Safety Assessment of Hexamethylene Diisocyanate (HDI ... · Safety Assessment of Hexamethylene Diisocyanate (HDI) Polymers as Used in Cosmetics Status: Revised Draft Final Report

Safety Assessment of Hexamethylene Diisocyanate (HDI) Polymers

as Used in Cosmetics

Status: Revised Draft Final Report for Panel Review Release Date: May 13, 2016 Panel Meeting Date: June 6-7, 2016

The 2016 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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MEMORANDUM

To: CIR Expert Panel and Liaisons

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

Date:

May 13, 2016

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

Attached is the revised draft final report of 19 hexamethylene diisocyanate (HDI) polymers as used in cosmetics. [HDIply062016rep] 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. 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.

At the March 2016 meeting, the Panel revised the conclusion from December, 2015 and issued a safe as used conclusion for 17 HDI polymers and an insufficient data conclusion for the other 2 HDI polymers. The data the Panel requested to evaluate the safety of these 2 ingredients are:

• Molecular weight • If the molecular weight is below 1000 Da, then solubility in formulation, dermal absorption,

and/or 28-day dermal toxicity • If soluble or dermally absorbed, then systemic toxicity, including genotoxicity, carcinogenicity,

and reproduction/developmental toxicity, may be needed The Panel considered a suggestion from the CIR Science and Support Committee (CIR SSC) to use the existing data on molecular weight and the same rationale used to conclude that methoxy PEG-17/methoxy PEG-11/HDI crosspolymer is too large to penetrate the skin (the size of individual monomers are known to be too large to penetrate the skin), to extend the safe as used conclusion to more of the ingredients listed in the insufficient data conclusion from December 2016.

No new data were submitted. Council comments were addressed. [HDI062016PCPC]

The Panel should examine the Abstract, Discussion, and Conclusion in this draft final report to make sure that they adequately address the Panel’s concerns, and, if so, issue a final report.

mailto:[email protected]

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

SAFETY ASSESSMENT FLOW CHART

INGREDIENT/FAMILY ___Hexamethylene Diisocyanate (HDI) Polymers _________________________

MEETING ____June 2016_________________________________________________________________

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 Jan 6, 2016;

April 12, 2016

60 day Public comment period

Draft FR

Table Different Conclusion

(March 2016)

PUBLISH Final Report

DRAFT REPORT Sept 2015

DRAFT TENTATIVE REPORT

Dec 2015

DRAFT FINAL REPORT Mar 2016; June 2016

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 issued a tentative report for public comment with the conclusion that

the following 7 hexamethylene diisocyananate (HDI) polymers are safe as used: HDI/trimethylol hexyllactone crosspolymer bis-C16-20 isoalkoxy TMHDI/PEG-90 copolymer bis-lauryl cocaminopropylamine/HDI/PEG-100 copolymer* HDI/Di-C12-14 alkyl tartrate/hydrogenated dilinoleyl alcohol

copolymer

methoxy PEG-17/methoxy PEG-11/HDI crosspolymer PEG-240/HDI copolymer bis-decyltetradeceth-20 ether steareth-100/PEG-136/HDI copolymer

The Panel concluded that the data on the following 12 HDI polymers are insufficient to determine safety: bis-hydroxyethyl acrylate poly(1,4-butanediol)-9/TMHDI

copolymer* bis-isostearyl 1,4-butanediol/HDI/hydrogenated dimer

dilinoleyl alcohol 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/PEI-45/SMDI crosspolymer* HDI/PPG/polycaprolactone crosspolymer methoxy PEG-17/methoxy PEG-11/HDI isocyanurate trimer

crosspolymer* PPG-26/HDI copolymer* stearyl HDI/PEG-50 copolymer*

Distributed for comment only -- do not cite or quote

The data that are needed to evaluate the safety of these 12 ingredients are: • Molecular weight • If the molecular weight is below 1000 Da, then solubility in formulation, dermal absorption, and/or 28-

day dermal toxicity • If soluble or dermally absorbed, then systemic toxicity, including genotoxicity, carcinogenicity, and

reproduction/developmental toxicity, may be needed Data on residual monomers in two cosmetic products and the molecular weight of

HDI/PPG/polycaprolactone crosspolymer (one of the ingredients with an insufficient data conclusion) were submitted.

March, 2016 – The CIR Science and Support Committee (CIR SSC) submitted comments that

suggests that by using the existing data on molecular weight (including the new unpublished data), and using the approach used to determine that methoxy PEG-17/methoxy PEG-11/HDI crosspolymer is too large to penetrate the skin, the safe as used conclusion can be extended to 9 of the 12 ingredients included in the insufficient data conclusion in this safety assessment.

The Panel considered the new data and the SSC’s suggestion. A revised conclusion was reached and a new tentative report was issued. The new conclusion is:

The CIR Expert Panel concluded that the following 17 HDI polymers are safe in cosmetics in the present The CIR Expert Panel concluded that the following 17 HDI polymers are safe in cosmetics in the present practices of use and concentration described in this safety assessment:

• HDI/Trimethylol Hexyllactone Crosspolymer • Bis-C16-20 Isoalkoxy TMHDI/PEG-90 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* • 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 available data are insufficient to make a determination that the following 2 ingredients are safe under the intended conditions of use:

• Bis-Hydroxyethyl Acrylate Poly(1,4-Butanediol)-9/TMHDI Copolymer* • 1,4-Butanediol/Succinic Acid/Adipic Acid/HDI Copolymer*

June, 2016 – The Panel should issue a final report.


HDI Polymers Data Profile for June, 2016. 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 HDI Polymers - March, 2016

Dr. Marks’ Team DR. MARKS: … If not, let's move on to HDI. And Lillian Becker is still on the hot

seat here. So this is hexamethlyene diisocyanate. This is a draft final report. DR. SLAGA: But she's sitting in Don's seat. DR. MARKS: That what happens when Don comes in late. And I'm sitting in

Curt's seat. This is new, but it seems to be working. At the December meeting the Panel issued a safe as use conclusion for seven

HDI polymers and an insufficient data conclusion for the other 12 HDI polymers. The Panel requested to evaluate the safety of these 12 ingredients. The data needed was molecular weight. No molecular weight is below 1,000 Daltons, insolubility, formulation, et cetera. And then if soluble, then systemic toxicity. That's on the first paragraph. Let me see.

Then we -- the last paragraph of the first page of the memo refers to a CIR Science and Support Committee's comments in which they suggest that there be a change in that conclusion since their evaluation, molecular weights, indicate that, perhaps, we could include more ingredients as safe since the concerns are all based on molecular weights. So tomorrow what I think our team will be proposing is amended draft final report. In this case, I think we have to go back on it. Sixteen now would be safe. Three would be insufficient because of unknown molecular weight. And I'll go back. We'll discuss the inhalation in a minute. So let me go to page 40. That's the conclusion as it stands now. And you see on page 40 the ingredients which -- the seven, which in our present conclusion are considered safe. And then below that, in which there's insufficient data of 12 ingredients. And subsequent to the scientific committee's recommendation, it would just be three as I interpret it that would be still insufficient. And that would be the top two; this hydroxyethyl acrylate, et cetera, this isostearyl 14, butyl, diene, et cetera. And then skipping down to the fourth one, 1,4 butanediol, et cetera. That those three would be the ones that are insufficient. Did I interpret that correctly and do you all --

DR. SHANK: You did. DR. MARKS: -- agree with that conclusion? I see Ron Hill -- DR. HILL: Absolutely not. DR. MARKS: -- shaking his head. DR. HILL: I absolutely disagree because what I was after on the molecular

weight was information about the low- end, the presence of low-end molecules. The monomers are not prohibitively large in terms of molecular weight in any of those that I can see. Except in some monomers like pullulan, for example. But in general, the monomers are not prohibitive molecular weight for absorption. It's not like -- first of all it's not like a thousand is some magic cutoff and above that it's a hard stop. But second of all, quite a few of these monomers are much less. So we've got at least data for one of these that says there's.9 percent of some THF soluble fraction. So.9 percent doesn't seem like very much except that a couple of these that are in use are used at 12 percent and 30 percent in lead [leave?]-on products. So what I was looking for and we have them for the ones that we've said sufficient, is in characterization of the low-end molecular weight. In other words, how many -- how much is there. Are -- they're small because it's polymer. So polymers, you make mixtures. You always make mixtures. And so in the few cases like the PEG- 240/HDI copolymer, we know the molecular weight is large, but we also have data that confirms there's nothing below 10,000. We have that for all the -- all of them are -- essentially all of the ingredients or we have sensitization for the ones that we thought were good.

DR. EISENMANN: But one thing. There wasn't an error. This methoxy PEG-17,


methoxy PEG-11/HDI crosspolymer? DR. HILL: Yeah. DR. EISENMANN: You have data on methoxy PEG-17, methoxy PEG-11/HDI

isocyanurate trimer crosspolymer. DR. HILL: Yes. DR. EISENMANN: That's the one that should be safe. DR. HILL: But we don't have -- DR. EISENMANN: We have no data on the other one. DR. HILL: We don't have good data on that one that you're talking about. First

of all, it's a different monomer because we have this isocyanurate trimer -- DR. EISENMANN: And -- DR. HILL: -- and we don't have any sensitization data on -- DR. EISENMANN: It's a fully cross length [linked?] polymer. You do have

sensitization data. DR. HILL: Not on that trimer. Only the monomer, it's different. As soon as you

have that trimer and not HDI itself as the monomer, it's different. And you don't have sensitization for anything that contains that trimer that I see. I looked at the -- I looked at -- we've only have sensitization data for four of these, four of them. Four of the ones up at the top seven and nothing down below the line. And if we're going to get sensitization it'll be from something below molecular weight that's in there. Not the polymers. They're too big to sensitize anybody for anything.

So as long as we're -- to molecular weight that's not soluble, can't even get into skin cells or any other cells, we're good.

DR. MARKS: So Beth, maybe I'll have you comment. And then Ron Shank, you had actually -- Ron Hill you refer to the 1,000 as I recall. Ron Shank, you were the one that proposed that cutoff. And --

DR. SHANK: Yes. DR. MARKS: -- if I got the sense, Ron, you were fine with what the Science and

Support Committee had recommended. And -- but I may have -- DR. SHANK: I was, yes. DR. MARKS: -- missed it. You were. Okay. DR. HILL: But the recommendation is based on the large molecular weight of the

monomers that go into the polymers and that's not what the story is here. They're not. And that's my point. They're not. And then -- so below the line we have any information at all about molecular weight on just the bis-methoxy PEG 10 dimethyl MEA/HDI/bis-PEG-10- dimethicone copolymer. We do have some molecular weight information on that. That's --

DR. MARKS: Let's go to page 72 and 73 because that is the memo from the Science and Support Committee. And they give the reasoning. And Ron Shank, you were fine with the reasoning within that.

DR. SHANK: I was, yes. DR. MARKS: Seventy-two -- DR. EISENMANN: You see, it was the reasoning that was used in the

discussion to support the safety of one of the polymers that was in the safe category. And so they just extended it.

DR. HILL: But the information, in that case, was that we had information that the word no substances in that ingredient with molecular weight below 10,000.

DR. EISENMANN: On the ingredient you had no -- absolutely no information on that topic.

DR. HILL: Which one are we talking about?


DR. EISENMANN: The HDI. DR. HILL: Hang on. DR. EISENMANN: The one that's -- the short one versus -- it's the PEG-PEG -- DR. HILL: Okay, hang on. Just tell me which one because I noted down here

what data I just wrote right out to the side in that list of safe and unsafe. The trimethylol hexyllactone crosspolymer? Is that the one you're talking about?

DR. EISENMANN: No, I'm talking about -- DR. LANGE: The fifth one down in the conclusions. DR. HILL: Methoxy PEG-17, methoxy PEG-11? DR. EISENMANN: Yes. DR. HILL: But we have sensitization data for that one. DR. EISENMANN: No, you don't have anything. DR. HILL: Yeah, yes, there is. We have sensitization on that guy. DR. EISENMANN: I doubt it. DR. HILL: I'm pretty sure. We spent a ridiculous amount of time

finding -- tracking stuff down on this report. And that's why I have this. It was in a Wave 2 maybe last time.

DR. MARKS: Well, it should be in the table this time if there's a sensitization table. I've got to admit, I was going based by molecular weight. And once swayed by the memo as it sounds like Ron Shank, you were. Tom, do you have any comments?

DR. SLAGA: I do. Ron Shank, I agree with the finding. DR. MARKS: Yeah. DR. HILL: Where's the read across? DR. MARKS: What page is that? DR. EISENMANN: That is 48. DR. MARKS: Page 48, Lillian, points out -- Lillian Becker, that is, points

out -- because it looks like I'm not going to be specific here. And that's where the table isn't confirmed.

DR. EISENMANN: Yeah, you have it on the isocyanurate trimer crosspolymer. DR. HILL: Yeah, that methoxy 17, we had animal but not human sensitization

data, but -- DR. EISENMANN: Right, but it's on the isocyanurate trimer crosspolymer. It's

the two names are exactly the same -- DR. HILL: Where? No, it says -- DR. EISENMANN: It's the first -- DR. HILL: -- HDI crosspolymer on that one. Page 17, methoxy PEG-11/HDI

crosspolymer. DR. EISENMANN: I'm looking at Table 11, Sensitization Study (inaudible). DR. HILL: I was too. DR. EISENMANN: It's the first study. DR. HILL: Which page is Table 11. I have it written down somewhere. DR. EISENMANN: I don't have the page number. MS. BECKER: That would be page 48. DR. HILL: Forty-eight. Okay, because that's -- I was working mainly from Table

11 but also the text. DR. EISENMANN: You didn't get a lot of details about the study, but they did do

a study on that. DR. HILL: It was a Magnusson-Kligman maximization test using guinea pigs

following an OECD TG 406 protocol. What we didn't have was concentration. So that


was -- you're right. But -- okay, in there it says HDI isocyanurate, but it doesn't have that in the ingredient list. So, okay, I didn't catch that because it's down a line somehow. So is that a different ingredient then what's actually in our list because the PEG-17, PEG-11/HDI doesn't say isocyanurate trimer?

