Safety Assessment of Polysorbates As Used in Cosmetics

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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.

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MEMORANDUM

To: CIR Expert Panel and Liaisons

From: 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.

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Public Comment CIR Expert Panel Re-Review Rpt Status

15 years New Data; or announce OR request since last

Re-review to 60 day public comment period Panel PRIORITY LIST Mar 2015

Are new data cause to reopen?

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 . YES NO Previously unreviewed ingredients were also added. DRAFT AMENDED DAR REPORT* Are new ingredients appropriate for inclusion/re-open? Table Table IDA TAR

Yes No

IDA Notice IDA RE-REVIEW SUMMARY DRAFT TENTATIVE Draft TAR AMENDED REPORT 60 day public comment period

Table

Tentative Amended Report Mar 2015 Issue TAR

Draft FAR DRAFT FINAL 60 day Public comment period AMENDED REPORT June 2015

Table

Table Different Conclusion

Final Amended Issue PUBLISH Report 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. Distributed for comment only -- do not cite or quote

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. Distributed for comment only -- do not cite or quote

Polysorbate Data Profile for June, 2015. Writer - Lillian Becker Repeated dose Sensitizatio ADME Acute toxicity Irritation toxicity n Use Oral Dermal Inhale Oral Dermal Ocular Animal Irr. Dermal Human Irr Dermal Animal Sensitization Human Sensitization toxicity Repro/Devel Genotoxicity Carcinogenicity Phototoxicity Penetration Dermal Log K Inhale Irritation

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 ON laurate 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 O O O O O O O O oleate 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 N diisostearate Distributed for comment only -- do not cite or quote

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 O O O tetraoleate laurate (PEG-30 sorbitol tetraoleate Distributed for comment only -- do not cite or quote

laurate) Sorbeth-2 hexalaurate Sorbeth-2 hexaisostearate PEG-40 sorbitan perisostearate Sorbeth-6 hexastearate Sorbeth-150 hexastearate Sorbeth-2 hexaoleate Sorbeth-40 hexaoleate (PEG- 40 sorbitol hexaoleate) Sorbeth-50 O O O hexaoleate (PEG- 50 sorbitol hexaoleate) PEG-40 sorbitan ON O O O peroleate Sorbeth-2 hexacaprylate/ca prate Sorbeth-12 hexacocoate Sorbeth- 2/oleate/dimer dilinoleate crosspolymer

Sorbitan N monooleate, ethoxylated Sorbitan N N N N monolaurate, ethoxylated Sorbitan N N N N monstearate, ethoxylated Sorbitan esters O O O O O O O O O O N – New data O – Data from previous reports Distributed for comment only -- do not cite or quote

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.

Distributed for comment only -- do not cite or quote

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.

Distributed for comment only -- do not cite or quote

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 -- Distributed for comment only -- do not cite or quote

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. Distributed for comment only -- do not cite or quote

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 Distributed for comment only -- do not cite or quote

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 agents. DR. HILL: But we concluded unsafe for hair straightening agents. 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. Distributed for comment only -- do not cite or quote

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 Distributed for comment only -- do not cite or quote

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 agent, 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? Distributed for comment only -- do not cite or quote

(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. Distributed for comment only -- do not cite or quote

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? Distributed for comment only -- do not cite or quote

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. Distributed for comment only -- do not cite or quote

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? Distributed for comment only -- do not cite or quote

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. Distributed for comment only -- do not cite or quote

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 Distributed for comment only -- do not cite or quote

