Safety Assessment of Polysorbates as Used in Cosmetics

Safety Assessment of Polysorbates as Used in Cosmetics Status: Draft Final Amended Report for Panel Review Release Date: May 22, 2015 Panel Meeting Date: June 15-16, 2015 The 2015 Cosmetic Ingredient Review Expert Panel members are: Chair, Wilma F. Bergfeld, M.D., F.A.C.P.; Donald V. Belsito, M.D.; Ronald A. Hill, Ph.D.; Curtis D. Klaassen, Ph.D.; Daniel C. Liebler, Ph.D.; James G. Marks, Jr., M.D.; Ronald C. Shank, Ph.D.; Thomas J. Slaga, Ph.D.; and Paul W. Snyder, D.V.M., Ph.D. The CIR Director is Lillian J. Gill, D.P.A. This report was prepared by Lillian C. Becker, Scientific Analyst/Writer. Cosmetic Ingredient Review 1620 L Street, NW, Suite 1200 Washington, DC 20036-4702 ph 202.331.0651 fax 202.331.0088 cirinfo@cir-safety.org

Commitment & Credibility since 1976 MEMORANDUM To: From: CIR Expert Panel and Liaisons Lillian C. Becker, M.S. Scientific Analyst and Writer Date: May 22, 2015 Subject: Draft Final Amended Report of Polysorbates as Used in Cosmetics Attached is the draft final amended report of Polysorbates as used in cosmetics. [PSorba_062015_Rep] In March, 2015, the Panel issued a tentative amended report with a conclusion of safe as used when formulated to be nonirritating. This safety assessment combined 3 previous reports and added new polysorbate ingredients. There were three polysorbate ingredients reported in the VCRP but were not listed in the Dictionary (PEG-20 sorbitan laurate, PEG-20 sorbitan stearate, and PEG-30 sorbitan beeswax). The Council has asserted that PEG-20 sorbitan laurate is another term for polysorbate 20 and PEG-20 sorbitan stearate is another term for polysorbate 60. Therefore, these two ingredients do not add to the ingredient count of this report. On the other hand, there is no reason to not add PEG-30 sorbitan beeswax to the report. The report now has a total of 80 ingredients. Industry comments have been addressed. [PSorba_062015_Council] The Council would like the Panel to consider whether or not the cyto/genotoxicity study of polysorbate 20 (reference 44) should remain in the genotoxicity section or be moved to a cytotoxicity section. In this study, the authors considered the results of multiple assays (MTT, DAPI, DNA fragmentation, DNA fragmentation, alkaline comet, and annexin V apoptosis assays) to come to a conclusion on genotoxcity. While these individual assays should stay together for continuity and understanding of the paper, should they be moved to a different section in the report? No new data have been submitted. The Council is conducting a concentration of use survey on PEG- 40 sorbitan laurate. The Panel is to examine the Abstract, Discussion, and Conclusion to ensure that they reflect the Panel s thinking. The Panel is to issue a final amended report. 1620 L Street, NW Suite 1200, Washington, DC 20036 (Main) 202-331-0651 (Fax) 202-331-0088 (Email) cirinfo@cir-safety.org (Website) www.cir-safety.org

Public Comment CIR Expert Panel Re-Review Rpt Status announce 15 years since last OR New Data; or request 60 day public comment period PRIORITY LIST Re-review to Panel Mar 2015 The original polysorbates report was published in 1984. It was proposed that the RR also include the ingredients in the PEG Polysorbates (2000) and Sorbeth Beeswax (2001) reports. Previously unreviewed ingredients were also added. DAR Table Are new data cause to reopen? YES DRAFT AMENDED REPORT* Table IDA TAR NO Are new ingredients appropriate for inclusion/re-open? Yes No 60 day public comment period IDA Notice Draft TAR IDA DRAFT TENTATIVE AMENDED REPORT RE-REVIEW SUMMARY Table Table Tentative Amended Report Mar 2015 Issue TAR 60 day Public comment period Draft FAR DRAFT FINAL AMENDED REPORT June 2015 Table Table Different Conclusion PUBLISH Final Amended Report Issue FAR *If Draft Amended Report (DAR) is available, the Panel may choose to review (and issue a TAR: if not, CIR staff prepares DAR for Panel Review.

History Polysorbates 1984 Report on polysorbates 20, 21, 40, 60, 61, 65, 80, 81, and 85 published with a safe as used conclusion. 2000 A safety assessment was published of a re-review if the above polysorbates as well as additional polysorbates with a safe as used conclusion. 2001 A safety assessment was published of Sorbeth-6 beeswax, Sorbeth-8 beeswax, and Sorbeth-20 beeswax with a safe as used conclusion. March, 2015 The Panel reviewed the re-review document. The safety assessment was reopened to combine three reports on various polysorbates, add new ingredients, and to remove the caveat concerning the use of PEGs on damaged skin from the sorbeth beeswaxes. A safe as used conclusion was issued. June, 2015 The Panel is to review the Abstract, Discussion and Conclusion and issue a final amended report.

ADME Polysorbate Data Profile for June, 2015. Writer - Lillian Becker Repeated dose Sensitizatio Acute toxicity Irritation toxicity n Phototoxicity Carcinogenicity Genotoxicity Repro/Devel toxicity Sensitization Human Sensitization Animal Dermal Irr Human Dermal Irr. Animal Ocular Irritation Inhale Dermal Oral Inhale Dermal Oral Use Log K ow Dermal Penetration Polysorbate 21 ON O O O O O Sorbeth-6 laurate PEG-10 sorbitan ON laurate PEG-40 sorbitan N laurate Polysorbate 20 ON ON O ON ON O O O O O ON O O PEG-44 sorbitan ON laurate PEG-75 sorbitan N laurate PEG-80 sorbitan laurate ON Polysorbate 40 ON O O O O O O O O O PEG-80 sorbitan O O palmitate Sorbeth-3 isostearate PEG-2 sorbitan isostearate PEG-5 sorbitan isostearate PEG-20 sorbitan ON isostearate PEG-3 sorbitan N stearate PEG-4 sorbitan O O O stearate Polysorbate 61 ON O O O PEG-6 sorbitan stearate Polysorbate 60 ON O O O O ON ON O O ON O O O Polysorbate 65 ON O O O O O PEG-40 Sorbitan ON Stearate PEG-60 sorbitan N stearate PEG-3 sorbitan ON oleate Polysorbate 81 ON ON O O O N N O PEG-6 sorbitan N oleate PEG-20 sorbitan oleate O O O O O O O O Polysorbate 80 O ON ON ON O O O O O O O ON ON O O PEG-40 sorbitan oleate PEG-20 sorbitan N cocoate Sorbeth-2 cocoate PEG-40 sorbitan O O O O lanolate PEG-75 sorbitan lanolate Sorbeth-2 beeswax Sorbeth-6 N O O O O beeswax Sorbeth-8 beeswax Sorbeth-20 ON O O O O O beeswax PEG-40 sorbitan diisostearate N

