:

• Method of manufacturing with regards to end capping, and quantification of any residual end-capping agents

• Stability of these ingredients in formulation • Quantification of any residual diisocyanate, including HDI, trimethylhexanediisocyanate

(TMHDI), and saturated decyl methylene diphenyldiisocyanate (SMDI) • HRIPT of HDI/trimethylol hexyllactone crosspolymer at the greatest concentration of use

(31%) or higher • Repeated dose inhalation data Exposure to diisocyanates (such as HDI) in the work place is one of the leading causes of occupational asthma, and has been associated with airway irritation and asthma-like symptoms, hypersensitivity pneumonitis, rhinitis, and accelerated lung deterioration. Diisocyanates can also cause both irritant and allergic contact dermatitis, as well as skin and conjunctival irritation. Thus, some of the data requested are needed to be sure that these diisocyanate monomers are neither present in the ingredients as manufactured, nor are released in formulations.

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The Council has submitted updated concentration of use information and HRIPT data on products containing HDI trimethylol hexyllactone crosspolymer at up to 30.7%. [HDIply092015Data1-4] Council comments have been addressed. [HDIply122015PCPC]

The requested structures of these ingredients have been added to the report. These structures are best representations based on the Dictionary definitions. The Chemistry section has been appropriately updated. Data that were submitted to the Panel as Wave 2 data for the September, 2015 meeting have been added.

The Panel is to examine the data on the HDI polymers included in this report and determine if the data are sufficient to issue a tentative report. If so, the Panel should be prepared to formulate a conclusion, provide the rationale in the Discussion, and issue a tentative report for public comment. If the data are not sufficient for making a determination of safety and an insufficient data conclusion is reached, the Panel is to provide a listing of the data that are needed.

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SAFETY ASSESSMENT FLOW CHART

INGREDIENT/FAMILY _____Hexamethylene Diisocyanate (HDI) Polymers _________________________________

MEETING ________Dec 2015______________________________________________________________________________________

Public Comment CIR Expert Panel Report Status

Priority List INGREDIENT

PRIORITY LIST

SLR

June 18, 2015

60 day public comment period

Draft Report

Table IDA TR

IDA Notice Sept 22, 2015

IDA

Draft TR

Table

Tentative Report

60 day Public comment period

Draft FR

Table Different Conclusion

PUBLISH Final Report

DRAFT REPORT Sept 2015

DRAFT TENTATIVE REPORT

Dec 2015

DRAFT FINAL REPORT

Issue TR

Issue FR

Table

Table

Table

History – HDI Polymers

2014 – HDI polymers were added to the 2015 priority list. June, 2015 – SLR posted with the following data request:

• Chemical and physical properties; • Impurities data; including data on hexamethylene diisocyanate, in particular, including how it is

entrapped in or scrubbed from the final ingredient, and how much is biologically available in the final ingredient;

• Toxicokinetics data, specifically dermal absorption of these ingredients; if these ingredients were to have appreciable dermal absorption and other toxicokinetic data are not adequate, toxicity data, including reproductive/developmental toxicity and carcinogenicity data, are needed, as are genotoxicity data; these data may not be crucial if these ingredients have no appreciable dermal penetration, however, if these data were available, even though dermal penetration might be expected to be negligible, the data would strengthen the safety assessment;

• Oral and inhalation toxicity data; • Dermal, ocular, and other mucous membrane toxicity data, including irritation and sensitization

data; and • Any other relevant safety information that may be available.

September, 2015 – Insufficient Data Announcement

The data that are needed to evaluate the safety of these 19 ingredients are: • Method of manufacturing with regards to end capping, and quantification of any residual end-

capping agents • Stability of these ingredients in formulation • Quantification of any residual diisocyanate, including HDI, trimethylhexanediisocyanate (TMHDI),

and saturated decyl methylene diphenyldiisocyanate (SMDI) • HRIPT of HDI/trimethylol hexyllactone crosspolymer at the greatest concentration of use (31%) or

higher • Repeated dose inhalation data

December, 2015 – The Panel is to examine new data and issue a tentative report

Distributed for comment only -- do not cite or quote

HDI Polymers Data Profile for December, 2015. Writer – Lill Becker

ADME Acute toxicity

Repeated dose toxicity Irritation Sensitization

Derm

al P

enetration

Log Kow

Use

Oral

Derm

al

Inhale

Oral

Derm

al

Inhale

Ocular A

nimal

Ocular In V

itro

Derm

al Anim

al

Derm

al Hum

an

Derm

al In Vitro

Anim

al

Hum

an

In Vitro

Repro/D

evel

Genotoxicity

Carcinogenicity

Phototoxicity

HDI/Trimethylol Hexyllactone Crosspolymer X X X X X X

Bis-C16-20 Isoalkoxy TMHDI/PEG-90 Copolymer X X X

Bis-Hydroxyethyl Acrylate Poly(1,4-Butanediol)-9/TMHDI Copolymer

Bis-Isostearyl 1,4-Butanediol/HDI/Hydrogenated Dimer Dilinoleyl Alcohol Copolymer

Bis-Lauryl Cocaminopropylamine/HDI/ PEG-100 Copolymer

Bis-Methoxy PEG-10 Dimethyl MEA/HDI/Bis-PEG-10 Dimethicone Copolymer

1,4-Butanediol/Succinic Acid/Adipic Acid/HDI Copolymer

Cholesterol/HDI/Pullulan Copolymer

Decyl HDI/PEG-180 Crosspolymer

Diethylene Glycol/DMAP Acrylamide/PEG-180/HDI Copolymer

X

HDI/Di-C12-14 Alkyl Tartrate/Hydrogenated Dilinoleyl Alcohol Copolymer

X X

HDI/PEI-45/SMDI Crosspolymer HDI/PPG/ Polycaprolactone Crosspolymer X

Methoxy PEG-17/Methoxy PEG-11/HDI Crosspolymer X

Methoxy PEG-17/Methoxy PEG-11/HDI Isocyanurate Trimer Crosspolymer

X X X X X X X

PEG-240/HDI Copolymer Bis-Decyltetradeceth-20 Ether X X X X X X X X X

PPG-26/HDI Copolymer Steareth-100/ PEG-136/HDI Copolymer X X X X X

Stearyl HDI/PEG-50 Copolymer


Search Strategy - Hexamethylene Diisocyanate (HDI) Polymers SCIFINDER Structure search: 1401318-08-8 – 1 hit. Not useful. 1268856-56-9 – no hits. 1027785-01-5 – 1 hit. Not useful. 1037784-92-1 – 1 hit. Not useful. 937238-35-2 – 59 hits. None useful. 918477-41-5 – 2 hits. Not useful 302791-95-3 – 1 hit. Not useful. 206263-39-0 – 1 hit. Not useful. 206263-36-7 – 7 hits. None useful. 119553-67-2 – 46 hits. None useful. Term Search HDI/Trimethylol Hexyllactone Crosspolymer Bis-C16-20 Isoalkoxy TMHDI/PEG-90 Copolymer Bis-Hydroxyethyl Acrylate Poly(1,4-Butanediol)-9/TMHDI Copolymer Bis-Isostearyl 1,4-Butanediol/HDI/Hydrogenated Dimer Dilinoleyl Alcohol Copolymer Bis-Lauryl Cocaminopropylamine/HDI/PEG-100 Copolymer Bis-Methoxy PEG-10 Dimethyl MEA/HDI/Bis-PEG-10 Dimethicone Copolymer 1,4-Butanediol/Succinic Acid/Adipic Acid/HDI Copolymer 119553-67-2 Cholesterol/HDI/Pullulan Copolymer Decyl HDI/PEG-180 Crosspolymer Diethylene Glycol/DMAP Acrylamide/PEG-180/HDI Copolymer HDI/Di-C12-14 Alkyl Tartrate/Hydrogenated Dilinoleyl Alcohol Copolymer 1268856-56-9 HDI/PEI-45/SMDI Crosspolymer HDI/PPG/Polycaprolactone Crosspolymer 302791-95-3 Methoxy PEG-17/Methoxy PEG-11/HDI Crosspolymer Methoxy PEG-17/Methoxy PEG-11/HDI Isocyanurate Trimer Crosspolymer PEG-240/HDI Copolymer Bis-Decyltetradeceth-20 Ether PPG-26/HDI Copolymer Steareth-100/PEG-136/HDI Copolymer 103777-69-1 Stearyl HDI/PEG-50 Copolymer 117 hits. None useful. ECHA SPREADSHEET AND WEBSITE “HDI” find all – HDI oligomers, isocyanurate, uretdione, iminooxadiazinedione, biuret, and allopanate were not useful. CAS Nos – no hits. HPVIS – CAS NOs. No hits. PUBMED "hexamethylene diisocyanate" OR HDI AND polymer OR copolymer – 25549 hits. 1 useful. + tox* 1647 hits, not containing “HDI” "hexamethylene diisocyanate" OR HDI – 1232 hits "hexamethylene diisocyanate" OR "hdi" AND "polymer" – 81 hits, not useful INCI names – no hits.


https://scifinder.cas.org/scifinder/substances/answers/B407DF10X86F35093X44CE1F6A1BA2296E31:B4085893X86F35093X1963F06733F7374814/1.html?key=REGISTRY_1401318-08-8&title=1401318-08-8&launchSrc=sublist&pageNum=1&nav=eNpb85aBtYSBMbGEQcXJxMDC1MLSOMLCzM3Y1ADIMLQ0M3YzMDM3NnYzNzY3sTA0ASpNKi5iEMxKLEvUy0nMS9fzzCtJTU8tEnq0YMn3xnYLJgZGTwbWssSc0tSKIgYBhDq_0tyk1KK2NVNluac86GZiYKgoYGBgYAQamFHCwB0cGuAaFB_k7-MaXMLAmZlbkF9UAtRRXMhQx8AMVMcFVJcP4gAdy1RUhuoEp_z8nNTEvLMKRQ1X5_x6B3RCFMwJBQwAozpDpQ&sortKey=SUBSTANCE_ID&sortOrder=DESCENDING











CAS Nos. – No hits. "hexamethylene di-isocyanate" OR "HDI" AND polymer OR "co-polymer" AND tox* - 81 hits. 0 useful "hexamethylene diisocyanate" AND sensitiz* AND polymer – 6 hits. 0 useful. "hexamethylene diisocyanate" AND irritation AND polymer – 3 hits. 0 useful. "hexamethylene diisocyanate" AND genotox* AND polymer – 1 hit. Not useful. "hexamethylene diisocyanate" AND mutagen* AND polymer - 0 hits "hexamethylene diisocyanate" AND ocular AND polymer - 0 hits "hexamethylene diisocyanate" AND eye AND polymer - 0 hits GOOGLE SEARCH - INCI names and CAS Nos. A few chem props and 1 NICNAS.


Transcripts September, 2015 HDI Polymers

Dr. Marks’ Team DR. MARKS: …The next ingredients are the HDI polymers hexamethylene diisocyanate. This is

the review of these ingredients. There are 19 of them. Just note that HDI has been reported to cause occupational asthma, so we'll have to deal with that with these ingredients. So the 19 ingredients that were in the report are they all okay? Yes. And then do we have any needs, Ron, Ron, or Tom? We've got some data on wave 2. Was that helpful?

DR. SLAGA: Yes, to me wave 2 was very helpful. No HDI monomer (inaudible) not an irritant or no sensitization. Not a mutagen.

DR. BERGFELD: Would you say that last part again? I'm sorry. DR. MARKS: Not a mutagen. Not a teratogen, did you say? DR. SLAGA: I said not a mutagen. DR. MARKS: Mm-hmm. DR. SHANK: I had a question on the stability of the ingredient and formulation. I have no feeling

for that, so if the chemist could address that. DR. HILL: Repeat again. I was looking for something. DR. SHANK: I had question on the stability of the ingredients. When they're in formulation is

there any release of the HTMI [HDI?] from the polymer? The polymer seems to be fine. I was just wondering if HDI could leave the polymer when it's put into formulation?

DR. SLAGA: Good point. DR. SHANK: We might be able to handle that in the discussion. Otherwise, I thought wave 2

answered my questions. DR. HILL: Actually, that's an incredibly important question and I did ask that related to a couple

because -- I've debated whether to say this on the record or not, but I will anyway. The toxicologist can correct me where I stray a little bit. As I understand, one component of delayed toxicology that occurred after the Bhopal explosion in 1984 in India, methisocyanate, of course the entry was long use in that particular case. Glutathione actually reacted with it which is normally a detox route. Then carried it elsewhere in the body where it then released. We essentially regenerated methisocynante or something similar that could then react with macromolecules there. I don't know if it was just glutathione or also potentially thiols in the blood proteins.

But in any case, we do need to have a high level of certainty that any of these that get into the system that we don't have something form reversibly, and that, at least, most of these are generating ureas. I think the others are generating carbonates. There shouldn't be any concern, but we do need to have high level of confidence that that sort of process can't occur, and we do need to definitely address it in the discussion for every single ingredient, effectively.

DR. MARKS: When I received the data, and maybe I missed it in wave 2, for HDI trimethylol hexyllacton cross polymer it had the most uses at 345 at a concentration of 31 percent in a leave on. I didn't see any HRIPT or animal sensitization on that particular ingredient. For me, I would have liked to seen HRIPT at 31 percent for that ingredient, and if that's safe then non-sensitizer then I felt comfortable. Did I miss that in wave 2, Lillian, at all?