example, polysorbate 61, where usually we see these large numbers and it's indicative of the size of the PEGol group or the PPG group. In this particular case it seems to have nothing to do with that. So as an example, the PEGeths are all named consistently in that regard. When you see a number, then that's giving you some sense of the size of it. But for the polysorbates, that's not the case. So polysorbate 61, N = 4 is the prominent molecular weight here. So that some way needs to be flagged in the table, and I actually had issues with exactly how that table is organized, which I made note of. So I just wanted to bring everybody's attention to that in the review. And also for consideration as to how that might be addressed in the dictionary, now that we've merged these reports. DR. BERGFELD: Okay. DR. HELDRETH: Yeah, a lot of times we do amend the definitions in table one and we'll put it either in italics or bracketed. Would you like to see something like that for those ones where the nomenclature is different, even though we're looking at similar types of molecules? DR. HILL: I think one thing was the exact way that the table's organized and the other thing is I made the comments here in part because I wanted to bring this to the attention of the dictionary crew, to have some scrutiny of this and make sure that, again, that that's clarified in those descriptions some time in the future. So yes, I mean, bracketed notations might be called for. And you could -- you know what or what not to do at this point. DR. BERGFELD: All right, shall we restate the motion Dr. Belsito? DR. BELSITO: Okay, so we're going with a safe as used for all of them. DR. BERGFELD: Um hum. DR. BELSITO: When formulated -- DR. MARKS: That's correct, when -- DR. BELSITO: I was moved on to the next one as well. DR. MARKS: So reopen and tentative final, safe with non-irritating conclusion. DR. BELSITO: Right. DR. BERGFELD: All right, so we'll call for the question then, if everybody's ready. Are you ready? All in favor? Unanimous. So we're moving on then, as you have all already done. Moving on to the next ingredient Dr. Marks.

Distributed for comment only -- do not cite or quote

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

ABSTRACT This is a safety assessment of 80 polysorbates as used in cosmetics. These ingredients mostly function as surfactants in cosmetics. The safety assessment combined the polysorbates reviewed in 3 former safety assessments and polysorbates that had not been assessed for safety into 1 report. The Cosmetic Ingredient Review (CIR) Expert Panel (Panel) reviewed relevant data related to these ingredients. The Panel concluded that polysorbates were safe as cosmetic ingredients in the practices of use and concentration of this safety assessment when formulated to be nonirritating. This conclusion supersedes the conclusion reached in the 3 former safety assessments.

INTRODUCTION This is a re-review of the available scientific literature and unpublished data relevant to assessing the safety of polysorbates as used in cosmetics; these ingredients mostly function as surfactants in cosmetics (Table 1). This safety assessment combines polysorbates reviewed in 3 previous safety assessments with other polysorbates that have not been reviewed by the CIR Panel into a group of 80 polyethoxylated sorbitan or sorbitol esters of fatty acids (Table 2). These ingredients have a common core structure of sorbitan or sorbitol, etherified with polyethyoxy (PEG) chains, and esterified with fatty acids. In a safety assessment published in 1984, the CIR Panel concluded that the following 9 polysorbates were safe as used:1

Polysorbate 20 Polysorbate 65 Polysorbate 21 Polysorbate 80 Polysorbate 40 Polysorbate 81 Polysorbate 60 Polysorbate 85 Polysorbate 61

Other polysorbates, which are also polyethoxylated sorbitan or sorbitol esters of fatty acids and contain a PEG moiety, have been reviewed by the CIR Panel. In 20002, a safety assessment was published with a safe as used conclusion for the following 33 PEG sorbitan/sorbitol fatty acid esters:

PEG-20 sorbitan cocoate PEG-40 sorbitan stearate PEG-40 sorbitan diisostearate PEG-60 sorbitan stearate PEG-2 sorbitan isostearate PEG-20 sorbitan tetraoleate PEG-5 sorbitan isostearate PEG-30 sorbitan tetraoleate PEG-20 sorbitan isostearate PEG-40 sorbitan tetraoleate PEG-40 sorbitan lanolate PEG-60 sorbitan tetraoleate PEG-75 sorbitan lanolate PEG-60 sorbitan tetrastearate PEG-10 sorbitan laurate PEG-20 sorbitan triisostearate PEG-40 sorbitan laurate PEG-160 sorbitan triisostearate PEG-44 sorbitan laurate PEG-18 sorbitan trioleate PEG-75 sorbitan laurate Sorbeth-40 hexaoleate (previously PEG-40 sorbitol PEG-80 sorbitan laurate hexaoleate) PEG-3 sorbitan oleate Sorbeth-50 hexaoleate (previously PEG-50 sorbitol PEG-6 sorbitan oleate hexaoleate) PEG-80 sorbitan palmitate Sorbeth-30 tetraoleate laurate (previously PEG-30 PEG-40 sorbitan perisostearate sorbitol tetraoleate laurate) PEG-40 sorbitan peroleate Sorbeth-60 tetrastearate (previously PEG-60 sorbitol PEG-3 sorbitan stearate tetrastearate) PEG-6 sorbitan stearate