DR. EISENMANN: There's still (inaudible). Right now they aren't listed. One without the same name, accept --

DR. HILL: Okay. DR. EISENMANN: -- one is the isotryate. That one is fully cross-length polymer

according to the supplier. DR. HILL: All right, HDI with (inaudible) crosspolymers in the safe list. I don't

see PEG-17, methoxy PEG-11 that has an isocyanurate on the list. DR. EISENMANN: It's in the insufficient data list. DR. HILL: Okay. DR. EISENMANN: I think you mistake -- those two should be flipped. DR. HILL: Oh no, yeah, no -- oh, okay, I see what you're saying. I see what

you're -- but we have sensitization on not -- oh, okay, I see. Yes, I get it. DR. MARKS: So, Ron Hill, to me a couple things. One with -- I thought the

memo explained why these were large molecules or maybe some little residual monomer. But the other is clinically. There are no case reports. So the allergy to any of these includes --

DR. HILL: They're not in use. DR. MARKS: Oh. DR. HILL: None of them are in use. Or only a few of them are in use. DR. MARKS: Yeah, but they're no -- so to me I find both the molecular weights,

the explanation in that, and then the lack of any clinical alerts is reassuring to me about sensitization.

DR. HILL: Well -- DR. MARKS: And we have is both animal and human studies with the HRIPT.

And we often don't have sensitization data on it; every ingredient within a group. DR. HILL: Yes, but sometimes then the read-across is valid and sometimes it's

not. And again, I'll say -- and -- I mean I guess a pragmatic way of looking at it is this type of sensitization is not going to kill anybody. They're going to get --

DR. MARKS: Well I wouldn't -- DR. HILL: -- red and itchy and then we -- DR. MARKS: I -- DR. HILLS: -- know there's a problem. DR. MARKS: I -- well I wouldn't base my conclusion on just getting red and itchy.

If your face is red and itchy and swollen and your eyes and -- the -- I'll put it in quotes the epidemic of methylisothiazoline known is not insignificant at this point. So I --

DR. HILL: I had a deodorant reaction myself that plagued me for 10 days. I was miserable and life was bad.

DR. MARKS: Yeah, so I wouldn't -- DR. HILL: It was to a quaternium. DR. MARKS: I wouldn't give a pass on, well, it's an insignificant reaction to it.

It's a significant reaction. It's -- there is, I think, scientific data on molecular weight and then the lack of any reports that make me reassured that these ingredients are safe from a sensitization point of view.

DR. HILL: And again I say we have no data on molecular weight. We have no data on molecular weight on the low end which was where it would matter. The high end -- you know, we know that average molecular weight is 10,000. We still don't know what's going on with


the low end in those mixtures. And when you have a polymer it's always a mixture. DR. MARKS: Okay, so I think -- Carol or Beth if you have no more comments,

what I will do is -- I get the sense Tom and Ron Shank are in favor of increasing the ingredients to 16 now with three insufficient based on the Scientific Committee's recommendation. And I'll move -- I think this has to be amended. We can't just say editorial changes because we now have switched a number of ingredients into the safe category. And then we have three because of unknown molecular weight. And, Ron Hill, obviously tomorrow you can dissent in the vote and I -- and bring your concerns up if that's -- Tom and Ron or you comfortable moving forward with that conclusion?

DR. SHANK: Yes, I was even willing to discuss the other three, but certainly the nine that the committee addressed.

DR. MARKS: Okay, and Tom you're okay with that? DR. SLAGA: Yes. DR. MARKS: So I'll make that motion tomorrow. We'll see what the Belsito team

comes out with. And they may be similar to you, Ron. We'll find out. That's -- DR. HILL: I don't know and I won't have to say much tomorrow because this will

be captured in the transcript unless they -- DR. MARKS: Well I think because it is it's going to come up for a vote. DR. HILL: It'll go out again. Yeah. DR. MARKS: Yeah, it will go out again, but I think it'll go out again hopefully

unless we find -- get more information with that conclusion. DR. BERGFELD: Can I ask? Is it possible to put the concerns of the

monomer -- basically impurity, I guess, into the discussion? DR. SHANK: Sure. DR. BERGFELD: A little bit of discussion -- DR. MARKS: Yeah. DR. BERGFELD: -- regarding it shouldn't be there or at low concentrations.

Okay. DR. MARKS: I think if I read the memo correctly from the Science and Support

Committee, it said less than one percent of the monomers. So it'd be a small amount if -- and obviously that needs to be captured.

And the other thing this brings up again, the inhalation document, and that's on page 39. I wanted to highlight that. Any comments? Oh, Lillian Becker, you were going to ask something.

MS. BECKER: I was just going to ask Dr. Hill if he's got any preferred language for talking about the monomers at least.

DR. HILL: Well it's not just the monomers, it's anything below molecular weight I think. So when I was looking at impurity as -- I was looking at two things. One was polymers that aren't completely formed so that their small molecular weight potentially self-penetrable/absorbable enough to where we could get sensitization events. And the other was looking at what we had for characterization of the isocyanates themselves. And in some cases where it just says less than 100 PPM, that's a pretty high amount for something like that even if -- when we have something being used at 10 percent or 30 percent which a couple of these are. But I think that less than 100 PPM is based on old analytical technology. I'd like for somebody to come back and look and say, yes, it's really less than five PPM or something like that would make us all feel more comfortable. But I think it's based on data and analytical technology that those numbers came.

Yeah, so -- and like I said, I think analytical characterization of anything low molecular weight. And then as well as -- you've already got language in there about unreacted


isocyanate and I think those concerns are pretty well put to bed. But again, you can see from the data -- if you look at the data it's not zero. So we're aware of that and that's great. That's the kind of data I'd look -- I wanted to see and I'm glad to see. And then if you do the numbers, we're well below thresholds that we have to normally worry about. But then low molecular weight, there are a few of these monomers that are, by their nature, a bit reactive and so you can generate a hapten and sensitize.

MS. BECKER: Okay. DR. BERGFELD: I'm not understanding what you want in the discussion then. DR. HILL: Maybe nothing. Let's see what comes up tomorrow. I think that's the

point. DR. BERGFELD: Okay. DR. HILL: But I have some notes here, comments dropped in, so it'll give you

more to go on if that's what you're -- MS. BECKER: Yes, thank you. DR. MARKS: Okay, let's move on to the inhalation paragraph on page 39. Ivan,

do you want to comment first and then -- DR. BOYER: Well -- DR. MARKS: -- or this may be short, but I -- DR. BOYER: Yeah, I think we've had our discussion of the inhalation framework

and background document and some suggested language. For when it's appropriate, it has -- is in this case too. So --

DR. MARKS: Okay. DR. BOYER: -- I'll simply conclude to the statement about one microgram per

kilogram per day. An interpretive statement after that. And will -- it include some language that's sort of recapping that in the discussion. And we'll modify the background document.

DR. MARKS: Ron Shank, fine? DR. SHANK: That's fine. DR. MARKS: Okay, Tom, Ron Hill? Okay. DR. BERGFELD: Could I ask a question? As we look at the hair -- or excuse

me, the hair dye, I guess we call it reference that we've put up on the website. Will this inhalation go up? And two, how many -- how often will it be re-reviewed because we have a review system for the hair dyes about every couple of years and it's somewhat updated yearly.

DR. BOYER: Well the last time the aerosols document was reviewed was in 2014.

DR. BERGFELD: Okay. DR. BOYER: And we were doing it again now. So we haven't talked about a

regular schedule, but I guess we can put the aerosols document like the hair dye epidemiology document on a kind of -- a schedule to at least take a look at every couple of years or so.

DR. BERGFELD: Okay, thank you. DR. GILL: I would just add, Wilma, that we are -- we will be reviewing all of our

boilerplates probably every three years. DR. BERGFELD: Okay. DR. GILL: But we'll have them on a rotation basis. So they will be reviewed and

they will be made public. And of course we've changed them as issues like powders come up. DR. MARKS: Okay, so after this robust discussion on HDI polymers, tomorrow

I'm going to move that we have an amended draft final report. Sixteen ingredients are now safe. Three are still insufficient because of unknown molecular weight. And we'll see where that goes. Next ingredient.

DR. HILL: Before we move on, I guess, again on the HDI and it's a related issue.


I almost think that that group is misnamed because it -- we seem to be sort of brushing under the rug that the four different monomers here -- or at least three different monomers that we're talking about. And that's -- again, I was looking at very closely whenever we talked about sensitization issues and so forth. So I'm not suggesting that we necessarily change the name because I couldn't come up with anything good, but I just want to make it very clear and I hope the discussion makes it very clear because there was a place in the introduction where it wasn't clear. It said something along the lines that these all contain HDI and they don't because as soon as you put a couple methyl groups on there, it's no longer HDI, it's trimethyl HDI. It's SSM HDI. They're different molecules. They're different monomers. If sensitization is an issue, if toxicology is an issue because they're reactive. They're analogs, yes, but that's the best we can say. And so to the extent that they are quote unquote structurally similar, that depends on what toxicological endpoint we're talking about. What biological endpoint we're talking about. So we have to be sure that the language is clear that they don't all contain HDI.

DR. MARKS: Okay,

Dr. Belsito’s Team

DR. BELSITO: Okay, so we're on to hexamethylene diisocyanate HDI polymers we give a little bit of Wave 2. I think we should change the name because this Wave 2 is more like a ripple 2 and tsunamis 2, so I know exactly how much work is going to come.

DR. SYNDER: I'm glad there's only one hundred eleven pages. DR. BELSITO: It was ripple, not wave. We've had a few tsunamis'. Okay, HDI.

At the December meeting we issued a tentative report with the conclusion that the seven HDI polymers are safe as used and insufficient data conclusion for twelve of the HDI polymers used. We got additional data in this document and in wave two looking at molecular wave [weight?] monomer for two of the ingredients that were found to be insufficient. The CAR [CIR] CSC suggested the rationale large molecular size that the seven ingredients used to support safety could support the nine ingredients designated as insufficient and Wave II address the molecular weight of another one, the methoxide PEG 17, methoxy PEG 11 HDI isocyanurate trimer crosspolymer. So we got new data but let me just point out that at the last meeting our group was comfortable with going safe as used but the others weren't.

DR. LIEBLER: Ron Shank brought up the concern about the low molecular weight and significant dermal absorption of these eight and we deferred to his concern at a discussion in the full Panel session and having gone over this much more carefully in light of the Counsel's comments I agree and think we can certainly clear all but two of these.

DR. BELSITO: Which two can't we clear? I just asked you based on instruction and additional data the limited molecular weight information why can't we clear all of these? Because I think that the reports of the low molecular weight, I think they are the starting materials and we are already told that the level of HDI monomer is very low. Does it make sense that any of these would have a molecular weight less than five hundred based upon structure?

DR. LIEBLER: On, no. In fact the only two that I had a harder time justifying were the one for butanediol acid, adipic acid and HDI copolymer and the cholesterol HDI pullulan copolymer and that was simply because the description wasn't sufficient enough for me to inspect the structures. All the other ones that I looked at, I looked at our table that the structures in them and looked at the minimum number of repeating units of the polymer as described and I did the quick calculation and they were all way over a thousand. So, I think we can, and I drafted a little sentence to put in on PDF 39, which is under the discussion that is basically PDF 39, it would be one, two, three, fourth paragraph, and it would be in the middle, safety of other but all ingredients in the group, and I would say inspection of the chemical structure formulas of most of these


ingredients indicate that even the most minimal possible polymers would have molecular weights greater than one thousand and thus would have no significant dermal absorption.

DR. BELSITO: And that is true of all of them or you said that there were two you had concerns with?

DR. LIEBLER: The two that I had concerns with the, as I said, the one for butanediol succinic acid one and the cholesterol one.

DR. BELSITO: So do we need information on those? Are those insufficient? DR. LIEBLER: Yes, I think they are still insufficient. So if you go to, for example,

Table 1, let's just take the example of PDF 42 and you look at the first two entries the DECLO HDI and the diethylene glycol HDI. In these structures you have these repeating units for example in the first one, right in the middle of the bottom chain, it has this parenthesis CH2 CH20 with the subscript 180, so if you just multiply that molecular weight out you have over a thousand just based on that little piece of the molecule. So I went through these structures and just did that check and I can clear them all except for the two I mentioned based on doing that without any other information. I didn't know what to do with those other two.

DR. BELSITO: And those again were the butanediol? DR. LIEBLER: The butanediol and the cholesterol. The butanediol one is shown

on PDF 41. In fact, the bottom two entries are the butanediol and the cholesterol one. They are just a verbal description. The butanediol one it shows a chain, it shows xxx, it doesn't show how many so I can't argue that there wouldn't be any small less than molecular weight of a thousand forms of this in a mixture unless somebody provided me with some other information. At the very bottom on the cholesterol one it is just a very brief verbal description without any of the documentation that is provided with these others above it which show how many repeating units minimally will be present.