DR. SHANK: Which compound was that? DR. MARKS: It's the HDI trimethylol hexyllacton cross polymer [HDI/trimethylol hexyllactone

crosspolymer]. That's the one that had the most uses at 345. DR. SLAGA: At 31 percent? DR. MARKS: 31 percent was its use concentration. DR. SADRIEH: We had the same comment that there wasn't any sensitization data on that one. DR. MARKS: Yes, so to me I would suggest an insufficient data notice since this is the first time

looking for either animal, or I'd prefer an HRIPT at 31 percent for that ingredient, and then we could also have a second need is the stability of ingredients, any release of the HDI.


DR. HILL: I also wanted to have some sense of how they were handling the end capping. Again, the usual concern. If there's something being done with the alkylating ingredient that we're not left with any significant residuals of those. I'm not sure that that's actually how it's being done, but we don't have full information on that.

DR. MARKS: So repeat that, Ron Hill. DR. HILL: How the end capping is being done, at least the nature of the kinds of reagents that

are used. Because the products are, I think, reasonably similar in nature, but the chemistries vary between these in a number of cases which potentially affects the issues in any given one, so what you say about that high concentration with that particular one is correct. But there are a couple of others were [where?] I didn't have the sense of certainty that reversibility of the chemistry, just what Dr. Shank was talking about at the beginning would be the same. That's a key issue.

Also, the end capping, what you asked me to repeat is are there any agents of an alkylating type nature. So they'd either be epoxides or chlorinated derivatives or something along those lines that could alkylate to do the end capping. Because we're talking about derivatizing and alcohol group in that end capping reaction.

DR. MARKS: So I'll ask you tomorrow, Ron Hill -- DR. HILL: Okay. DR. MARKS: -- to clarify that. Would that come under method of manufacturer? DR. HILL: Yes. Method of manufacturer. DR. MARKS: Lillian, did you find anything in wave 2, I didn't see it, but for an HRIPT at that -- MS. BECKER: No, there's a couple sensitization tests. DR. MARKS: Yes, but not -- MS. BECKER: But not anywhere close to 30 percent. DR. MARKS: Okay. So what I would do tomorrow is move that we issue an insufficient data

notice since this is the first review and I'd like to see the HRIPT at 31 percent for the HDI trymethalol hexalactin [HDI/trimethylol hexyllactone crosspolymer] cross polymer. We'd like to see the stability of ingredient. Is there any release of HDI and then method of manufacturer, the end capping issue?

DR. HILL: And then a couple of these polymers we have carboxylic acids, and it's not immediately clear to me what the nature of the products are when they react first with the isocyanate. I'm assuming we might get carbonate diesters or carbonate diester, but I'm not 100 percent clear, so I wanted from the method of manufacturer a little more information about the chemistry. I don't think they'd be giving away and trade secrets to divulge that.

DR. MARKS: Again, I'll ask you probably to clarify, but I'll but that in capping and chemistry. Okay. So does that sound -- so team, insufficient data notice for those three issues?

DR. SADRIEH: So I just wanted to clarify, so we did say that quantification of the residual HDI in cosmetic formulations would be data that we would want to have?

DR. MARKS: Yes. DR. SADRIEH: Okay. DR. MARKS: Basically we'd want to know how stable is it. DR. SADRIEH: Okay. DR. MARKS: Go ahead, Ron, if you want to clarify. I was not going to -- is there any release of

HDI and then at that point we deal with it if there is. DR. SADRIEH: In the formulation? The carbonate formulation? DR. HILL: Yes. I think it wouldn't be HDI it would be the potential, given the nature of the

chemistry. I doubt that there's any, but the potential for regenerating isocyanate. In other words, a reversible formation.

The other thing I wanted to point out in terms of the chemistry is the wave 2 data there's a statement or an analogous polymer and we really don't know what analog is and means in terms of toxicity without determining pertinent mechanisms of action. So there's read across, on the one hand, but when we say analog or analogous that's a nebulous term like similarity of structure, but it really has little meaning.


DR. SADRIEH: Yes. DR. HILL: Without having some idea of what the toxicological endpoints would be. MS. BECKER: Carol was real nice and chased down what the analogous polymer was. DR. HILL: That was the isoforin-, whatever it is, right? MS. BECKER: But it is steareth 100 PEG-136 HDI copolymer. DR. HILL: It's the what? Say again. MS. BECKER: The steareth 100. DR. HILL: Yes. MS. BECKER: PEG-136 HDI copolymer. DR. HILL: Okay. DR. MARKS: Okay. Any other comments? DR. HILL: Hang on one second. We need to be very clear in the report, because we're talking

about reversibility, that we're not always using HDI as the isocyanate here. They're actually four different isocyanate encompassed in these ingredients. There's HDI. There's TMHDI. There's SMDI. And there's desel [decyl?] HDI. I believe that those are actually four different monomer reactants. I don't have any information to suggest otherwise.

So we need to be very clear and possibly even do read across as a group, which I did on my own. We've got HDI, TMHDI, desel [decyl?] HDI, and SMDI. Those are four different isocyanates. The SMDI is a diphenyl. Let's see, and so what I said was these are four different molecules, four different monomer. This goes to read across because and sensitization resulting from heptane formation or any cancer promotion events, excuse me, resulting from alkalization of tissue, macromolecules or mucous membranes or nasal passages or lung structure would not expected to be in common between the differing monomer. There's four different monomers. Even though the chemistry itself would be essentially the same. Reaction rates would not necessarily be the same between them which would affect tissue distribution which would be particularly noteworthy in the case of potentially reversibly formed either glutathione or blood cell surface style conjugates if that occurs at any level. I can give you that, but I think I dropped it as a comment in the report, so. Actually, I did drop it as a comment in the report.

DR. MARKS: Ron Shank, you were going to say something? DR. SHANK: I really hesitate to bring this one up, but it is a Herculean task to give us a couple of

structures? DR. HILL: I've asked for a number of them, actually, all these. DR. SHANK: You have -- DR. HILL: All the ones in the table. DR. SHANK: -- hexamethyline diocicyadae, but we don't have structures, actual -- DR. HELDRETH: We can certainly make sure best estimations in the fact that, you know, if we're

going to draw it out it will look like a block polymer, but these aren't necessarily going to be block copolymers. But we can lay out those individual residues in a line and you can use your imagination for how they may actually come together whether it be linearity or whether there be some sort of cross linking throughout the structure.

A lot of those end results depends on the reaction conditions, even if we're talking about the same starting materials. So that's why we hesitated to put any significant structures in here. But I'd be happy to put some representative ones in there if that would help.

DR. HILL: Yes. Because low molecular weight impurities always potentially represent an issue. And plus it gives you some sense of it. I mean, we know what those monomers are, but it would be nice if the report had a structure of trimethyl propane. A structure of hydroxyl ethyl alkylate. A structure of isothere 14 butainedyal. I don't think it would be a ton of work, and we have another chemist on board, which actually I didn't realize at the time I put comments on here that I think we need to hire another chemist to make sure they can do all of these things. So depending on the facility which our other people can do that.

An accrue a database so that if it's needed again somewhere down the line somebody can just go in and get -- I don't know if you use a chem draw or what, but just go in and grab a structure. Even might think


about that. DR. HELDRETH: Yes. That actual type of database is actually in the works. DR. HILL: I'm assuming it was, but I just -- DR. MARKS: So can I -- DR. HILL: -- in case you need to justify your time doing that. DR. MARKS: Is that it? Should I include that in insufficient data notice? DR. HILL: No. DR. MARKS: I kind of thought that, but I wanted to confirm. We'll make that a, how do I want

say, Bart? DR. SHANK: An aside. DR. HILL: And I can make sure of that. DR. MARKS: A notice, but not an insufficient data notice. Okay. Any other comments? DR. HILL: Yes. I did have a question about the EU exclusion that's on Page 11. I presume that

it referred to residual glycol impurity not as something was actually as a cosmetic ingredient? I mean, effect and functionally it's the same, but I assume they're referring to residual?

DR. EISENMAN: The exact wording in the regulation is as traces in ingredients. DR. HILL: That's what I thought it was. I just wanted to confirm. DR. MARKS: So Ron Shank, a question I have for you is, and maybe this would be answered by

any release of HDI and the stability ingredients, the HDI causing occupational asthma, if the amount of HDI released is minuscular then that should be a non-issue. Is that your reasoning?

DR. SHANK: Yes. DR. MARKS: Would you address it in the discussion -- DR. SHANK: Yes. DR. MARKS: -- for Lillian to note the occupational asthma and why we're not concerned about it. DR. HILL: If we've got urease, carbonate diesters and carbonate esters then there should be no

potential for regenerate in an isocyanate, but just wanted to confirm that that's, in fact, the case. DR. MARKS: So we'll address that in the discussion you heard because I think that's an

important event which needs to be addressed in the report. DR. HILL: If we didn't have the known occupational sensitization that'd be another story, but. DR. MARKS: Yes, exactly. Okay. Any other comments. Tomorrow I'll move an insufficient data

notice. The stability HDI release, the end capping chemistry, method of manufacturer, and then the HRIPT 31 percent for the HDI trimetholyl hexillacton cross polymer. Okay. Any other comments? If not we'll move on to the next ingredient which is citrus fruit.

Dr. Belsito’s Team DR. BELSITO: Okay, so we're moving to Hexamethylene diisocyanates and this is this the first

time we're looking at this report. So I guess one of the first questions that I had while I'm trying to open this is that they look like we had used a read across on isoflurane diisocyanate and I was wondering if that is a cosmetic ingredient. Are there others and should we add all of the other isocyanates in with this report because they're all going to have sort of similar toxicities. And in fact, HTI as far as I know, is the strongest sensitizer in terms of if there's any residual monomer level. Because isn't there -- okay, wait a minute. I'm having problems getting rid of clay here. But isn't there one read across on an isoflurane monomer? I thought there was.

So they -- you talk about an -- and I guess analogous read across in Wave 2 and I didn't know what the analogous -- what the analog was you were reading across from.

MS. BECKER: Yes, Carol will check that out for us and the analogous read across was stearate 100, peg 136 HDI copolymer which is one of our ingredients.

DR. BELSITO: Okay, so that will -- when Wave 2 is incorporated it will state that that was the read across.

MS. BECKER: It -- well I'll just put that data in.


DR. BELSITO: Okay. MS. BECKER: And I won't be putting it in under the other names. DR. BELSITO: So in Wave 2 we got the high-end molecular Wave and there was no residual

monomer that could be detected. So below levels of detection, non-irritating and sensitizing to 30 percent. Hundred percent was non-irritating in vitro. We got negative Ames. We got negative in vitro ocular. This particle size was respirable. It was used on -- in powders and I said team question mark.

DR. SNYDER: Was that in the new data? DR. BELSITO: No. DR. SNYDER: No. DR. BELSITO: And then with the new data and Wave 2 the inhalation issue it says sprays

seemed to have disappeared with Wave 2 data. Is that true? It's not used in any sprays? MS. BECKER: Well it says -- DR. BELSITO: Because it was in the initial report and then in Wave 2 with the updated

concentration of use. MS. BECKER: One item is a cream. Now let's see if that takes care of all of it. DR. BELSITO: And I said large (TRACK 3 - inaudible), non -- no sensitization irritation. Only

issue is particle size and respiratory toxicity for use in a facial powder (TRACK 3 - inaudible). DR. SNYDER: Same as before. DR. BELSITO: Well, same as with the clays -- DR. SNYDER: Yes. DR. BELSITO: -- we're looking at. Curt, Dan, comments? DR. LIEBLER: I don't have any other comments on the respiratory. DR. BELSITO: Do we need it? DR. LIEBLER: I don't know, do we? Are there -- DR. BELSITO: To spray powder and the particle size is potentially respirable. DR. LIEBLER: So I was concerned about the residual impurities that the Wave 2 took care of

that for me. DR. BELSITO: Mm-hmm. DR. LIEBLER: There's also the Wave 2 data in the memo from Beth that have a lot of summaries

of results but my question was will the reports be provided for inspection like we technically get. DR. BELSITO: Well some of that Wave 2, was this one of the ones that was echo [ECHA]? MS. BECKER: The Wave 2, no. DR. LIEBLER: Product data sheets (TRACK 3 - inaudible). MS. BECKER: Those are product data sheets. DR. BELSITO: Oh, okay. MS. BECKER: You've got what they're going to give us. DR. BELSITO: Yeah, we're not going to get the individual data if it's echo [ECHA] or product data

sheets. MS. BECKER: Mm-hmm. DR. LIEBLER: So then we're going to have the summaries of the test, the toxicity test, the

(inaudible) data. MS. BECKER: Only what's in the -- DR. LIEBLER: Only what's in the -- MS. BECKER: -- Wave 2 data. DR. BELSITO: This is just material safety data sheet data. DR. LIEBLER: Oh, all right. I did have additional concerns and these are pretty big unreactive

model charts. DR. BELSITO: Right, without residual (inaudible). DR. LIEBLER: Right, I mean without a (inaudible) residual reactive component I'm not


particularly concerned about any respiratory irritation sensitization issues. DR. BELSITO: What about chronic inhalation? DR. LIEBLER: I mean, well, only to the extent that with any particle could give you, you know,

responses to chronic particle inhalation. DR. BELSITO: Uh-huh. DR. LIEBLER: Nothing special to this particular ingredient family though. One other level -- DR. BELSITO: Well we don't have data on toxicity. Do we need it? Do we need any more

inhalation data because this could be used in a powder that's respirable? DR. LEIBLER: No, I don't think so but I normally would defer to Paul on that question like that. DR. SNYDER: Well I think we're -- and I think we didn't ask for it because we did it in clay but we

said there was just one -- here it also has 15 percent in a respirable, that's powder range. And we have a particle use up to what percent? Two percent.

