Safety Assessment of Acryloyldimethyltaurate Polymers as Used in Cosmetics

Transcription

1 Safety Assessment of Acryloyldimethyltaurate Polymers as Used in Cosmetics Status: Draft Final Report for Panel Review Release Date: March 7, 207 Panel Meeting Date: April 0-, 207 The 207 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 620 L Street, NW, Suite 200 Washington, DC ph fax cirinfo@cir-safety.org

2 Commitment & Credibility since 976 MEMORANDUM To: From: CIR Expert Panel and Liaisons Lillian C. Becker, M.S. Scientific Analyst and Writer Date: March 7, 207 Subject: Safety Assessment of Acryloyldimethyltaurate Polymers as Used in Cosmetics Attached is the Draft Final Report of Acryloyldimethyltaurate Polymers as used in cosmetics. [ACTAPY2207Rep] These ingredients are reported mostly to function as dispersing agent nonsurfactant, emulsion stabilizers, opacifying agent, and viscosity increasing agents aqueous. In September 206, the Panel issued a tentative report with the conclusion that these Acryloyldimethyltaurate Polymers are safe in cosmetics in the present practices of use and concentration described in this safety assessment for public comment. These ingredients are large molecules and should not penetrate the skin. The Panel advised that formulators should use current good manufacturing practices (cgmps) to ensure that residual monomers (i.e., vinyl formamide and methacrylamidolauric acid) are minimized in these ingredients and the final products. No new data have been submitted. Council comments have been addressed. [ACTAPY2207PCPC] 207 VCRP data were incorporated into the report. The greatest changes were for Ammonium Acryloyldimethyltaurate/VP Copolymer and Hydroxyethyl Acrylate/Sodium Acryloyldimethyl Taurate Copolymer, which increased by 28 and 68 uses, respectively, with a similar pattern of use. Please review the Discussion to ensure that it captures the rationale for the report conclusion. Please review the Abstract and Conclusion to ensure that they capture the Panel s thinking. The Panel should be prepared to issue a Final Report. 620 L Street, NW Suite 200, Washington, DC (Main) (Fax) ( ) cirinfo@cir-safety.org (Website)

3 SAFETY ASSESSMENT FLOW CHART INGREDIENT/FAMILY Acryloyldimethyltaurate Polymers MEETING April 207 Public Comment CIR Expert Panel Report Status Priority List INGREDIENT PRIORITY LIST SLR Jan 4, day public comment period Draft Report DRAFT REPORT Mar 206 Table Table IDA TR IDA Notice Apr, 206 Draft TR IDA DRAFT TENTATIVE REPORT Sept 206 Table Table Tentative Report October, 206 Issue TR 60 day Public comment period Draft FR DRAFT FINAL REPORT Apr 207 Table Table Different Conclusion PUBLISH Final Report Issue FR

4 History Acryloyldimethyltaurate Polymers January, 206 SLR was issued with the following data requests: Clarification that the CAS no is actually ammonium acryloyldimethyltaurate/vinyl formamide copolymer. Data related to this CAS no. have been found but the associated chemical appears not to be a polymer. Ingredient-specific method of manufacture and impurity data for cosmetics for each of these ingredients Dermal penetration data Repeated dose dermal and inhalation toxicity data for each of these ingredients at or above the reported concentrations of use Reproductive and developmental toxicity data for each of these ingredients at or above the reported concentrations of use Additional dermal and ocular irritation data for any of these ingredients for which there is no data at or above the reported concentrations of use Additional irritation and sensitization data for any of these ingredients for which there is no data at or above the reported concentrations of use March, 206 The Council confirmed that CAS no does not belong to any of these ingredients. The Panel issued an Insufficient Data Announcement asking for: Molecular weight ranges Impurities data, including data on any residual acrylamide, vinyl formamide, and methacrylamidolauric acid monomers Sensitization data for Hydroxyethyl Acrylate/Sodium Acryloyldimethyl Taurate Copolymer at 4.3% or greater Polyacryloyldimethyltaurate Polyoxymethylene Melamine was removed from the report because it is the salt of two polymers and did not fit in with the rest of the ingredients. September, The Panel issued a Tentative Report with the conclusion that acryloyldimethyltaurate polymers are safe in cosmetics in the present practices of use and concentration described in this safety assessment. Some data on molecular weight, impurities, dermal/oral toxicity, genotoxicity, and/or sensitization of Sodium Polyacryloyldimethyl Taurate and Acrylamide/Sodium Acryloyldimethyltaurate/Acrylic Acid Copolymer were submitted. Updated concentration of use data were also submitted. The Panel noted that these are large molecules and that dermal penetration would be unlikely to occur. The Panel advised that formulators should use current good manufacturing practices (cgmps) to ensure that residual monomers (i.e., vinyl formamide and methacrylamidolauric acid) are minimized in these ingredients and the final products. The Panel noted that the presence of acrylamide is limited to 5 ppm in cosmetic formulations containing Polyacrylamide and that this limit was also appropriate for the acryloyldimethyltaurate polymers. April, 207 The Panel is to examine the draft final report. After examining the Abstract, Discussion, and Conclusion, a Final Report should be issued.

5 Acryloyldimethyltaurate Polymers Data Profile for April, 207. Writer Lillian Becker ADME Acute toxicity Repeated dose toxicity Irritation Sensitization Phototoxicity Carcinogenicity Genotoxicity Repro/Devel In Vitro Human Animal Dermal In Vitro Dermal Human Dermal Animal Ocular In Vitro Ocular Animal Inhale Dermal Oral Inhale Dermal Oral Use Log K ow Dermal Penetration Acrylamide/Sodium Acryloyldimethyltaurate Copolymer Acrylamide/Sodium Acryloyldimethyltaurate/Acrylic Acid Copolymer Ammonium Acryloyldimethyltaurate/Beheneth -25 Methacrylate Crosspolymer Ammonium Acryloyldimethyltaurate/ Carboxyethyl Acrylate Crosspolymer Ammonium Acryloyldimethyltaurate/Laureth- 7 Methacrylate Copolymer Ammonium Acryloyldimethyltaurate/Steareth- 25 Methacrylate Crosspolymer Ammonium Acryloyldimethyltaurate/Steareth- 8 Methacrylate Copolymer Ammonium Acryloyldimethyltaurate/Vinyl Formamide Copolymer Ammonium Acryloyldimethyltaurate/VP Copolymer Ammonium Polyacryloyldimethyl Taurate Dimethylacrylamide/Sodium Acryloyldimethyltaurate Crosspolymer HEA/Sodium Acryloyldimethyltaurate/Steareth- 20 Methacrylate Copolymer Hydroxyethyl Acrylate/Sodium Acryloyldimethyl Taurate Copolymer Polyacryloyldimethyltaurate Polyoxymethylene Melamine Sodium Acrylate/Acryloyldimethyltaurate/ Dimethylacrylamide Crosspolymer Sodium Acrylate/Sodium Acryloyldimethyl Taurate Copolymer Sodium Acrylate/Sodium Acryloyldimethyl Taurate/Acrylamide Copolymer Sodium Acryloyl Dimethyl Taurate/PEG-8 Diacrylate Crosspolymer Sodium Acryloyldimethyl Taurate/Acrylamide/VP Copolymer X X X X X X X X X X X X X X X X X X X X X X X X X X X X X X X X X X X X X X

6 Acryloyldimethyltaurate Polymers Data Profile for April, 207. Writer Lillian Becker ADME Acute toxicity Repeated dose toxicity Irritation Sensitization Phototoxicity Carcinogenicity Genotoxicity Repro/Devel In Vitro Human Animal Dermal In Vitro Dermal Human Dermal Animal Ocular In Vitro Ocular Animal Inhale Dermal Oral Inhale Dermal Oral Use Log K ow Dermal Penetration Sodium Acryloyldimethyltaurate/ Methacrylamidolauric Acid Copolymer Sodium Acryloyldimethyltaurate/VP Crosspolymer Sodium Polyacryloyldimethyl Taurate X X X X

7 Search Strategy Acryloyldimethyltaurate Polymers SciFinder Compounds searched by identifiers (text and structure): hits hit, not useful hits, not useful hits hits, not useful hits, 0 hits hit, not useful hits hits, 0 useful hits, 0 useful hits, 0 useful hits, selected biological/tox/properties 203 hits, removed patents 4 hits, 0 useful hits, removed patents 3 hits, 0 useful hits, removed patents 7 hits, 0 useful hits, removed patents 6 hits, 0 useful Compounds searched by identifiers (text and structure): 234 hits removed patents, 32 hits. Refine toxicity 2 hits, 0 useful Refine repro* 0 hits Refine geno* 0 hits Refine carcinogen 0 hits Refine bio hit, not useful NICNAS Acrylamide/Sodium Acryloyldimethyltaurate/Acrylic Acid Copolymer Ammonium Acryloyldimethyltaurate/Carboxyethyl Acrylate Crosspolymer Ammonium Acryloyldimethyltaurate/Vinyl Formamide Copolymer (2-Acrylamido-2-methylpropanesulfonic acid, ammonium salt) Ammonium Acryloyldimethyltaurate/VP Copolymer (Aristoflex AVC) Hydroxyethyl Acrylate/Sodium Acryloyldimethyl Taurate Copolymer Sodium Acrylate/Acryloyldimethyltaurate/ Dimethylacrylamide Crosspolymer Cosing Database Hits on: Acrylamide/Sodium Acryloyldimethyltaurate Copolymer, Acrylamide/Sodium Acryloyldimethyltaurate/Acrylic Acid Copolymer, Sodium Acrylate/Sodium Acryloyldimethyl Taurate/Acrylamide Copolymer, Sodium Acryloyldimethyl Taurate/ Acrylamide/VP Copolymer