So anyway, those two I just don't have enough information to absolutely counter Ron's concern about the minimum molecular weight. All the others the minimum possible molecular weight couldn't possibly be less than a thousand period.

DR. BELSITO: So you clear his methoxy PEGs, those two and you cleared his HDI dye?

DR. SNYDER: We cleared everything except for these two. DR. BELSITO: Everything except for two and PEG 240. DR. SYNDER: Okay. DR. LIEBLER: I would assume that upon closer inspection they would come to

the same conclusion but if they don't they still raise this issue. I can talk through what I just mentioned more succinctly.

DR. BELSITO: So safe as used except for one for butanediol and HDI copolymer and the cholesterol HDI pullulan copolymer for which we need molecular weight.

DR. LIEBLER: Molecular weight range. DR. LIEBLER: If we had data on the molecular weight range we could clear

those for dermal absorption. I think all the issues go away. DR. BELSITO: Any other points with these? DR. SNYDER: No. DR. KLAASEN: No. DR. BELSITO: So, safe as used except for two for which we will need molecular

weight. I have highlighted those on the table one where we get the chemical structure. So moving off of the HDI polymers.


DAY TWO DR. BERGFELD: Moving into the last ingredient in this category, the HDI, Dr.

Marks? DR. MARKS: We have before us the memo from Lillian Becker with the draft

final report and if you look at the top of that memo, it talks about our previous conclusion in December that there are seven HDI polymers. They are safe and the other 12 are insufficient because of molecular weight, et cetera. The CIR Science and Support Committee submitted comments and our team thought that those comments were good and we move now that there be an amended draft final report which states now that 16 are safe and three are insufficient because of unknown molecular weight, which is listed below there and that conclusion would be seen on page 40 and page -- the memo from the Science and Support Committee on page 72, 73 so let's go to page 40.

And to be specific of the -- in the conclusion, the only ones now which would be insufficient are bis-hydroxyethyl acrylic et cetera, that's the number one ingredient in that insufficient list. The number two ingredient, bis-isostearyl et cetera and the number four ingredient 1, 4 butanediol et cetera on page 40.

DR. BERGFELD: Is that a motion? DR. MARKS: Yes. DR. BERGFELD: A comment or second from Belsito's side? DR. BELSITO: Yeah, give me a second because we only had two that were

concerned around molecular weight and I can let Dan -- we had three? Is that correct, Dan? I thought there were just two?

DR. LIEBLER: I had only two. What I did -- so briefly what I did was I went back to the table because in light of Ron's expressed concern last time, I went back to table one with the structures to see if I looked at the structure where the number of repeating units in some of these structures was defined and I had to pull up my calculator and I used 1,000 as a magic number. If it cleared 1,000, it was okay and I am going back to look at the one that you mentioned, bishydroxydiol poly 1,4 butandiol which has nine repeats of the -- and that's a -- let's see, one, two, three, four carbon and oxygen times nine. I think that gets you over the hump, I mean with the rest of the structure there so it barely clears it so we can flip a coin on that one but that's what I did with the others. With the rest of them that the Science and Sports Committee may have done the same thing, you know, they are clearly well above 1,000 and I was fine with that so this one is close and I could go either way on it.

DR. BERGFELD: Ron Hill? DR. HILL: Other than the possibility of having crossed two of the polymers, I

think the list at the bottom should all stay in insufficient because I wasn't concerned about the polymers themselves. I was concerned about low molecular weight characterization and we had one of these ingredients where we had almost 1 percent extractable into THF fraction which wouldn't be much if these were being used at.

Percent but we have some leave ons being used up to ten and in one case 30 percent.

Sensitization events would come from really these -- any residual, either the isocyanates or something that might be formed from that in reverse. We only had sensitization data on four of these. We certainly aren't covering the SMDI, which is a totally different molecule than HDI or TMHDI. We did resolve yesterday that we did have data for one that had the trimer in and so we have two that are just 17 -- excuse me -- methoxy PEG-17, methoxy PEG-11. There is one that is the HDI cross polymer which currently appears in the top list, we have no data for that. We don't have molecular weight, we don't have sensitization, we don't have impurities, we don't have anything and then we do have a trimer down in the lower list that


probably should pop up to the top because that's the one that we had some sensitization data on. The other issue is that for two of these ingredients, and I am assuming the number is high because these are probably old analytical technology, what we have is less than 100 PPM; that's a pretty big number when we are talking about these isocyanates, less than 100 PPM of residual isocyanate and we are seeing residual isocyanite levels in the ones that are well characterized which is actually almost all of the ones at the top of the page. There are data about the residual isocyanate levels and they are not zero so that's the point.

So I thought we should have sensitization data that covers the full range of the monomers, we have all of that the SMDI so that we are kind of covered on but we ought to have more information about low molecular weight extractables and again, and I apologize to the people who actually sent the data from the THF extractables, but it tells us there are some low molecular weight components there and again, one percent is nothing if we are putting it on the skin or mucus wherever at .5 percent but these are leave on and in some cases 10 percent and 30 percent so for me, I am going to vote against if we are going to include any of these except the ones that are up at the top and one more down at the bottom. I am just letting that out.

DR. BERGFELD: Any other comments? DR. BELSITO: I guess the major issue do we go with insufficient for two or do

we go insufficient for three so Dan I am -- DR. LIEBLER: I am happy to go the same was [ones?] as you suggest so we'll

have three that were insufficient and I think you've identified them all. DR. BELSITO: I will second that then. DR. BERGFELD: So we're going to second it and we approve -- anyone else

would like to comment? Paul? Curt? Tom? Ron? Jake? No? Can we identify the three just to make sure, please?

DR. MARKS: So it's on page 40 and if you go under the list of ingredients or in the insufficient column, it's the first one, bis-hydroxiethyl acrylic poly 1,4 butanediol et cetera. The second ingredient, bis-isostearyl 1,4 butanediol HDI et cetera and then the fourth ingredient 1,4 butanediol succinic acid, adaptic acid HDI copolymer. Is that correct?

DR. LIEBLER: We have a different three, I'm sorry. Okay, so I was okay with the second item in that bulleted list, bis-isostearyl because again, as I described, my little back of the envelope calculation on molecular weight range so the minimum sized polymer would be what is depicted in that structure there and that was over 1,000 so I said that one is okay. The one that I actually had off my list and if somebody talks me into it, I am fine with the way it is, the cholesterol HDI pull copolymer because we didn't have anything on that, didn't even have a structure with an assertion of numbers of repeating units, something that I could go with because all of this was trying to deal with Ron's concern last time of the molecular weight range, distribution range and how significant a fraction of it was likely to be low and absorbable and we thought about less than 1,000 and I had nothing to go on with the cholesterol HDI pullian copolymer so that's why that one is off my list. If somebody's got more info on that?

So we could be four or -- DR. BELSITO: The ones that we had, Dan, were the 1,4 butanediol succinic acid

and adipic acid HDI copolymer, that's the one you have? DR. LIEBLER: Yes. DR. BELSITO: And then the cholesterol one Dan just said. DR. MARKS: We did not have that on our list and I think again, do you want to

comment, Carol on -- because that was going to be safe with the committee. DR. EISENMANN: You reviewed pullian and I don't remember which report it's

in and based on that review, itself is very large. It's like a -- it's over 1,000 to 8,000. It's in the footnote to the memo from CIR that it's the size of pullian.


DR. LIEBLER: Really? DR. EISENMANN: Yes. DR. LIEBLER: In the memo we just got? DR. EISENMANN: Yes. DR. LIEBLER: Okay, then I read way too fast. DR. EISENMANN: So if you look in that report, you reviewed cholesterol and

you've reviewed pullian and pullian itself is very large. DR. LIEBLER: Thanks, my concern is alleviated. DR. BELSITO: Okay, so just for my information, which -- DR. MARKS: Three? DR. BELSITO: Yeah, which three are we getting rid of. DR. MARKS: I am not going to say all the names again. Number one, number

two and number four in that list. Does that, Dan, correspond to what you felt would be insufficient?

DR. LIEBLER: Yes, I thought that number two -- I'm sorry that number two was okay --

DR. MARKS: But that's the one where there was a -- DR. LIEBLER: Number one was close. DR. MARKS: Close. DR. LIEBLER: And I said okay, we'll give you one -- if I give you one, you give

me two -- DR. MARKS: Okay. DR. LIEBLER: And we'll agree on three and it's a done deal. DR. MARKS: We'll agree on four is insufficient. DR. LIEBLER: Four is insufficient -- excuse me, not three. DR. MARKS: Yeah so sure, we'll trade horses on this one. DR. LIEBLER: So the excluded list, if I may, is the first one, this hydroxiethyl

acrylic poly, 1,4 butanediol 9 PM HDI copolymer and the 1,4 butanediol succinic acid, adipic acid, HDI copolymer?

DR. MARKS: Correct. DR. BELSITO: So it's 1, 2, and 4 on the list that remain insufficient? DR. MARKS: No, 1 and 4. DR. BELSITO: Only two are insufficient? I thought you had three insufficient.

You're confusing the heck out of me. DR. MARKS: That's because Dan and I have been trading horses. DR. BELSITO: So which two are now insufficient? DR. MARKS: 1 and 4. DR. BELSITO: 1 and 4? DR. MARKS: Correct. DR. BERGFELD: Now that we've done that, any other comments by the panel

members on this declaration of 1 and 4. Paul, Curt, are you okay with it? Tom? Ron? Oh you're voting against, all right. All right, I am going to call to question then, all those in favor of this conclusion with the insufficiency 1, and 4, okay? Against? One. And I guess that's it.

(Motion passed, 7 for, 1 against)


Transcripts HDI Polymers - December, 2015 Dr. Marks’ Team

DR. MARKS: The next group of ingredients are the hexamethylene diisocyanate (HDI) polymers.

There are 19 ingredients. In the September meeting, we issued an Insufficient Data Announcement with the needs which are bulleted by Lillian. Method of manufacture, end capping, stability, residual diisocyanate, HRIPT, repeat dose inhalation.

Part of it was addressed in this report and we have Wave 2 data that addresses these. Ron's and Tom, we are at the stage of issuing a tentative report, can we now conclude that these are safe?

DR. SHANK: (inaudible) DR. MARKS: We need more. DR. SHANK: Some of them seem to be safe, but not all of them. Five of them are safe as

used, because they are very large, not likely to be absorbed. We have skin data. There are 12 that are insufficient, and we need molecular weight and solubility to skin penetration.

I was concerned, in some of the information that we got, the molecular weight range was less than 500 to tens of thousands, so this must be a very complex mixture, if that information is correct.

DR. HILL: I think polymers have different characters. DR. SHANK: Less than 500 molecular weight polymer? DR. HILL: Yeah. DR. SHANK: Then we have the potential for absorption. DR. HILL: I raised that last time. DR. SHANK: The ones where we do have molecular weight ranges, there are five of them.

Do you want me to read them? DR. MARKS: Safe for five where molecular weight is large. DR. SHANK: Yes. DR. MARKS: I think it's going to be important. I'm trying to think of the best way to do it,

whether it is to go right after the Abstract, list the ingredients. What are the names again? DR. SHANK: The five that I have as safe is HDI/trimethylol hexyllactone crosspolymer. MS. BECKER: First on the list. DR. MARKS: I may be calling on you tomorrow to list these. It's the first one. Let me

highlight that and make it safe. Page 22. Which is the next one? DR. SHANK: Bis-C16-20 isoalkoxy, the second one. The fifth one, Bis-Lauryl

cocaminopropylamine/HDI/PEG-100 copolymer. HDI/Di-C12-14. Methoxy PEG-17/Methoxy PEG-11/HDI crosspolymer.

DR. MARKS: That is your five. DR. SHANK: I have two more. PEG-240/HDI copolymer Bis, et cetera. The last one,

Steareth-100/PEG-136/HDI copolymer. I thought the data was sufficient. DR. HILL: Do you have those marked where I could see them? My take on this was different

because I reiterated the fact that we have four different monomers here and we only have read across for HDI itself based on the data. I wanted to see how much overlap there was.

That was a TMHDI. That's good. HDI, HDI, HDI. DR. MARKS: Again, Ron, your reason is these are large molecules, and certainly would not -- DR. SHANK: The molecular weight range was given and they are fairly large, so systemic

toxicity is not a concern. DR. HILL: Agreed. DR. SHANK: We must have the irritation and sensitization on those. DR. MARKS: The ones that are not highlighted, insufficient. DR. SHANK: I had seven listed.


DR. MARKS: Yes, and the others are insufficient, and you want to get molecular weight? DR. SHANK: Yes. DR. MARKS: The other needs, if absorbed? DR. SHANK: If absorbed, we need reproductive developmental toxicity and genotoxicity.

Also, solubility. If these are solids, they are not likely to be absorbed. DR. HILL: I was looking to see in the read across table the ones that I did not like. I don't

think we have data to support hydroxyethyl acrylate poly 1,4-Butanodiol- 9/TMHDI copolymer, because it's TMHDI not HDI. I don't think we have data to support dimethyl MEA, except that's a large one, so we might be okay there.

DR. MARKS: We will have a split conclusion. It's actually safe for seven ingredients and insufficient for the rest. Jay?

DR. ANSELL: The Methoxide PEG-17 (inaudible). DR. MARKS: The HDI/trimethylol hexyllactone crosspolymer, at the greatest concentration,

31 percent. We had data on that. That was fine. DR. HILL: Which one? DR. MARKS: It's in the memo of the insufficient data, getting an HRIPT of HDI/trimethylol

hexyllactone. That's okay. Safe for the seven ingredients where the molecular weight is large and known, and insufficient for the rest is how I will put it. How does that sound?