DR. BELSITO: I mean this is the first time we're looking at this document so. DR. SNYDER: We'll ask for it. DR. LIEBLER: Yeah, I think we should ask for it. DR. SNYDER: Okay. DR. BELSITO: So we're asking for chronic inhalation? DR. SNYDER: Well we know it's -- the acute inhalation is positive right after two milligrams per

liter. DR. BELSITO: Mm-hmm. DR. SNYDER: So we -- based on that and the fact that it's respirable, we need to ask for it. DR. BELSITO: So what do we ask for? Which -- polymer. DR. SNYDER: Which one is in there? Which one is in the powder? MS. BECKER: The HDI PPG polycaprolactone crosspolymer. DR. BELSITO: HDI and PPD? MS. BECKER: PPG. DR. SNYDER: PPG. DR. BELSITO: Polylactin? MS. BECKER: Polycaprolactone crosspolymer. DR. BELSITO: And do we ask for a concentration or just chronic inhalation? MS. BECKER: That's up to 11.8. DR. SNYDER: There is about five uses there. Created in 10 percent. DR. BELSITO: In powders. DR. SNYDER: Mm-hmm. DR. BELSITO: So insufficient for HDI PPG polycaprolactone crosspolymer, chronic inhalation. MS. BECKER: There's the other one with powder. It may be a powder, it's not necessarily a

powder. And also HDI/trimethylol hexyllactone crosspolymer. DR. BELSITO: At what concentration? MS. BECKER: 12.6. DR. BELSITO: So either one, right? One set is fighting the other. DR. SNYDER: Yes. DR. LIEBLER: Yeah. DR. BELSITO: HDI -- what is it all again? DR. SNYDER: Trimethylol. DR. BELSITO: Trimethylol. DR. LIEBLER: The first one in table five. DR. BELSITO: HDI/trimethylol -- DR. SNYDER: Hexyllactone. DR. BELSITO: Hexyllactone crosspolymer.


DR. SNYDER: Crosspolymer. That's the major ingredient. That has the most uses. DR. BELSITO: But we could take chronic respiratory for either one. DR. LIEBLER: Correct. DR. BELSITO: Okay, so insufficient for chronic respiratory for either HDI PPG polycaprolactone

crosspolymer or HDI trimethylol hexyllactone crosspolymer. Okay, discussion points that it's large, doesn't penetrate, and that there's essentially undetectable isomer -- monomer.

DR. LIEBLER: Right, so it's the usual thing to say to take care to minimize residual monomer. DR. BECKER: Mm-hmm. Good practices. DR. BELSITO: Right. DR. SNYDER: So do we need impurities to these diisocyanates or actins? DR. BELSITO: Yeah, the diisocyanates -- I mean HDI is a major issue. DR. SNYDER: Yeah. DR. BELSITO: -- because it can cause significant asthma but it can cause significant skin

allergy. So it's both a Type 1 and a Type 4. DR. SNYDER: Okay. DR. BELSITO: So if there were monomer it would be a big, big issue -- DR. SNYDER: Yeah. DR. BELSITO: -- but it's not. MS. BECKER: Right, Wave 2. DR. LIEBLER: Oh. MS. BECKER: We took care of that. DR. LIEBLER: Okay, okay. Yeah, less than half (inaudible). DR. BELSITO: Okay, that's -- I don't have anything else to say on this, so. DR. LIEBLER: Same here. DR. BELSITO: Okay. MS. BECKER: Okay, so just insufficient for inhalation -- DR. BELSITO: Chronic inhalation from one or the other, or if that's two. MS. BECKER: Okay. DR. ANSELL: Could we change from chronic not specified for duration but inhalation toxicity? DR. BELSITO: Fine. MS. BECKER: Mm-hmm. DR. BELSITO: But if it's just acute it's not going to help us. DR. ANSELL: Yeah, but I -- we know it's going to have that with chronic (inaudible) so the

insoluble particle. And so the toxicology by chronic exposure is well defined. It has nothing to do with the structure, it has to do with inhalation of the polymers -- you know, particles.

DR. BELSITO: Okay, then, you know, give us whatever information you can give us that will help us decide on safety. You know, if you have a polymer of similar size and you have some chronic inhalation on that since they seem relatively inert, that could be used as " (inaudible)"

MS. BECKER: Okay. DR. BELSITO: Okay. DR. HELDRETH: That goes to your question about isoflurane and are there other ingredients like

that. I'm sure there are quite a few. The inking [INCI] committee uses a different acronym. They call it IPDI instead of HPDI.

DR. BELSITO: Okay. DR. HELDRETH: But it would be a significant addition I think. There's more of those than there

are of these, so. DR. BELSITO: Well, you know, I mean at least from a sensitization and -- issue, HDI is much

more potent. So HDI would clear the isofluranes unless they were used at a much higher concentration. So it's up to you if you want to -- I mean, I don't know what their uses are since this bubble jumped ahead of those


because of uses. But I think you could easily do a lot of read across from HDI to isofluranes and any of the other isocyanates that might -- polymers that might be used.

DR. HELDRETH: Okay, I think at this point it would be a significant challenge for the analyst the reinstruct --

DR. BELSITO: Okay, that's fine. DR. HELDRETH: -- (inaudible), but I agree we'll remember this report when do the isofluranes

and we can use all of that read across from this report if that's all right with that. DR. BELSITO: That's fine, I was just, you know, raising the question -- DR. HELDRETH: Sure. DR. BELSITO: -- because I think I did that probably because maybe I did -- I don't -- I did this a

long time ago when I first got this. But when it said read across analog and I didn't know what the analog was -- DR. HELDRETH: Sure. DR. BELSITO: -- I think I thought maybe it was isoflurane and then I was wondering how relevant

that would be to sensitization. I probably went into the dictionary -- DR. HELDRETH: Sure. DR. BELSITO: -- found that there was a isoflurane in (inaudible) that we could include in all of

those. But I don't remember why I thought that. DR. HELDRETH: Okay. DR. BELSITO: Okay, anything else with the HDI? So then we're moving on to polymerized

tetramethylcyclo- tetrasiloxane.

Day two DR. BERGFELD: All right, thank you. Moving on to the next ingredient, the HDIs, Dr. Marks. DR. MARKS: So, this is safety assessment of hexamethylene diisocyanate HDI polymers, and

this is the first review. There are 19 ingredients. We got a number of data from Wave 2, but we felt that we still did not have enough data to move forward with a tentative report, so we move that an insufficient data notice be issued. We want to know what the stability of the ingredients is. Is there any release of HDI?

We also want to know the chemistry in end-capping -- that would be in the method of manufacture -- and, in an HRIPT at 31 percent or in animal sensitization at that concentration, to confirm that HDI/trimethylol hexyllactone crosspolymer is not a sensitizer at that concentration.

DR. BERGFELD: Belsito team, comment? DR. BELSITO: Well, we thought it was insufficient also but not for the reasons that the Marks

team did. It's used in face powders and, again, was a respirable range so we wanted some more data on that. In terms of sensitization and irritation, we really thought it was all right. I mean, the analysis showed that there was (inaudible) limits of detection for isocyanate monomers. And then we had a study here -- dermal nonhuman up to 30 percent was not a dermal irritant in 14 days. In terms of sensitization, let's see --

DR. MARKS: Yeah, I didn't see any sensitization data, and this particular ingredient has the most uses -- 345 -- and a leave-on concentration of 31 percent. So, I wanted to be reassured, even though there was no irritation, that there was no sensitization.

DR. BELSITO: Yeah, the concentrations weren't specified in those. You know, as long as we're going insufficient, we can add more data.

The other thing that I did want to point out, particularly because throughout this document we're being told that they were using an analog to compare to, and when we were reading it we weren't sure what the analog was, and I was wondering if it was another potential isocyanate like isophorone isocyanate. And so Bart actually looked in the dictionary, and there is a huge number of other isocyanate polymers, including isophorone isocyanate polymers that are in fact used in cosmetic products. And so I raised the question whether we should consider including all of them since HDI is really considered to be the most sensitizing of the isocyanates both in terms of type 1 sensitization for respiratory and type 4 for skin. But Bart suggested that we hold off and just do the HDI because the isophorones are a rather large number and that if we get through this we could use this


potentially for helping read across for the isophorone. So, I did just one, since we're going insufficient at this point, to point out that there are other isocyanate polymers that one might consider including in the report, but it's been recommended that it not be.

DR. HILL: And I raised the issue yesterday that actually we don't have just one isocyanate here. There are four. There's HDI; there's TMHDI; there's decile HDI; and there's SMDI. So, we actually have four different monomers, and we actually lack sensitization information to capture that full array of different monomers, and I was not happy with the idea that we could do straight read-across that being the case.

So, I'm not -- it kind of got brushed in veiled fashion. I don't know if it was veiled really, but it was less than obvious until you got down into the chemistry tables and looked really carefully at each of those ingredients by ingredient, which I did. So, I wanted to make sure that that got there.

I also had the issue with the analogous polymer. I also had the issue with the inhalation potentially, but I wanted to see what you all thought, and the reason, you know, we have the securities data but it's only one of the ingredients -- it's the PEG-240 HDI copolymer and I really think we need to have that ingredient or we need to have that information, particularly depending on what -- the end-capping is almost certainly done with epoxides or it could be chloro substitute and compounds that are reactive, but something reactive is being used to react with those alcohol moiateece end-caps, which is why I raised that issue. And if there are any residuals, and we have residual characterization for just one of these, we really need it for all -- every single one.

So, that was my contention in this case. DR. BERGFELD: Don. DR. BELSITO: As a nonchemist, just tell me out, why is this end-capping important? DR. HILL: Because you would use a reactive compound to do it. It would be an electrophile, so it

would be either an epoxide or a chlo, chlorohalogen -- excuse me, halogenated carbon compound -- and if there are any residues there, those can react with tissue macromolecules and --

DR. BELSITO: We have information on residues. DR. HILL: We have it for -- what's that? DR. BELSITO: We have information on residues and impurities. DR. HILL: For one compound, one -- DR. BELSITO: So, you want them for every one? DR. HILL: Yes, every one, because there's no -- there are different polymers. What they're using

for end- capping is going to be different in every single case, and I think, you, you know, without having that information -- and I don't see why we couldn't get it. I mean, they surely have some kind of specifications. Even if it's a specification sheet, that are saying we're staying below these levels, that would be enough for me. And there must be a specification sheet for these if they're selling them.

DR. LIEBLER: So, I'm not certain that these are all or any necessarily end-capped unless there's something stated in the report that I just skipped over as I read it. You know, polymers may be end-capped and they may not be end- capped. It just depends on the requirements of the chemical, you know --

DR. HILL: The way I read the language as it applied here was that these are all end-capped or maybe most of them are end-capped. If that's not the case, then tell us it's not the case.

DR. LIEBLER: So we can have that point clarified, and then if there is end-capping by a reactive electrophile, certainly residual electrophile would be a very reasonable thing to look at. I think in Wave 2 it was a description for one ingredient -- this intrakoshein flex HDI di-C12-C14 alkyl tartrate, where they indicated the residual HDI is less than a half ppm and that the polymerization is terminated by the addition of ethanol. In fact, I think if they'd terminate polymerization by adding ethanol, it's going to be hard to end-cap it unless you really scrub the ethanol out.

DR. HILL: Well, no, because all of these are actually terminated with alcohols or something comparable, and then they end-cap the ones that they say they're end-capping, which means they've got to come back and react with the alcohol groups with something reactive. So, it will be an epoxide, or it will a chlorinated carbon, almost certainly, and that's what we've seen in other modified polymers, for example. There'll be these modifying agents. And without having to have trade secrets revealed, I'm thinking they have specification sheets


at least that give us some sense of that. So, I mean, I'd like to at least troll out there and see what we can get on that and decide if I -- at the end -- and also again we have four different isocyanates, so if we're trying to read across from one that's the HDI to those other three, I don't believe that we can do that -- well, unless we have data to show that they've actually screened for those residues as well and make sure that it's gone.

DR. LIEBLER: Yeah, I'd like to see the residual impurities, particularly the HDI and the other isocyanates for the other ingredients.

DR. BERGFELD: Let me recap. The two of you -- DR. LIEBLER: But not end-cap. (Laughter) DR. BERGFELD: Now, after all this chemical discussion, what did we end up with in getting the

impurity residues? DR. BELSITO: We ended up with all the requests for Marks plus the Belsito request for

expiration. DR. BERGFELD: Well, I know, but we're talking about the chemistry here for a minute. Is that

what we ended up with -- the impurities of the residues for all of the complexes? Okay. And then, Jim, would you mind listing the other needs please. DR. MARKS: Yes. So, stability in the impurities section -- I presume it would occur, particularly

the release of HDI. Is there any -- and the other things that Dan had mentioned. Under the method of manufacturing the chemistry, clarify whether or not this end-capping really is an issue or not. The HRIPT or animal sensitization -- they confirm that 31 percent of HDI trimethylol hexyllactone crosspolymer is not a sensitizer at that concentration. And inhalation data.

DR. BERGFELD: Don, do you need to add to that please? DR. BELSITO: Yeah, that it's in a face powder, that the size was respirable, and again we're

assuming that there will be no residual -- significantly residual isocyanate monomers present. So, you're not going to have a reactive substance, you're going to have an inert substance. But we'd like a little data on effects of chronic inhalation of (inaudible) inert particles.