8 Transcripts - Acryloyldimethyltaurate Polymers September, 206 Dr. Marks Team DR. MARKS: If nothing more, we'll move on to the next ingredient. And that's going to be the accrual [Acryloyl] dimethyltaurate polymers. So in April of this year, we issued an insufficient data announcement. The needs are listed there in Lillian's memo, molecular weight ranges, impurities, data and sensitization for the hydroxyethyl accrulate sodium accrual dimethyltaurate polymer [Hydroxyethyl Acrylate/Sodium Acryloyldimethyl Taurate Copolymer] at 4.3 percent or greater. Tom and Ron and Ron, did we get enough data on the molecular weights, the monomers? DR. SHACK: I think it's -- we only got the two compounds. DR. EISENMANN: You've got the molecular weight for six compounds and you have an acrymalide limit in the polyacrylamide report of five PPM [ppm] and finished products which you can put in this report which it will be helpful if it was in this report also. DR. SHACK: Right and do we have limits in any other documents for vinyl formamide or methylacrylamidolauric acid? If we could specify maximum levels for those three impurities, then I'd say that the report can go safely (inaudible), DR. MARKS: So maximum levels -- we already have -- you mentioned -- DR. SHACK: The pyramid. DR. MARKS: Acrymalide -- and that was from the previous report -- DR. EISENMANN: The polyacrymalide report has a 5 PPM limit in finished products. DR. HILL: I agree with him. We've covered one monomer but I believe we have a total of three or four -- I think three that I asked about and the two that he mentioned were the ones that I had written down here. DR. MARKS: So which ones do we -- so we have a limit for the acrylamides of five parts per million? DR. HILL: Yes, and we have data for -- what do we have, sensitization and so forth for six of them, five, six actual hard data. I'd like the data for two or three as I recall it. DR. MARKS: One, two, three, four, five, possibly the hydroxiethyl acrylade sodium acryla dimethyl teltrate, that was -- I had a question, was it really at 00 percent where we had a human sensitization but it's being used at 3.6 percent so presumably, that (inaudible) stage. And that last -- the fourth bullet point sensitization for the hydroxyethyl acrylade sodium acryl dimethyl copolymer 4.3 percent or greater, it's actually being used at 3.6 percent of leaveons so I am not exactly sure why Don wanted that percent and we have an HRIPT that is okay. Questions the concentration but -- I thought the sensitization data was okay. DR. SLAGA: Yeah, I think the sensitization irritation and genotoxicity is okay. DR. HILL: And noting that there is still no inhalation data of any kind for any of these, my concern would only be monomer release and resulting sensitization and Hayes inferential track, for example -- that's when the sensitization where we actually had data, was proxy for it and not clear about the read across to any of the ones where we actually don't have hard data. DR. MARKS: So let me go back over -- so really the thing we are focusing on now is the level of monomers, is that correct? So we had the maximum level for the acrylamides, the five parts per million from a previous report and again, that one, Karol [Carol], was -- one ingredient or ingredients from -- DR. EISENMANN: Polyacrylamide and the level is in the finished product and not the ingredient. DR. HILL: But I don't think we have any way to set the level for the dimethyl taurate monomer and that's the core ingredient in this group so I think what we are being asked to do is read across from the ones that we do have data. We just don't have the comfort level I would like to be able to make

9 that read across. DR. MARKS: So, Ron Shank, which ones do you want? Which monomer levels for which ingredients? DR. SHACK: Vinyl formamide and methyl acryloamidolauric acid. I am trying to see how much is being used. DR. HILL: I think that last one is really pertinent to one ingredient, if I am not mistaken. DR. SLAGA: That last monomer? DR. HILL: Yes, I think so. DR. EISENMANN: I think vinyl formamid is only one ingredient also. DR. HILL: I believe that's correct. DR. EISENMANN: So if you include those two insufficient, that's -- DR. HILL: That might be another way to go. I'll let my team contemplate that. The team of which I am a part. DR. MARKS: Where the heck is -- all these have so many names and -- DR. SHACK: I agree. DR. MARKS: So that would be a way to go, declare all the ingredients that are safe except for two and then where's the vinyl formamid listed on here? DR. EISENMANN: The eighth one down. DR. MARKS: Ah. DR. HILL: What's the use concentration? DR. MARKS: I don't -- DR. SHACK: Does it appear to be in use? DR. HILL: It doesn't appear to be in use. DR. SHACK: I can't find it in the use table. DR. HILL: Because it's not in use. DR. SHACK: Okay. MS. BECKER: Look at table five. DR. SHACK: I am trying to. DR. HILL: All right, 32. (End of Track 5) DR. HILL: I didn't note it down this round. Which one is the one that has the loramidopropyl, or no, it's loramido-, is it, I've got it written here. DR. MARKS: Ammonium acryloyldimethyl. DR. HILL: Why don't I have it written down. It's irritating. DR. MARKS: So what did we decide with ammonium acryloyldimethyl taurate vinyl for formamide copolymer? That's going to be insufficient? DR. SCHACK: Yes. DR. HILL: Yes. DR. MARKS: And we want the level of monomer in that? DR. SHANK: The level of vinyl formamide. DR. MARKS: And then the second one was the, now which one was the lauric acid? DR. SCHACK: That's what I'm trying to find now. DR. EISENMANN: It's the third from the end in the first -- DR. MARKS: One, two, three. DR. EISENMANN: Those are in the same order as their own introduction. It's sodium (inaudible) lauric acid. DR. HILL: There it is. DR. MARKS: Which-- DR. HILL: Third. It indicates there's a use and no data. What's the concentration.

10 DR. EISENMANN:.035 percent is the concentration. DR. MARKS: Where is it on? MS. BECKER: Page 32. DR. MARKS: Oh. It's the first one here. So the sodium acryloyldimethyl taurate / methacryloyl (mido) [amido] lauric acid copolymer, is that right? DR. SHANK: Yes, sir. DR. MARKS: And you want the level of the lauric acid in that? DR. HILL: Well, there's a monomer that would be used to make that. DR. MARKS: A monomer. DR. HILL: It's, it's not showing up in the VCRP, but it is showing up in the survey up to.35 percent, which is low, admittedly. But possible incidental inhalation, just powders though, right? Yeah, just powders. But it is apparently used in leave ons. DR. MARKS: Okay. So the monomer in that that we want to, we want to see a level of, which, which is the monomer specifically we should be asking for chemically? DR. HILL: It is in our insufficient list. DR. MARKS: Yeah. DR. SHANK: Methacrylamido lauric acid. DR. MARKS: Okay. So any other comments, (ten of) report were the conclusions safe except for one ammonium vinyl formamide. We want, there's more to that name. We want the level of vinyl formamide and in the sodium methacrylamido lauric acid, we want the level of that monomer. Anything else, Ron? Did I caput [capture?] that correct, Ron, Ron? DR. HILL: You have it right. DR. MARKS: And then, so this would be a tentative report, and then are we using the five parts per million from the polyacrylamide ingredient in the finished product as a reason that the others would be safe? How do we incorporate that into this paper? DR. HILL: It's statutory, isn't it? Isn't that a statutory limitat-, I don't know if in the U.S., in Europe? If it's statutory, I don't-- DR. EISENMANN: Well, Europe has the limit in them, but I don't know, it's not in the United States. DR. MARKS: Would that just be in the discussion? DR. HILL: Yeah, because it is a, it is an impurity, it's a monomer and that's usually how we deal with that because it falls under cgmp and make note of that limitation, and it was low as reasonably possible something like (inaudible), but otherwise reasonable achievable? DR. MARKS: Okay. So tomorrow, I'll move that a tentative report be issued with the conclusion that all these ingredients except for two will be safe, and that the two are the ones I mentioned earlier, the ammonium vinyl formamide and then the methacrylamido lauric acid polymers. Good, team? Tom, Ron, Ron, is that fine? DR. STAGA: Yes. DR. HILL: I can get on board with that. DR. BERGFELD: And, would you discuss what you're going to put in your discussion then regarding your insufficient especially. DR. MARKS: Basically, we want the level of the monomers, it's the level of vinyl formamide and then the level of the methacrylamido acrylic acid. DR. HILL: It may have been because of the potential for sensitization or any other deleterious effect that could result from having react among or remaining in the product at excessive levels. MS. BECKER: Say that again, please. DR. HILL: I'll try. Because of the potential for sensitization or any other deleterious, deleterious effect that could arise from the presence of excessive monomer level in these polymers that is not captured by data we have the via (read-a-cross). Hopefully it will show up in the transcript. MS. BECKER: Thank you.