ADME Polysorbate Data Profile for June, 2015. Writer - Lillian Becker Repeated dose Sensitizatio Acute toxicity Irritation toxicity n Phototoxicity Carcinogenicity Genotoxicity Repro/Devel toxicity Sensitization Human Sensitization Animal Dermal Irr Human Dermal Irr. Animal Ocular Irritation Inhale Dermal Oral Inhale Dermal Oral Use Log K ow Dermal Penetration PEG-4 sorbitan triisostearate PEG-20 sorbitan triisostearate PEG-160 sorbitan triisostearate PEG-3 sorbitan tristearate Sorbeth-3 tristearate Sorbeth-160 tristearate Sorbeth-450 tristearate PEG-2 sorbitan trioleate PEG-18 sorbitan trioleate Polysorbate 85 ON O O O O O O Sorbeth-20 tetraisostearate Sorbeth-30 N tetraisostearate Sorbeth-40 tetraisostearate Sorbeth-50 tetraisostearate PEG-60 sorbitan N tetrastearate Sorbeth-60 tetrastearate (PEG-60 sorbitol tetrastearate) Sorbeth-4 N tetraoleate Sorbeth-6 N tetraoleate PEG-20 Sorbitan Tetraoleate PEG-30 sorbitan N tetraoleate Sorbeth-30 N tetraoleate PEG-40 sorbitan ON tetraoleate Sorbeth-40 N tetraoleate PEG-60 sorbitan tetraoleate Sorbeth-60 N tetraoleate Sorbeth-20 pentaisostearate Sorbeth-30 pentaisostearate Sorbeth-40 pentaisostearate Sorbeth-50 pentaisostearate Sorbeth-40 pentaoleate Sorbeth-30 tetraoleate laurate (PEG-30 sorbitol tetraoleate O O O

Search Strategy - Polysorbates SciFinder Search Terms: Polysorbate 20, 9005-64-5, Polysorbate 21, Polysorbate 40, 9005-66-7, Polysorbate 60, 9005-67-8, Polysorbate 61, Polysorbate 65, 9005-71-4, Polysorbate 80, 9005-65-6, Polysorbate 81, Polysorbate 85, 9005-70-3 HITS: 9005-64-5 664; Remove patents 120; refine by index terms (toxicity, etc.) 120. 4 selected. - 9005-66-7-981; remove patents 365; refine by index terms (toxicity, etc.) 365. - 4482: remove patents 1245; refine by index terms (toxicity, etc.) 1245; English 922; Toxicity 66-2592; Remove patents 994; 9005-66-7, 9005-70-3 1044; remove patents 404; English 315; toxicity 17 hits, none useful. 9005-71-4 689; remove patents 136; English 98; 4 selected 9005-67-8 7818; 4779; remove patents 1428; English 1001; toxicity 70 hits; 4 selected 9005-65-6 33,579; 24,295; remove patents 9947; English 7337; toxicity 576; 1990 486; Index term toxicity 64; 4 selected Search Terms: PEG-2 Sorbitan lsostearate, PEG-5 Sorbitan lsostearate, PEG-20 Sorbitan Isostearate, PEG-40 Sorbitan Lanolate, PEG-75 Sorbitan Lanolate, PEG-10 Sorbitan Laurate, PEG- 40 Sorbitan Laurate, PEG-44 Sorbitan Laurate, PEG-75 Sorbitan Laurate, PEG-80 Sorbitan Laurate HITS: -Substance Identifier "PEG-20 Sorbitan Cocoate; PEG-4... - 12412; remove patents 4524; refine by index term toxicity - 225-4524 remove patents, English 3741; toxicity 276; Index term toxicity 276; 8 selected. Search Terms: PEG-3 Sorbitan Oleate, PEG-6 Sorbitan Oleate, PEG-20 Sorbitan Oleate, PEG-40 Sorbitan Oleate, PEG-80 Sorbitan Palmitate, PEG-40 Sorbitan Perisostearate, PEG-40 Sorbitan Peroleate, PEG-3 Sorbitan Stearate, PEG-6 Sorbitan Stearate, PEG-40 Sorbitan Stearate, PEG-60 Sorbitan Stearate -4866 hits, remove patents 1546 hits, English 1126 hits, Toxicology 49 hits - 4866- remove patents 1546 hits, refine "1980-" 1296 hits; refine "1990-" 990 hits Search Terms: PEG-30 Sorbitan Tetraoleate, PEG-40 Sorbitan Tetraoleate, PEG-60 Sorbitan Tetraoleate, PEG-60 Sorbitan Tetrastearate, PEG-4 Sorbitan Triisostearate, PEG-20 Sorbitan Triisostearate, PEG-160 Sorbitan Triisostearate, PEG-2 Sorbitan Trioleate, PEG-18 Sorbitan Trioleate, PEG-3 Sorbitan Tristearate 49 hits all patents except CIR report.