DR. MARKS: Yes, and that's what I meant by the inhalation data. DR. BERGFELD: Okay. Ron Hill? DR. BELSITO: Of course that could change if there's a monomer giving the IG sensitization with

this. DR. MARKS: Yes, that's the occupational asthma you're talking about. DR. BELSITO: Right. DR. MARKS: And that will need to be really talked about in the discussion. DR. BELSITO: In the discussion. DR. MARKS: Yeah. DR. BELSITO: But it goes away after it's all polymerized. DR. MARKS: Right, and really that's exactly right. It's the HDI, which is the agent causing the

occupational asthma. DR. BERGFELD: Don Hill has a comment. DR. HILL: Yeah, and I just wanted to -- and we also discussed yesterday briefly that we wanted

to be very sure about the nature of the crosslinking, that we were always getting urea for a carbamate diester or carbonate diester to make sure that we didn't have any risk for any of these that reversibility to regenerate an isocyanate.

And I reluctantly mentioned yesterday, because I didn't want to cast dispersion where there didn't need to be, that one of the things that was determined to have occurred -- and, again, these toxicologists were there -- after the Bhopal methyl isocyanate released it was glutathione, and blood cell thiols that carried that substance to remote locations in the body and released methyl isocyanate effectively in those tissues. So we need to make sure that there's no chance of that kind of chemistry happening or it's very minimal.

DR. LIEBLER: I think there's no chance of that kind of chemistry happening. DR. HILL: I don't think so either, but those were thiol esters that were produced that


greatly -- (inaudible) reaction to thiols. DR. LIEBLER: As long as we know that all the crosslinks are carbonate diesters, carbamate

diesters, or ureas and nothing else, then we're good. I agree. DR. BERGFELD: All right, call the question. All those in favor of insufficient and all the listed

clarifying -- MS. BECKER: Yes, just the -- before the residual monomers, do you want just one of each type

or do you want every single ingredient? DR. HILL: I wanted every single ingredient, and then if we can't get it because they're not in use,

then we know that's what the deal is. DR. BELSITO: And how long do you want stability for, and what kind of formulations do you want

stability for? DR. SHANK: Stability in the -- pardon me, not an impurity in the ingredient but stability of the HDI

in the polymer when it's put into a formulation and used. DR. BELSITO: So, do you have a specific formulation that you might be most concerned might

break down this polymer? DR. SHANK: I don't, because the chemistry goes beyond my capability. But HDI itself does have

significant toxicity. DR. BELSITO: I understand, but, you know -- so we have data on what's implied, that there's

basically no detectable monomer there. So, now you're saying in formulation what happens -- are their monomers released? Am I understanding your question correctly?

DR. SHANK: Yes. DR. BELSITO: There are hundreds of formulations out there, so, you know, do you want data for

every single formulation that's out there in industry? DR. SHANK: Something that the chemists would feel is representative would work for me. DR. BELSITO: Okay, chemists, can you help industry out as to what you might expect before

they do the data? DR. LIEBLER: Let me just -- if the issue of the stability of the polymer to revert and release

monomer is the question, your -- I don't -- and if that's predicated on the example of the isocyanate reaction with glutathione --

DR. HILL: It wasn't. DR. LIEBLER: Okay. I think that it's -- I don't -- I haven't seen anything that would suggest -- as

in the case of the alkonium clays where the very mild loading conditions suggested to me that mild on could be mild off. I don't see anything, you know, in the chemistry described like that that raises the concern of releasing of the original monomer. I have the question of the residual monomer left over from synthesis that's measurable. It was supplied for one product; we can get, I think, for others -- and then if there is end- capping chemistry, the identity and residual on the end- capping region.

I think that those are the likely issues for reactive chemicals present in these products, and the reversion of the chemistry of the monomer strikes me as very remote. So.

DR. SHANK: That's what I wanted to hear. Thank you. DR. BELSITO: So, do we need that data then? DR. SHANK: I think we just got a very good explanation that that data are not needed. DR. BERGFELD: Ron Hill. DR. HILL: Since this is used at not trivial concentrations in hair conditioners and hair tonics, I

would like something to assure me that we don't under conditions that we're hitting this with a hair dryer. That would be very different than --

DR. BELSITO: If anything, it would cure it more. DR. HILL: I'm telling you we need that information. DR. BERGFELD: Okay, I think that the minutes will reflect that and the summary of what has

been discussed will reflect that.


DR. MARKS: Yes, so I think the stability issue needs to be in the discussion, obviously. DR. BELSITO: A huge discussion point, of course. DR. BERGFELD: All right. DR. MARKS: Okay. DR. BERGFELD: I think we've voted, we've commented, we massaged the chemistry a little bit,

and I think we have a very long list of needs that will have to be addressed.


Safety Assessment of Hexamethylene Diisocyanate (HDI) Polymers

as Used in Cosmetics

Status: Draft Tentative Report for Panel Review Release Date: November 20, 2015 Panel Meeting Date: December 14-15, 2015

The 2015 Cosmetic Ingredient Review Expert Panel members are: Chair, Wilma F. Bergfeld, M.D., F.A.C.P.; Donald V. Belsito, M.D.; Ronald A. Hill, Ph.D.; Curtis D. Klaassen, Ph.D.; Daniel C. Liebler, Ph.D.; James G. Marks, Jr., M.D.; Ronald C. Shank, Ph.D.; Thomas J. Slaga, Ph.D.; and Paul W. Snyder, D.V.M., Ph.D. The CIR Director is Lillian J. Gill, D.P.A. This report was prepared by Lillian C. Becker, 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]


ABSTRACT This is a review of the available scientific literature and unpublished data relevant to assessing the safety of 19 hexamethylene diisocyanate (HDI) polymers as used in cosmetics. These ingredients are composed of copolymers, the monomers of which partially consist of hexamethylene diisocyanate (1,6-diisocyanatohexane) or modified variants of the HDI monomer. The functions of HDI polymers include viscosity increasing agents – aqueous, anticaking agents, and film formers. The Cosmetic Ingredient Review (CIR) Expert Panel (Panel) reviewed available data related to these ingredients. [The conclusion is to be determined]

INTRODUCTION This is a review of the available scientific literature and unpublished data relevant to assessing the safety of 19 HDI

polymers, listed below, as used in cosmetics. These ingredients are composed of copolymers, the monomers of which partially consist of hexamethylene diisocyanate (HDI; also known as 1,6-diisocyanatohexane) or modified variants of HDI. According to the International Cosmetic Ingredient Dictionary and Handbook (Dictionary), the reported functions of HDI polymers include viscosity increasing agents – aqueous, anticaking agents, and film formers (Table 1).1

• HDI/Trimethylol Hexyllactone Crosspolymer • bis-C16-20 Isoalkoxy TMHDI/PEG-90

Copolymer • bis-Hydroxyethyl Acrylate

Poly(1,4-Butanediol)-9/TMHDI Copolymer • bis-Isostearyl 1,4-Butanediol/HDI/Hydrogenated

Dimer Dilinoleyl Alcohol Copolymer • bis-Lauryl Cocaminopropylamine/HDI/PEG-100

Copolymer • bis-Methoxy PEG-10 Dimethyl

MEA/HDI/bis-PEG-10 Dimethicone Copolymer • 1,4-Butanediol/Succinic Acid/Adipic Acid/HDI

Copolymer • Cholesterol/HDI/Pullulan Copolymer • Decyl HDI/PEG-180 Crosspolymer

• Diethylene Glycol/DMAP Acrylamide/ PEG-180/HDI Copolymer

• HDI/Di-C12-14 Alkyl Tartrate/Hydrogenated Dilinoleyl Alcohol Copolymer

• HDI/PEI-45/SMDI Crosspolymer • HDI/PPG/Polycaprolactone Crosspolymer • Methoxy PEG-17/Methoxy PEG-11/HDI

Crosspolymer • Methoxy PEG-17/Methoxy PEG-11/HDI

Isocyanurate Trimer Crosspolymer • PEG-240/HDI Copolymer

bis-Decyltetradeceth-20 Ether • PPG-26/HDI Copolymer • Steareth-100/PEG-136/HDI Copolymer • Stearyl HDI/PEG-50 Copolymer

The CIR Panel has reviewed several of the constituents of these ingredients (Table 2).2-12 Polyethylene glycols

(PEG), PEG-10 dimethicone, adipic acid, succinic acid, cholesterol, pullulan, glycerin, and stearyl alcohol were determined to be safe as used. Methoxy PEG-10, decyltetradeceth-20, steareth-100, and PPG-26 were determined to be safe when formulated to be nonirritating.

The ingredients in this report are copolymers, each of which is synthesized, in part, from the monomer HDI. These ingredients are grouped together because their copolymers originate, in part, from this common diisocyanate monomer or a modified variant of the HDI monomer. Exposure to diisocyanates, such as HDI, in the work place is one of the leading causes of occupational asthma.13 Airway irritation and asthma-like symptoms, hypersensitivity pneumonitis, rhinitis, and accelerated lung deterioration have also been associated with exposure to diisocyanates. Diisocyanates can also cause irritant and allergic contact dermatitis, as well as skin and conjunctival irritation. Diisocyanates may act as haptens, associating with endogenous or extracellular protein carriers to induce an immune response. Covalent binding of a hapten to a protein is believed to be a mechanism for recognition of the allergen by the immune system and subsequent development of allergic responses. The ingredients in this report are not diisocyanates, but are end products of a polymerization process that includes HDI, or a variant thereof, as one of the starting materials (monomers). Accordingly, quantification of any residual HDI, or a variant thereof, in the final cosmetic ingredient may be paramount to determining safety.

CHEMISTRY

Definition, Structure, and Manufacture The definitions and approximate structures of the HDI polymers in this safety assessment are provided in Table 1.

These structures are best representations based on the definitions provided in the Dictionary.1 This group is composed of copolymers, the monomers of which include some variant of HDI (Figure 1).


Figure 1. Hexamethylene Diisocyanate

The other 3 isocyanate monomers herein are modified variants of HDI, namely trimethylhexanediisocyanate (TMHDI), saturated methylene diphenyldiisocyanate (SMDI), or the HDI trimer (Figure 2).

Figure 2. HDI variants. These polymers are produced by reactions of HDI with alkoxy-group-containing monomers, such as alcohols and

polyethers, which also may be used as end-capping units (Figure 3).

Figure 3. Bis-C16-20 Isoalkoxy TMHDI/PEG-90 Copolymer

Some of these polymers are linear, but when tri-functional monomers (e.g., glycerin) are used as reactants, branched

or cross-linked structures are probable. The degree of polymerization of these ingredients can be controlled to obtain a desired functionality, such as rheology modifier. Accordingly, the molecular weights and molecular volumes of these ingredients could vary widely, unless otherwise noted in use specifications. These polymers, by virtue of their monomers, contain both hydrophilic and hydrophobic groups. The ratio of hydrophilic and hydrophobic groups may vary within one ingredient name. In the absence of ingredient-explicit specifications, estimating some of the chemical and physical properties of these ingredients is challenging. These ingredients can potentially range from liquid to solid, soluble to insoluble, or non-penetrating to penetrating into the skin. However, aside from the potential presence of a diisocyanate or end-capping agent residue, these ingredients are likely to be similar to polyurethane-type polymers.

HDI/di-C12-14 alkyl tartrate/hydrogenated dilinoleyl alcohol copolymer is manufactured by the condensation of an isocyanate component (HDI) and molecules containing hydroxyl groups, specifically esters of tartaric acids and alkylic diol (di-C12-14 alkyl tartrate/hydrogenated dilinoleyl alcohol). Polymerization is terminated by the addition of ethyl alcohol (i.e., ethyl alcohol end-caps the polymer).


Physical and Chemical Properties As stated above, the physical and chemical properties of each these ingredients could vary widely depending on method of manufacture and the resulting structure and molecular weight. Available physical and chemical properties are presented in Table 3.

A supplier reported that HDI/trimethylol hexyllactone crosspolymer was available in two grades for cosmetics.14-16 The particle size distribution for grade 1 was reported to be: 100% <100 µm, 33.8% <10 µm, 5.5% <1 µm. The particle size distribution for grade 2 was reported to be: 100% <100 µm, 87.5% <10 µm, 7.1% <1 µm. Analysis of HDI/trimethylol hexyllactone crosspolymer from a second supplier showed that the overall distribution was: 100% <100 µm, 15.15% ≤10.42 µm, and 0% <1 µm (Table 4).