11 DR. HILL: That's my opinion, we'll see. But it would make me comfortable to state that. DR. MARKS: Okay. Any other comments about these [this] group of ingredients? If not, then let's move on to etidronic acids. Dr. Belsito s Team DR. BELSITO: And then we move on to acryloyldimethyltaurate polymers. And that's under dimethyltaurate polymers. DR. LIEBLER: Dimethyltaurate. DR. BELSITO: Dimethyltaurate, thank you. Not laurate. DR. LIEBLER: Just doing my job, doc. DR. BELSITO: Toralauralai. Okay. Okay, so at the March meeting this was another insufficient for these 2 polymers. We asked for molecular weight impurities, dermal/oral toxicity, genotox, and/or sensitization. We cut that on two ingredients in this report. And so the question is were -- so the maximum use here is 4.3 percent in the depilatory and 3.6 around the eye. We have no in vivo genotox, no repro, no molecular weights, no dermal absorption. But I wondered why we couldn't just restrict impurities per our prior acrylate and acrylamide reports, or does it remain unsafe for these impurities? And also, do we need in vivo genotox? Do we need repro? Do we need dermal absorption for these? DR. SNYDER: Not going to be absorbed. DR. LIEBLER: Right. They're not going to be absorbed. They're too large. DR. SNYDER: I had a question about the nomenclature. So the second sentence on the introduction says this group of ingredients comprises whole polymers, copolymers, and cross-link polymers, the monomers of which are at least partially composed of dimethyl laurate monomers. So a monomer comprised of a monomer? And then below we have listed crosspolymer and no cross-linked polymers. So is a crosspolymer a cross-link polymer? Standard nomenclature? MR. ANSELL: I don't think there is a crosspolymer. DR. SNYDER: Well, it's listed there, ammonium acryloyldimethyltaurate (inaudible) 25 crosspolymer. MS. BECKER: Yeah, there's crosspolymers. DR. SNYDER: But we don't list crosspolymers. We talk about homopolymers, copolymers, and cross-link polymers. MS. BECKER: As far as I know, cross-link polymers are similar to cross polymers. DR. SNYDER: And then is ammonium polyacryloyldimethyl taurate, is that -- if it doesn't say copolymer then it's a homopolymer? I was confused by some of this. There's two of them that don't list whether they're a crosspolymer or a copolymer or -- DR. LIEBLER: Which ones? DR. BELSITO: Ammonium polyacryloyldimethyl taurate. Just is that. And then the last one, the sodium polyacryloyldimethyl taurate. DR. LIEBLER: So those are just polymers of acryloyldimethyltaurate. DR. BELSITO: They're not copolymers. They're not crosspolymers. DR. LIEBLER: It says -- well, the ones you just mentioned were just polymers. DR. BELSITO: Okay. DR. LIEBLER: They're not copolymers. Copolymers are if you had two different things and you polymerize them together. DR. BELSITO: Right. DR. LIEBLER: And a crosspolymer is if you make a kind of polymeric structure and/or a partial polymeric structure and then you further polymerize that or cross-link them. DR. SNYDER: So it could be -- DR. LIEBLER: Crosspolymer.

12 DR. SNYDER: Not all -- not all copolymers are cross-linked polymers. MR. ANSELL: Right. DR. SNYDER: And then where's the homopolymer? Where does that come in? DR. LIEBLER: Homopolymers like the same polymer. MR. ANSELL: A polymer of a single monomer. DR. BELSITO: So sodium polyacryloyldimethyl taurate would be a homopolymer? DR. LIEBLER: Yes. Do we have homopolymer data names? DR. BELSITO: No, we don't have them in the names. DR. LIEBLER: Okay. MS. BECKER: It's in the definition. DR. BELSITO: Right, but it's not the INCI name, so that's why Paul isn't seeing it listed when we list the names. MS. BECKER: Right. DR. BELSITO: It's a definition. DR. LIEBLER: Oh, I see. The first line of the definition of structure is what's confusing. Okay, yeah. They are composed of whole polymers. In other words, polymers of one ingredient. Copolymers, which are polymers formed from two ingredients, and cross-link polymers are when you main chains and then you cross-link them. So, and those could either be homopolymeric or copolymeric chains that are then cross-linked. DR. SNYDER: But where does crosspolymer come from? DR. BELSITO: Cross-linked. DR. LIEBLER: So that's a good question, and I don't know. That's a good one for a real polymer chemist. Is there a distinction really between a crosspolymer and a cross-linked polymer? MR. ANSELL: I've got to believe that's an INCI issue. DR. LIEBLER: Yeah. DR. SNYDER: And then what about the monomers of which at least are partially composed of monomers? MS. BECKER: Right. The monomers -- DR. BELSITO: What page are you on? DR. SNYDER: The same, second page of the introduction. Or the second half after the comma. MS. BECKER: The monomers, at least all of them have acryloyldimethyltaurate. DR. LIEBLER: Yeah, you don't need the last monomer. DR. SNYDER: Let's take that last monomer out. DR. LIEBLER: So the last word of that sentence should be deleted. Well, I mean, I asked because I try to look at them as groups to see what data we have on cross-linked data we have on copolymers. But some of them I didn't know where they fit in. DR. BELSITO: Okay. DR. LIEBLER: Well -- DR. BELSITO: I'm sorry, go ahead. MR. ANSELL: No, I was just going to say the cross-linking takes the molecular weight to essentially infinite, incalculable. DR. BELSITO: Huge. MR. ANSELL: Really huge. DR. BELSITO: So in our discussion, it says, in addition, these ingredients are large molecules and then soluble in water. However, if you go to PDF page 9, it says on the third paragraph, acrylamide sodium acryloyldimethyltaurate, (inaudible) copolymer is reported to be soluble in water right up to 27 percent and forms an aqueous clear colorless liquid. So what does that do to our argument that they're not water soluble? That was new data that was received. DR. SNYDER: Does that seem plausible that it would be water soluble?

13 DR. BELSITO: I don't know. It's new data. I'm not the chemist. I'm just pointing that out, that we say it's not water soluble. We have new data that says it is. DR. KLAASSEN: Was that the monomer? DR. BELSITO: It's just -- so we need to look at the data that was submitted for the acrylamide sodium acryloyldimethyltaurate. MS. BECKER: Page 57 of the PDF. Is that what you're looking at? DR. BELSITO: It says solids. MR. ANSELL: So the (inaudible). DR. BELSITO: Right. It says physical description solids percent in water. DR. LIEBLER: It doesn't say solubility. DR. BELSITO: It doesn't say soluble. It says how it's provided; right? DR. LIEBLER: Right. Yes. That's exactly. So that shouldn't be -- so we need to go back. DR. BELSITO: Molecular weight, 250,000? DR. LIEBLER: Right. Huge. So we need to go back up where Don was just pointing out, not represent that as a solubility in water. It's provided at that amount of solids in water. MS. BECKER: Agreed. DR. BELSITO: So then page 9 we need to get rid of that. DR. LIEBLER: So you can just say is provided in water at 27 percent. DR. SNYDER: Would you do it to any other section? DR. LIEBLER: And I would skip the "and forms a clear, colorless liquid," because that's a little bit misleading. MS. BECKER: Okay. MR. ANSELL: Yeah, solids in water. MS. FIUME: Yep, there it is, page 56. Is that the right one? It says on the bottom of page 56, the trade name, it says it's water soluble. MS. BECKER: (Inaudible) neutralized and is water soluble. DR. BELSITO: Yep. MS. BECKER: But they are talking about the product as provided, not the polymer itself, possibly, probably. DR. LIEBLER: So the physical description on PDF still does not refer to solubility because that percent is like -- that's not a way you would express solubility anyway. MR. ANSELL: Yeah, the specs are, you know, percent solids in water, although you're right, that sentence does use the word "water soluble." DR. LIEBLER: I don't know if it's truly soluble or of it's highly solvate in suspension or highly hydrated in suspension. So I think -- DR. BELSITO: Well, it's -- yeah, it can't be because otherwise it's not a solution; right? DR. LIEBLER: Yeah, it's a solution if it's soluble. DR. BELSITO: Okay. DR. LIEBLER: Otherwise, it's a suspension. DR. BELSITO: Right. DR. SNYDER: But that's the same way that she describes all the tox studies where they dosed animals. It was a was it percent water solution. DR. BELSITO: So it would imply that it is soluble. MR. ANSELL: No, it's solids in water. DR. BELSITO: No, but it -- DR. LIEBLER: So just because it's solid in water doesn't -- I mean, soluble is a chemically-defined phenomenon. DR. BELSITO: But it says it is manufactured as a low viscosity solution. So it's not saying it's a dispersion. It's a solution. And you just said solution said it's soluble in water; right?