DR. GILL: I don't think we hear a difference. I thought I heard other needs you were asking for, that you asked for before and didn't receive.

DR. HILL: I think they are the same needs, where the monomer was not HDI but one of these others, we shouldn't try to read across sensitization when the monomer changes.

MR. HAGAN: This was in the first set, for one of the TMHDI materials. DR. ANSELL: Where was that? MR. HAGAN: This was in the original data call. DR. HILL: I see. I do see that. That was one of the safe ones. DR. MARKS: Any other comments? MS. BECKER: We got information on the HDI/PPG/polycaprolactone, does that work for you,

Dr. Shank? That's in the Wave 2 data. DR. HILL: Right, Wave 2, listing number three in the memo, right. MS. BECKER: Correct. DR. HILL: The actual data comes. Yes, thank you. MS. BECKER: Not in the report, in Wave 2. DR. HILL: Data 3; right? MS. BECKER: Yes. DR. HILL: No, that's not the Wave 2. Data 3. This is from Tashiki. Manufacturing process,

residual monomer analysis, including residual HDI. 100 bpm is a lot of HDI, I think. They are using a not very sensitive detection method, although I can see why. What we don't have is some sort of molecular weight range here.

DR. MARKS: Safe for the seven ingredients, and I'm not going to repeat those, and insufficient data for the remainder, requiring solubility, molecular weight, if absorbed, genotox, carcinogenicity, et cetera. Ron, am I summarizing that correctly?

DR. SHANK: Yes. DR. ANSELL: Can you confirm the (inaudible). DR. MARKS: I have highlighted the HDI crosspolymer, not the -- DR. ANSELL: I think we submitted data on the isocyanurate. DR. HILL: There was data on the isocyanurate. DR. MARKS: And did that include the molecular weight and solubility? Because that's a big -- SPEAKER: Let's see.


DR. ANSELL: I know in Wave 2 it included sensitization. SPEAKER: Yeah, but I don't think -- DR. SHANK: Which one are you questioning, Jay? DR. ANSELL: You know, in your read-through you gave number five. DR. SHANK: Which column? Left or -- DR. ANSELL: Right-hand column. DR. SHANK: Right-hand column? DR. ANSELL: Number five, which is the HDI cross-polymer. We're curious as to whether you

meant the isocyanate trimer cross-polymer. Because we did provide data on that. DR. HILL: Quite a bit of it, actually. DR. MARKS: I think Ron shows the cross-polymer because of the large molecular weight.

And then you date that on the isocyanular rate, but it was mainly sensitivity. Again, not molecular weight solubility. So that's what, I think, Ron was making his cuts based on.

DR. SHANK: Yes. DR. ANSELL: Okay. DR. MARKS: I shouldn't speak for you, Ron, but that's how I interpret it. DR. SHANK: Yes. DR. HILL: Yeah, because at the table it's definitely telling us less than 1,000, but then we do

have a lot of data on that one. The question is -- DR. BECKER: (Inaudible)? DR. HILL: I've got Pink[PEG?] 17, Pink[PEG?] 11, HDI isocyanurate trimer crosspolymer. DR. MARKS: Yes, that's the one. DR. HILL: In your table it says "molecular weight less than 1,000." That's Table 3, which is

on -- DR. BECKER: We have inhalation. We have irritation. DR. ANSELL: That was on Ron's safe list. It was the one after that that we were curious

about. (Discussion off the record)

DR. MARKS: Okay. Anything else? So we may be seconding a motion that it concurs with our conclusion. If not, I'll put forth our conclusion, safe for seven ingredients and insufficient for the rest, and the main thing is solubility and molecular weight and referring to absorption, and we'll see where that gets us. Does that sound good? Ron, Tom, Ron?

DR. SLAGA: Right. DR. MARKS: Okay. SPEAKER: I think so. DR. MARKS: Okay. If nothing else on this ingredient, we'll move on to the next.

Dr. Belsito’s Team

DR. BELSITO: …We're now going to hexamethylene diisocyanate polymers as used in cosmetics. It's under HDI. So we had gone insufficient at the last meeting asking for stability, sensitization, irritation, and capping and we got all that. We did not get inhalation data, but now we have this powder report that we can put in. The monomer issue was addressed in Wave 2 and we have to add a heavy metal boilerplate, but I thought with all of those we could go safe as used.

DR. LIEBLER: I agree. DR. BERGFELD: I agree. DR. BELSITO: Paul? Curt? DR. SNYDER: Yes, I'm fine with safe as used. DR. KLAASSEN: Yes, safe as used.


DR. BELSITO: Anything else in the discussion other than an issue in terms of stability, monomer release and heavy metal boilerplate?

DR. SNYDER: I had a question about this idea of grade 1 and grade 2. DR. BELSITO: Where? DR. SNYDER: I've got that in my notes. I've got to look at that. Grade 1 had 34 percent less

than 10 micron sized and the grade 2 had 88 percent less than 10 micron in size, so what grade is used in cosmetics or could it be either one, or do we -- it's the first time we've ever run into a grade of any ingredient.

DR. BERGFELD: What page are you on? DR. BECKER: That's 24 in the PDF. That is the terminology in the submission. I just took it

as two -- as both of them being cosmetic grade, just different -- slightly different formulations of the same polymers.

DR. HELDRETH: Remember that these polymers can be -- vary widely even if you use the same starting materials. If you change the ratio of the starting materials, the length of the reaction, the heat of the reaction, you can get a very different looking composition in the final polymer, so that you would have the difference between 33.8 percent versus 87.5 percent. That would be easy to do without changing any of the monomers.

DR. BOYER: And there is a related table on PDF page 32, is table 4. Apparently this information came from two suppliers. Presumably they're cosmetic ingredient suppliers specifically.

DR. BECKER: This is data submitted to NICNAS. Is that how everybody's saying it? DR. BEST: It was actually three grade 1 and grade 2 then second suppliers. They're all

different. DR. BOYER: I think one supplier provides the ingredient in 2 grades and the other -- DR. BEST: It's three grades it seems like. Three grades, three types but two suppliers

naturally. DR. BELSITO: So here we don't know whether the -- it's a powder or a spray so we would

need to bring in our powder discussion in this report, correct? Because if you look at use, it's asterisk and it says it's not specified whether it's a powder or a spray.

DR. BOYER: I would say probably we should because if you look at that table you're seeing that there's significant proportion that could be respirable if it's included in the loose powder, and it doesn't agglomerate with some of the other ingredients in the formulation.

DR. EISENMANN: Bur [But?] the particle size of the ingredient may not reflect particle size of the finished product. You can, you know, things kind of attach to the -- they'll mix things together, and you're not going to have individual particles, so --

DR. BOYER: Right, in most cases I think that's true, so it's just this circumstance where you don't get that agglomeration. We don't have information about how well it agglomerates with the other ingredients in the formulation.

DR. BELSITO: But we don't know the other ingredients in the formulation, so, I mean, but we have to bring in that discussion --

DR. EISENMANN: So part of the powder discussion should be that the particle size of the finished product should be -- most of it should be non-respirable, but I don't know what the talc -- I don't remember the size of the talc that we're using as an example but it should be somewhat like that.

DR. BEST[?]: But haven't we generally been talking about these ingredients in and of themselves, not finished products? Wasn't that coming up earlier?

DR. BELSITO: That was my point. DR. BEST: Sorry, (inaudible), yes. DR. BELSITO: We can't say that it's going to agglomerate in formulation because we don't

know what it's going to be formulated with, so we have to deal with what we have here. DR. BOYER: But we can say -- we do know something about the product categories, so if it's

used in a compact formulation, just based on a category name, we might say that it's very unlikely that you are


going to get -- DR. BELSITO: Pressed powder, rather than -- DR. BOYER: Right, pressed powder or something that is kind of oily and so on, whereas the

real concern would be if the product was a loose powder, and that's where -- DR. BERGFELD: It's very rare to have loose powder anymore in a cosmetic for a female;

very, very rare. DR. BELSITO: There's still dusting powders out there. DR. BERGFELD: Not very many. It's hard to buy them. DR. BOYER: And we do have the category of face, the neck powders and so on, so that's

where we would be concerned. DR. BECKER: It is used in a face powder at 3 of the 12.6 percent. DR. BERGFELD: You're saying (inaudible) Compressed face powder and that? DR. BOYER: And the next step would be to decide whether or not we want to include those

two to three sentences to address the unlikelihood that anybody's going to be exposed even in a loose powder to any significant amounts of respirable ingredient.

DR. BELSITO: Well then, I think in this case you look at what it's used at. Let me go back there, so it says incidental inhalation powders, 3.2, a range of 2 to 10.8. Then it has footnote C and D; C not specified whether a powder or a spray. It is possible that these products may be powders, but is specified whether the reported use are powders, so we don't know that those powders are necessarily pressed-powder face makeup. I mean we don't -- at least I don't think we know. So then I think we have to go back to that sort of boilerplate language that we have that, okay, you know, pressed powder is really not an issue. They're not going to be released, and then we did this back of the napkin calculation for talc and found out that you would have to get exorbitantly high concentrations to have any inert effect on the lung, and so that this boiler plate is going to be very relevant in explaining why we don't -- are not asking for additional respiratory toxicity on this group of ingredients, but I think we just established the boilerplate so I think we can say that and move on, so safe as used. It'll come back to us as a tentative final. It's been a change in the conclusion, and we'll look and see how you included that powder boilerplate, and we can finesse that. That will simply be editorial and go from there.

DR. LIEBLER: Good by me. DR. KLAASSEN: Ivan, you've used as a background -- some of the talc data that you found.

I think there's also been very similar studies done with silicone dioxide, and you might kind of compare -- I mean I think it's kind of the same conclusion, but it might be better to have two examples instead of one.

SPEAKER: Okay. DR. BELSITO: Except you don't want to put silicone dioxide in water. DR. KLAASSEN: Why? DR. BELSITO: Doesn't it explode? DR. KLAASSEN: No, not that I know of. DR. BELSITO: Okay. DR. LIEBLER: That's just an urban legend circulating in the dermatology community.

(Laughter) DR. BELSITO: I see. Okay. DR. SNYDER: What literature have you been reading? DR. BELSITO: I don't know. I might go on the hit list if it says explosive literature. Okay. DR. SNYDER: Good.

Day Two

DR. BERGFELD: …Okay, moving on to the next ingredient, Dr. Belsito, the HDI. DR. BELSITO: Okay. So these are the hexamethylene diisocyanate polymers. The


September meeting, we issued an insufficient data announcement for 19 of the ingredients in the report, requesting method of manufacturing on end-capping agents, quantification of any residual diisocyanate, information on stability, and an HRIPT on HDI/trimethylol hexyllactone crosspolymer at the greatest concentration of use.

Much of the information that we needed was submitted in Wave 2. And we felt that based upon the submitted information we could go with a safe as used conclusion for this group of ingredients.

DR. BERGFELD: Is there a second? DR. MARKS: No. I'm going to ask Ron Shank to comment because there were seven

ingredients which he felt, because of their large molecular weight, he was not concerned they could be safe. And if we go on page 22, those were the -- if I go down the bullets, the first and second bullets are the HDI, et cetera, the bis-C16-20, et cetera, and we do down the fifth, these would all be safe because their molecular weight is large, bis-lauryl.

And if we go in the second column, the second one down, the HDI/Di-C12, et cetera; the methoxy PEG, et cetera; the PEG-240/HDI, et cetera; and the steareth-100/PEG; and then all the other ones would be insufficient. We need the molecular weight, the solubility, and if absorbed then the usual toxicologic data to confirm their safety if they're absorbed, like repro and geno.

Did I capture that correctly, Ron Shank? DR. SHANK: You did. DR. BERGFELD: Anything to add, Ron? DR. SHANK: No. DR. BERGFELD: Any other comment before we ask Belsito's team to comment? DR. KLAASSEN: Which ones did you want to eliminate? DR. MARKS: We didn't eliminate. We split it into -- yeah, so the safe were seven. And again,

on the left- hand column, the first and second bulleted ingredient, the HDI/trimethylol -- DR. KLAASSEN: Okay. DR. MARKS: -- the bis-C16-20, and then the fifth ingredient, the bis-lauryl, those would be

safe. DR. BELSITO: But not bis-methoxy? DR. MARKS: Pardon? DR. BELSITO: But not bis-methoxy PEG-10? DR. MARKS: That's correct, not bis-methoxy. And then on the right-hand column, the HDI/Di,

that's the second one down; and then the fifth one down, the methoxy PEG-17; and then skipping the next one and then we go to the PEG-240 is safe; and then the last one we state would be the steareth-100.

DR. BERGFELD: Dan? DR. SHANK: So maybe more of a negative (inaudible) since it states some irritation. DR. MARKS: Right, we're not concerned about -- DR. LIEBLER: Yeah, so the bis-methoxy PEG-10 is one of the ones you're -- DR. MARKS: Insufficient. DR. LIEBLER: -- insufficient on? Okay. So one reason that didn't trigger for me is if it's a

PEG-10, it's already reasonably big. I don't know what the exact molecular weight is, but I looked at that and I thought that that is a large molecule. But I don't object to asking for the additional data, so I would support that.