The reported molecular weights of these HDI polymers range from <500 Da to 75,000 Da.17-21 For the molecular weight range of bis-C16-20 isoalkoxy TMHDI/PEG-90 copolymer, 1.5% was reported to be <1000 Da and 1.2% was <500 Da.20 In analysis of bis-lauryl cocaminopropylamine/HDI/PEG-100 copolymer, HDI/di-C12-14 alkyl tartrate/hydrogenated dilinoleyl alcohol copolymer, and steareth-100/PEG-136/HDI copolymer, no particles of <1000 Da were detected.18,19,21 The molecular weights of three batches of PEG-240/HDI copolymer bis-decyltetradeceth-20 ether were reported to range from approximately 4000-75,000 Da.17

Impurities The ingredients bis-lauryl cocaminopropylamine/HDI/PEG-100 copolymer and bis-C16-20 isoalkoxy TMHDI/PEG-90 copolymer were reported to contain <1 ppm mercury, <3 ppm arsenic, and <10 ppm lead.22 The residual amount of HDI in HDI/di-C12-14 alkyl tartrate/hydrogenated dilinoleyl alcohol copolymer is reported to be <0.5 ppm.21 In an analysis of 3 batches of PEG-240/HDI copolymer bis-decyltetradeceth-20 ether, ethylene oxide (detection limit <1 ppm) and dioxane (detection limit <10 ppm) were not detected.17 Formaldehyde was detected at 1 and 2 ppm. No residual HDI was detected (detection limit <20 ppm). According to a product safety sheet, methoxy PEG-17/methoxy PEG-11/HDI isocyanurate trimer crosspolymer is not expected to contain antimony, arsenic, bismuth, cadmium, chromium, copper, iron, lead, mercury, manganese, nickel, palladium, platinum, and tin.23 Zinc may be present as a technical impurity at <25 ppm. Dibutyl phosphate may be present at a maximum concentration of approximately 100 ppm. Zinc 2-ethylhexanoate may be present at a maximum concentration of approximately 80 ppm. It is expected that there will be approximately 1% residual water and that no volatile organic materials will persist by the end of the drying process. Butylhydroxytoluene (BHT) may be present as a technical impurity at <20 ppm.

USE Cosmetic

The safety of the cosmetic ingredients included in this safety assessment is evaluated based on the data the Panel receives from the U.S. Food and Drug Administration (FDA) and the cosmetics industry on the expected cosmetic use of ingredients. The data from the FDA are those it collects from manufacturers on the use of individual ingredients in cosmetics by cosmetic product category in its Voluntary Cosmetic Registration Program (VCRP). Those received from the cosmetic industry are submitted in response to a survey conducted by the Personal Care Products Council (Council) of the maximum reported use concentrations by category.

According to the 2015 VCRP data, HDI/trimethylol hexyllactone crosspolymer has the greatest number of reported uses and is reported to be used in 354 formulations, which includes 348 leave-on products and 6 rinse-off products (Table 5).24 Fifty of these formulations are powders, 13 are lipsticks, and 329 have dermal contact. Five other ingredients were reported by the VCRP to be used in 21 or fewer cosmetic formulations. According to the 2015 Council survey, the highest maximum concentration of use of the ingredients in this safety assessment was reported to be 31% for HDI/trimethylol hexyllactone crosspolymer in foundations, a leave-on product; it is also used up to 11.7% in rinse-off products.25,26 The next highest reported concentrations of use are for HDI/PPG/polycaprolactone crosspolymer (up to 11.8% in face powders) and steareth-100/PEG-136/HDI copolymer (up to 2.5% in tonics, dressings and other hair grooming aids). Table 6 lists the HDI polymers with no reported uses. HDI/di-C12-14 alkyl tartate/hydrogenated dilinoleyl alcohol copolymer, HDI/trimethylol hexyllactone crosspolymer, and methoxy PEG-17/methoxy PEG-11/HDI crosspolymer were reported to be used in formulations that come in contact with mucus membranes (highest concentration reported to be 15.1%). HDI/trimethylol hexyllactone crosspolymer, HDI/di-C12-14 alkyl tartrate/hydrogenated dilinoleyl alcohol copolymer, and methoxy PEG-17/methoxy PEG-11/HDI crosspolymer were reported to be used in formulations that could be incidentally ingested (highest concentration reported to be 15.1%). HDI/di-C12-14 alkyl tarrate/hydrogenated dilinoleyl alcohol copolymer, HDI/trimethylol hexyllactone crosspolymer, HDI/PPG/polycaprolactone crosspolymer, and PEG-240/HDI copolymer bis-decyletradeceth-20 ether were reported to be used in formulations that are applied near the eye (highest concentration reported to be 19.6%).

HDI/trimethylol hexyllactone crosspolymer, diethylene glycol/DMAP acrylamide/PEG-180/HDI copolymer, HDI/PPG/polycaprolactone crosspolymer, PEG-240/HDI copolymer bis-decyltetradeceth-20 ether, and steareth-100/PEG-


136/HDI copolymer were reported to be used in tonics, dressings and other hair grooming aids; face and neck products; body and hand products; and indoor tanning preparations that may be sprays and could possibly be inhaled. The highest reported aerosol use of these ingredients is reportedly 2.5%. In practice, 95% to 99% of the droplets/particles released from cosmetic sprays have aerodynamic equivalent diameters >10 µm.27-30 Therefore, most droplets/particles incidentally inhaled from cosmetic sprays would be deposited in the nasopharyngeal and bronchial regions and would not be respirable (i.e., they would not enter the lungs) to any appreciable amount.28,29

Diethylene glycol/DMAP acrylamide/PEG-180/HDI copolymer is restricted under the rules governing cosmetic products in the European Union; none of the other ingredients in this report are restricted from use in any way.31 Specifically, the European Union restricts the content of traces of diethylene glycol to a total of 0.1% in any finished cosmetic product, including the amount of diethylene glycol as traces in ingredients contained in polymers, such as diethylene glycol/DMAP acrylamide/PEG-180/HDI copolymer.

TOXICOKINETICS Absorption, Distribution, Metabolism, and Excretion

Data on toxicokinetics of HDI polymers were not found in the published literature and no unpublished data were provided.

TOXICOLOGICAL STUDIES

Single Dose (Acute) Toxicity Dermal

Data on acute dermal toxicity of HDI polymers were not found in the published literature and no unpublished data were provided.

Oral – Non-Human The acute oral LD50 was >10,000 mg/kg in rats (n=5/sex) for a product consisting of bis-cocaminopropylamine/HDI/ PEG-100 copolymer (concentration not specified) and butylene glycol.32

HDI/trimethylol hexyllactone crosspolymer (5000 mg/kg) administered by intragastric feeding caused no clinical signs or mortalities (Table 7).14-16 The oral LD50 of methoxy PEG-17/methoxy PEG-11/HDI isocyanurate trimer crosspolymer was reported to be >2000 mg/kg in rats.23 The oral LD50 of PEG-240/HDI copolymer bis-decyltetradeceth-20 ether was reported to be >2000->2500 mg/kg in rats.17 The oral LD50 for steareth-100/PEG-136/HDI copolymer was reported to be >10,000 mg/kg in rats; clinical signs included bristled fur, diarrhea and dirty fur around the anal region due to feces.18 Inhalation – Non-Human METHOXY PEG-17/METHOXY PEG-11/HDI ISOCYANURATE TRIMER CROSSPOLYMER The acute inhalation LC50 of methoxy PEG-17/methoxy PEG-11/HDI isocyanurate trimer crosspolymer was reported to be >1.99 mg/L when administered in a dust/mist for 4 h in rats.23 The test was conducted in accordance with the Organization for Economic Cooperation and Development Test Guideline (OECD TG) 403.

Repeated Dose Toxicity Data on dermal, oral, or inhalation repeated dose toxicity of HDI polymers were not found in the published literature

and no unpublished data were provided.

REPRODUCTIVE AND DEVELOPMENTAL TOXICITY Data on the reproductive and developmental toxicity of HDI polymers were not found in the published literature and

no unpublished data were provided.

GENOTOXICITY METHOXY PEG-17/METHOXY PEG-11/HDI ISOCYANURATE TRIMER CROSSPOLYMER

Methoxy PEG-17/methoxy PEG-11/HDI isocyanurate trimer crosspolymer (concentration not specified) was not mutagenic in an Ames test, with or without metabolic activation.23

PEG-240/HDI COPOLYMER BIS-DECYLTETRADECETH-20 ETHER

PEG-240/HDI copolymer bis-decyltetradeceth-20 ether (concentration not specified) was not genotoxic when tested in accordance with OECD TG 471 (bacterial reverse-mutation test).17 No further details were provided.


STEARETH-100/PEG-136/HDI COPOLYMER In an Ames test conducted according to OECD GL 471, steareth-100/PEG-136/HDI copolymer was not mutagenic

to Salmonella typhimurium (strains TA98, TA100, TA1535, and TA1537) and Escherichia coli (strain WP2uvA) at up to 5000 µg/plate.18

CARCINOGENICITY

Data on the carcinogenicity of HDI polymers were not found in the published literature and no unpublished data were provided.

IRRITATION AND SENSITIZATION Irritation

Dermal – Non-Human HDI/trimethylol hexyllactone crosspolymer (100%), Methoxy PEG-17/methoxy PEG-11/HDI isocyanurate trimer

crosspolymer (concentration not specified), steareth-100/PEG-136/HDI copolymer (100%; 0.5 g; dry) were not dermal irritants in rabbits (Table 8). 14-16,18,23 PEG-240/HDI copolymer bis-decyltetradeceth-20 ether was not a dermal irritant in guinea pigs up to 30%.17 Dermal – Human HDI/TRIMETHYLOL HEXYLLACTONE CROSSPOLYMER

HDI/trimethylol hexyllactone crosspolymer (100% as a dry powder) was not a dermal irritant in a human patch test (Table 8).14-16 Two foundations containing HDI/di-C12-14 alkyl tartrate/ hydrogenated dilinoleyl alcohol copolymer (1.7% and 3.19%) were not irritating in human patch tests.21

Dermal - In Vitro BIS-C16-20 ISOALKOXY TMHDI/PEG-90 COPOLYMER

A mixture containing 30% bis-C16-20 isoalkoxy TMHDI/PEG-90 copolymer (16.67%, 50%, and 100% in water; actual concentration: 5%, 15%, 30%) was tested for potential sensitization using an EpiDerm™ Skin Model In Vitro Toxicity Testing System.20 The assay did not result in a significant reduction in normal human-derived epidermal keratinocytes. The test substance is predicted to be non-irritating.

METHOXY PEG-17/METHOXY PEG-11/HDI ISOCYANURATE TRIMER CROSSPOLYMER Methoxy PEG-17/methoxy PEG-11/HDI isocyanurate trimer crosspolymer (concentration not specified) was predicted to be non-irritating to the skin in an in vitro test for corrosion of human skin.23 The test was conducted in accordance with the OECD TG 431.

Methoxy PEG-17/methoxy PEG-11/HDI isocyanurate trimer crosspolymer (concentration not specified) was predicted to be non-irritating in an in vitro test for skin irritation using reconstructed human epidermis.23 The test was conducted in accordance with the OECD TG 439. PEG-240/HDI COPOLYMER BIS-DECYLTETRADECETH-20 ETHER

The reported ET50 (effective time of exposure to reduce tissue viability to 50%) for PEG-240/HDI copolymer bis-decyltetradeceth-20 ether in a EpiDerm MTT Viability Assay was reported to be >24.0 h.17 The test substance was rated as non-irritating. No further details were provided.

Ocular – Non-Human – In Vivo HDI/TRIMETHYLOL HEXYLLACTONE CROSSPOLYMER

In an eye irritation study of HDI/trimethylol hexyllactone crosspolymer (100%), mild to moderate conjunctival redness and mild chemosis were observed in 4 of 6 rabbits 24 and 48 h after administration into the eyes (Table 9).14-16 The authors considered the particle size (at least 92.9% > 1 µm; Table 4) and the water insolubility of the tested polymer and concluded that the eye irritation observed was likely attributable to mechanical abrasion rather than to chemical irritancy. Methoxy PEG-17/methoxy PEG-11/HDI isocyanurate trimer crosspolymer (concentration not specified) was a slight irritant in rabbits.23 PEG-240/HDI copolymer bis-decyltetradeceth-20 ether (up to 30%) was not an ocular irritant in rabbits.17 Steareth-100/PEG-136/HDI copolymer (100%) was classified as a non-irritant in the eyes of rabbits.18

Ocular – In Vitro PEG-240/HDI COPOLYMER BIS-DECYLTETRADECETH-20 ETHER

The reported RC50 (the concentration at which 50% of the treated eggs show a positive response) for PEG-240/HDI copolymer bis-decyltetradeceth-20 ether in a chorioallantoic membrane vascular assay (CAMVA) was >100%.17 No further details were provided.


The reported score for PEG-240/HDI copolymer bis-decyltetradeceth-20 ether in a bovine corneal opacity and permeability (BCOP) assay was calculated to be approximately 2.74.17 No further details of the study were provided. A score of 0-3 indicate an ocular non-irritant.

Sensitization

Non-Human METHOXY PEG-17/METHOXY PEG-11/HDI ISOCYANURATE TRIMER CROSSPOLYMER

In a Magnusson Kligman maximization test, methoxy PEG-17/methoxy PEG-11/HDI isocyanurate trimer crosspolymer (concentration not specified) was not sensitizing in guinea pigs (Table 10).23 In a skin sensitization assay (species not specified), PEG-240/HDI copolymer bis-decyltetradeceth-20 ether (30%) was not a dermal sensitizer.17

Human HDI/TRIMETHYOL HEXYLLACTONE CROSSPOLYMER In human repeated insult patch tests (HRIPT) of 2 foundations containing HDI/trimethylol hexyllactone crosspolymer (30.7% and 10%), there were no signs of dermal irritation or allergic contact dermatitis observed (Table 10).33,34 In an HRIPT of bis-C16-20 isoalkoxy TMHDI/PEG-90 copolymer (30%), 1 subject exhibited barely perceptible erythema 48 h after the challenge.20 In an HRIPT of PEG-240/HDI copolymer bis-decyltetradeceth-20 ether (concentration not specified) there was no evidence of dermal irritation or allergic contact sensitization.17

SUMMARY

This is a review of the scientific literature and unpublished data relevant for assessing the safety of 19 HDI polymers as used in cosmetics. These ingredients consist of copolymers, the monomers of which are partially comprised of hexamethylene diisocyanate (1,6-diisocyanatohexane). The functions of HDI polymers include viscosity increasing agents-aqueous, anticaking agents, and film formers.