14 DR. LIEBLER: Mm-hmm. DR. BELSITO: So what they're saying is that it is soluble in water. DR. SNYDER: Because I know the ocular irritation in animals -- a solution containing perkylomide, blah blah blah, percent in water, tested at 00 percent, was nonirritating. And then it's the same thing for all tox data. DR. BELSITO: And so it's confusing. So you're chemist heart and mind is saying there's no way that this is soluble, yet the manufacturer is telling us that it is. And what do we say, the manufacturer is wrong? Because part of our argument for not asking for other toxicity endpoints is that these aren't absorbed and they're not water soluble. That's in our discussion. DR. LIEBLER: Well, I think it's more important to say that it's not absorbed because of its high molecular weight. I mean, these things are used because they form films. And it's possible that this would meet the definition of solubility and that a very, very big molecule of this is -- it's got all these polar groups on it, these carboxyls and the sulfates. It is highly hydrated and surrounded by a shell, a huge shell of water molecules, and thereby, it's technically soluble. And then once it evaporates it forms this film on the surface of whatever it evaporated on. So -- MR. ANSELL: It's not going to affect its absorption. DR. LIEBLER: Yeah. MR. ANSELL: It's systemic (inaudible). DR. LIEBLER: Yeah, that part's not going to make it absorbable. It's still too big. DR. BELSITO: So then we need to get rid of the discussion about the fact that they are not soluble in water as an argument that they're not absorbed. DR. LIEBLER: Right. That's not the reason they're not absorbed. DR. SNYDER: Well, in the discussion she doesn't use an argument. She just says these ingredients are large molecules and should not be absorbed by the skin. DR. BELSITO: She does use it in the discussion. It's the third - where is that? DR. SNYDER: Is that in the summary or in the discussion? DR. BELSITO: No, it's three lines up from the bottom of the discussion, above the conclusion. It says, "In addition, these ingredients are large molecules and insoluble in water, which supports the view that they are unlikely to be absorbed (inaudible) local effects on the respiratory tract." DR. LIEBLER: So we'll just remove "the insoluble in water." DR. SNYDER: Yeah, that sentence come out. MS. BECKER: For the tox data, is there anything else I need to reword or is that represented okay? DR. BELSITO: Hold on. I need to just do this. Does anyone else have issues with tox? I guess on page 22, in the tables there were, for sensitization there were no Ns. There were no Ns in any of those studies. Not a single study said how many animals? If you go to Table 9. MS. BECKER: Yes. MR. ANSELL: The Miller test, N9, control 0. MS. BECKER: N, not specified, specified 02, not specified 50, 00. DR. BELSITO: Okay. So I missed that, obviously. It says they stressed -- this is in the discussion, the third paragraph, the panel expressed concerns about residual monometers and impurities and to use good manufacturing practices to limit impurities. I just said, do we have any limits on any of these or we've stopped expressing limits? To limit impurities. I mean, what is -- MS. BECKER: There is a limit in the acrylamide report for how much in the final product. DR. BELSITO: So do we want to say that? MR. ANSELL: Five PPM. DR. BELSITO: Where we've specified limits, do we want to give those limits here again? MR. ANSELL: It would be consistent. DR. LIEBLER: So the only impurities reference is in the sodium polyacryloyldimethyl taurate where it says it's less than 0 ppm acrylamide. The others don't specify a minimum amount or a

15 remaining amount of the monomer. DR. BELSITO: I understand, but my point is if you look at the monomers that we previously reviewed, have we set limits? And if we have, I think they should be brought in here into the discussion. DR. SNYDER: Well, for the ones we have data on, but for the ones we don't have data on, we can't -- we have no basis for the limit. DR. LIEBLER: And this is really not acrylamide monomer that's used to make these. A monomer is acryloyldimethyltaurate. DR. BELSITO: Okay. So you're fine with just saying limit impurities? DR. LIEBLER: I could certainly live with that. DR. BELSITO: Okay. So then we don't need to specify. So we're going safe as used here? DR. LIEBLER: Mm-hmm. Yep. DR. BELSITO: Anything that needs to be added to the discussion? DR. LIEBLER: In the second sentence or second paragraph of the discussion, these ingredients are large and should not be absorbed by the skin. I would just emphasize that this is consistent with the favorable safety profile in dermal and oral toxicity studies. MS. BECKER: Say that again. DR. LIEBLER: Okay. MS. BECKER: Are you rewording or adding to? DR. LIEBLER: I'm adding to. DR. BELSITO: Adding to. MS. BECKER: Okay. DR. LIEBLER: So you have the sentence, these ingredients are large..., okay, and then after that you can say this is -- these findings are consistent with the favorable safety profile in dermal and oral toxicity studies. Because they would appear to be nonabsorbed from the skin or the gut. DR. BELSITO: Anything else to go into the discussion? Paul? DR. SNYDER: No. Kurt? DR. KLAASSEN: No. DR. BELSITO: Okay. So the discussion is fine. We're adding Dan's comments about consistent with a favorable safety profile and dermal and oral tox. Getting rid of the "and insoluble in water" in the third line, and our conclusion is safe as used. Okay. Anything else on these? And it's taurate, not laurate. DR. LIEBLER: Gotcha. Got your back, Don. DR. BELSITO: Ouch. DAY TWO DR. BERGFELD: Moving on to the next one, one of the polymers, Dr. Marks, dimethyltaurate polymers. DR. MARKS: Which is actually the acryloyldimethyltaurate polymers. And in April, we issued an insufficient data announcement with molecular weight ranges we needed data on; impurities; sensitization data, which we felt we could move on with a tentative report that has a conclusion safe for these ingredients as set forth. Two of them, the ammonium acryloyldimethyltaurate/vinyl formamide copolymer, we wanted to know the level of the vinyl formamide; and then the sodium acryloyldimethyltaurate/methacrylamidolauric acid copolymer. And we wanted to know the level of the methacrylamidolauric acid level. And then in the discussion we would mention that in previous reports of the acrylamides we had a 5 parts per million maximum acrylamide monomer in the finished product. DR. BERGFELD: Comments by Dr. Belsito's team? DR. BELSITO: Well, we thought we could go ahead and say that all of them were safe as used, so I'll let

16 Dan address the chemistry of those two polymers that you're excluding. DR. MARKS: And I'll let Ron Shank comment on why you picked those two out, Ron. DR. LIEBLER: I think I'd just like to hear from Ron. I mean, I can see that the information about some of the residual monomers just isn't there. So I agree with that, although my level of concern given the nature of these, but I'd like to just hear it from Ron or Ron. DR. SHANK: There are three monomers -- acrylamide, vinyl formamide, and methacrylamidolauric acid -- where I felt we needed some information or could we put in a maximum level limitation on the finished product? We have data for the acrylamide, but I couldn't find anything for the vinyl formamide or the methacrylamidolauric acid. If we could put a limit on those, then they're all safe. DR. LIEBLER: Yes, my understanding of these with respect to the monomers that are used here is that they're not from acrylamide, but they're from the acryloyldimethyltaurate. So that's the common monomer to this group. The vinyl formamide, yes, that's another material it's copolymerized with and, you're right, we don't have anything on that. And the methacrylamidolauric acid might be the one I'd be more concerned about than any of them simply because it's probably the least volatile precursor, and we don't have any information on it. And so I'm not sure what to do with it because if we put a limit on it, you know, do you have a thought about what we would do, you know, what number and what rationale we might come up with? So anyway, you know, I mean, I think you have a point and I'm not really sure how to deal with it. Either ask for more information or come up with some rationale to set a limit, and I'm not sure what the rationale should be. DR. MARKS: The fortunate thing is this would go out as a tentative report, so we would have time to think about it and get also responses from the Science and Support Committee and see whether a level could be determined or whether or not we -- a safe level or whether or not we can find out the level of these monomers. DR. BERGFELD: Ron Hill? DR. HILL: Yes, my thinking was that all of the other ones were covered by data that we actually in testing other of these that had those monomers in it, and those two were not. And I thought one of those two we didn't have any indication it was in use. Am I wrong? I was trying to find the use table before I had to click that button, but I thought there was one of them that -- DR. BELSITO: Remember, we have -- I mean, again, we oftentimes don't have data on all of these. I mean, the highest leave-on for these is 3.6 percent and rinse-off is 4.3 and that's for the hydroxyethyl acrylate/sodium acryloyldimethyltaurate copolymer. And I guess from my point of view, again, not being a general toxicologist, just understanding skin, so what endpoints are you concerned about? And even if you have levels of impurities do you know at what level the molecules or the residual monomers that you're concerned about would affect that endpoint? Because if you don't, even if we get that, then how can we -- you know, if we don't have data on a dose response or some mechanism? DR. HILL: That's why I wanted those left insufficient. We don't have the data, that's the point. And the rest of them we have data to cover. DR. BELSITO: But, Ron, why were you concerned about those two? Simply because lack of data or you're aware of some toxicologic endpoint that they can -- DR. HILL: Lack of data. DR. LIEBLER: So these would be -- DR. SHANK: Or reactive components. DR. LIEBLER: So in both cases these are essentially alpha-beta unsaturated carbonyl precursors that may be present as contaminants. And one would think with those that you'd mainly be worried about sensitization, particularly with these polymers. They're not going to really do much else, but if there's residual material on the skin, palpable sensitization.