Search Terms: Sorbeth-2 Beeswax, Sorbeth-6 Beeswax, Sorbeth-8 Beeswax, Sorbeth-20 Beeswax. Sorbeth-2 Cocoate, Sorbeth-2 Hexacaprylate/Caprate, Sorbeth-12 Hexacocoate, Sorbeth-2 Hexaisostearate, Sorbeth-2 Hexalaurate, Sorbeth-2 Hexaoleate, Sorbeth-40 Hexaoleate (PEG-40 Sorbitol Hexaoleate), Sorbeth-50 Hexaoleate (PEG-50 Sorbitol Hexaoleate), Sorbeth-6 Hexastearate, Sorbeth-150 Hexastearate 3 hits. Not useful Search Terms: Sorbeth-3 Isostearate, Sorbeth-6 Laurate, Sorbeth-2/Oleate/Dimer Dilinoleate Crosspolymer, Sorbeth-20 Pentaisostearate, Sorbeth-30 Pentaisostearate, Sorbeth-40 Pentaisostearate, Sorbeth-50 Pentaisostearate, Sorbeth-40 Pentaoleate, Sorbeth-20 Tetraisostearate, Sorbeth-30 Tetraisostearate, Sorbeth-40 Tetraisostearate, Sorbeth-50 Tetraisostearate, Sorbeth-4 Tetraoleate, Sorbeth-6 Tetraoleate, Sorbeth-30 Tetraoleate, Sorbeth-40 Tetraoleate, Sorbeth-60 Tetraoleate, Sorbeth-30 Tetraoleate Laurate (PEG-30 Sorbitol Tetraoleate Laurate), Sorbeth-60 Tetrastearate (PEG-60 Sorbitol Tetrastearate), Sorbeth-3 Tristearate, Sorbeth- 160 Tristearate, Sorbeth-450 Tristearate 16 hits, none useful. 90 total selections when duplicates removed. ECHA CAS Nos and INCI names. 3 hits.

Transcripts Polysorbates March, 2015 Dr. Marks Team DR. MARKS: Next ingredient is the polysorbates. This is a rereview, and the previous polysorbates, 20, 21, 40, 60, 61, 65, 80, 81 and 85 and 1984 were found to be safe. It's being proposed that we add two other reports in which the conclusions of these polysorbates were safe and additionally add polysorbate ingredients that have been identified and not been previously reported so that we would have a total of 79 ingredients. I think if it's just a rereview and we do not reopen it, the addition of these other ingredients would have to be no-brainers, otherwise we would need to reopen it. These are surfactants. We would actually have to change the conclusion, I think, if we end up, say, formulate to be nonirritating, which we've done in the past. With that kind of background, Tom, Ron, and Ron, what's your sense of where we should go with this rereview? If we look on page 22, Lillian outlines the ingredients that were previously reviewed in 84 and found safe and then in 2000 and in these new ones, and then 2001 there are three more, and then if we go on page 23 we see 35 more ingredients that have been added. It seems to me we have to reopen it if we're going to add all this, but that's -- I'm not sure we can say these are no-brainers. If we're combining reports and are going to be -- even if we're changing the conclusions a little bit, we still have to reopen. Tom, Rons, reopen? DR. SHANK: I agree to reopen to change the conclusion to remove the caveat about damaged skin and reopen in order to add the other ingredients. DR. SLAGA: I agree too. DR. MARKS: Ron Hill? DR. HILL: Actually the biggest issue I identified was the dictionary descriptions of some of these because if you look at the sorbeths, those appear to actually be sorbitol esters. Then there's some other cases where the esters are actually sorbetan, which is a mixture of compounds and esters of those, but then the dictionary description describes them as sorbitol or then they say sorbitan, but then over in the description it's sorbitol without clarifying in any way that what's going on is under the conditions where you make the esters and PEGylate them. There's actually thermal rearrangements and dehydrations going on. Other than that and the question about mixing low molecular weight sorbitans with low molecular weight PEGeths, I think it's still a good group. I think we need to reopen, and I don't think the conclusions are actually going to change in regard to any of them. DR. MARKS: Actually Ron Shank just mentioned one. Why do you remove that at this point? But go ahead, Ron. Why would you remove the damaged skin? DR. SHANK: My understanding is we put that caveat in in response to the review of the pigs [PEGS?] applied to burned tissue. We now know that that's not appropriate for considering cosmetic use. With the pig [PEG?] report, I don't remember which one we removed that. DR. MARKS: Right. DR. SHANK: We said we should remove it from the other pig [PEG?] derivative reports that have the same caveat. DR. MARKS: Yeah. Okay, yes. MS. BECKER: The paragraph explaining that's on PDF page 22 under the sorbeth beeswaxes. DR. MARKS: Okay. Obviously the ones that have been reviewed and found safe, I don't think we have to discuss them as putting them together in one report. Is there anything in the 35 new ingredients that there are concerns? I didn't hear that. That's --

DR. EISENMANN: I have one. That one crosspolymer, does it belong? I mean -- DR. MARKS: This is page 23. DR. EISENMANN: -- it's big, it's (inaudible), but it doesn't really fit the same pattern as the other ingredients, but it's up to you. DR. MARKS: Obviously that's why I asked. Carol, you don't like the sorbeth 2 olyate dimir dilynlate crosspolymer? [ Sorbeth-2/Oleate/Dimer Dilinoleate Crosspolymer] You would eliminate that? DR. EISENMANN: Correct. It's probably safe, but we are going to need information on it and it doesn't necessarily fit the pattern of the other ones. DR. HILL: I had that flag, but I didn't have it in my cheat notes here. But I think the way I had it flagged was to say I can see arguments for keeping it in. Are we going to create an orphan that'll never, ever get reviewed if we leave it out in this particular case? I don't know if we should care about that. DR. MARKS: Ron Shank, Tom? DR. SLAGA: I didn't have any problem leaving it in, but I see your point. The data that we have in here, the new data, doesn't change anything. DR. MARKS: Repeat that Carol: Why did you want it eliminated? Because actually we don't eliminate it for lack of toxicity. It's more 'does it fit into this class of compounds,' so -- DR. EISENMANN: Correct. DR. MARKS: -- if it were no-brainer, we would eliminate it, but you don't feel it chemically -- do we need Bart here to -- Lillian, you want to speak for him? Did Bart all these? DR. BECKER: Yes, this is Bart's group. I don't know why he decided this was included. DR. HILL: I didn't see it as being totally unreasonable to include. It is dissimilar in terms of structure from the others, but not so far off the map that it's unreasonable. I wouldn't take issue with Bart including it. DR. MARKS: You could do Read Across with that. DR. HILL: I think so, although we have no data on it. DR. MARKS: Yeah, that's why I asked. DR. HILL: That thing's not in use. Isn't that one that's not -- DR. EISENMANN: It's probably not in use, and because this is the rereview, I don't contact suppliers, so you wouldn't expect to get any information on it. I just didn't know that it -- I mean, it's different. That's -- you know. DR. HILL: We could leave it in and make it insufficient then if anybody ever wanted to use it (inaudible). (Laughter) DR. MARKS: That's exactly in the discussion. DR. EISENMANN: In a rereview, you don't add ingredients unless the other ingredients support the safety of them. If the current ingredients support the safety of this ingredient, which you know nothing about really -- DR. MARKS: Carol, I take a little different tact is that if we do not reopen it, it's a rereview without reopening then it has to be no-brainers. But we've decided we're going to reopen this, so everything's on the table now as if it were a new report. DR. EISENMANN: No, you -- DR. MARKS: Is that incorrect? DR. EISENMANN: I don't see it that way because I usually don't go back to suppliers. You still reopen and add the things that are related. The data in the current report should support the safety of the additions. If the data in the report still support the safety of this ingredient, then that's fine. But if it doesn't, you shouldn't open and have an insufficient ingredient. DR. MARKS: No, I'd say we wouldn't reopen and just not include those ingredients.