Exposure to diisocyanates, such as HDI, has caused occupational asthma, hypersensitivity pneumonitis, rhinitis, and accelerated lung deterioration.

The residual amount of HDI in HDI/di-C12-14 alkyl tartrate/hydrogenated dilinoleyl alcohol copolymer was reported to be <0.5 ppm. In an analysis of 3 batches of PEG-240/HDI copolymer bis-decyltetradeceth-20 ether, no residual HDI was detected (detection limit <20 ppm).

According to the 2015 VCRP data, HDI/trimethylol hexyllactone crosspolymer is used in 354 formulations, 348 of which are leave-on products and 6 of which are rinse-off products. The highest concentration of use was reported to be 31% for HDI/trimethylol hexyllactone crosspolymer in leave-on products. The next highest reported concentrations of use are for HDI/PPG/polycaprolactone crosspolymer which is used up to 11.8% in face powders and steareth-100/PEG-136/HDI copolymer which is used up to 2.5% in tonics, dressings and other hair grooming aids.

The acute oral LD50 was >10,000 mg/kg in rats for a product consisting of bis-cocaminopropylamine/HDI/ PEG-100 copolymer and butylene glycol. In an acute oral toxicity study using rats, a dose of 5000 mg/kg HDI/trimethylol hexyllactone crosspolymer administered by intragastric feeding caused no clinical signs or mortalities. The oral LD50 of methoxy PEG-17/methoxy PEG-11/HDI isocyanurate trimer crosspolymer was reported to be >2000 mg/kg in rats. The acute oral LD50 for PEG-240/HDI copolymer bis-decyltetradeceth-20 ether ranged from >2000->2500 mg/kg in rats. The oral LD50 for steareth-100/PEG-136/HDI copolymer was reported to be >10,000 mg/kg in rats.

The acute inhalation LC50 of methoxy PEG-17/methoxy PEG-11/HDI isocyanurate trimer crosspolymer was reported to be >1.99 mg/L for a 4-h exposure.

Methoxy PEG-17/methoxy PEG-11/HDI isocyanurate trimer crosspolymer and steareth-100/PEG-136/HDI copolymer were not mutagenic in Ames tests. PEG-240/HDI copolymer bis-decyltetradeceth-20 ether was not genotoxic in a bacterial reverse mutation assay.

HDI/trimethylol hexyllactone crosspolymer at 100% was not a dermal irritant of the intact or abraded skin of rabbits. Methoxy PEG-17/methoxy PEG-11/HDI isocyanurate trimer crosspolymer was reported to be dermally non-irritating in rabbits. PEG-240/HDI copolymer bis-decyltetradeceth-20 ether up to 30% was not a dermal irritant in guinea pigs in irritation assays. Steareth-100/PEG-136/HDI copolymer at 100% was not dermally irritating to rabbits.

Foundations containing HDI/di-C12-14 alkyl tartrate/hydrogenated dilinoleyl alcohol copolymer at 1.7% and 3.19% were not irritating in human primary skin irritation tests. In a human patch test of HDI/trimethylol hexyllactone crosspolymer at 100% (as a dry powder), there were no effects observed when the patch was removed.

In an EpiDerm™ Skin Model In Vitro Toxicity Testing System, a mixture containing bis-C16-20 isoalkoxy TMHDI/PEG-90 copolymer at up to 30% was predicted to be non-irritating. Methoxy PEG-17/methoxy PEG-11/HDI isocyanurate trimer crosspolymer (concentration not specified) was predicted to be non-irritating in an in vitro test for corrosion of human skin and in an in vitro test for skin irritation using reconstructed human epidermis. The reported ET50 for PEG-240/HDI copolymer bis-decyltetradeceth-20 ether in an EpiDerm MTT Viability Assay was reported to be >24 h.

HDI/trimethylol hexyllactone crosspolymer at 100% was a slight ocular irritant (thought to be due to mechanical abrasion) but was not an ocular irritant according to the approved criteria of NOHSC. Methoxy PEG-17/methoxy PEG-11/HDI isocyanurate trimer crosspolymer was a slight irritant in rabbits in an acute eye irritation/corrosion assay. PEG-


240/HDI copolymer bis-decyltetradeceth-20 ether was not an ocular irritant up to 30% in rabbits. Steareth-100/PEG-136/HDI copolymer at 100% was classified as a non-irritant in the eyes of rabbits

The ocular RC50 was >100% and the BCOP score was 2.74 for PEG-240/HDI copolymer bis-decyltetradeceth-20 ether.

Methoxy PEG-17/methoxy PEG-11/HDI isocyanurate trimer crosspolymer was not sensitizing in guinea pigs in a Magnusson/Kligman maximization test. PEG-240/HDI copolymer bis-decyltetradeceth-20 ether, up to 30%, was not a dermal sensitizer when challenged up to 30%.

In a HRIPT, bis-C16-20 isoalkoxy TMHDI/PEG-90 copolymer at 30% was not a dermal sensitizer. In HRIPTs of 2 foundations containing HDI/trimethylol hexyllactone crosspolymer at 10% and 30.7%, there were no signs of dermal irritation or allergic contact dermatitis observed. In a HRIPT, PEG-240/HDI copolymer bis-decyltetradeceth-20 ether did not demonstrate any indication of dermal irritation or allergic contact sensitization.

DRAFT DISCUSSION

[The Discussion section will be further developed at the December, 2015 Panel meeting] The CIR Expert Panel examined the available data, which included method of manufacture and impurity data, acute

oral and inhalation toxicity, genotoxicity, dermal and ocular irritation data, and sensitization data. These ingredients are not mutagenic and studies present no evidence of toxicity at concentration of use levels. The results of the assays for ocular and dermal irritation and dermal sensitization showed that there were no concerns that these ingredients would be irritating or sensitizing under the conditions of use. The Panel noted that these ingredients are large, unreactive molecules that will not penetrate uncompromised skin.

The Panel noted that the HDI monomer can cause occupational asthma, hypersensitivity pneumonitis, rhinitis, and accelerated lung deterioration. After examining the method of manufacture and impurity data, the Panel was comfortable that there would not be any residual HDI monomer, or the related TMHDI, decyl HDI, and SMDI monomers, in these ingredients. Manufacturers and formulators should continue to use good manufacturing practices to ensure that these monomers are not present in these ingredients and in formulation.

The CIR Expert Panel recognizes that there are data gaps regarding use and concentration of these ingredients. However, the overall information available on the types of products in which these ingredients are used and at the concentrations provided indicate a pattern of use which was considered by the Expert Panel in assessing safety.

Unpublished data on steareth-100/PEG-136/HDI copolymer were submitted with the suggestion that the data be used as read across for HDI/di-C12-14 alkyl tartrate/hydrogenated dilinoleyl alcohol copolymer, bis-C16-20 isoalkoxy TMHDI/PEG-90 copolymer, bis-lauryl cocaminopropylamine/HDI/PEG-100 copolymer; the Panel found the data to be appropriate for read across. Although there were noted gaps in the available safety data for other HDI polymers in this safety assessment, the available data on many of the ingredients are sufficient, and similarity between structure activity relationships can be extrapolated to support the safety of the entire group.

The Panel discussed the issue of incidental inhalation exposure from tonics, dressings and other hair grooming aids; face and neck products; body and hand products; and indoor tanning preparations that may be sprays. Limited data available from an acute inhalation study suggest little potential for respiratory effects at relevant doses. The Panel noted that 95%-99% of droplets/particles would not be respirable to any appreciable amount. Coupled with the small actual exposure in the breathing zone and the concentrations at which the ingredients are used, the available information indicates that incidental inhalation would not be a significant route of exposure that might lead to local respiratory or systemic effects. The Panel considered other data available to characterize the potential for HDI polymer to cause systemic toxicity, irritation, sensitization, and genotoxicity. A detailed discussion and summary of the Panel’s approach to evaluating incidental inhalation exposures to ingredients in cosmetic products is available at http://www.cir-safety.org/cir-findings.

CONCLUSION

To be determined.


http://www.cir-safety.org/cir-findings

TABLES

Table 1. Definitions, idealized structures, and functions of the HDI polymers in this safety assessment.1,CIR Staff Ingredient/CAS No. Definition Function HDI/Trimethylol Hexyllactone Crosspolymer

HDI/Trimethylol Hexyllactone Crosspolymer is a cross-linked condensation polymer formed from the reaction of hexamethylene diisocyanate (HDI) with the esterification product of trimethylolpropane with 6 to 7 moles [equivalents] of hexyllactone.

Anticaking agent

bis-C16-20 Isoalkoxy TMHDI/PEG-90 Copolymer

Bis-C16-20 Isoalkoxy TMHDI/PEG-90 Copolymer is a copolymer of trimethylhexanediisocyanate (TMHDI) and PEG-90 end-capped with a branched alcohol containing 16 to 20 carbons.

Viscosity increasing agent - aqueous

[one example of an “iso”] bis-Hydroxyethyl Acrylate Poly(1,4-Butanediol)-9/TMHDI Copolymer

bis-Hydroxyethyl Acrylate Poly(1,4-Butanediol)-9/TMHDI Copolymer is a copolymer of poly(1,4-butanediol)-9 and trimethylhexanediisocyanate (TMHDI) end-capped with hydroxyethylacrylate.

Film former

bis-Isostearyl 1,4-Butanediol/ HDI/Hydrogenated Dimer Dilinoleyl Alcohol Copolymer

bis-Isostearyl 1,4-Butanediol/HDI/Hydrogenated Dimer Dilinoleyl Alcohol Copolymer is a copolymer of hexamethylene diisocyanate (HDI), and hydrogenated dilinoleyl alcohol endcapped with isostearyl 1,4-butanediol.

Viscosity increasing agent - nonaqueous

bis-Lauryl Cocaminopropylamine/HDI/ PEG-100 Copolymer

bis-Lauryl Cocaminopropylamine/HDI/PEG-100 Copolymer is a copolymer of cocoaminopropylamine, PEG-100, and hexamethylene diisocyanate (HDI) end-capped with lauryl alcohol.

Viscosity increasing agent - nonaqueous

[wherein R represents the fatty alkyl chain residues from coconut] bis-Methoxy PEG-10 Dimethyl MEA/HDI/bis-PEG-10 Dimethicone Copolymer

bis-Methoxy PEG-10 Dimethyl MEA/HDI/bis-PEG-10 Dimethicone Copolymer is a copolymer of hexamethylene diisocyanate (HDI), dimethylethanolamine and bis-PEG-10 dimethicone endcapped with PEG-10 monomethyl ether.

Hair conditioning agent

1,4-Butanediol/Succinic Acid/Adipic Acid/HDI Copolymer 119553-67-2

1,4-Butanediol/Succinic Acid/Adipic Acid/HDI Copolymer is a copolymer of 1,4-butanediol, succinic acid, adipic acid, and hexamethylene diisocyanate monomers.

Abrasive, binder, film former

Cholesterol/HDI/Pullulan Copolymer

Cholesterol/HDI/Pullulan Copolymer is a copolymer of cholesterol, hexamethylene diisocyanate, and pullulan monomers.

Emulsion stabilizer, humectant, viscosity increasing agent - aqueous


Table 1. Definitions, idealized structures, and functions of the HDI polymers in this safety assessment.1,CIR Staff Ingredient/CAS No. Definition Function Decyl HDI/PEG-180 Crosspolymer

Decyl HDI/PEG-180 Crosspolymer is a copolymer of hexylmethylene diisocyanate (HDI), PEG-180, and decyl alcohol monomers crosslinked with glycerin.

Viscosity increasing agent - aqueous

[wherein R is glycerin, PEG-180, or decyl alcohol] Diethylene Glycol/DMAP Acrylamide/PEG-180/HDI Copolymer

Diethylene Glycol/DMAP Acrylamide/PEG-180/HDI Copolymer is a copolymer of diethylene glycol, dimethylaminopropyl (DMAP) acrylamide, PEG-180, and hexamethylene diisocyanate (HDI) monomers.

Hair conditioning agents/ skin protectants, skin-conditioning agent - miscellaneous

[wherein n is 2 or 180] HDI/Di-C12-14 Alkyl Tartrate/Hydrogenated Dilinoleyl Alcohol Copolymer 1268856-56-9

HDI/Di-C12-14 Alkyl Tartrate/Hydrogenated Dilinoleyl Alcohol Copolymer is a copolymer of 1,6-hexamethylene diisocyanate (HDI), di-C12-14 alkyl tartrate, and hydrogenated dilinoleyl alcohol, chain-terminated by ethyl alcohol.

Film former

HDI/PEI-45/SMDI Crosspolymer

HDI/PEI-45/SMDI Crosspolymer is the crosslinked polymer formed by the reaction of PEI-45 with saturated methylene diphenyldiisocyanate (SMDI) and hexamethylene diisocyanate (HDI). [PEI is an acronym for polyethylenimine.]

Absorbent, dispersing agent - nonsurfactant

[crosslinker/crosslinking is not defined] HDI/PPG/Polycaprolactone Crosspolymer 302791-95-3

HDI/PPG/Polycaprolactone Crosspolymer is a cross-linked condensation polymer of polycaprolactone, a sorbitol initiated polypropylene glycol with hexamethylene diisocyanate and trimethylolpropane.