17 So another way around this is if there were sensitization data that were negative. I think that would pretty much eliminate the concern. DR. SHANK: Okay. DR. BERGFELD: So is the Marks team agreeing to that? And so how would you move then? How would you deal with this? DR. MARKS: Well, like I said, we issue a tentative conclusion with all the ingredients are safe with the exception of the two ingredients we've been discussing. That would insufficient at this point. And then, as Dan said, if we have sensitization data, then that would put to rest. DR. BELSITO: But if you had sensitization data, then you'd also need to know the level of impurities in the material that was not sensitizing because you could have another material that had a higher level of monomer that could be sensitizing. So I'm not sure that sensitization data alone will address what you're asking. If your only concern is sensitization, then why don't we go ahead with all of them being safe as used with formulated not to be sensitizing. And then we don't have to worry about whether Company X has slightly more residual monomer than Company Y if that's your toxicologic endpoint of concern. DR. HILL: But then the people who are marketing these products that don't have sensitization data on them and they haven't seen any need to get them, I think would be -- the onus would be on them to document non-sensitizing, and I view that as an unnecessary exercise for those companies that are marketing those. Because if we restrict to that, that means they -- at least under the Consumer Commitment Code, I believe they would have to document that or in some way justify it. DR. BELSITO: I don't think a person -- I mean, and, you know, certainly Beth and Don can comment, but I don't think any major personal care products company goes ahead and markets a product that they have not tested to assure that it's not sensitizing and irritating. Now, obviously, they're not testing it on millions of people and there's always a margin of error, but, I mean, there's been some testing that's been done. It's not like they just say, okay, CIR said this was all fine and we're just going to throw it at them. DR. HILL: I think the testing's been done; we don't have the data. Why don't we have the data? I guess that's what I'm driving at. DR. BELSITO: Because the testing would be formulation, not specific ingredient. DR. HILL: I got you. DR. JONAS: And that one of the ingredients isn't used, the vinyl formamide. If you see Table 5, it's not even in use. DR. HILL: That's fine. I knew there was one that didn't seem to be in use and I couldn't remember which of the two and I didn't make notes. DR. LIEBLER: We have three ingredients or more that actually -- about six or seven of them that are tested in humans non-sensitizing by HIRPTs. And that's probably one of the reasons I wasn't feeling terribly persnickety about residual monomer with the compounds that -- with this whole class, honestly, because they're not that well -- it's not that well documented on residual monomer for most of them anyhow. So another approach might be to simply panel this in the discussion and say that, you know, efforts should be made to minimize the presence of residual monomer, and deal with it that way. Because, I mean, we can ask. It's in an early stage, but we might not get it and then we can think about that. DR. HILL: So I think we know we won't get on the one because it's not news. DR. LIEBLER: Of course, having just said that on the record, we might not need it. (Laughter) Anyway, but we have to vote, so. DR. BELSITO: Well, this is -- would go out as a tentative final, right? So if we send it out as a tentative final and then change the conclusion that all of them are safe when --

18 DR. MARKS: No, it'll go out as a draft tentative because we issued an insufficient data announcement, so next is the draft tentative, then the draft final. DR. BELSITO: I don't know. This was insufficient at the last meeting. DR. MARKS: Announcement. MS. BECKER: This is coming back from an insufficient. DR. MARKS: Announcement. MS. BECKER: As a tentative. DR. MARKS: Yes, it would go as a tentative report. So we're actually going to have two more looks at this. I would just remark, Don, we do use non-sensitizing the botanicals because it's a mixture. I think when we have individual chemicals where we know the chemistry I'd be very hesitant because pretty soon we could get to say -- we could cover any lack of sensitization data as formulate to be non-sensitizing. So I like, Dan, your approach that perhaps in the discussion -- so, Panel, do you feel fine to second the motion of the Belsito team and then in the discussion handle the sensitization issue and then we'll see what we fine [find]? DR. BERGFELD: It's your motion. It's your motion. DR. MARKS: Oh, it's my motion. Oh, yes. DR. SHANK: Yes. DR. MARKS: Yes, it's such a long discussion I forgot I moved it. I knew I was intending to report. DR. BELSITO: You would have to retract your motion. DR. MARKS: Yes, I'll retract my motion. Is that okay, Team? SPEAKER: Yes. DR. MARKS: Yes. DR. BERGFELD: And so what is the motion? DR. MARKS: All these ingredients would be safe. DR. BERGFELD: And then you're handling the discussion in the discussion. DR. MARKS: We're handling the issue of the monomers for those two ingredients we discussed: the vinyl formamide monomer and methacrylamidolauric acid monomer in the discussion. DR. BERGFELD: This is a motion. Second? DR. BELSITO: Second. DR. BERGFELD: Belsito, second. Ron Hill? DR. HILL: I just wanted to say that if in the event there are reactives present, there are other things that reactives can do in the skin besides sensitize. Sensitization is a sentinel and I think it's a very good sentinel. And I've not seen any cases where that sentinel would fail to indicate something else that might happen with the reactive in the skin. So that -- while sensitization in terms of an endpoint and in terms of data needs is important. It's not my only concern in terms of what might happen biologically when you have a reactive present. So that's a comment I wanted to make about that. DR. BERGFELD: Are you suggesting something else be added to the discussion in the document? DR. HILL: No. No, I am not. DR. BERGFELD: Okay. DR. HILL: But it's going to explain my vote in a moment. DR. BERGFELD: Okay, very good. Any other discussion? Otherwise, we'll call for the vote. All those in favor, indicate by raising your hand. Those abstaining? I guessed. DR. HILL: I'm opposed. DR. BERGFELD: You're opposed, okay. One negative and the rest voting for it. All right, good discussion, good resolution. DR. MARKS: Just for clarity, Ron Hill, what other biologic endpoints? Because I'd like to know or, you

19 know, what else are you concerned about? DR. HILL: The answer (inaudible). Skin cancer. And that's what you're worried about, if reacting chemicals like these are -- skin cancer, right? I'm not the expert here, Tom. DR. SLAGA: Well, it's unfortunate that those (inaudible) would be below (inaudible). I can't imagine it would be sufficient to cause cancer. DR. HILL: Well, look, we had data that had the concentrations of the monomers and that we knew they were very low, then I fully agree, we can protect against reactives and I think that would be the case. But the absence of data isn't the assurance of safety. DR. BERGFELD: Anything else to add? All right, seeing nothing, we'll move on to the next ingredient. March, 206 Dr. Marks Team DR. MARKS: So, we had a draft report on the acryloyldimethyltaurate polymers. This is the first review of these ingredients, and so the first question would be for Ron, Ron, and Tom. This list of these ingredients, these polymers that is a little over a page -- are there any ingredients in that list which you think do not fit and should be removed? DR. HILL: Which table are you looking at, just so we're looking at the same place? DR. MARKS: Page 9 I went to. Let's see if that corresponds. No, that's -- I'm sorry. DR. HILL: Page 9? DR. MARKS: It is 9. MS. BURNETT: And page 9 will work. DR. MARKS: Okay. 9 is the use, yes. Okay. Sure, page 9 or I actually was looking at the one where it tabulates what testing had been done. But are there any of these ingredients which you feel should be eliminated from this group of these 22? DR. EISENMANN: The one that I thought was different is this polyacryloyldimethyltaurate polyoxymethylene melamine. It's too polymers. DR. HILL: Oh, yes, I forgot about that one. I forgot about that. DR. EISENMANN: It's two -- it's a salt of two polymers. It's not a -- DR. HILL: Sorry. DR. EISENMANN: So, we have two polymers linked by charges. It's a little bit different than the others. That's why I -- I just thought it was different, so I don't know if it belongs. DR. BERGFELD: Which one is that again? DR. MARKS: It's the second column, the second one down? Is that right, Carol, the hydroxyethyl acrylate? DR. EISENMANN: No, it's -- DR. HILL: No, the other one. MS. BECKER: The the third one down. DR. MARKS: Oh, the third one. DR. HILL: Polyacryloyldimethyltaurate. DR. EISENMANN: Acryloyl -- correct. DR. MARKS: Okay, thank you. Third one down. The polyacryloyldimethyltaurate poly. DR. HILL: My note on this says that if it's to stay in -- I was looking for direct information about the molecular weight of that component as well as the other bit about method of manufacture, some