That's the key. But any rate, Tom, Ron, and Ron, Ron Shank? You want to comment on that? Maybe my approach is not yours, but to me if we reopen it then whatever structurally, chemically is similar you can put in the report. DR. BECKER: Just to point out in table 1 with all the descriptions, Bart also put the ingredients in subgroups and the sorbeth to crosspolymer is in its own group by itself. DR. GILL: We've talked about another ingredient where the committee discussed reopening but not including the ingredients that worked similar or were no-brainers. Since this is a reopen, if you feel that it is different, so different it shouldn't be included, then you just don't include it. We would make it insufficient. DR. HILL: From my chemical point-of-view on this, I'm sitting here thinking might we be able to find a patent that gives some sense of how big this polymer is because on the flip side, anything from the toxicology end, if there was anything, would in fact fit this grouping very well. Anything that might happen to this, if it did, would fit with this grouping very nicely, and I think we could add it to the conclusion. If we had some sense it's 50,000 molecular weight or it's 900. Since we're not contacting a supplier, because I don't know that anybody's supplying it because it's not in use, the only source of information we probably would have is either the company that was making it, if we could find out who that was, or a patent describing this particular material. We don't usually do that, but -- and I see Dr. Gill shaking her head. DR. MARKS: We're spending a lot of time on this one ingredient, which is appropriate. Tom, include or exclude? I heard it was fine to include, but Tom? DR. SLAGA: I said if was fine. DR. MARKS: Fine. Ron? DR. SHANK: If we include it and then ask for more data on that, that is not consistent with our pattern of adding compounds in the rereview. If you need more data on this crosspolymer, I would take it off of the list of those to be added. DR. MARKS: Do you need more data, Ron Shank? DR. SHANK: I don't. DR. MARKS: You don't? DR. SHANK: I don't. Dr. Hill does. DR. MARKS: You don't. DR. HILL: I guess needing some sense of the molecular weight is more data, right? But if we're actually reopening it that's different than a rereview, but we're not reopening it. We just had that discussion. DR. MARKS: We reopen. We change at least the one conclusion, and we're going to leave that ingredient in for the time being, the polymer. We'll see what the Belsito team says tomorrow. I don't think it'll be difficult to arrive at a consensus if it's different. Conclusion: Safe, nonirritating, issue a tentative report, tentative final? DR. SHANK: Yes. DR. HILL: Yes. DR. SLAGA: Yes. DR. HILL: The other thing I wanted to bring to everybody's attention is, that unlike some of the groups where the -20, -80, like that actually correlate to polymer number, there are a number of these ingredients that just seem to be random, -81, -160, whatever, that they don't correspond in some of those cases with molecular size, so just something to note. DR. WEINTRAUB: I just have a question. Something I noted in my review was that PEG 8 and 50, I believe it is, enhanced activity of known carcinogens. I was wondering how the Panel is addressing that information? That was the albuterol specifically. DR. HILL: I think we've had extensive discussions about the things that are general tumor promoting before and come to the conclusion that there's no slick way to deal with that in most

cases unless it's something like a phorbol ester, but that's just my sense of where we've landed to date. DR. SLAGA: The important thing is if there's a carcinogen in this mixture then do you have that potential to enhance it, but we have in this case, unless there's mixtures of other cosmetics on the same time, I don't see a problem with that. It wouldn't enhance anything in this particular group. DR. MARKS: Does that answer your question, Rachel? DR. WEINTRAUB: No, because how do we know that it is mixed with? Now, are you saying the assumption that it wouldn't be mixed with these known carcinogens? DR. SLAGA: Yeah. If this is added to some cosmetic at one time, there has to be a carcinogen to enhance it, we wouldn't allow that, right? DR. SADRIEH: Like formaldehyde? DR. MARKS: Does that make sense? We don't consider cosmetic ingredients that are carcinogens to be safe in a personal care product. Hence even if this were to enhance a carcinogen it'll be in the discussion and in the data, but it wouldn't be an issue because we don't feel these -- that would not be included. I don't know if that is helpful? DR. SADRIEH: Formaldehyde is a carcinogen. DR. MARKS: Tom, you want to address that? DR. SLAGA: There's no formaldehyde in here, is there? DR. SADRIEH: There's formaldehyde in cosmetics. DR. HILL: Only nail polish. DR. SADRIEH: And hair straightening s. DR. HILL: But we concluded unsafe for hair straightening s. DR. WEINTRAUB: Yeah, but it's still in the product. DR. HILL: There are coal tar hair dyes that fall under the exception that -- DR. WEINTRAUB: Right, so that -- DR. HILL: -- I think, have known potential carcinogens. DR. WEINTRAUB: Right, and that's what I was thinking. I was thinking of coal tar. DR. MARKS: Is that in the discussion emphasized? Because the point you make, Rachel, could be addressed by emphasizing that in the discussion. That's a good point you have. What do you think, Tom? DR. SLAGA: That's usually emphasized in the discussion. DR. MARKS: Do you want to bring that up tomorrow, Tom, just so it's addressed. DR. SLAGA: Yeah. DR. MARKS: Under write editorial comments. Rachel, does that seem reasonable to you? DR. WEINTRAUB: I think it's reasonable. DR. MARKS: Okay. Lillian, do you have that? MS. BECKER: I was checking to see if it's in hair products. The polysorbate 80 is definitely in hair coloring products, so I got that part. And exactly what phrasing would you want included in that discussion or is there a keyword you want in there, please? DR. HILL: Which ones were the ones identified as the problem children in terms of promotion capability and where is that -- I was trying to remind -- MS. BECKER: Table 10. DR. HILL: Table 10. DR. MARKS: Do you want Dr. Slaga to give you that wording by tomorrow? MS. BECKER: Sure. DR. MARKS: Unless you can do a write-off. He'll do it offline and then bring that up tomorrow.