DR. BERGFELD: Paul? Curt? Don? DR. BELSITO: I'm not a chemist, so I'll refrain except that I'm not aware of -- what are you

concerned about with the low molecular weight? Absorption, systemic toxicity? What are we asking for? DR. SHANK: Yeah, if -- DR. BELSITO: If they do penetrate, what are we asking for? What are our concerns? DR. SHANK: If they do penetrate, we're asking for mutagenicity, reproductive, the usual

systemic toxicology profile. If we could get the molecular weight range for each of these, that would be very


helpful. DR. MARKS: And the solubility. DR. SHANK: And the solubility. Some of these I think are solids. DR. BERGFELD: Any other -- DR. SHANK: I hate to go ahead when I don't know the chemistry. DR. LIEBLER: No, I mean, I agree with you and I think it's something that we should insist on.

In this case, I will point out the difference here is that you actually do have a formula and you do have some information in the case of that PEG-10 I just mentioned, for example. A PEG-10 polymer contains at least 10 PEG units, so, you know, that enhances the size. But I have no objection to asking for the data at this point.

DR. BERGFELD: So we've had a motion which has not been seconded. Do we have another motion?

DR. MARKS: Do we need to withdraw the first motion? If we do, fine. DR. BERGFELD: Well, it's not been seconded. DR. MARKS: Yeah, okay. So the second motion -- or not the second motion, our team would

move that the items that I highlighted be safe, a tentative report, we go out with those, would be safe and the remaining ingredients would be insufficient.

DR. BELSITO: Insufficient for? DR. MARKS: For basically molecular weight and solubility. Then if we find there are still

concerns after that, then we would want the systemic tox. But the first insufficient data needs we have are molecular weight and solubility.

DR. BELSITO: Manufacturing impurities, no? DR. MARKS: Ron, do you need -- no. DR. BELSITO: So molecular weight -- DR. MARKS: And solubility. DR. BELSITO: -- and solubility. And if -- DR. SHANK: The second tier would then be absorption. DR. BELSITO: If soluble, if molecular weight less than what? What's your cutoff for asking for

additional data? DR. SHANK: A thousand. DR. BELSITO: Molecular weight less than 1,000. Solubility (inaudible) K-O-W, what are you

asking for? DR. SHANK: The solubility in formulations. Are these solids or -- DR. BELSITO: Well, they're film-forming agents. They're anti-viscosity agents. They're

anti-caking agents. So does industry want to comment on what a product looks like that has those functions, what its state would be? It certainly wouldn't be gaseous.

DR. SNYDER: It would seem to me we would want chemical composition and solubility unless they give us dermal absorption. So we'd take either one to assess the absorption issue. And then if it's not absorbed, then it's not an issue. But if it's absorbed, then we would want to go to a carcinogenicity and reproductive developmental studies.

DR. LIEBLER: I think all of this could be solved with the molecular weight information. DR. SHANK: I think so, too. DR. HILL: And we got it for one of them, I mean, because they gave us -- this was the

bis-C16-20 isoalkoxy, they gave percentage below 1,000, another percentage below 500. So if we had that information for all of them, I think we could make better conclusions.

DR. BERGFELD: So is there a second to Dr. Marks' motion? DR. GILL: Can I clarify what we really need? I think I heard Dan said this could be solved

with information on the molecular weight. If they don't provide that, then solubility? DR. BERGFELD: I think they wanted both. Did you want both, solubility and molecular

weight?


DR. LIEBLER: I think -- well, I shouldn't speak for Ron. DR. SHANK: I would start first with molecular weight range for each one and see where we

are. DR. LIEBLER: If we're a low molecular weight on these and low is in -- there's not a magic

number -- DR. BELSITO: Ron said less than 1,000. DR. LIEBLER: Yeah, but generally less than 1,000. Then we're concerned about absorption

and then we start asking about toxicity end points, as well. I suspect -- DR. BELSITO: And absorption -- DR. LIEBLER: -- given the nature -- DR. BELSITO: -- do you want 28-day dermal or -- DR. LIEBLER: Yeah, and I suspect given the nature of these ingredients and what they're

used for, they're going to be high molecular weight or they would be useless for the purposes, but we just don't have the information. So it's a point well taken. I support it. I would second that motion.

DR. BERGFELD: The motion's been seconded. And what do you think you heard, Lillian? We need to get just molecular weights for now?

DR. GILL: Within that range of not -- DR. BELSITO: Twenty-eight-day dermal, how do you want absorption? Franz chamber,

molecular weight, I mean, we need to give industry some guidance as to exactly what kind of data we want. DR. SHANK: Start with molecular weight and then if there are some very small molecular

weight -- this is going to be a range, I suspect, for these compounds. And if there are significant small molecular weights in this, then we would ask for solubility. And in formulation is it a form of a molecule that can penetrate the skin? If we think there is penetration, then we would want that information, how much is penetrated.

Now, some of these are used at very low concentrations, so maybe it's not going to be an issue. But until we know more about the these other compounds, at least I would like to start with molecular weight and see where we are.

One of these compounds has -- let's see if I can find it -- a molecular weight range of less than 500 to tens of thousands, but that compound is used at 0.025 percent. And if it's a solid, there isn't going to be an absorption even though the range would indicate that something could be absorbed.

DR. BELSITO: Okay. DR. SHANK: So without the information of the molecular weights, we're blind or I'm blind. DR. BELSITO: So let me just summarize. So you say molecular weight less than 1,000, then

we want solubility in formulation, and if soluble, some type of study looking at skin penetration. And I'm assuming this could be absorption study in a chamber or a 28-day dermal. Is that fair?

DR. SHANK: Yes. DR. BERGFELD: Any other -- DR. KLAASSEN: In regard to that first request, the molecular weight, and you said it'll

probably be a range, and I guess what we probably also need is kind of what fraction is the monomer? If it's like 450 to 10 million, then how much of it is 450? So I think it'd be nice to know the portion of that's still a monomer because that's -- probably when it gets to be the trimer we don't need to worry about it anymore. It's the monomer that we're possibly concerned about.

DR. BERGFELD: Okay. Ron Hill, you have another comment? DR. HILL: Well, I was just going to say, you know, a trimer of these monomers would still be

small, so I think a molecular weight distribution. And I would have felt more comfortable with having -- we've got some, but not for all -- an indication of how low is low on these isocyanates, which is a major concern because, in particular, even with regard to sensitization we've got four different isocyanates here. Sensitization to one would not necessarily carry over. But conversely, lack of sensitization to one of these monomers -- or excuse me, isocyanates if it reacts with tissue wouldn't necessarily clear the other three. So


we actually had data on two of them out of the four, so that's another point is the smaller molecular weight, the greater the chance, if we have something that's liquid, small molecular weight, that there could be monomer -- excuse me again, isocyanate that in their residual. And it would be awfully nice to get information to suggest, yes, it's below so many PPM or so many PPB.

DR. LIEBLER: So, Lillian, on PDF page 32, one of the tables is part of Table 3, which is Chemical and Physical Properties, down the third table from the bottom, Methoxy PEG-17/Methoxy PEG-11/HDI Isocyanate Trimer Crosspolymer, it lists the molecular weight as less than 1,000. That's just not possible given the components that are listed. Plus, the thing is a solid powder that has a melting point of greater than 200, so that 1,000 has got to be a mistake. Somebody might have --

DR. EISENMANN: What it actually says, the molecular weight of the extracted bulk polymer part, less than 1 percent from a representative with below about 1,000 daltons.

DR. LIEBLER: Okay. So that essentially is documentation of what I would think of as sort of an impurity.

DR. EISENMANN: Correct. DR. LIEBLER: As opposed to the substance itself -- DR. EISENMANN: Right. DR. LIEBLER: -- or the ingredient itself, which is much bigger. DR. EISENMANN: Right. DR. LIEBLER: So that's perhaps just a misinterpretation of some of the information provided. DR. EISENMANN: Right. So less than 1 percent is -- DR. LIEBLER: Right, is the small -- yeah, right. DR. EISENMANN: Right. DR. LIEBLER: Okay. So anyway, we need to fix that. I suspect these are all going to come

in big and it'll be end of discussion. DR. BERGFELD: All right. Any other discussion? I hope not. (Laughter) Let's call the

question. All those in favor of this conclusion, which is? Can we just reread the conclusion? DR. MARKS: Let me go back to it. DR. BERGFELD: Some are safe and some are not. DR. MARKS: Yes, you got it. The seven that had large molecular weights would be seven

that I mentioned prior and the remainders, until we get either the molecular weight or the solubility, that they would be insufficient.

DR. BERGFELD: Thank you. I'm going to call the question. All those in favor of this conclusion, please indicate by raising your hand. Thank you. Unanimous.


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: Revised Draft Final Report for Panel Review Release Date: May 13, 2016 Panel Meeting Date: June 6-7, 2016

The 2016 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. The functions of HDI polymers include anticaking agents, viscosity increasing agent – aqueous, and film formers. These ingredients are copolymers, the monomers of which include HDI or other diisocyanates. The HDI monomer can cause occupational asthma and other ailments. The Cosmetic Ingredient Review (CIR) Expert Panel (Panel) reviewed available data related to these ingredients and determined that there would be no significant residual isocyanate monomers in these ingredients. The Panel concluded that 17 of these ingredients are safe in cosmetics in the present practices of use and concentration and the available data are insufficient to make a determination that 2 of these ingredients are safe.

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

hexamethylene diisocyanate (HDI; also known as 1,6-diisocyanatohexane) polymers, listed below, as used in cosmetics. These ingredients are copolymers, the monomers of which partially consist of HDI, or other diisocyanates. 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 non-irritating.

The ingredients in this report are copolymers, each of which is synthesized, in part, from the monomer HDI or other diisocyanate analogs. These ingredients are grouped together because their copolymers originate from these common diisocyanate monomers. 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 to generate haptens by reacting with and covalently bonding to endogenous proteins to induce an immune response. Hapten formation is believed to be a mechanism for recognition of an 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 an analog, as one of the starting materials (monomers). Accordingly, quantification of any residual diisocyanate in the final cosmetic ingredient may be paramount to determining safety.

CHEMISTRY

Definition and Structure 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 analog of HDI (Figure 1).


Figure 1. Hexamethylene Diisocyanate.

The other 3 diisocyanate monomers herein are analogs of HDI, namely trimethylhexanediisocyanate (TMHDI), saturated methylene diphenyldiisocyanate (SMDI), and the HDI trimer (Figure 2).

Figure 2. HDI analogs. 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 product having 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.


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

A supplier reported that HDI/Trimethylol Hexyllactone Crosspolymer was available in two grades for cosmetics (Table 4).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. Another source reported that the average particle size is 12-18 µm.17 A fourth source reported that the average particle size range of HDI/PPG/Polycaprolactone Crosspolymer was 12-19 µm.18

For the molecular weight range of Bis-C16-20 Isoalkoxy TMHDI/PEG-90 Copolymer, 1.5% of the ingredient was reported to be <1000 Da and 1.2% was <500 Da.22 It was reported that the molecular weight of Bis-Methoxy PEG-10 Dimethyl MEA/HDI/Bis-PEG-10 Dimethicone Copolymer is >1000 Da.24 In an analysis of Bis-Lauryl Cocaminopropyl-amine/HDI/PEG-100 Copolymer, HDI/Di-C12-14 Alkyl Tartrate/Hydrogenated Dilinoleyl Alcohol Copolymer, and Steareth-100/PEG-136/HDI Copolymer, no compounds <1000 Da were detected.20,21,23,25 The molecular weight of HDI/PPG/Poly-caprolactone Crosspolymer was reported to be >10,000 Da.26 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.19

Methoxy PEG-17/Methoxy PEG-11/HDI Isocyanurate Trimer Crosspolymer is reported to be fully crosslinked, and its MW is reported to be infinite.27 This polymer contains a 0.9% soluble fraction (in tetrahydrofuran) with a MW >1000 Da.

HDI/C12-14 Alkyl Tartrate Hydrogenated Dilinoleyl Alcohol Copolymer, as supplied, is reported to be stable for 16 weeks in temperatures from 5-50˚C.25

Method of Manufacture

HDI/Di-C12-14 Alkyl Tartrate/Hydrogenated Dilinoleyl Alcohol Copolymer is reported to be 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).23 Polymerization is terminated by the addition of ethyl alcohol (i.e., ethyl alcohol end-caps the polymer).

HDI/Trimethylol Hexyllactone Crosspolymer is reported to be manufactured by mixing an isocyanate prepolymer (HDI/trimethylolpropane/ε-caprolactone) and a solvent for aqueous suspension polymerization at 30-100˚C for 1-6 h.17 The resulting polymer is washed with water. The product is dried at 95˚C followed by classification, sterilization, and packaging. Alkylation and endcapping agents are not used in this process.

HDI/PPG/Polycaprolactone Crosspolymer is reported to be manufactured by the same process as the HDI/Trimethylol Hexyllactone Crosspolymer, with the addition of propylene oxide/D-glucitol in the mix for the aqueous polymerization.18

Steareth-100/PEG-136/HDI Copolymer and Bis-Lauryl Cocaminopropylamine/HDI/PEG-100 Copolymer are manufactured by placing pre-dried polyethylene glycol and diisocyanate together with a catalyst.28 The reaction is allowed to proceed to completion to consume the free diisocyanate. A high boiling aliphatic alcohol or surfactant molecule is used to consume the unreacted isocyanate groups at the ends of the polymer chains and thereby act as an end-capping agent.