20 impurities, and maybe based on that information a little bit more to be determined. So, if they want it out, I'm okay with that, too. DR. MARKS: So, Ron Shank and Tom, you like the idea of removing that since it's structurally different? MS. BECKER: If you want to look at the structure, page 6 of the PDF at Table. DR. HILL: Thank you. DR. MARKS: Ron Shank, what do you think? DR. SHANK: And you call that salt? I'm having a hard time picturing what that is. DR. HELDRETH: So, the sulfate on the first polymeric residue would be deprotonated, whereas one of those nitrogens on the melamine would be protonated. So, they're going to be attracted to each other. It's not going to be like chlorotic salt. But you're going to have opposite charges that are going to keep those two bodies in close approximation. DR. SHANK: Okay, so what's polymeric about all of this? The sulfate is ionized and then binds to point 2 or 3 of the hydroxyl groups on the other? DR. HELDRETH: One of the nitrogens. One of the nitrogens will be protonated. DR. SHANK: Okay. Yeah, it's interesting, because it's not repeated. Or just two molecules together. DR. HELDRETH: The polyacryloyldimethyltaurate polymer, and it will have essentially -- DR. MARKS: 0M. DR. HELDRETH: -- a negative charge to it, and then the melamine polymer with essentially a net positive charge to it, and those opposite charges will keep those two polymers together. DR. SHANK: Okay, so the values of x and y are greater than. DR. HELDRETH: Certainly greater than. It would be on that window. We need specific information. DR. SHANK: Okay, thank you. DR. HELDRETH: Sure. DR. MARKS: So, remove -- or keep in? DR. BERGFELD: It's your first draft. Maybe you can call for that information. DR. HILL: My thinking was along the lines of since we are at the point of probably asking for more information on a number of these -- but maybe I'm the only one who thinks that, but I'm thinking we're going to ask for some more information. We could make the decision after we see what we get, because if you toss it out, when if ever will it be reviewed? Is it in use? I thought it was not, but -- DR. MARKS: Ron Shank, what's your feeling? DR. HILL: Not in use. DR. MARKS: So, we aren't going to receive information more than likely. DR. BERGFELD: And I believe -- DR. SHANK: Well, for all of them I would like to know the range of molecular weights of these. DR. MARKS: Okay, so shall we leave this -- yeah, we'll get to what the needs are. I just want to -- So, Bart, why did you include it since you -- and that's what we're talking about, structurally. Usually these are made that they're structurally similar, chemically similar. DR. HELDRETH: Right, so when we're looking at these polymers, you know, if in reality it ends up that they're of significant size and we're not worried about systemic absorption and its global effects, then what we're probably most concerned with outside from irritation and sensitization is residual monomer, or monomer that may be cleaved off of the polymer. And so I grouped all these ingredients together that share a certain type of monomer in common, and in this case they all have at least a taurate monomer in common. Now, this specific ingredient that we're talking about is really two polymers. One of those does have that taurate core monomeric repeat unit in it. The other one does not that forms the salt. So, it is like the other ingredients in that it has that shared monomeric starting material but, unlike the other ingredients, it also has some additional polymer that forms the salt. DR. EISENMANN: That additional polymer has a CIR insufficient data conclusion also.

21 DR. SHANK: As insufficient? DR. EISENMANN: Data conclusion already. DR. SHANK: So, they know me. DR. EISENMANN: Right. Right, so you have two polymers together on one (inaudible). The one that's attached to it has insufficient data conclusion. DR. MARKS: Seems like that's enough that we should remove it. DR. SLAGA: Remove it. I would. DR. MARKS: Okay, let me -- DR. HELDRETH: I mean, it's your choice to remove it, or you could keep it in and by default it's going to be insufficient as well so that there's -- if we don't get data on it, you'll have a conclusion that says "insufficient, zero use." DR. HILL: At a level of -- if we don't mind split conclusions, I like the idea of keeping it in and landing there, because then if somebody does decide they want to use it or it is in fact in use, the (inaudible) will take a couple of years and then come back and support it. DR. HELDRETH: Well, in this case, if there are zero uses, there's no reason to wait. It's a final. DR. HILL: No, I know, I get that. I'm saying leave it in, it's just whether they like split conclusion or not -- because I think we'll end up with the rest of them probably being fined. DR. MARKS: I'd remove it, but Tom, Ron, what do you want to do? Do you want to -- since we're going to come to an insufficient if we keep it? DR. SLAGA: Remove. DR. HILL: Yeah. DR. SHANK: I agree. DR. MARKS: Okay, so we'll plan on removing that one. That's page 9. Let me go back -- DR. BERGFELD: Excuse me, but it is in the dictionary, correct? DR. SHANK: Yes. DR. HELDRETH: Mm-hmm. DR. BERGFELD: So, my opinion for this team is that you maybe ought to leave it in so it's covered, if it doesn't take too much work. I mean, this is the first draft. DR. MARKS: Ron? Tom? DR. SHANK: Leave it in? Now? DR. SLAGA: Remove. DR. MARKS: Okay, so -- DR. SHANK: Well, in the entire group, it's the only salt, is it not? DR. HELDRETH: It's the only salt of this type, yes, where you have two polymers that coordinate. DR. SHANK: Polymers? DR. HILL: They all had to be salts, because we've got the sulfate. DR. HELDRETH: The sulfate, excuse me. This is just the only one where the cation is -- DR. HILL: So, another polymer. DR. MARKS: Remove. So, tomorrow I'm going to say remove and will -- and then I think, Ron Hill, Wilma, you can express an opinion about leaving it in, and we'll see how we land on that. And that was, again, the language. I mean, that's -- I don't have to -- oh, here it is (inaudible) get it here. Poly polyacryloyldimethyltaurate. Okay. Do you have it? Thank you. Now, needs. I heard Ron Shank earlier mention you would like the molecular weights. So, if we need -- DR. SHANK: The range? DR. MARKS: Yeah, molecular weight range. And obviously the reason there is that they're a low molecular range, in the low molecular weight range. Then we would need absorption, et cetera. DR. SHANK: Correct. DR. MARKS: Need for absorption. Any other needs? Go ahead, Ron.

22 DR. HILL: Well, just because it fits, yeah, impurities, and I note here that the EU has a restriction on acrylamide levels as an impurity. And I also notice that there's one of these that has a vinyl formamide monomer rather than acrylamide. So, those are really the main ones that we'd be concerned with here. DR. MARKS: So, repeat that, Ron. You would want to -- DR. HILL: Impurities really directed toward acrylamide and vinyl formamide. DR. MARKS: And so in that case, Ron Hill, you want to know whether acrylamide or vinyl acrylamide is an impurity and, if so, how much or you want none of that. DR. HILL: It will be an impurity. And, like I say, the EU restricts levels to.3 percent I think it is. I just -- I don't think they have a similar restriction on the vinyl formamide, but there's one of these that has that in there as a monomer, and the reactivity would be expected to be similar. DR. HELDRETH: Yes, and this Panel has also concluded that acrylamide monomers should be not greater than 5 ptm [ppm] in polyacrylamides. DR. HILL: Yeah, okay. DR. MARKS: Yeah, that's -- DR. HILL: (Inaudible) we landed, so. DR. MARKS: Yeah, previous conclusion on page 9 was nonirritating, and acrylamide monomer is not greater than 5 parts per million. DR. HILL: You're right. DR. MARKS: So, I guess the question there is do we repeat that in this document, or do you want the impurities anyway? We're going to end up with that statement without a doubt. DR. HILL: I would still like -- because I think that information will be out there, and I realize I'm asking a couple people to do some work, but I still think we should have -- because these are different polymers than the others we've looked at. And then due diligence suggests we look and see what's known about that, because I'm pretty sure people will be paying attention and will have some data. DR. MARKS: Okay. So, that's two needs. Any other needs? DR. HILL: And also, again, that other monomer that's in there in that one ingredient. DR. MARKS: Any -- go ahead. MS. BECKER: Which one? The other one? DR. HILL: Yeah, it's -- hang on, I'm trying to find the full ingredient name because I have it flagged in the structure table. MS. BECKER: Page 9? DR. HILL: Well, I'm going back to page 9, but we're headed flagged ones in the structure table. MS. BECKER: Is that the vinyl formamide. DR. HILL: Yeah. There's only one that says "vinyl" actually. I just searched it and then I got -- I abandoned the search. I closed the search, so -- MS. BECKER: Okay. DR. HILL: But, yeah, that's the only one, and I was looking to see if it was in use is why I moved off of that. You got it? MS. BECKER: Um-hmm. DR. HILL: Okay. MS. BECKER: Mm-hmm. Thank you. DR. MARKS: Any other needs? DR. HILL: It's not in use, so we'll probably not get that information. At least we don't have a record of its use.