Anticaking agents, bulking agent

[wherein R is the residue of HDI and either PPG or Polycaprolactone] Methoxy PEG-17/Methoxy PEG-11/HDI Crosspolymer

Methoxy PEG-17/Methoxy PEG-11/HDI Crosspolymer is a copolymer of methoxy PEG-17, methoxy PEG-11, and hexamethylene diisocyanate (HDI) crosslinked by water and the addition of sodium hydroxide.

Anticaking agent

[wherein R is a PEG chain or another HDI residue]


Table 1. Definitions, idealized structures, and functions of the HDI polymers in this safety assessment.1,CIR Staff Ingredient/CAS No. Definition Function Methoxy PEG-17/Methoxy PEG-11/HDI Isocyanurate Trimer Crosspolymer

Methoxy PEG-17/Methoxy PEG-11/HDI Isocyanurate Trimer Crosspolymer is a copolymer of methoxy PEG-17, methoxy PEG-11, and hexamethylene diisocyanate (HDI) trimer in which the free isocyanate groups are crosslinked by water to form urea linkages.

Anticaking agent

[wherein R is a PEG chain and R’ is either hydrogen or part of a urea-like linkage with another HDI trimer] PEG-240/HDI Copolymer bis-Decyltetradeceth-20 Ether

PEG-240/HDI Copolymer bis-Decyltetradeceth-20 Ether is a copolymer of PEG-240, decyltetradeceth-20, and hexamethylene diisocyanate monomers.

Viscosity increasing agent – aqueous

PPG-26/HDI Copolymer PPG-26/HDI Copolymer is a copolymer of hexamethylene diisocyanate and

PPG-26 monomers. Film former, plasticizer

Steareth-100/PEG-136/HDI Copolymer 103777-69-1

Steareth-100/PEG-136/HDI Copolymer is a copolymer of steareth-100, PEG-136, and hexamethylene diisocyanate monomers.

Viscosity increasing agent – aqueous


Stearyl HDI/PEG-50 Copolymer is a copolymer of hexylmethylene diisocyanate, PEG-50, and stearyl alcohol monomers.

Film former

Table 2. Previous safety assessments of components/monomers of HDI polymers in this safety assessment.

Constituent and ingredient group report Conclusion

Maximum reported concentration of use

reported for ingredients in the latest safety assessment

or re-review Reference Polyethylene glycols (PEGs) - triethylene glycol and any PEGs ≥ 4

Safe for use in cosmetics in the present practices of use and concentration.

85% 2,4,7

PEG-10 dimethicone - polyoxyalkylene siloxane copolymers, alkyl-polyoxyalkylene siloxane copolymers, and related ingredients


22% hair; 15% dermal 3,5

Methoxy PEG-10, decyltetradeceth-20, steareth-100 - alkyl PEG ethers

Safe as used when formulated to be nonirritating

32% in a product to be diluted; 25%

9

Adipic acid, succinic acid - dicarboxylic acids, salts, and esters


26% in a product to be diluted; 0.4%

10

Cholesterol Safe as used. 3% 8,35 Pullulan - microbial polysaccharide gums Safe for use in cosmetics in the present

practices of use and concentration. 12% hair; 17% in oral hygiene; 6% in dermal

11

Glycerin Safe for use in cosmetics in the present practices of use and concentration.

99.4% 6

PPG-26 - propylene glycol, tripropylene glycol, and PPGs

Safe as used when formulated to be nonirritating.

99% in product to be diluted; 73% in dermal

12

Stearyl alcohol with oleyl alcohol and octyl dodecanol

Safe as used. 56% 6,35


Table 3. Chemical and physical properties of hexamethylene diisocyanate polymers.

Property Value Reference

HDI/trimethylol hexyllactone crosspolymer Physical Form Fine powder 14-16 Color White to pale yellow 14-16 Molecular Weight g/mol >10 000 14-16 Density/Specific Gravity @ 20oC 1100-1250 14-16 Melting Point oC >225 14-16

Bis-C16-20 isoalkoxy TMHDI/PEG-90 copolymer Color Translucent 22,36 Molecular Weight g/mol Average >7000 20 Density/Specific Gravity @ 25oC 1.03-1.08 20 Viscosity kg/(s m)@ oC 3-10 20

Bis-Lauryl Cocaminopropylamine/HDI/PEG-100 Copolymer Color Translucent 22 Molecular Weight g/mol >10,000 19

HDI/di-C12-14 alkyl tartrate/hydrogenated dilinoleyl alcohol copolymer Physical Form Viscous liquid 21 Color Yellow 21 Odor Characteristic 21 Molecular Weight g/mol >25,000 21 Viscosity kg/(s m)@ 25oC 3-5 21

Methoxy PEG-17/Methoxy PEG-11/HDI Isocyanurate Trimer Crosspolymer Physical Form Solid, powder, granules 23 Color White 23 Odor Odorless 23 Molecular Weight g/mol <1000 37 Bulk Density kg/m3 @ 20 oC ~246 23 Melting Point oC >200 23

PEG-240/HDI Copolymer bis-Decyltetradeceth-20 Ether Molecular Weight g/mol 4000-75,000 17

Steareth-100/PEG-136/HDI copolymer Physical Form Powder 38 Color White 38 Molecular Weight g/mol >15,000 18 Melting Point oC 53-63 38 Water Solubility Dispersible 38

Table 4. Reported particle size distribution for 2 grades of HDI/trimethylol hexyllactone crosspolymer from 1 supplier

and another sample from a second supplier.14-16

<100 µm (%)

<10 µm (%)

<1 µm (%)

Median diameter

(µm) Grade 1 100 33.8 5.5 12.54 Grade 2 100 87.5 7.1 6.16 Second supplier 100 15.15* 0 12.0-18.0** * ≤ 10.42 µm ** Average diameter


Table 5. Frequency of use according to duration and exposure of HDI polymers.24-26

Use type Uses

Maximum Concentration

(%) Uses


(%) Uses


(%) Uses


(%)

HDI/Trimethylol Hexyllactone Crosspolymer

Bis-C16-20 Isoalkoxy TMHDI/PEG-90

Copolymer

Diethylene Glycol/DMAP

Acrylamide/PEG-180/ HDI Copolymer

HDI/Di-C12-14 Alkyl Tartrate/Hydrogenated

Dilinoleyl Alcohol Copolymer

Total/range 354 0.0096-31 NR 0.6 6 NR NR 0.026-7.6 Duration of usea

Leave-on 348 0.0096-31 NR 0.6 1 NR NR 0.026-7.6 Rinse-off 6 11.7 NR NR 5 NR NR NR

Diluted for (bath) use NR NR NR NR NR NR NR NR

Exposure type Eye area 118 0.049-19.6 NR 0.6 NR NR NR 1.2

Incidental ingestion 13 0.0096-15.1 NR NR NR NR NR 0.026-7.6

Incidental Inhalation-sprays 34b; 33c NR NR NR 1b NR NR NR

Incidental inhalation-powders

50; 33c 3-12.6; 0.78-14.4d NR NR NR NR NR NR

Dermal contact 329 0.059-31 NR NR NR NR NR 1.2 Deodorant (underarm) NR NR NR NR NR NR NR NR

Hair-noncoloring NR NR NR NR 6 NR NR NR Hair-coloring NR NR NR NR NR NR NR NR

Nail 1 0.21-0.96 NR NR NR NR NR NR Mucous

Membrane 13 0.0096-15.1 NR NR NR NR NR 0.026-7.6

Baby NR NR NR NR NR NR NR NR

HDI/PPG/ Polycaprolactone

Crosspolymer

Methoxy PEG-17/ Methoxy PEG-11/ HDI

Crosspolymer

PEG-240/HDI Copolymer

bis-Decyltetradeceth-20 Ether

Steareth-100/PEG-136/ HDI Copolymer

Total/range 21 2-11.8 1 0.025 2 1-2 1 0.87-2.5 Duration of use

Leave-on 21 2-11.8 1 0.025 2 1-2 1 1.6-2.5 Rinse-off NR NR NR NR NR 1 NR 0.87

Diluted for (bath) use NR NR NR NR NR NR NR NR

Exposure type Eye area 4 5-9.8 NR NR 1 1.9-2 NR NR

Incidental ingestion NR NR 1 NR NR NR NR NR

Incidental Inhalation-sprays 5b; 2c NR NR NR 1b 2b NR 2.5b

Incidental inhalation-powders 3; 2c 3-11.8;

2-10.8d NR NR NR 2d NR NR

Dermal contact 19 2-11.8 NR 0.025 2 1-2 NR 1.6 Deodorant (underarm)

NR NR NR NR NR NR NR 1.6e

Hair-noncoloring NR NR NR NR NR 1-2 1 2.5 Hair-coloring NR NR NR NR NR 1 NR 0.87

Nail NR NR NR NR NR NR NR NR Mucous

Membrane NR NR 1 NR NR NR NR NR

Baby NR NR NR NR NR NR NR NR NR = Not Reported; NS = Not Surveyed; Totals = Rinse-off + Leave-on Product Uses. Note: Because each ingredient may be used in cosmetics with multiple exposure types, the sum of all exposure type uses may not equal the sum total uses. a 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. b It is possible these products may be sprays, but it is not specified whether the reported uses are sprays. c Not specified whether a powder or a spray, so this information is captured for both categories of incidental inhalation. d It is possible these products may be powders, but it is not specified whether the reported uses are powders. e Not spray products.


Table 6. HDI polymer ingredients that have no reported uses.24-26 Bis-Hydroxyethyl Acrylate Poly(1,4-Butanediol)-9/TMHDI Copolymer

Bis-Isostearyl 1,4-Butanediol/HDI/Hydrogenated Dimer Dilinoleyl Alcohol Copolymer

Bis-Lauryl Cocaminopropylamine/HDI/PEG-100 Copolymer Bis-Methoxy PEG-10 Dimethyl MEA/HDI/Bis-PEG-10 Dimethicone Copolymer

1,4-Butanediol/Succinic Acid/Adipic Acid/HDI Copolymer Cholesterol/HDI/Pullulan Copolymer Decyl HDI/PEG-180 Crosspolymer HDI/PEI-45/SMDI Crosspolymer Methoxy PEG-17/Methoxy PEG-11/HDI Isocyanurate Trimer Crosspolymer

PPG-26/HDI Copolymer


Table 7. Acute oral toxicity of HDI polymers in this safety assessment. Ingredient Animal; n Results; Methods Reference HDI/Trimethylol Hexyllactone Crosspolymer

Wistar rats (n=5/sex), 5000 mg/kg administered by intragastric feeding caused no clinical signs or mortalities

14-16

Methoxy PEG-17/methoxy PEG-11/HDI Isocyanurate Trimer Crosspolymer

Rats; not specified LD50=>2000 mg/kg. OECD TG 423 23

PEG-240/HDI Copolymer Bis-Decyltetradeceth-20 Ether

Rats; not specified >2500 mg/kg 17

PEG-240/HDI copolymer bis-decyltetradeceth-20 ether

Rats; not specified >2000 mg/kg 17

Steareth-100/PEG-136/HDI Copolymer

Rats; 5/sex >10 000 mg/kg. No mortalities during dosing and the observation period. At 24 h post dosing, 3 rats had bristled fur, diarrhea and dirty fur around the anal region due to feces; all of which resolved at 48 h after dosing. At necropsy, 2 rats had pinhead-sized, cartilaginous elevations on the forestomach mucous membrane; all other necropsies were unremarkable.

18

OECD TG= Organization for Economic Cooperation and Development Test Guideline

Table 8. Irritation assays of HDI polymers. Ingredient (concentration) Assay Results Reference

Non-Human HDI/Trimethylol Hexyllactone Crosspolymer (100%)

Primary irritation study in rabbits (n=6); intact and abraded skin

Slight irritation of the skin was observed in 5 of 6 rabbits. 1 rabbit showed well-defined erythema and slight edema 24 and 72 h after administration. The irritation scores were below the threshold for classifying a test substance as an irritant according to the criteria of NOHSC.

14-16

Methoxy PEG-17/Methoxy PEG-11/HDI Isocyanurate Trimer Crosspolymer (concentration not specified)

OECD TG 404 in rabbits Non-irritating 23

PEG-240/HDI Copolymer bis-Decyltetradeceth-20 Ether (3%, 10%, or 30% in a PG solution)

Single dose in guinea pigs Not a dermal irritant 17

PEG-240/HDI Copolymer bis-Decyltetradeceth-20 Ether (3%, 10%, or 30% in a PG solution)

14-Day open-application cumulative assay in guinea pigs

Not a dermal irritant 17

Steareth-100/PEG-136/HDI Copolymer (100%; 0.5 g; dry)

OECD TG 404 in male rabbits (n=3) Primary Irritation Index=0/8 18

Human HDI/trimethylol hexyllactone crosspolymer (100% as a dry powder)

24-h Patch test (n=21 male, 23 female),

No effects observed. It was noted that this study may not be predictive of effects that may occur upon exposure to this substance in moist formulations.

14-16

HDI/di-C12-14 Alkyl Tartrate/ Hydrogenated Dilinoleyl Alcohol Copolymer (1.7%) in a foundation product

Primary skin irritation test (n=20) under semi-occlusion.

Average irritation index was 0.0, the product was classified as non-irritating

21

HDI/di-C12-14 Alkyl Tartrate/ Hydrogenated Dilinoleyl Alcohol Copolymer (3.19%) in a foundation product

Primary skin irritation test (n=20) under semi-occlusion.