Impurities HDI The residual amount of HDI in HDI/Di-C12-14 Alkyl Tartrate/Hydrogenated Dilinoleyl Alcohol Copolymer raw material was reported to be <0.5 ppm (Table 5).23 The residual diisocyanate was reported to be below the limit of detection (0.017%) for Bis-Lauryl Cocaminopropylamine/HDI/PEG-100 Copolymer and Steareth-100/PEG-136/HDI Copolymer; there was no free HDI detected for both of these ingredients at temperatures up to 150˚C.29 Residual HDI was <100 ppm in HDI/Trimethylol Hexyllactone Crosspolymer and HDI/PPG/Polycaprolactone Crosspolymer.17,18 No residual HDI was detected (detection limit <20 ppm) in an analysis of 3 batches of PEG-240/HDI Copolymer Bis-Decyltetradeceth-20 Ether.19 In an analysis of a skin care cream and a makeup cream that contained HDI/Trimethylol Hexyllactone Copolymer (preformulated with silica; 5% as a plastic powder), and HDI/PPG/Polycaprolactone Crosspolymer (preformulated with silica; 2.4% as a plastic powder), the amount of HDI monomer was below the limits of detection (0.4 ppm) in both of these products.30

Other Impurities

Bis-C16-20 Isoalkoxy TMHDI/PEG-90 Copolymer and Bis-Lauryl Cocaminopropylamine/HDI/PEG-100 Copolymer were reported to contain <1 ppm mercury, <3 ppm arsenic, and <10 ppm lead.31

In an analysis of HDI/PPG/Polycaprolactone Crosspolymer, ε-caprolactone was present at 240 ppm and D-glucitol at 0.07 ppm, but there was no trimethylolpropane detected (detection limit < 2 ppm) or propylene oxide (detection limit <1 ppm).18

In an analysis of 3 batches of HDI/Trimethoylol Hexyllactone Crosspolymer, it was reported that the levels of ε-caprolactone ranged from 66 to 73ppm and trimethylolpropane from 4 to 12 ppm.17


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, or tin; extraction experiments detected no organic materials into water.32 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. At the end of the drying process, it is expected that there will be approximately 1% residual water and no volatile organic materials will persist. Butylhydroxytoluene (BHT) may be present as a technical impurity at <20 ppm. The extractable oligomer (< approximately 1000 Da) of this crosspolymer was <1%. 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.19 Formaldehyde was detected at 1 and 2 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 FDA collects data 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 2016 VCRP data, HDI/Trimethylol Hexyllactone Crosspolymer has the greatest number of reported uses and is reported to be used in 385 formulations, which includes 378 leave-on products and 7 rinse-off products (Table 6).33 Fifty-three of these formulations are powders, 11 are lipsticks, and 360 have dermal contact. The other ingredients that had reported uses were used in 24 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.34,35 Table 7 lists the HDI polymers with no reported uses.

Concentration of use data were received for Methoxy PEG-17/Methoxy PEG-11/HDI Isocyanurate Trimer Crosspolymer, but uses were not reported in the VCRP, therefore, it should be presumed that there is at least 1 use for the reported concentration. This is also true for Bis-C16-20 Isoalkoxy TMHDI/PEG-90 Copolymer (1 use in mascara) and HDI/Di-C12-14 Alkyl Tartrate/Hydrogenated Dilinoleyl Alcohol Copolymer. 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 come in contact with mucus membranes (highest concentration reported to be 15.1% in lipsticks). 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% in lipsticks). HDI/Trimethylol Hexyllactone Crosspolymer, Bis-C16-20 Isoalkoxy TMHDI/PEG-90 Copolymer, HDI/Di-C12-14 Alkyl Tartrate/Hydrogenated Dilinoleyl Alcohol Copolymer, 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% in eye shadow).

Additionally, 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 maximum reported concentration of these ingredients in a likely aerosol product is 2.5% in tonics, dressings, and other hair grooming aids. In practice, 95% to 99% of the droplets/particles released from cosmetic sprays have aerodynamic equivalent diameters >10 µm.36-39 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.37,38 HDI/trimethylol hexyllactone crosspolymer and HDI/PPG/polycaprolactone crosspolymer were reported to be used in face powders at up to 12.6% and 11.8%, respectively, and could possibly be inhaled. Conservative estimates of inhalation exposures to respirable particles during the use of loose powder cosmetic products are 400- to 1000-fold less than protective regulatory and guidance limits for inert airborne respirable particles in the workplace.40-42

The European Union restricts the content of traces of diethylene glycol to a total of 0.1% in any cosmetic product, including the trace amount of diethylene glycol contained in polymers, such as Diethylene Glycol/DMAP Acrylamide/PEG-180/HDI Copolymer.43

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 HDI/Trimethylol Hexyllactone Crosspolymer (5000 mg/kg) administered by gavage caused no clinical signs or

mortalities to rats (Table 8).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.32 The oral LD50 of PEG-240/HDI Copolymer Bis-Decyltetradeceth-20 Ether was reported to be >2000->2500 mg/kg in rats.19 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.20 The acute oral LD50 was >10,000 mg/kg in rats (n=5/sex) for a cosmetic ingredient mixture consisting of Bis-Cocaminopropylamine/HDI/ PEG-100 Copolymer (concentration not specified) and butylene glycol.44 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.32 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.32 No further details were provided.

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).19 No further details were provided.

Steareth-100/PEG-136/HDI Copolymer

In an Ames test conducted according to OECD TG 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.20

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), and Steareth-100/PEG-136/HDI Copolymer (100%; 0.5 g; dry) were not dermal irritants in rabbits (Table 9). 14-16,20,32 PEG-240/HDI Copolymer Bis-Decyltetradeceth-20 Ether was not a dermal irritant in guinea pigs up to 30%.19


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 9).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.23

Dermal - In Vitro

In in vitro studies, Methoxy PEG-17/Methoxy PEG-11/HDI Isocyanurate Trimer Crosspolymer (concentration not specified), PEG-240/HDI copolymer Bis-decyltetradeceth-20 ether, and a mixture containing 30% Bis-C16-20 Isoalkoxy TMHDI/PEG-90 Copolymer were predicted to be non-irritating (Table 9).19,22,32

Ocular – Non-Human – In Vivo

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 10).14-16 The authors considered the particle size (at least 92.9% > 1 µm as shown in 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 ocular irritant in rabbits.32 PEG-240/HDI Copolymer Bis-Decyltetradeceth-20 Ether (up to 30%) was not an ocular irritant in rabbits.19 Steareth-100/PEG-136/HDI Copolymer (100%) was classified as a non-irritant in the eyes of rabbits.20

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%.19 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 2.74.19 A score of 0-3 indicate an ocular non-irritant. No further details of the study were provided.

Sensitization

Non-Human 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 11).32 In a skin sensitization assay (species not specified), PEG-240/HDI Copolymer Bis-Decyltetradeceth-20 Ether (30%) was not a dermal sensitizer.19

Human 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 11).45,46 In an HRIPT of Bis-C16-20 Isoalkoxy TMHDI/PEG-90 Copolymer (30%), one subject exhibited barely perceptible erythema 48 h after the challenge.22 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.19

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 partially are comprised of HDI, or an analog thereof. 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 reported ranges of molecular weights of these HDI polymers are from <500 Da (a small percentage of the ingredients) to 75,000 Da. 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. In an 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 compounds of <1000 Da were detected. The molecular weight of HDI/PPG/Polycaprolactone Crosspolymer was reported to be >10,000 Da. 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. Methoxy PEG-17/Methoxy PEG-11/HDI Isocyanurate Trimer Crosspolymer is reported to be fully crosslinked, and its MW is reported to be infinite.

The residual amount of HDI in HDI/Di-C12-14 Alkyl Tartrate/Hydrogenated Dilinoleyl Alcohol Copolymer was reported to be <0.5 ppm. The residual diisocyanate was reported to be below the limit of detection for Bis-Lauryl Cocaminopropylamine/HDI/PEG-100 Copolymer and Steareth-100/PEG-136/HDI Copolymer. Residual HDI was <100 ppm


in HDI/Trimethylol Hexyllactone Crosspolymer and HDI/PPG/Polycaprolactone Crosspolymer. In an analysis of 3 batches of PEG-240/HDI Copolymer Bis-Decyltetradeceth-20 Ether, no residual HDI was detected (detection limit <20 ppm).

In an analysis of a skin care cream and a makeup cream that contained HDI/Trimethylol Hexyllactone Copolymer and silica (5% as a plastic powder) and HDI/PPG/Polycaprolactone Crosspolymer and silica (2.4% as a plastic powder), respectively, the amount of HDI monomer was below the limits of detection in both of these products.

According to 2016 VCRP data, HDI/Trimethylol Hexyllactone Crosspolymer is used in 385 formulations, 378 of which are leave-on products and 7 of which are rinse-off products. The five other ingredients that had reported uses by the VCRP were used in 24 or fewer cosmetic formulations. The highest concentration of use was reported to be 31% for HDI/Trimethylol Hexyllactone Crosspolymer in leave-on products.

The acute oral LD50 was >10,000 mg/kg in rats for a product mixture 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 gavage 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, Steareth-100/PEG-136/HDI Copolymer, and PEG-240/HDI Copolymer Bis-Decyltetradeceth-20 Ether were not mutagenic in Ames tests.

HDI/Trimethylol Hexyllactone Crosspolymer at 100% was not a dermal irritant on 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, and Steareth-100/PEG-136/HDI Copolymer at 100% was not dermally irritating to rabbits. PEG-240/HDI Copolymer Bis-Decyltetradeceth-20 Ether up to 30% was not a dermal irritant to guinea pigs in irritation assays.

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 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 the National Occupational Health and Safety Commission of Australia (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% in a CAMVA assay of PEG-240/HDI Copolymer Bis-Decyltetradeceth-20 Ether. In a BCOP assay, PEG-240/HDI Copolymer Bis-Decyltetradeceth-20 Ether was scored as an ocular non-irritant.

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 an 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.

DISCUSSION

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. Three of these ingredients were not mutagenic in bacterial assays. Molecular weights for some of the ingredients were reported to range from <500 to 75,000. There were no toxicokinetic, repeated dermal toxicity, and reproductive/developmental data found in the published literature or submitted by Industry. The results of the assays for ocular and dermal irritation and dermal sensitization showed that there were no concerns that the tested ingredients would be irritating or sensitizing under the conditions of use.

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.

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 significant residual HDI (or TMHDI, SMDI, or HDI isocyanurate trimer) monomers in these ingredients.


Manufacturers and formulators should continue to use good manufacturing practices (GMPs) to ensure that these monomers are not present in these ingredients and in formulation.

The Panel expressed concern regarding heavy metals that may be present in these ingredients. They stressed that the cosmetics industry should continue to use GMPs to limit these impurities in the ingredient before blending into cosmetic formulation.

These ingredients vary in size depending on the manufacturing process. Manufacturers and formulators should use GMPs to ensure that polymers with low molecular weights (<1000 Da) are not present in cosmetic products.

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, and Bis-Lauryl Cocaminopropylamine/HDI/PEG-100 Copolymer; the Panel found the data to be appropriate for read across for these three ingredients.

Inspection of the chemical structural formulas of most of the ingredients indicated that even the most minimal possible polymers would have molecular weights >1000 Da, because at least one of the monomers was >1000 Da, and thus would have no significant dermal absorption. For example, it was noted that the PEG monomers (PEG-17 and PEG-11) were large, and that the resulting crosspolymer, Methoxy PEG-17/Methoxy PEG-11/HDI Crosspolymer, would therefore be large enough that it would not penetrate intact skin; there is no concern about systemic exposure.

The Panel discussed the issue of incidental inhalation exposure from products that may be sprays (e.g., tonics, dressings and other hair grooming aids; face and neck products; body and hand products; indoor tanning preparations and from face powders). These ingredients are reportedly used at concentrations at up to 2.5% in products that may be sprayed and aerosolized, and at up to 12.6% in cosmetic products that may become airborne. The molecular weight of several of these ingredients was reported to be 7000 Da or greater; some ingredients had no reported molecular weight data. Limited data available from an acute inhalation study of Methoxy PEG-17/Methoxy PEG-11/HDI Isocyanurate Trimer Crosspolymer suggest little potential for respiratory effects at concentration of use. The Panel noted that droplets/particles from spray and loose-powder cosmetic products would not be respirable to any appreciable amount. Furthermore, these ingredients are not likely to cause any direct toxic effects in the upper respiratory tract, based on the properties of the HDI polymers and on data that shows that these ingredients are not irritants. 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. In addition, these ingredients are large macromolecules, insoluble in water, and chemically inert under physiological conditions or conditions of use, which supports the view that they are unlikely to be absorbed or cause local effects in the respiratory tract. 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.

Molecular weights were not provided for Bis-Hydroxyethyl Acrylate Poly(1,4-Butanediol)-9/TMHDI Copolymer and 1,4-Butanediol/Succinic Acid/Adipic Acid/HDI Copolymer; it could not be concluded that these ingredients would not penetrate the skin. Therefore, the data needs for these two ingredients are:

• Molecular weight distribution • If the molecular weight is below 1000 Da, then solubility in formulation, dermal absorption, and/or 28-day dermal

toxicity study • If soluble or dermally absorbed, then systemic toxicity data including genotoxicity, carcinogenicity, and

reproduction/developmental toxicity


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

CONCLUSION

The CIR Expert Panel concluded that the following 17 HDI polymers are safe in cosmetics in the present practices of use and concentration described in this safety assessment:

• HDI/Trimethylol Hexyllactone Crosspolymer • Bis-C16-20 Isoalkoxy TMHDI/PEG-90 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* • 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 available data are insufficient to make a determination that the following 2 ingredients are safe under the intended conditions of use:

• Bis-Hydroxyethyl Acrylate Poly(1,4-Butanediol)-9/TMHDI Copolymer* • 1,4-Butanediol/Succinic Acid/Adipic Acid/HDI Copolymer*

*Not reported to be in current use. Were ingredients in this group not in current use to be used in the future, the expectation is that they would be used in product categories and at concentrations comparable to others in this group.