There were 2 ingredients that were included in the 2000 report, but were not listed in the International Cosmetic Ingredient Dictionary and Handbook3 (Dictionary) at the time of the original review, and are not listed as cosmetic ingredients in the current Dictionary.4 One is PEG-18 sorbitan trioleate, which has 1 use listed in the Food and Drug Administration’s (FDA) Voluntary Cosmetic Registration Program (VCRP)5 and is therefore included in this safety assessment. However, PEG-20 sorbitan tetraoleate has no uses listed in the VCRP, so is not included in this safety assessment. In 20016, a safety assessment was published with a safe as used conclusion for the following sorbitan beeswaxes:

Sorbeth-6 beeswax (previously PEG-6 sorbitan beeswax) Sorbeth-8 beeswax (previously PEG-8 sorbitan beeswax) Sorbeth-20 beeswax (previously PEG-20 sorbitan beeswax)

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At the time of the safety assessment on these sorbeth beeswaxes, the Panel had recommended that cosmetic formulations that included PEGs (specifically PEG-6, PEG-20, and PEG-75) not be used on damaged skin. Since then, PEGs have been re- reviewed and the Panel has removed the caveat that PEGs should not be used on damaged skin.7 The following 35 ingredients from the Dictionary, which are also polyethoxylated sorbitan or sorbitol esters of fatty acids, are additions to this group:

PEG-20 sorbitan oleate Sorbeth-20 pentaisostearate PEG-40 sorbitan oleate Sorbeth-30 pentaisostearate PEG-4 sorbitan stearate Sorbeth-40 pentaisostearate PEG-4 sorbitan triisostearate Sorbeth-50 pentaisostearate PEG-2 sorbitan trioleate Sorbeth-40 pentaoleate PEG-3 sorbitan tristearate Sorbeth-20 tetraisostearate Sorbeth-2 beeswax Sorbeth-30 tetraisostearate Sorbeth-2 cocoate Sorbeth-40 tetraisostearate Sorbeth-2 hexacaprylate/caprate Sorbeth-50 tetraisostearate Sorbeth-12 hexacocoate Sorbeth-4 tetraoleate Sorbeth-2 hexaisostearate Sorbeth-6 tetraoleate Sorbeth-2 hexalaurate Sorbeth-30 tetraoleate Sorbeth-2 hexaoleate Sorbeth-40 tetraoleate Sorbeth-6 hexastearate Sorbeth-60 tetraoleate Sorbeth-150 hexastearate Sorbeth-3 tristearate Sorbeth-3 isostearate Sorbeth-160 tristearate Sorbeth-6 laurate Sorbeth-450 tristearate Sorbeth-2/oleate/dimer dilinoleate crosspolymer

The VCRP reported a single use for PEG-30 sorbitan beeswax, which is not listed in the Dictionary.4,5 Since there is a use reported, this ingredient is included in this safety assessment. CIR has conducted safety assessments of the acids and related chemical structure moieties of the ingredients in this safety assessment (Table 2). The Panel concluded that beeswax, coconut acid, isostearic acid, lanolin acid, oleic acid, lauric acid, myristic acid, stearic acid, and multiple stearates were safe as used.8-16 An array of alkyl esters and numerous PEGs were also assessed to be safe as used.7,17,18 Sorbitan esters have been reviewed, and safe as used conclusions were reached.19- 21 Much of the new data included in this safety assessment were found on the European Chemicals Agency (ECHA) website.22-24 The ECHA website provides robust summaries of information generated by industry, and it is those summary data that are reported in this safety assessment when ECHA is cited. Some of this data are for sorbitan monolaurate, ethoxylated, and sorbitan monostearate, ethoxylate; these 2 chemicals fit the general definition of several of the ingredients in this report with the same CAS No. (ie, polysorbate 21, PEG-10 sorbitan laurate, PEG-40 sorbitan laurate, polysorbate 20, PEG-44 sorbitan laurate, PEG-75 sorbitan laurate, and PEG-80 sorbitan laurate all have the CAS No. 9005-64-5). It is expected that data under these chemicals names are for one or some mixture of the ingredients with that CAS No and are useful for read across information.