23 DR. BERGFELD: Are you going to make some kind of statement, depending on the molecular weight, whether you'll need absorption, blah-blah-blah? Is it -- it's not a weighted document with a lot of information. DR. MARKS: Yeah, basically what I interpreted -- that's why I had asked Ron -- we need -- the first need was molecular weight range to decide on the need for absorption data basically, and then obviously it's absorbed, and then we need to know the tox from that. And then, second, the impurities, the acrylamide and vinyl acrylamide levels. DR. HILL: Let me just say this also about the absorption on that, because I'm not looking for that information. We've got a polymer that has the sulfonate groups on them, every one of which is very strongly acidic, which means effectively a permanent negative charge, and there are many of those negative charges sitting on the polymer, so the chances that they would be drug even through a mucous membrane is quite small. DR. MARKS: So, you wouldn't need them -- DR. HILL: I'm not worried about that or anything systemic. DR. MARKS: Shall we, Ron Shank, just leave it as an 8 and see what the reaction we get back as? We're going to -- I think at this point I will be moving for an insufficient data notice so we can see the reaction we get back if what you're saying, Ron Hill, is acceptable. DR. HILL: I mean, they may just come back and give us these high molecular weights some extensive negative charges and use that as their rationale, and I would be comfortable with that response. DR. MARKS: Yeah. DR. SLAGA: That would be fine with me. DR. MARKS: Okay, and then any other needs, Tom? Do you need any from a -- DR. SLAGA: I think there's plenty of acute toxicity (inaudible) genotoxin. DR. MARKS: Do you think we're going to have a -- it's -- the irritation and sensitization data were okay, and I only asked Lillian and I asked her -- prepped her for this question. There's a number of the sensitization data, the HRIPTs. In parentheses it said assume at a hundred percent, and I wondered how we got that assumption a hundred percent. They're actually used at relatively low concentrations somewhere around -- of the ones that are used the most, those over a 50 uses, 65 to used as the concentration is from 2.3 to 4 percent in the leave-on. So, I was reassured that all the sensitization data was okay, but it seems like a hundred percent is a lot when it's only being used in the 3 to 4 percent range. But at any rate, Lillian, do you want to comment on the assumption that the sensitivity testing was done at a hundred percent? MS. BECKER: The sources I have are NICNAS summaries, and they give the ingredient and the test and the results and without saying what was tested or if there was a vehicle or anything else. So, if they're just saying this was applied, I'm assuming a hundred percent, but I have no definitive. So, that's why I just put -- didn't say a hundred percent; I said assumed. DR. MARKS: Is that okay with you guys? I was reassured by that. Okay, any other comments about these ingredients? MR. BEST: My only comment is that (inaudible) we have we standards from other (inaudible) or Australia that are sort of put out there. It would be nice to have some -- since they're being used here at a higher rate that there be some discussion of, you know, if we decide that's okay why it's okay or why the levels were drawn where they were by other prohibitive bodies, because that always jumps out at me. DR. MARKS: Okay, so tomorrow we'll -- did we capture that, your concerns? MR. BEST: Sure. DR. MARKS: And where would you put those in the discussion? MR. BEST: Sorry, it's on page for us to discuss, right -- both the Australian and the EU body? DR. MARKS: Mm-hmm.

24 MR. BEST: Talk about where it -- what safe levels there are. There are no -- they're being used, right? The use tables are slightly higher levels for some of those ingredients here? DR. MARKS: Yeah. MR. BEST: So, if you have I think maybe just even under where you say what the levels are for the bodies we could -- if the panelists are saying they're safe as used at the concentrations, you know, as used now, we could say why the EU in Australia drew this level -- why this level -- why the Panel thinks this higher level is okay that were being used at, I think, even just right there where it is. MS. BECKER: Very often, the limits are the requested limits by the applicants, and they didn't look at any higher use as such -- MR. BEST: Yeah, I know, and that's been before this Panel before. I think that would be fine, I mean unless you guys think it's inappropriate. But it seems like a red flag, I think (inaudible) with this, you know, even as I'm sort of learning this and doing this. I mean, I -- and I remember that coming up before, but it might be just good to have a sentence that explains that. I think it makes it seem less mysterious, less frightening. DR. GILL: Michael, sometimes we don't know. MR. BEST: Right. DR. GILL: And I think when our Panel looks at the data presented to them and they've drawn a conclusion based on the data in front of them, which is what we typically say based on what was reviewed and presented, I'd be a little cautious in getting into how they've made their decision and everything that they -- that went into their decision-making. So, it may be a little sticky for our Panel to start concluding why the Europeans and Australians and others made their decisions and how. MR. BEST: No, fair enough. I just -- I think (inaudible), it seems odd, right? I mean, it seems odd that, okay, if you're at these other places, and I think there sometimes is a general idea that maybe you're (inaudible). I don't think that's always true, actually, but, you know what I mean? So, it doesn't raise a flag in my head (inaudible) so I just thought I'd bring it up, but maybe there's no good way to address it. DR. GILL: And I think that's a legitimate point, because we often get asked that question. It's just sometimes we don't always know. Their decision-making process is a little different than ours. When we look at some of their decisions -- and we'll look at one today -- we can elaborate a little more on that. But I think a general statement might be beyond what the Panel can say at the time. MR. BEST: Okay, thank you. DR. HILL: I would like to add to my monomer list -- DR. GILL: Yes. DR. HILL: Methacrylamidolauric acid. DR. MARKS: Metha -- DR. HILL: Methacrylamidolauric acid. It's looking at -- it's the last entry in the structured table -- no, it's not either. Last entry on page 7, the first page of Table I think. DR. GILL: Hmm-mm, no. DR. HILL: No, it's not either. It's somewhere in the middle of Table. DR. MARKS: What page is Table? DR. HILL: It starts on page 4, I believe DR. GILL: To what, 7, because that's where the -- DR. MARKS: Yeah. DR. HILL: Let me look at -- the ipad is actually quicker at this. All right, so it starts on page 4, and I believe that's the last entry on page 7. Yes, the last entry on page 7.

25 DR. MARKS: Okay, so I think at this point what I'll be doing for our team tomorrow is moving an insufficient data notice that we are moved from the ingredient list to polyacryloyldimethyltaurate polyoxymethylene methane. Is that correct? I kind of stumbled through that long name. DR. BERGFELD: Language. DR. MARKS: And then the needs are, one, the molecular range, the (inaudible) if absorption data is needed, and then, two, the impurities that acrylamide vinyl acrylamide and the methacrylamide acid levels. And, Ron, I asked you to comment on those three I have. And that will be -- and we'll see what the Belsito team -- how they react. Does that sound good, team members? DR. SHANK: Sounds good. We have some sensitization data. Can we use that to cover all of the compounds in the list? DR. MARKS: Yeah, I thought it was, because we had the -- we have the compounds with the most use, highest use, and we have a range in there. So, I thought it was fine. DR. HILL: Well, I did have a note in here. Felt like I was being a malcontent today, but I did have a note in here that I felt like we ought to have sensitization data to cover the full range of monomers, at least the reactive monomers. So -- but that was just my thinking. So then in that case, that are a few more that you'd like to see the testing on, but -- so, are we making any requests for additional sensitization data at all right now? We didn't say that for our team, right? DR. MARKS: Correct. DR. HILL: Okay. DR. BERGFELD: Ron, can you answer how stable are these? DR. HILL: I think the polymers are stable, and we wouldn't be worried about that. It would just be residual. If there's any sensitization, I strongly believe, based on everything I know, it would be coming from any residual monomers. So, for me it was stepwise if we had good characterization of that, and we knew because, again, that won't be zero but it'll be some small level. If we had that data, we wouldn't necessarily need any more of the sensitization, and it isn't the way I was thinking about that. DR. SLAGA: You already asked for those impurities. DR. HILL: I did. So, that was my thinking on how that went -- I guess a chemistry way of looking at it instead of a sensitization way. But I'm good with omitting that, partly because I think the other team may ask for it. (Laughter) And if not, I'm still good because I've asked for impurities. If we don't get that, then I'd like to see sensitization of the full range of monomers. DR. MARKS: Okay, any other comments? So, we're going to have it in an insufficient data notice, so we're going to be saying ingredients, these 2 ingredients, and assuming that we remove the one ingredient we didn't like. Okay? Any other comments? Dr. Belsito s Team DR. BELSITO: So 22 ingredients dispensing agents non surfactants emulsion stabilizers of pacifying viscosity the lead ingredient is hydroxyethylate is used in 474 formulations 45 are leave on. Two products in bath have the highest concentration, 4.3 percent depilatories, the highest leave on, I guess, is 3.6 in an eyeliner. Women with acute toxicity geno irritation and sensitization of repro or developmental or carcinogenicity and I guess what we can discuss while my windows are starting is industry has asked us to reconsider whether the Polyacryloydimethyltaurate Polyoxymethylene Melamine should remain in this report because it is a salt of two powders. SPEAKER: Polymers.