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

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% 8,47 Pullulan - microbial polysaccharide gums Safe for use in cosmetics in the present

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

hygiene; biosaccharide gum-1 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% 6,47


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 @ 20oC kg/m3

g/mL 1100-1250

0.6 14-16

17 Melting Point oC >225 14-16

Bis-C16-20 isoalkoxy TMHDI/PEG-90 copolymer Color Translucent 31,48 Molecular Weight g/mol Average >7000 22 Density g/mL @ 25oC 1.03-1.08 22 Viscosity kg/(s m)@ oC 3-10 22

Bis-Lauryl Cocaminopropylamine/HDI/PEG-100 Copolymer Color Translucent 31 Molecular Weight g/mol >10,000 21

Bis-Methoxy PEG-10 Dimethyl MEA/HDI/BIS-PEG-10 Dimethicone Copolymer Molecular Weight g/mol >1000 24

HDI/di-C12-14 alkyl tartrate/hydrogenated dilinoleyl alcohol copolymer Physical Form Viscous liquid 23 Color Yellow 23 Odor Characteristic 23 Molecular Weight g/mol >25,000 23 Viscosity kg/(s m)@ 25oC 3-5 23

HDI/PPG/polycaprolactone crosspolymer Molecular Weight g/mol >10,000 26 Density g/mL 0.6 18

Methoxy PEG-17/Methoxy PEG-11/HDI Isocyanurate Trimer Crosspolymer Physical Form Solid, powder, granules 32 Color White 32 Odor Odorless 32 Molecular Weight g/mol >1000

Infinite 49 27

Density g/mL @ 20 oC ~0.246 32 Melting Point oC >200 32

PEG-240/HDI Copolymer Bis-Decyltetradeceth-20 Ether Molecular Weight g/mol 4000-75,000 19

Steareth-100/PEG-136/HDI copolymer Physical Form Powder 50 Color White 50 Molecular Weight g/mol >15,000 20 Melting Point oC 53-63 50 Water Solubility Dispersible 50

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. Residual diisocyanate in HDI polymers. Ingredient Residual diisocyanate Reference HDI/Di-C12-14 Alkyl Tartrate/Hydrogenated Dilinoleyl Alcohol Copolymer

<0.5 ppm 23

Bis-C16-20 Isoalkoxy TMHDI/PEG-90 Copolymer Below limit of detection (0.02%)a

51

Bis-Lauryl Cocaminopropylamine/HDI/PEG-100 Copolymer

Below limit of detection (0.017%)

29

Steareth-100/PEG-136/HDI Copolymer Below limit of detection (0.017%)

29

HDI/Trimethoylol Hexyllactone Crosspolymer <100 ppm 17 HDI/PPG/Polycaprolactone Crosspolymer <100 ppm 18 PEG-240/HDI Copolymer Bis-Decyltetradeceth-20 Ether

Below limit of detection (20 ppm)

19

a Trimethylhexanediisocyanate

Table 6. Frequency of use and concentration according to duration and exposure of HDI polymers.33-35

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 385 0.0096-31 NR 0.6 6 NR NR 0.026-7.6 Duration of usea

Leave-on 378 0.0096-31 NR 0.6 1 NR NR 0.026-7.6 Rinse-off 7 11.7 NR NR 5 NR NR NR

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

Exposure type Eye area 139 0.049-19.6 NR 0.6 NR NR NR 1.2

Incidental ingestion 11 0.0096-15.1 NR NR NR NR NR 0.026-7.6

Incidental Inhalation-sprays 33b; 39c NR NR NR 1b NR NR NR

Incidental inhalation-powders 53; 39c 3-12.6; 0.78-

14.4d NR NR NR NR NR NR

Dermal contact 360 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 12 0.0096-15.1 NR NR NR NR NR 0.026-7.6

Baby NR NR NR NR NR NR NR NR


Table 6. Frequency of use and concentration according to duration and exposure of HDI polymers.33-35

Use type Uses


(%) Uses


(%) Uses


(%) Uses


(%)

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 Total/range 24 2-11.8 3 NR NR 0.025 4 1-2

Duration of use Leave-on 24 2-11.8 1 NR NR 0.025 4 1-2 Rinse-off NR NR NR NR NR NR NR 1

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

Exposure type Eye area 4 5-9.8 NR NR NR NR 3 1.9-2

Incidental ingestion NR NR 1 NR NR NR NR NR

Incidental Inhalation-sprays 6b; 3c NR NR NR NR NR 1b 2b

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

2-10.8d NR NR NR NR NR 2d

Dermal contact 22 2-11.8 NR NR NR 0.025 4 1-2 Deodorant (underarm) NR NR NR NR NR NR NR NR

Hair-noncoloring NR NR NR NR NR NR NR 1-2 Hair-coloring NR NR NR NR NR NR NR 1

Nail NR NR NR NR NR NR NR NR Mucous

Membrane NR NR 3 NR NR NR NR NR

Baby NR NR NR NR NR NR NR NR

Steareth-100/PEG-136/ HDI Copolymer

Total/range 1 0.87-2.5 NR = Not Reported; Totals = Rinse-off + Leave-on + Diluted for Bath Product 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.

Duration of use Leave-on 1 1.6-2.5 Rinse-off NR 0.87

Diluted for (bath) use NR NR

Exposure type Eye area NR NR

Incidental ingestion NR NR

Incidental Inhalation-sprays NR 2.5b

Incidental inhalation-powders NR NR

Dermal contact NR 1.6 Deodorant (underarm) NR 1.6e

Hair-noncoloring 1 2.5 Hair-coloring NR 0.87

Nail NR NR Mucous

Membrane NR NR

Baby NR NR

Table 7. HDI polymer ingredients that have no reported uses.33-35 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 PPG-26/HDI Copolymer Stearyl HDI/PEG-50 Copolymer


Table 8. 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 32


Rats; not specified LD50=>2500 mg/kg 19


Rats; not specified LD50=>2000 mg/kg 19

Steareth-100/PEG-136/HDI Copolymer

Rats; 5/sex LD50=>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.

20

OECD TG= Organization for Economic Cooperation and Development Test Guideline

Table 9. Dermal 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 32

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 19

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 19

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

OECD TG 404 in male rabbits (n=3)

Primary Irritation Index=0/8 20

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

23

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.

23

In Vitro Mixture containing 30% Bis-C16-20 Isoalkoxy TMHDI/PEG-90 Copolymer (16.67%, 50%, and 100% in water; actual concentration: 5%, 15%, 30%)

EpiDerm™ Skin Model In Vitro Toxicity Testing System

The test substance is predicted to be non-irritating. 22


OECD TG 431, in vitro test for corrosion of human skin

Predicted to be non-irritating to the skin 32


OECD TG 439, in vitro test for skin irritation using reconstructed human epidermis

Predicted to be non-irritating 32


EpiDerm MTT Viability Assay ET50>24.0 h 19

ET50= effective time of exposure to reduce tissue viability to 50% NOHSC= National Occupational Health and Safety Commission of Australia PG=propylene glycol


Table 10. 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


OECD TG 405 Slight irritant 32

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

Ocular irritation study

Not an ocular irritant 19

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

OECD TG 405 (n=3) Classified as a non-irritant 20

PG=propylene glycol

Table 11. Dermal 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 32

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 19

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

45

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

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

46

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.

22

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

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

19

HRIPT=human repeat insult patch test


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6. Becker, LC, Bergfeld, WF, Belsito, DV, Hill, RA, Klaassen, CD, Liebler, DC, Marks Jr, JG, Shank, RC, Slaga, TJ, Snyder, PW, and Gill, LJ. Safety assessment of glycerin as used in cosmetics. Washington, DC, Cosmetic Ingredient Review. 2015. pp. 1-24.

7. Bergfeld, WF, Belsito, DV, Hill, RA, Klaassen, CD, Liebler, DC, Marks Jr, JG, Shank, RC, Snyder, PW, and Andersen, FA. Final report of the Cosmetic Ingredient Review Expert Panel: amended safety assessment of triethylene glycol and polyethylene (PEGs) -4, -6, -7, -8, -9, -10, -12, -14, -16, -18, -20, -32, -33, -40, -45, -55, -60, -75, -80, -90, -100, -135, -150, -180, -200, -220, -240, -350, -400, -450, -500, -800, -2M, -5M, -7M, -9M, -14M, -20M, -23M, -25M, -45M, -65M, -90M, -115M, -160M, and -180M and any PEG >= 4. Washington, DC, Cosmetic Ingredient Review. 2010. pp. 1-49.

8. Elder, RL. Final report on the safety assessment of cholesterol. Journal of the American College of Toxicology. 1986;5(5):491-516.

9. Fiume, MM, Heldreth, B, Bergfeld, W, Belsito, D, Hill, R, Klaassen, C, Liebler, D, Marks Jr, J, Shank, R, Slaga, T, Snyder, P, and Andersen, F. Safety assessment of alkyl PEG ethers as used in cosmetics. International Journal of Toxicology. 2012;31(Suppl 2):169S-245S.

10. Fiume, MM, Heldreth, B, Bergfeld, W, Belsito, D, Hill, R, Klaassen, C, Liebler, D, Marks Jr, J, Shank, R, Slaga, T, Snyder, P, and Andersen, F. Final report of the Cosmetic Ingredient Review Expert Panel on the safety assessment of dicarboxylic acids, salts, and esters. International Journal of Toxicology. 2012;31(Suppl. 1):5S-76S.

11. Fiume, MM, Heldreth, B, Bergfeld, WF, Belsito, DV, Hill, RA, Klaassen, CD, Liebler, DC, Shank, RC, Slaga, TJ, Snyder, PW, and Andersen, FA. Safety assessment of microbial polysaccharide gums as used in cosmetics. Washington, DC, Cosmetic Ingredient Review. 2012. pp. 1-52.

12. Fiume, MM, Bergfeld, W, Belsito, D, Hill, R, Klaassen, C, Liebler, D, Marks Jr, J, Shank, R, Slaga, T, Snyder, P, and Andersen, F. Safety assessment of propylene glycol, tripropylene glycol, and PPGs as used in cosmetics. International Journal of Toxicology. 2012;31(Suppl. 2):245S-260S.

13. Silva, A, Nunes, C, Martins, J, Dinis, T, Lopes, C, Neves, B, and Cruz, T. Respiratory sensitizer hexamethylene diisocyanate ihibits SOD 1 and induces ERK-dependent detoxifying and maturation pathways in dendritic-like cells. Free Radical Biology and Medicine. 2014;72:238-246.

14. National Industrial Chemicals Notification and Assessment Scheme (NICNAS). Full public report: HDI/trimethylol hexyllactone crosspolymer. Sidney, Australia, NICNAS. 2008. http://www.nicnas.gov.au/__data/assets/pdf_file/0006/10122/PLC763FR.pdf. Report No. PLC/763. pp. 1-7.

15. National Industrial Chemicals Notification and Assessment Scheme (NICNAS). Full Public Report; HDI/trimethylol hexyllactone crosspolymer. Sidney, Australia, NICNAS. 2010. http://www.nicnas.gov.au/__data/assets/word_doc/0004/6934/PLC946FR.docx. Report No. PLC/946. pp. 1-8.

16. National Industrial Chemicals Notification and Assessment Scheme (NICNAS). Full public report: HDI/trimethylolhexyllactone crosspolymer. Sidney, Australia, NICNAS. 2012. https://www.google.com/url?sa=t&rct=j&q=&esrc=s&source=web&cd=1&ved=0CB4QFjAAahUKEwjBn6zC7tbIAhWGHx4KHVV0CAI&url=http%3A%2F%2Fwww.nicnas.gov.au%2F__data%2Fassets%2Fword_doc%2F0014%2F6701%2FEX175FR.docx&usg=AFQjCNFKsAdQeJmSF3qnpTjLE26RHoTomQ. Report No. EX/175 (PLC/946). pp. 1-9.

17. Toshiki Pigment Co. 2015. HDI Polymer CIR Requirement: HDI/Trimethylol Hexyllactone Crosspolymer. Unpublished data submitted by Personal Care Products Council.

18. Toshiki Pigment Co. 2015. HDI Polymer CIR Requirement: HDI/PPG/Polycaprolactone Crosspolymer. Unpublished data submitted by Personal Care Products Council.

19. Anonymous. 2015. Information data sheet of PEG-240/HDI Copolymer Bis-Decyltetradeceth-20 Ether. Unpublished data submitted by Personal Care Products Council.


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20. Elementis Specialties. 2015. RHEOLUXE® 811 (INCI: Steareth-100/PEG-136/HDI Copolymer): Toxicity dossier. Unpublished data submitted by Personal Care Products Council.

21. Elementis Specialties. 2015. RHEOLUXE® 812 (INCI: Bis-Lauryl Cocaminopropylamine/HDI/PEG-100 Copolymer (and) Butylene Glycol): Toxicity dossier. Unpublished data submitted by Personal Care Products Council.

22. Elementis Specialties. 2015. RHEOLUXE® 880 (INCI: Bis-C 16-20 Isoalkoxy TMHDI/PEG-90 Copolymer): Toxicity dossier. Unpublished data submitted by Personal Care Products Council.