DR. HILL: I was trying to remember if the 50 and the 80 actually have any correlation in that particular group because, like I say, some of these numbers seem to be just random ingredient numbers and no relation to size. DR. MARKS: Carcinogen promotion, is that what the issue is? MS. BECKER: She's talking about (inaudible) dermal penetration, enhancement of carcinogenesis (inaudible). DR. HILL: I probably shouldn't have said promotion. I don't know what the right word is, but -- DR. WEINTRAUB: Table 10 is a penetration enhancement setting, and albuterol is penetration enhancement, not carcinogenesis -- nothing under carcinogenesis on that and -- DR. HILL: -- is where it comes up probably. Sorbates enhance the activity of known chemical carcinogens. 'Enhance' means nothing, right? It's technically so imprecise. I mean -- does it mean promotion? Does it mean growth rate of tumors that are already formed? What does it mean? DR. MARKS: What page again was that on PDF? Twenty -- DR. HILL: Twenty-three, but then the discussion in the transcript was back a few pages because that's way back to, what, 1984 or was it the 2000 report? DR. MARKS: Tomorrow, even though I won't be the one, I believe, making the motion, if the Belsito team doesn't comment about this I will bring it up as an editorial comment. Tom, I'll ask you to -- DR. HILL: It's the 2000 report where this was discussed. DR. MARKS: -- discuss it, and we'll handle it in the discussion. Yes. DR. HILL: It's a 2000 report where this was actually discussed for, so maybe there's further -- I didn't pay that much attention to it, honestly. We'll look at that report and see what's discussed in there. DR. MARKS: Tom's going to clarify this and then get together with Lillian and then word the editorial change for the discussion to emphasize that concern. DR. WEINTRAUB: But what about the fact that these two ingredients do appear to be -- or at least from what I can tell quickly, at least 80 or at least one of them appears to be in hair coloring products? How doe the Panel deal with that? DR. HILL: I'm going to have to read Sivak and Goyer. DR. SLAGA: Coal tar's been grandfathered into the hair dye, the -- DR. BERGFIELD: (inaudible) considered rinse offs. DR. SLAGA: Yeah. DR. WEINTRAUB: It's grandfathered in, but it's still a carcinogen. DR. BERGFIELD: But they're considered rinse off as well, temporary exposure. DR. SLAGA: Exposure (inaudible) on that. DR. MARKS: I think what we'll do is we'll give time for Tom to think about it. We'll bring it up tomorrow, and then we'll have a robust discussion tomorrow to try and handle this. It'll also give Ron and Ron time to think about it also. But I think it's a very good point you bring, Rachel, because now this is a carcinogen enhancer, and now we put it in with known carcinogens like coal hair dye and -- DR. EISENMANN: The hair dyes currently in use are not carcinogens. DR. SLAGA: Right. DR. MARKS: Are not? Oh. DR. EISENMANN: Coal tar hair dyes is a class of compounds. DR. SLAGA: Right. DR. EISENMANN: They were originally made from coal tar, but they're not necessarily made that way anymore. The bad actors, for the most part, have been removed from the market. There still may be a few that come up positive in some genotoxicity test, but for the most part

they're not positive in mammalian studies anymore. I don't think we should be characterizing all hair dye ingredients as carcinogens because that's just not true. DR. WEINTRAUB: That's not what I said. I just said those with -- that would happen to contain coal tar. DR. EISENMANN: No, hair dyes don't really contain coal tar. It's a term that's not of a class of ingredients. Coal tar is not in hair dyes. DR. MARKS: For me, that caveat is really important to capture in the editorial comments, perhaps, to go that specific and say when you bring it up the ingredients are not carcinogens in the hair dyes. DR. SLAGA: Now if you took a carcinogen that we know can affect the skin, not just taking benzopyrene, in a high amount that definitely this would have some effect. I agree with you; the coal tar statement should be completely changed, but everything's been so grandfathered in and even the way it's processed now as well as being exposed to the hair of the skin on the scalp, it's a very short time. I don't think there is a real problem. If you left it on the skin, benzopyrene, for a long time with this, sure, you would probably get enhancement. DR. HILL: The Sivak and Goyer appears to be a submission by CTFA of unpublished comments in response to the CIR tentative report on polysorbates back in 1983, so I guess I can't go out and find that reference. Would it be possible include language in the discussion because this issue was raised something to the effect of formulators should not include ingredients of this class along with compounds with known genotoxicity or mutagenicity activity or something like that? I don't -- DR. FIUME: PDF page 124 is from the original report, and it also talked about this issue and concentration range and what the Panel thought at that point -- that can be used as a starting point with the discussion as well. DR. BERGFIELD: Are you going to open or not open this ingredient? (Laughter) DR. MARKS: What page number is that? DR. FIUME: PDF 124. DR. MARKS: One-twenty-four. DR. BERGFIELD: It's in a previous report. DR. MARKS: One-twenty-four. Yes, we reopen and with a tentative final safe nonirritating, and then we're going to have discussion whether or not we include that sorbeth 2 olyate dimir dilynlate Crosspolymer [Sorbeth-2/Oleate/Dimer Dilinoleate Crosspolymer], and then we'll have the editorial comment concerning carcinogen enhancement. Yes, reopen. Thank you. (Laughter) I thought I had stated that a while ago, but then Rachel brought up the important point of this issue with carcinogen enhancement, which I think obviously needs to be addressed. Any other comments? If not, it's lunch. DR. BERGFIELD: Yes, I would like to make a comment. I think that for us to put in a discussion that it shouldn't be put with a genotoxic or blah, blah, blah ingredient -- DR. HILL: I was BSing. (Laughter) DR. BERGFIELD: -- would be a horrible -- DR. HILL: I'm BSing. I was BSing. DR. BERGFIELD: -- a horrible statement. DR. HILL: I think I was trying to prove the ridiculousness of anything we could put there by -- DR. SLAGA: It should be very mild. DR. MARKS: Yeah. I remember I -- Tom is going to meet with Lillian and word. Okay. It's 12:02. Usually my Panel members accuse me of disregarding the clock. Do you want to break for lunch or should we move on to the next one? (Laughter) DR. SLAGA: Can we leave to go to the bathroom?