Average irritation index was 0.05 at the first reading and 0.00 at the second reading. The product was classified as non-irritating.

21

NOHSC= National Occupational Health and Safety Commission of Australia PG=propylene glycol


Table 9. Ocular irritation studies of HDI polymers using rabbits.

Ingredient (concentration) Assay Results Reference HDI/Trimethylol Hexyllactone Crosspolymer (100%)

Ocular irritation study (n=6)

Mild to moderate conjunctival redness and mild chemosis were observed in 4 of 6 rabbits 24 and 48 h after administration. 1 rabbit still showed redness 4 days after exposure, which was resolved 7 days after exposure. Mild chemosis was observed in 1 rabbit on day 1; this was resolved by day 2. The mean scores for observations 24, 48 and 72 h after exposure were 1.0 for redness and 0.1 for chemosis. It was concluded that the test substance was a slight ocular irritant but not classified as an ocular irritant according to the criteria of the NOHSC. The authors considered the particle size (at least 92.9% > 1 µm; Table 4) and the water insolubility of the tested polymer and concluded that the eye irritation observed was likely attributable to mechanical abrasion rather than to chemical irritancy.

14-16

Methoxy PEG-17/Methoxy PEG-11/HDI Isocyanurate Trimer Crosspolymer (concentration not specified)

OECD TG 405 Slight irritant 23

PEG-240/HDI Copolymer bis-Decyltetradeceth-20 Ether (3%, 10%, or 30% in PG solution)

Ocular irritation study Not an ocular irritant 17

Steareth-100/PEG-136/HDI Copolymer (100%; 0.1 g)

OECD TG 405 (n=3) Classified as a non-irritant 18

PG=propylene glycol

Table 10. Sensitization studies of HDI polymers Ingredient (concentration) Assay Results Reference

Non-Human Methoxy PEG-17Methoxy PEG-11/HDI Isocyanurate Trimer Crosspolymer (concentration not specified)

Magnusson Kligman maximization test using guinea pigs; OECD TG 406

Not sensitizing 23

PEG-240/HDI copolymer bis-decyltetradeceth-20 ether (30% in PG solution)

Skin sensitization assay (species not specified); challenged at 3%, 10%, and 30%.

Not a dermal sensitizer 17

Human HDI/Trimethylol Hexyllactone Crosspolymer in a foundation product (30.7%; 0.1-0.15 g)

HRIPT (n=50) No signs of dermal irritation or allergic contact dermatitis observed

33

HDI/Trimethylol Hexyllactone Crosspolymer in a foundation product (10%; 200 µL)

HRIPT (n=110) No signs of dermal irritation or allergic contact dermatitis observed

34

bis-C16-20 Isoalkoxy TMHDI/PEG-90 Copolymer (30% active in PG/water; 0.2 g)

HRIPT (n=48) One subject exhibited barely perceptible (0.5) erythema 48 h after the challenge.

20

PEG-240/HDI Copolymer bis-Decyltetradeceth-20 Ether (concentration not specified)

HRIPT (n not specified) No evidence of dermal irritation or allergic contact sensitization.

17

HRIPT=human repeat insult patch test


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2015 VCRP Data - hexamethylene diisocyanate polymers DIETHYLENE GLYCOL/DMAP ACRYLAMIDE/PEG-180/HDI COPOLYMER

05A - Hair Conditioner 1

DIETHYLENE GLYCOL/DMAP ACRYLAMIDE/PEG-180/HDI COPOLYMER

05C - Hair Straighteners 4

DIETHYLENE GLYCOL/DMAP ACRYLAMIDE/PEG-180/HDI COPOLYMER

05G - Tonics, Dressings, and Other Hair Grooming Aids

1

6 HDI/PPG/POLYCAPROLACTONE CROSSPOLYMER

03C - Eye Shadow 1

HDI/PPG/POLYCAPROLACTONE CROSSPOLYMER

03D - Eye Lotion 1


03F - Mascara 2


07B - Face Powders 3


07C - Foundations 2


07F - Makeup Bases 1


07I - Other Makeup Preparations 2


12C - Face and Neck (exc shave) 2


12F - Moisturizing 5


12J - Other Skin Care Preps 2

21 METHOXY PEG-17/METHOXY PEG-11/HDI CROSSPOLYMER

07E - Lipstick 1


03D - Eye Lotion 1



STEARETH-100/PEG-136/HDI COPOLYMER

05I - Other Hair Preparations 1


HDI/TRIMETHYLOL HEXYLLACTONE CROSSPOLYMER

03A - Eyebrow Pencil 1


03C - Eye Shadow 78


03D - Eye Lotion 15


03F - Mascara 11


03G - Other Eye Makeup Preparations 13


04C - Powders (dusting and talcum, excluding aftershave talc)

1


07A - Blushers (all types) 25


07B - Face Powders 49


07C - Foundations 40


07E - Lipstick 13


07F - Makeup Bases 8


07G - Rouges 1


07H - Makeup Fixatives 1


07I - Other Makeup Preparations 9


08G - Other Manicuring Preparations 1


12A - Cleansing 2


12C - Face and Neck (exc shave) 30


12D - Body and Hand (exc shave) 3




12G - Night 4


12H - Paste Masks (mud packs) 4


12J - Other Skin Care Preps 15


13B - Indoor Tanning Preparations 1

354


Memorandum

TO: Lillian Gill, D.P.A.Director - COSMETIC INGREDIENT REVIEW (CIR)

FROM: Beth A. Lange, Ph.D. Industry Liaison to the CIR Expert Panel

DATE: August 10, 2015

SUBJECT: Updated Concentration of Use by FDA Product Category: HDI Polymers


Concentration of Use by FDA Product Categories – HDI Polymers*

HDI/Trimethylol Hexyllactone Crosspolymer Bis-C16-20 Isoalkoxy TMHDI/PEG-90 Copolymer Bis-Hydroxyethyl Acrylate Poly(1,4-Butanediol)-9/TMHDI Copolymer Bis-Isostearyl 1,4-Butanediol/HDI/Hydrogenated Dimer Dilinoleyl Alcohol Copolymer Bis-Lauryl Cocaminopropylamine/HDI/PEG-100 Copolymer Bis-Methoxy PEG-10 Dimethyl MEA/HDI/Bis-PEG-10 Dimethicone Copolymer 1,4-Butanediol/Succinic Acid/Adipic Acid/HDI Copolymer Cholesterol/HDI/Pullulan Copolymer Decyl HDI/PEG-180 Crosspolymer Diethylene Glycol/DMAP Acrylamide/PEG-180/HDI Copolymer HDI/Di-C12-14 Alkyl Tartrate/Hydrogenated Dilinoleyl Alcohol Copolymer HDI/PEI-45/SMDI Crosspolymer HDI/PPG/Polycaprolactone Crosspolymer Methoxy PEG-17/Methoxy PEG-11/HDI Crosspolymer Methoxy PEG-17/Methoxy PEG-11/HDI Isocyanurate Trimer Crosspolymer PEG-240/HDI Copolymer Bis-Decyltetradeceth-20 Ether PPG-26/HDI Copolymer Steareth-100/PEG-136/HDI Copolymer Stearyl HDI/PEG-50 Copolymer

Ingredient Product Category Maximum Concentration of Use

HDI/Trimethylol Hexyllactone Crosspolymer Eyebrow pencil 2.5-2.6% HDI/Trimethylol Hexyllactone Crosspolymer Eyeliner 2.5-5% HDI/Trimethylol Hexyllactone Crosspolymer Eye shadow 2.5-19.6% HDI/Trimethylol Hexyllactone Crosspolymer Eye lotion 3.5-8.9% HDI/Trimethylol Hexyllactone Crosspolymer Eye makeup remover 11.7% HDI/Trimethylol Hexyllactone Crosspolymer Mascara 0.049-3% HDI/Trimethylol Hexyllactone Crosspolymer Other eye makeup preparations 6.7% HDI/Trimethylol Hexyllactone Crosspolymer Blushers 3-19.6% HDI/Trimethylol Hexyllactone Crosspolymer Face powder 3-12.6% HDI/Trimethylol Hexyllactone Crosspolymer Foundation 0.24-31% HDI/Trimethylol Hexyllactone Crosspolymer Leg and body paints 0.098% HDI/Trimethylol Hexyllactone Crosspolymer Lipstick 0.0096-15.1% HDI/Trimethylol Hexyllactone Crosspolymer Makeup bases 0.059-6.9% HDI/Trimethylol Hexyllactone Crosspolymer Makeup fixatives 7% HDI/Trimethylol Hexyllactone Crosspolymer Other makeup preparations 2.1-4% HDI/Trimethylol Hexyllactone Crosspolymer Other manicuring preparations 0.21-0.98% HDI/Trimethylol Hexyllactone Crosspolymer Face and neck products

Not spray 0.97-14.4%

HDI/Trimethylol Hexyllactone Crosspolymer Body and hand products


Not spray 0.78-2% HDI/Trimethylol Hexyllactone Crosspolymer Moisturizing products

Not spray 0.72-3%

HDI/Trimethylol Hexyllactone Crosspolymer Night products Not spray

0.98%

HDI/Trimethylol Hexyllactone Crosspolymer Other skin care preparations 17.3% HDI/Trimethylol Hexyllactone Crosspolymer Suntan products

Not spray 0.44%

Bis-C16-20 Isoalkoxy TMHDI/PEG-90 Copolymer

Mascara 0.6%


Other eye makeup preparations 1.2%


Foundation 1.2%


Lipstick 0.026-7.6%

HDI/PPG/Polycaprolactone Crosspolymer Eye shadow 5-9.8% HDI/PPG/Polycaprolactone Crosspolymer Blushers 4% HDI/PPG/Polycaprolactone Crosspolymer Face powder 3-11.8% HDI/PPG/Polycaprolactone Crosspolymer Foundations 4-6.9% HDI/PPG/Polycaprolactone Crosspolymer Face and neck products

Not spray 2-10.8%

HDI/PPG/Polycaprolactone Crosspolymer Body and hand products Not spray

7%

Methoxy PEG-17/Methoxy PEG-11/HDI Isocyanurate Trimer Crosspolymer

Rouges 0.025%


Eye lotion 1.9-2%


Hair conditioners 1%


Tonics, dressings and other hair grooming aids

2%


Hair bleaches 1%


Foundations 1%


Makeup bases 2%


Face and neck products Not spray

2%


Moisturizing products Not spray

2%


Other skin care preparations 1.2%

Steareth-100/PEG-136/HDI Copolymer Tonics, dressings and other hair grooming aids

2.5%


Steareth-100/PEG-136/HDI Copolymer Hair dyes and colors 0.87% Steareth-100/PEG-136/HDI Copolymer Deodorants

Not spray 1.6%

*Ingredients included in the title of the table but not found in the table were included in the concentration of use survey, but no uses were reported

Information collected in 2015 Table prepared July 2, 2015

Updated August 5, 2015: HDI/Di-C12-14 Alkyl Tartrate/Hydrogenated Dilinoleyl Alcohol Copolymer added other eye makeup preparations and foundations; added 7.6% for lipstick


Personal Care Products Council

Memorandum

TO: Lillian Gill, D.P.A.

Committed to Safety, Q uality & Innova tion

Director- COSMETIC INGREDIENT REVIEW (CIR)

FROM: Beth A. Lange, Ph.D. Industry Liaison to the CIR Expert Panel

DATE: September 16, 2015

SUBJECT: Comments on the Draft Report Prepared for the September 2015 CIR Expert Panel Meeting: Safety Assessment of Hexamethylene Diisocyanate (HOI) Polymers as Used in Cosmetics

Key Issue The European restriction on diethylene glycol in cosmetics is misrepresented in the Cosmetic Use

section. This section currently says: "including the amount of diethylene glycol contained in polymers". This is not correct. EU Annex lii 186 is for diethylene glycol "as traces in ingredients". The diethylene glycol bound in the polymer is not part of the restriction.

The Summary should include information on monomer levels (especially HOI) found in these polymers.

Additional Considerations Table 2- For the reader not familiar with CIR reports, the first column of this table is confusing. As

the reference title provides the name of the ingredient group, perhaps only the constituent of interest is needed in the first column of this table.

Table 5 - There is no ongoing concentration of use survey for ingredients in this report. "The Council is conducting a survey of the concentration of use for the ingredients added to this report." needs to be deleted.

HDI/Di-C12-14 Alkyl Tartrate/Hydrogenated Dilinoleyl Alcohol Copolymer needs to be updated with the revised table. The low concentration in lipstick was reported to be 0.026% not 0.26% as indicated in Table 5.

Methoxy PEG-17/Methoxy PEG-11/HDI Crosspolymer- The concentration reported in rouges was 0.025% not 0.25% as indicated in Table 5.

1620 L Street, N.W., Suite 1200 I Washington, D.C. 20036 1 202.331.1770 I 202.331.1969 (fax) I www.personalcarecouncll.org


Reference 14- There are three different NICNAS assessments (all with similar information) PLC/763 2008, PLC/946 201 0 and EX/175 2015. It is not clear which assessment reference 14 represents. The link is to PLC/763, but EX/175 and PLC/946 are also stated and the date provided (20 12) is for EX/175.

Wave 2 -The concentration of HDI!Di-C12-14 Alkyl TartratefHydrogenated Dilinoleyl Alcohol Copolymer in the second human irritation test was 3.19% not 7.5% as stated in the memo. The 7.5% concentration represents the amount ofthe mixture oftwo polymers (INTERCOSHINE FLEX and IDC).

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