23. Intercos SpA. 2015. Summary infomation on Intercoshine FLEX (INC: HDI/Di-Cl2-14 Alkyl Tartrate/Hydrogenated Dilinoleyl Alcohol Copolymer). Unpublished data submitted by Personal Care Products Council.

24. Anonymous. 2016. Information about the structure and molecular weight of Bis-Methoxy PEG-10 Dimethyl MEA/HDI/Bis-PEG-10 Dimethicone Copolymer. Unpublised data submitted by the Personal Care Products Council.

25. Personal Care Products Council. 11-23-2015. Information on HDI/Di-C12-14 Alkyl Tartrate Hydrogenated Dilinoleyl Alcohol Copolymer. Unpublished data submitted by Personal Care Products Council.

26. Toshiki Pigment Co. 2016. Statement regarding molecular weight of Plastic Powder CS-400 (HDIIPPG/Polycaprolacton Crosspolymer). Unpublished data submitted by Personal Care Products Council.

27. Personal Care Products Council. 2-22-2016. Methoxy PEG-17 /Methoxy PEG-11/HDI lsocyanurate Trimer Crosspolymer. Unpublished data submitted by Personal Care Products Council.

28. Elementis Specialties. 2015. HDI polymer manufacturing process. Unpublished data submitted by Personal Care Products Council.

29. Elementis Specialties. 2015. HDI polymer stability at hair dryer temperatures. Unpublished data submitted by Personal Care Products Council.

30. Asahi Kasei Corporation. 2016. Quantitative analysis report of HDI monomers in cosmetics. Unpublished data submitted by Personal Care Products Council.

31. Elementis Specialties. Rheoluxe®: The next big idea in rheology. 2013. http://www.elementis-specialties.com/esweb/webproducts.nsf/allbydocid/BD50EB128351565F85257DAA004A3D08/$FILE/Rheoluxe%20880%20PDS.pdf

32. Anonymous. 2015. Safety data sheet: Methoxy PEG-17/Methoxy PEG-11/HDI Isocyanurate Trimer Crosspolymer. Unpublished data submitted by Personal Care Products Council.

33. Food and Drug Administration (FDA). Frequency of use of cosmetic ingredients; FDA Database. Washington, DC, FDA. 2016.

34. Personal Care Products Council. 8-10-2015. Updated Concentration of Use by FDA Product Category: HDI Polymers. Unpublished data submitted by Personal Care Products Council.

35. Personal Care Products Council. 7-7-2015. Concentration of Use by FDA Product Category: HDI Polymers. Unpublished data submitted by Personal Care Products Council.

36. Johnsen MA. The Influence of Particle Size. Spray Technology and Marketing. 2004;14(11):24-27.

37. Bremmer HJ, Prud'homme de Lodder LCH, and van Engelen JGM. Cosmetics Fact Sheet: To assess the risks for the consumer; Updated version for ConsExpo 4. 2006. http://www.rivm.nl/bibliotheek/rapporten/320104001.pdf. Date Accessed 8-24-2011. Report No. RIVM 320104001/2006. pp. 1-77.

38. Rothe H. Special aspects of cosmetic spray safety evaluation. 2011. Unpublished information presented to the 26 September CIR Expert Panel. Washington D.C.

39. Rothe H, Fautz R, Gerber E, Neumann L, Rettinger K, Schuh W, and Gronewold C. Special aspects of cosmetic spray safety evaluations: Principles on inhalation risk assessment. Toxicol Lett. 8-28-2011;205(2):97-104. PM:21669261.

40. CIR Science and Support Committee of the Personal Care Products Council (CIR SSC). 11-3-2015. Cosmetic Powder Exposure. Unpublished data submitted by the Personal Care Products Council.

41. Aylott RI, Byrne GA, Middleton, J, and Roberts ME. Normal use levels of respirable cosmetic talc: preliminary study. Int J Cosmet Sci. 1979;1(3):177-186. PM:19467066.

42. Russell RS, Merz RD, Sherman WT, and Sivertson JN. The determination of respirable particles in talcum powder. Food Cosmet Toxicol. 1979;17(2):117-122. PM:478394.

43. European Commission. Cosing database. http://ec.europa.eu/growth/tools-databases/cosing/. European Commission. Last Updated 2015.


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44. Elementis Specialties. 2013. RHEOLUXE® 812 (INCI: Bis-Lauryl Cocaminopropylamine/HDI/PEG-100 Copolymer (and) Butylene Glycol): Product data sheet. Unpublished data submitted by Personal Care Products Council.

45. Anonymous. 2003. Clinical safety evaluation repeated insult patch test of a foundation product containing 30.7% HDI/Trimethylol Hexyllactone Crosspolymer. Unpublished data submitted by Personal Care Products Council.

46. Product Investigations Inc. 2011. Determination of the irritating and sensitizing propensities of a facial leave-on product containing 10% HDIITrimethylol Hexyllactone Crosspolymer on human skin. Unpublished data submitted by Personal Care Products Council.

47. Andersen, FA. Annual review of cosmetic ingredient safety assessments - 2004/2005. International Journal of Toxicology. 2006;26(Suppl. 2):1-89.

48. Elementis Specialties. Rheoluxe 880. 2013. http://www.elementis-specialties.com/esweb/webproducts.nsf/allbydocid/BD50EB128351565F85257DAA004A3D08/$FILE/Rheoluxe%20880%20PDS.pdf

49. Anonymous. 2015. Product safety information: Methoxy PEG-17 /Methoxy PEG-11 /HDI Isocyanurate Trimer Crosspolymer. Unpublished data submitted by Personal Care Products Council.

50. Elementis Specialties. Rheolate® FX 1100. 2014. http://www.elementis-specialties.com/esweb/webproducts.nsf/allbydocid/7B32FBB822C84F3485257B260048DE2B/$FILE/PDS-RHEOLUXE%C2%AE%208%2011.pdf

51. Kanoles C. Letter to Carol Eisenmann, Personal Care Products Council concerning the CIR Safety Assessment of Hexamethylene Diisocyanate (HDI) Polymers. 8-6-2015. Unpublished data submitted by the Personal Care Products Council.




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2016 VCRP Data for HDI Polymers

05A - Hair Conditioner DIETHYLENE GLYCOL/DMAP ACRYLAMIDE/PEG-180/HDI COPOLYMER

1

05C - Hair Straighteners DIETHYLENE GLYCOL/DMAP ACRYLAMIDE/PEG-180/HDI COPOLYMER

4

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

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

1

6

03A - Eyebrow Pencil HDI/TRIMETHYLOL HEXYLLACTONE CROSSPOLYMER

1

03B - Eyeliner HDI/TRIMETHYLOL HEXYLLACTONE CROSSPOLYMER

3

03C - Eye Shadow HDI/TRIMETHYLOL HEXYLLACTONE CROSSPOLYMER

91

03D - Eye Lotion HDI/TRIMETHYLOL HEXYLLACTONE CROSSPOLYMER

16

03F - Mascara HDI/TRIMETHYLOL HEXYLLACTONE CROSSPOLYMER

13

03G - Other Eye Makeup Preparations HDI/TRIMETHYLOL HEXYLLACTONE CROSSPOLYMER

15

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

HDI/TRIMETHYLOL HEXYLLACTONE CROSSPOLYMER

1

07A - Blushers (all types) HDI/TRIMETHYLOL HEXYLLACTONE CROSSPOLYMER

27

07B - Face Powders HDI/TRIMETHYLOL HEXYLLACTONE CROSSPOLYMER

52

07C - Foundations HDI/TRIMETHYLOL HEXYLLACTONE CROSSPOLYMER

41

07E - Lipstick HDI/TRIMETHYLOL HEXYLLACTONE CROSSPOLYMER

11

07F - Makeup Bases HDI/TRIMETHYLOL HEXYLLACTONE CROSSPOLYMER

8

07G - Rouges HDI/TRIMETHYLOL HEXYLLACTONE CROSSPOLYMER

2

07H - Makeup Fixatives HDI/TRIMETHYLOL HEXYLLACTONE CROSSPOLYMER

1

07I - Other Makeup Preparations HDI/TRIMETHYLOL HEXYLLACTONE CROSSPOLYMER

9

08G - Other Manicuring Preparations HDI/TRIMETHYLOL HEXYLLACTONE CROSSPOLYMER

1

10E - Other Personal Cleanliness Products

HDI/TRIMETHYLOL HEXYLLACTONE CROSSPOLYMER

1

12A - Cleansing HDI/TRIMETHYLOL HEXYLLACTONE CROSSPOLYMER

2

12C - Face and Neck (exc shave) HDI/TRIMETHYLOL HEXYLLACTONE CROSSPOLYMER

35

12D - Body and Hand (exc shave) HDI/TRIMETHYLOL HEXYLLACTONE CROSSPOLYMER

4

12F - Moisturizing HDI/TRIMETHYLOL HEXYLLACTONE CROSSPOLYMER

28


12G - Night HDI/TRIMETHYLOL HEXYLLACTONE CROSSPOLYMER

4

12H - Paste Masks (mud packs) HDI/TRIMETHYLOL HEXYLLACTONE CROSSPOLYMER

4

12J - Other Skin Care Preps HDI/TRIMETHYLOL HEXYLLACTONE CROSSPOLYMER

14

13B - Indoor Tanning Preparations HDI/TRIMETHYLOL HEXYLLACTONE CROSSPOLYMER

1

385

03C - Eye Shadow HDI/PPG/POLYCAPROLACTONE CROSSPOLYMER

1

03D - Eye Lotion HDI/PPG/POLYCAPROLACTONE CROSSPOLYMER

1

03F - Mascara HDI/PPG/POLYCAPROLACTONE CROSSPOLYMER

2

07B - Face Powders HDI/PPG/POLYCAPROLACTONE CROSSPOLYMER

3

07C - Foundations HDI/PPG/POLYCAPROLACTONE CROSSPOLYMER

3

07F - Makeup Bases HDI/PPG/POLYCAPROLACTONE CROSSPOLYMER

1

07I - Other Makeup Preparations HDI/PPG/POLYCAPROLACTONE CROSSPOLYMER

2

12C - Face and Neck (exc shave) HDI/PPG/POLYCAPROLACTONE CROSSPOLYMER

3

12F - Moisturizing HDI/PPG/POLYCAPROLACTONE CROSSPOLYMER

5

12G - Night HDI/PPG/POLYCAPROLACTONE CROSSPOLYMER

1

12J - Other Skin Care Preps HDI/PPG/POLYCAPROLACTONE CROSSPOLYMER

2

24

07E - Lipstick METHOXY PEG-17/METHOXY PEG-11/HDI CROSSPOLYMER

3

03D - Eye Lotion PEG-240/HDI COPOLYMER BIS-DECYLTETRADECETH-20 ETHER

2

03G - Other Eye Makeup Preparations PEG-240/HDI COPOLYMER BIS-DECYLTETRADECETH-20 ETHER

1

12F - Moisturizing PEG-240/HDI COPOLYMER BIS-DECYLTETRADECETH-20 ETHER

1

4

05I - Other Hair Preparations STEARETH-100/PEG-136/HDI COPOLYMER 1


There were no uses reported in the 2016 VCRP for:

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 HDI/Di-C12-14 Alkyl Tartrate/Hydrogenated Dilinoleyl Alcohol Copolymer HDI/PEI-45/SMDI Crosspolymer Methoxy PEG-17/Methoxy PEG-11/HDI Isocyanurate Trimer PPG-26/HDI Copolymer Stearyl HDI/PEG-50 Copolymer


TO:

FROM:

DATE:

SUBJECT:

Key Issues

Personal Care Products Council Committed to Safety, Quality & Innovation

Memorandum

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

Beth A. Lange, Ph.D. ---::Pt::::JWri,. . A, Industry Liaison to the CIR Expert Panel -;)..(/\-~ ~

April 19, 2016

Comments on the Revised Tentative Report: Safety Assessment of Hexamethylene Diisocyanate (HDI) Polymers as Used in Cosmetics (posted April 12, 2016)

Physical and Chemical Properties, Summary, Discussion- It is not correct to state that the molecular weights of"these HDI polymers range from <500 Da (a small percentage of the ingredients) to 75,000 Da". This statement should include the reported average molecular weights of the polymers, not the molecular weight of a small fraction of one polymer. The statement "a small percentage ofthe ingredients" suggests that a few of the ingredients have a MW <500 Da, this is not the case, only a 1.2% of one ingredient was reported to be <500 Da. The highest molecular weight reported is now infinite for the fully crosslinked Methoxy PEG-17/Methoxy PEG-11/HDI lsocyanurate Trimer Crosspolymer.

Discussion - In the Discussion, it would be helpful to state which polymers are considered safe because a least one monomer is greater than 1 000 Da.

Additional Considerations Cosmetic Use- Please delete "in ingredients" in the following sentence: "The European Union

restricts the content of traces of diethylene glycol to a total of 0.1% in any cosmetic product, including the trace amount of diethylene glycol in ingredients contained in polymers, such as Diethylene Glycol/DMAP Acrylamide/PEG-180/HDI Copolymer." as the restriction refers to the polymer not the "ingredients" in the polymer.

Discussion - Please correct: "concentration of us"

1620 l Street, N.W., Suite 1200 I Washington, D.C. 200361202.331.1770 I 202.331.1969 (fax) I www.personalcarecouncll.org


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Safety Assessment of Hexamethylene Diisocyanate (HDI ... · Safety Assessment of Hexamethylene Diisocyanate (HDI) Polymers as Used in Cosmetics Status: Revised Draft Final Report