(Laughter) DR. MARKS: Okay. I think we'll break for lunch, and we'll reconvene at 1:00, which probably means 1:05 or something, but we will reconvene at 1:00. Dr. Belsito s Team DR. BELSITO: Okay, polysorbates? DR. LIEBLER: Yes. DR. BELSITO: Okay. This is a re-review of polysorbates and other fatty esters of polyethoxylated sorbitol. Safety assessments, so the reports were '84, 2000, 2001, with conclusions, the ingredients were safe as used in cosmetics, and we've added 35 polysorbates that had previously not been reviewed. The ingredients are surfactants. And there are some studies showing penetration, or suggesting penetration enhancement for some of the polysorbates, mainly 20, 65 and 80. The frequency of use has increased significantly, highest use for sorbeth, polysorbate 21 at about almost 2,900; with an increase from 770. Use concentration went up for some but down for others, the highest use to 19.6 percent, for polysorbate 20, but increased to 25.6 for polysorbate 81 in a rinse off, so high number of increase. So, anyway, we reopened and we are adding this group. I said safe as used, but do we include all the add- ons, then discussion, penetration enhancement, impurities, ethyleneoxide, dioxide, and it says, before, irritancy at some of the reported use concentration, so should we add when formulated not to be irritating? DR. LIEBLER: Okay. It's also okay to reopen and add the other ingredients, but I think I'm okay with the polysorbates, and sorbeths, but the beeswax derivatives I'm not sure about, because I'm not entirely sure about the composition of the beeswax part of the ingredients in this context, because beeswax are basically really long chain, fatty esters, but there's other stuff in beeswax. And so I don't know if there's a sub -- fraction of beeswax that's used to make these sorbeth derivatives, and if that's the case, then I'm good with it, but if it ends up being mixtures of the polysorbates with other beeswax stuff, then maybe I'm not as good with it, so it depends on the composition. MS. BECKER: And I'm looking in the original report; beeswax complex mixtures, several chemical entities. DR. BELSITO: But we issued a safe as used for the beeswax. MS. BECKER: Yes. DR. LIEBLER: You did. And maybe I didn't review the beeswax. DR. BELSITO: There is no new beeswax that are added, are there? MS. BECKER: There is one. DR. LIEBLER: There was a beeswax sorbeth in the list, wasn't there? DR. SNYDER: Well, 2001 they did sorbeth 6 beeswax, sorbeth 8 and sorbeth 20. MS. BECKER: And we are adding one more. DR. BELSITO: We are adding -- I guess the one I had a question for you, Dan, was the sorbeth-2/oleate/dimer Dilinoleate crosspolymer. MS. BECKER: PDF page 187 has the information on the beeswax, if you want to look at it. DR. LIEBLER: Okay. I'll come back to that. MS. BECKER: Okay. DR. LIEBLER: The crosspolymer, I looked at that briefly, I didn't see a problem with including that. DR. BELSITO: Okay.

DR. LIEBLER: 187? MS. BECKER: 187, yes. DR. LIEBLER: No, I didn't look at this part. I'm sorry. I should have been minding my beeswax, huh. DR. BELSITO: Oh, you are getting so persnickety. DR. LIEBLER: Okay. Yeah, I don't have a problem with it then. Include them all. Yeah. MS. BECKER: Okay. DR. BELSITO: Okay. So safe as used, an in the discussion penetration enhancement, the usual ethylene oxide, dioxane impurities as before, and the conclusion safe as used when formulated not to be irritating, to cover some of the irritation data. DR. SNYDER: And so that -- penetration enhancement, what's the enhancement ratio? What's the relevant enhancement ratio? I'm not familiar with it. DR. BELSITO: I'm not sure we know. We just -- whenever it can enhance we just point that out. DR. SNYDER: It's albuterol, so is that for inhalation or something? DR. BELSITO: Yeah. DR. SNYDER: And is it relevant to us, do you know? DR. BELSITO: Well, I mean, our modus operandi has always been, when something shows any tendency to enhance penetration of anything, we throw it back on industry and say; and when this is included, make sure that for anything that we thought was safe because it's not absorbed, that this ingredient that's been reported to enhance penetration to caffeine, or albuterol, or indomethacin, or whatever it is, doesn't enhance penetration of that substance. So it's been sort of just a very glib response the minute we see any kind of penetration enhancement we've never looked at, because it has to be a factor of two or three or -- DR. SNYDER: That's why I asked because, you know -- DR. BELSITO: No. We've never done that. DR. SNYDER: Okay. DR. BELSITO: On page 23 of the PDF, under the summaries of previous safety assessments, there is something missing in the second paragraph. The second sentence, this is; as expected, the polysorbates are active at levels of biological structure and function from basic biochemical pathways to the cardiovascular and immune systems. Do you mean that they have affects on the cardiovascular and immune systems? I didn't understand what you were trying to say there. MS. BECKER: That's straight out of the original report. I don't mean anything by it. DR. LIEBLER: I read that, and I interpreted that that simply meant that from the pathway level to disease and physiology levels. DR. BELSITO: Okay. Then on page 24 of the PDF, and again I realize that these are historical and maybe based upon what Monice said before in the final report, if all the italics -- or Christina -- if all the italicized stuff disappears this isn't important, but the whole issue of PEGs on damaged skin, is that going to appear in this report? DR. SNYDER: No. MS. BECKER: No. DR. BELSITO: So all the italicized stuff will go away? MS. BECKER: Right. In the introduction there is a paragraph on it, under -- DR. BELSITO: Right. Yeah. I saw that but -- MS. BECKER: And that will be what's there, and plus we put in the discussion. DR. BELSITO: Right. Okay. So that whole thing on PDF page 24, about PEGs were readily absorbed by through damaged skin will never appear in this report?