26 DR. BELSITO: That's right, polymers, I'm sorry. COURT REPORTER: Just for the record could you pronounce that? DR. BELSITO: Cryloydimethyltaurate Polymers. Dan, do you want to comment on industries caurate? DR. SNYDER: Taurate. DR. BELSITO: Taurate, yes, sorry. DR. LIEBLER: I agree, the melamine containing salt of two polymers should be excluded from this report. All of the others are polymers of this basic structure and they do have either ammonium or sodium salt whereas the polymer combination involving melamine is, the melamine polymer is a strip of basic polymer that would form salts with the acidic taurate polymer and so the safety consideration for that one would be driven as much by the melamine polymer as it would be by the taurate polymers and since this report is really about the taurate polymers and their safety I think the melamine taurate salt is doesn't really belong in this group so I think it should be excluded. DR. BELSITO: Okay. Paul? Curt? Do you agree. DR. SNYDER: I agree. DR. KLAASSEN: Fine. DR. BELSITO: So we will exclude that and we already addressed that question. It's used in products that could be inhaled so we will need a respiratory boilerplate there. DR. SNYDER: Sprays and powders. DR. BELSITO: Right, sprays and powders. We don't have sensitization data for the ATA polymer which is the most frequently used and in the highest leave on concentration and I thought that was peculiar that we don't have data for the most frequent and highly used one. I don't think these are issues because I don't think they are going to get into the skin but I'm just pointing out that we have no sensitization data. DR. LIEBLER: No impurities and no -- DR. BELSITO: No method of manufacturing or impurities. DR. LIEBLER: No absorption. DR. BELSITO: No absorption and apparently we need those based on large molecules. So overall I say insufficient for manufacturing and impurities. They are large molecules so do we want to ask for 28-day dermal absorption and as long as we are going insufficient, I thought you really should have some sensitization data for the most frequently used product in the category. So I ask for sensitization of the HEA co-polymer at the highest concentration of use. DR. LIEBLER: I agree. Method of manufacture, impurities, particularly residual monomers and we might as well ask for the absorption if these come back documented big and low residual monomers the absorption concern goes away and then I will defer to Don on the sensitization data but I support per the insufficient request. DR. SNYDER: That's what I have. DR. BELSITO: So manufacturing impurities, especially monomers, absorption and sensitization in use concentration for the HEA co-polymer. When we are writing it up we can add the respiratory boilerplate and we are getting rid of the melamine compound. Anything else? DR. BELSITO: Okay, Day Two DR. BERGFELD: Good discussion, thank you. The next item or ingredient on the list under reports advancing is the dimethyltaurate polymers, Dr. Marks? DR. MARKS: So this is the first review of these 2 ingredients and our team -- first the issue of you

27 seeing Lillian Becker's memo there at the next to last paragraph, we felt that we should remove the polyacrylo dimethyltaurate polyoxymethalyn melamine. These two polymers didn't really belong with these other ingredients so we felt that we should issue a -- and I'll make this a motion of insufficient data notice. We wanted to find out what the molecular range of these ingredients were to decide on need for absorption data. We wanted to know more about the impurities, particularly the monomers, the acrylamide, the bi-acrylamide, the methyl acrylamide acid levels, particularly in light of the restrictions and that was it. Those two data needs so an insufficient data notice for our team. DR. BELSITO: We had those two and then on the fence, but as long as we are asking for insufficient sensitization that uses concentration of the highest and most frequently used, which is the AGA polymer copolymer which I found odd that it has the significantly highest number of uses. It's used in the highest concentration and we have no sensitization data on it so we are requesting that as well. DR. BERGFELD: I'm sorry, you're seconding the motion with that addition? DR. BELSITO: Yes. DR. BERGFELD: And I see a shake of the head by Jim and he -- DR. BELSITO: And agree with the deletion of the melamine, we did not think it belonged in that report. DR. BERGFELD: Okay, any further discussion regarding this ingredient? Okay, Lillian? MS. BECKER: Just a clarification, I thought I heard Dr. Marks' team want to remove and I thought I heard Dr. Belsito say just remove the melamine? DR. BELSITO: It was one large polymer that you wanted remove, right? DR. MARKS: Correct. MS. BECKER: Okay. DR. BELSITO: It was the melamine, that ended with melamine? DR. MARKS: That's correct. DR. BELSITO: And it was on the basis of the melamine component of that polymer that we felt it should be removed. DR. BERGFELD: Anything else? I'll call to question then. All those in favor? Unanimous. (Motion passed unanimously)

28 Safety Assessment of Acryloyldimethyltaurate Polymers as Used in Cosmetics Status: Draft Final Report for Panel Review Release Date: March 7, 207 Panel Meeting Date: April 0-, 207 The 207 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 620 L Street, NW, Suite 200 Washington, DC ph fax cirinfo@cir-safety.org

29 ABSTRACT The Cosmetic Ingredient Review (CIR) Expert Panel (Panel) assessed the safety of 2 acryloyldimethyltaurate polymers as used in cosmetics. The reported functions of these ingredients include dispersing agent nonsurfactant, emulsion stabilizers, opacifying agent, and viscosity increasing agent aqueous. The Panel expressed concern about residual monomers and impurities including acrylamide, vinyl formamide, and methacrylamidolauric acid monomers. They stressed that the cosmetics industry should continue to use current good manufacturing practices (cgmps) to limit impurities. The Panel concluded that acryloyldimethyltaurate polymers are safe in cosmetics in the present practices of use and concentration described in this safety assessment. INTRODUCTION This is a review of the published scientific literature and unpublished data provided by Industry relevant to assessing the safety of 2 acryloyldimethyltaurate polymers as used in cosmetics. This group of ingredients comprises homopolymers, copolymers, and crosslinked polymers, the monomers of which are at least partially composed of acryloyldimethyltaurate. According to the International Cosmetic Ingredient Dictionary and Handbook, the functions of these ingredients include dispersing agent nonsurfactant, emulsion stabilizer, opacifying agent, and viscosity increasing agent aqueous (Table ). The ingredients in this safety assessment are: Acrylamide/Sodium Acryloyldimethyltaurate Copolymer Acrylamide/Sodium Acryloyldimethyltaurate/Acrylic Acid Copolymer Ammonium Acryloyldimethyltaurate/Beheneth-25 Methacrylate Crosspolymer Ammonium Acryloyldimethyltaurate/Carboxyethyl Acrylate Crosspolymer Ammonium Acryloyldimethyltaurate/Laureth-7 Methacrylate Copolymer Ammonium Acryloyldimethyltaurate/Steareth-25 Methacrylate Crosspolymer Ammonium Acryloyldimethyltaurate/Steareth-8 Methacrylate Copolymer Ammonium Acryloyldimethyltaurate/Vinyl Formamide Copolymer Ammonium Acryloyldimethyltaurate/VP Copolymer Ammonium Polyacryloyldimethyl Taurate Dimethylacrylamide/Sodium Acryloyldimethyltaurate Crosspolymer HEA/Sodium Acryloyldimethyltaurate/Steareth-20 Methacrylate Copolymer Hydroxyethyl Acrylate/Sodium Acryloyldimethyl Taurate Copolymer Sodium Acrylate/Acryloyldimethyltaurate/ Dimethylacrylamide Crosspolymer Sodium Acrylate/Sodium Acryloyldimethyl Taurate Copolymer Sodium Acrylate/Sodium Acryloyldimethyl Taurate/Acrylamide Copolymer Sodium Acryloyl Dimethyl Taurate/PEG-8 Diacrylate Crosspolymer Sodium Acryloyldimethyl Taurate/Acrylamide/VP Copolymer Sodium Acryloyldimethyltaurate/Methacrylamidolauric Acid Copolymer Sodium Acryloyldimethyltaurate/VP Crosspolymer Sodium Polyacryloyldimethyl Taurate The Panel has previously reviewed polymers that are similar to the acryloyldimethyltaurate polymers (Table 2). Some of the ingredients in this report are copolymers with acrylate monomers; the Panel has reviewed the polyacrylates, and other acrylate copolymers, and concluded that they are safe as used when formulated to be non-irritating. 2 Some other ingredients in this report are copolymers with acrylamide monomers; polyacrylamides were found to be safe as used if the concentration of residual acrylamide monomers in formulation is not greater than 5 ppm, and Polyvinylpryrrolidone (PVP; another polymer with vinyl-type amide monomers) was found to be safe as used. 3,4 The Panel has also previously reviewed components/monomers of the acryloyldimethyltaurate polymers. The alkyl taurate amides and taurate salts were found to be safe when formulated to be non-irritating. 5 CHEMISTRY Definition and Structure The acryloyldimethyltaurate polymers are composed of homopolymers, copolymers and crosslinked polymers, the monomers of which are at least partially composed of acryloyldimethyltaurate. Figure. This monomer is common to all acryloyldimethyltaurate polymers, where M is a sodium cation or ammonium.