MS. BECKER: Correct; after the final version. DR. BELSITO: Right. Okay. So then, all of these comments and the italicize will go away. Okay, so on page 30 of the -- PDF 30 under genotoxicity in vitro. This says; when polysorbate 20-treated A549 cells were analyzed, yadi- yadi-yada; almost all of the treated cells were in early and late stages of apoptosis after 24 hours. Only A549 cells were used in this assay. And I just said, team, what do make of this? Is this a cell membrane effect? Is it relevant to cosmetic use? Are you with me? DR. SNYDER: Yeah. I am. MS. BECKER: You are in the in vitro study, polysorbate 20? DR. BELSITO: Yeah. MS. BECKER: Yes. That's one paper that did all of these, to come to the single conclusion. DR. BELSITO: Yeah. I mean I just personally, reading it I didn't know if it was anything important or not, I'm just posing it. DR. SNYDER: Is that a (inaudible)? DR. BELSITO: Yeah -- it's a membrane effect. DR. LIEBLER: No it's not -- DR. BELSITO: Right. DR. LIEBLER: I think it's -- I interpret that as being it's hard to do the assay, because there is so much toxicity. DR. BELSITO: That's what I interpret it, but I wanted some expert opinion. DR. LIEBLER: Right. DR. BELSITO: Okay. And when formulated to be nonirritating comes from the 30 days skin painting of polysorbate 60 in rabbits, where there was moderate irritation at 5 percent. I quite honestly, I don't really think they are irritating. I'd have no problems if people wanted to take when formulated, not to be irritating out of the conclusion, but I thought it didn't hurt. I mean, you've got polysorbate 81 up to 100 percent now causing ocular irritation, but? DR. LIEBLER: Yeah. You have more studies that are non-irritating, but one. DR. BELSITO: Right. That's just that one. So I threw in, when formulated to be non-irritating, to cover that study, but I'm really not that concerned, and if people felt strongly that it should be safe as used, I'm fine with that too. DR. LIEBLER: Or one where we say our default is - - it's not this specified irritations and conclusion. The other team feels very strongly that's a point we can give on. DR. BELSITO: Do you know what they say? MS. BECKER: I'm paging back. DR. BELSITO: I'm following one, insufficient. DR. SNYDER: You are presenting this one. MS. BECKER: Yes, non-irritating. DR. BELSITO: They didn't do no-irritating. MS. BECKER: Yes. DR. BELSITO: So let's stay with non-irritating, we don't need to fight over that. I mean, I don't think they are going to be irritating, but you know, then we don't have to defend that one study. And say well, you know, expert opinion, and then people will say, well there is a study, then maybe you are not such an expert. DR. LIEBLER: You need to save up stuff that you are going to give them in the meeting tomorrow. DR. BELSITO: What? DR. LIEBLER: You need to save chips, you are going to give them back them in the meeting tomorrow.

DR. BELSITO: Yeah, well. Yeah, we'll go with non-irritating. Okay. Anything else with these? MS. BECKER: They discussed our carcinogenicity promotion from the 1984 report. Is anybody concerned about? DR. BELSITO: No. I wasn't. DR. SNYDER: I didn't tag it, so I don't know if we'll get now that they -- I thought there was -- MS. BECKER: Page 92, if you want to look at it, on the PDF. DR. SNYDER: Under what category? MS. BECKER: Tumor enhancement, or is that the -- DR. BELSITO: It's from the -- DR. BELSITO: Actually not from tumor enhancement -- it's the next one down. You have 92, and then Table 93 on page 23. DR. BELSITO: Table 11, Paul, of the -- DR. SNYDER: Re-review? DR. BELSITO: Of the original, the safety report on polysorbates, the original safety assessment. You've got to go way down, it's a part of -- DR. SNYDER: If that is the Word, I didn't have it there. DR. BELSITO: Yeah. You didn't have the old report somewhere? DR. SNYDER: I'll have to see -- when you give me the Word-doc (inaudible) -- I have the new reports, but to go to the old -- to the PDF. DR. LIEBLER: So tumor enhancement. Is that what you are looking at? MS. BECKER: Yeah. DR. BELSITO: Search through Table 11. Just search through Table 11. Just search Table 11 in your Word document; you should come right to it. MS. BECKER: No. No. He's not going to have this, because this is all PDF -- DR. SNYDER: It's not in the Word document. MS. BECKER: -- of the Word document is only the report. DR. BELSITO: I see. MS. BECKER: Yes. So if you've got the PDF, it's page 93, if you are at the bottom of that page in the Table. DR. LIEBLER: Get your Adobe Acrobat subscription, Paul. DR. BELSITO: You know, the problem I have too, you need to show me again, is editing. All of my edits have been put in this as comments, because I can't add and delete, I can't figure out how to do that. DR. LIEBLER: No. Well you don't have capability within Adobe. It's not like a Word processing program. DR. BELSITO: Okay. DR. LIEBLER: There are some tools that you can use to cross outs, put a red line through them, I can show you that. DR. BELSITO: Yeah. Show me that. In insertions? DR. LIEBLER: Yeah. DR. BELSITO: Yeah. At one point I knew how to do it, now I've lost the ability. MS. FIUME: Well, it depends on which version of Adobe you have. DR. LIEBLER: Professional. MS. FIUME: Yeah, we don't have Pro, so we are very limited with what we can do in our document. DR. BELSITO: Oh, so when I get your documents, if I just do it off the memory stick, because I have Pro, so if I downloaded it and upgraded it, then I could do it?

MS. FIUME: No. It should open with the Pro, right, whatever is in the memory, it should open in the version you have on your computer? DR. BELSITO: Mine isn't. I can't edit. DR. LIEBLER: So I do mine in Adobe Acrobat Pro, which allows me those editing tools. If it was just Adobe Reader, which is the free -- DR. BELSITO: But you have to save the memory stick to your computer first? DR. LIEBLER: Yeah. DR. BELSITO: You see, I don't. I was working off the memory stick, and then it doesn't allow me to edit. MS. BECKER: You can open Pro -- DR. BELSITO: But if I save it, and then open it, it will open in my Pro, and then I can edit it. DR. LIEBLER: Correct. DR. BELSITO: So that's why I can edit some documents and not these. Thank you. And that's solves my problem, I think. DR. LIEBLER: Okay. DR. SNYDER: May I -- it's well discussed in the old report, I don't think there's anything new that we can pull up -- that was borne as changing our interpretation of that data. MS. BECKER: Does it need mentioning or discussing? DR. LIEBLER: I think if that all it is, that's fine, and then I would defer to Tom on that, he is the expert on this. DR. SNYDER: Yeah. I don't think there's anything. I mean, did you search tumor enhancement in the polysorbates to see if there was anything? Because, you know, there was a lot of stuff done around this window here. MS. BECKER: It did not come up with carcinogenicity, or (inaudible) star. DR. SNYDER: Yeah. I don't think there's anything new that would warrant just to change that. MS. BECKER: Okay. DR. BELSITO: Okay. Anything more on polysorbate? DR. SNYDER: No. DR. BELSITO: No. Day 2 DR. BELSITO: So this is a re-review of polysorbates and other fatty acids of polyoxyethylated sorbitol that were originally published in '84, 2000, 2001 with a conclusion that the ingredients are safe in use. And the report also has included 35 polysorbates that have not been previously reviewed. These are used as surfactants. And we thought that all of the proposed editions could be included, that we could go as safe as used when formulated to being non-irritating. Within the discussion, the fact that these are penetration enhancers, the usual, ethylene oxide, dioxin impurities and that is our motion. DR. MARKS: We second that motion. A little bit of discussion. We question whether sorbitan oleate, dimer dilinoleate, Crosspolymer [Sorbeth-2/Oleate/Dimer Dilinoleate Crosspolymer] should be included in the new ingredients. So we had a discussion about that. I'd be interested in your team's take on it. DR. BELSITO: We did also and Dan, do you want to comment? DR. LIEBLER: Although there are certainly some structural differences between that ingredient and the rest of the group, I think in terms of its chemical and physical properties use, likely lack of any sort of biological effects, I felt comfortable with it, even though it wasn't chemically the same.

DR. BERGFELD: And Ron Hill, you're shaking your head. That's a yes, you feel the same way? DR. HILL: I think that's where we landed from my end of the table yesterday. DR. BERGFELD: Thank you. We don't officially have to vote on a reopen, but we will vote. All those-- DR. MARKS: More comments. DR. BERGFELD: More comments? I'm sorry, go ahead. DR. MARKS: Yeah, and the other comment was, in the document it discusses carcinogen enhancement and Tom, do you want to take care of that in the editorial comments? We thought a discussion actually [inaudible] address that. DR. GILL [DR. SLAGA]: Lillian and I went over this on a publication that states this. To me to make a statement it enhances carcinogen is so broad, because there's many different structures in carcinogens. In the particular paper that states this, there was variable data with two carcinogens, and it was very weak. One was DMVA and the other was MM&G. They're really two different structures. But when there were repeats of that, it came out negative. So -- and then when they tried other types of carcinogens to see if there was enhancement, like methyl glantharine and benzyl tyrene, they were negative too. So we felt that it wasn't really -- it was overstated that it would enhance carcinogens. So it should be in the discussion so that there's no confusion. DR. BERGFELD: Any other comments? Yes, Ron Hill? DR. HILL: This is really a dictionary issue and not an issue for us. But the way that the descriptions are written, for some of them it traces back to the fact that when you PEGylate sorbitol, sometimes you get actual sorbitol. But then depending on the conditions used, you're making PEGeths, which is based on sorbitol, derivatized sorbitol, or you're making sorbitans, which are named differently. But the way the dictionary descriptions are doesn't make that clear. So you have a sorbitan by name and then it'll say derivatized sorbitol, something along those lines. So I flagged all of those in here because I think there is some clean up needed in the dictionary, and since there is being work done on the dictionary, there could be some closer scrutiny to avoid confusion of the nature of these ingredients, even if it's just adding a comment to the effect that under the conditions that the sorbitol is being PEGylated and depending on the conditions, we have sorbitol and sorbitan, which is actually a mixture of low molecular weight core structures, to which the PEGs and the esters are added. DR. MARKS: And then one other comment. Paul, would you in the conclusion, what you mentioned before, would you say this supersedes the 1984 report and it also supersedes those other two reports that thought polysorbates had been included? DR. SNYDER: That would be my preference. I've moved on to the next report. (laughter) DR. MARKS: Sorry, that doesn't change we're opening -- we're reopening and initialling a tentative final. But if that's the preference going forward, then we should be consistent in doing that in our conclusion. DR. SNYDER: Yeah, I mean, some of it's just my editorial finger. The report I'm looking at right now, the next one is -- we refer to our previous reports as assessments and reports. They're really final reports on safety assessments. And so we're kind of spitting those out and so I think we just need to be consistent, final report on the Safety Assessment Act published in what year. And so just -- 'cause we're getting these reports stacked one another. And so very clear about what we're talking about and what we're using as datasets, what conclusions we're superseding or changing or not changing. DR. BERGFELD: Ron Hill has a question. DR. HILL: I just also wanted to draw people's attention to -- because we're now in this report mixing substances that are named differently, at least by clear footnoting of the table. That, for