SUMMARIES OF PREVIOUS SAFETY ASSESSMENTS Polysorbates, 1984 The Polysorbates are a series of polyoxyethylenated sorbitan esters that differ with respect to the number of polymerized oxyethylene subunits and the number and type of fatty acid moieties present.1 They are used as general purpose, hydrophilic, nonionic surfactants in a variety of cosmetic products. Some of the Polysorbates are also approved by the Food and Drug Administration for use in various pharmaceuticals and food products. Studies employing radioactive tracer techniques show that the Polysorbates are hydrolyzed by pancreatic and blood lipases; the fatty acid moiety is released to be absorbed and metabolized, whereas the polyoxyethylene sorbitan moiety is very poorly absorbed and is excreted unchanged. … Most or all of these effects can most likely be related to the surface active properties of the intact Polysorbate molecule. Polysorbate 80 was shown to be nonmutagenic in the Ames and micronucleus tests. The polysorbates have been shown in numerous studies to be noncarcinogenic when administered in a variety of ways to laboratory animals, although Polysorbate 80 produced some neoplastic changes in mixed mouse epidermal and dermal in vitro tissue culture. Multiple studies have shown that the Polysorbates enhance the activity of known chemical carcinogens while not actually being carcinogenic themselves. Proposed mechanisms of this tumor enhancement effect include induction of cellular hyperproliferation, inhibition of DNA repair, and others. The Polysorbates also exhibit tumor growth inhibition activity under certain conditions. Extensive testing for acute and long-term oral toxicity in animals has resulted in evidence indicating the low order of toxicity with oral ingestion of the Polysorbates. Most of the reported toxicity can be attributed either directly or indirectly to the osmotic diarrhea caused by the polyoxyethylene sorbitan moiety retained within the intestinal lumen. Polysorbate 20 Distributed for comment only -- do not cite or quote

and product formulations containing 1.0 to 8.4 percent of Polysorbate 20, 40, 80, or 85 produced no evidence of acute or subchronic percutaneous toxicity, the only effects being erythema, edema, and desquamation at the site of application. Acute intravenous and intraperitoneal injection of the Polysorbates into rats or mice resulted in LD50 values indicative of a low order of parenteral toxicity. Daily intravenous injections of Polysorbates 60 and 80 into rabbits for up to 65 days produced pathology limited mainly to the renal and reticuloendothelial systems. The Polysorbates showed little potential for rabbit and mouse skin irritation in acute studies. Those of the Polysorbates that were tested in subchronic skin irritation tests for up to 60 days produced local skin reactions ranging from minimal inflammation to necrosis. These changes were attributable to damage of epidermal cell membranes by the emulsifying action of the Polysorbates. The Polysorbates produced no more than minimal, transient eye irritation in Draize rabbit eye irritation tests. Polysorbate 80 produced superficial, mild damage to the intestinal mucosae of rabbits and rats. Polysorbate 20 produced no inflammation when applied to the hamster cheek pouch, and Polysorbate 40 caused no inflammation when infused into the guinea pig urinary bladder. The Magnusson-Kligman guinea pig maximization test showed moderate to strong skin sensitization to Polysorbate 20 in one study. Another guinea pig skin sensitization assay reported no evidence of skin sensitization to Polysorbates 65 and 80. The Polysorbates have been ingested by human beings in situations ranging from an accidental administration of 19.2 g of Polysorbate 80 to an infant on 2 consecutive days to daily therapeutic administration of up to 6.0 g of Polysorbate 80 to adults for up to 4 years. These studies consistently showed little or no adverse effects from oral ingestion of the Polysorbates. Extensive clinical skin testing in the Schwartz prophetic patch test showed little potential for human skin irritation and no evidence of skin sensitization in a total of 580 subjects. A total of 1206 patients with eczema were tested in a chamber method 24-hour occlusive patch test for allergic contact dermatitis to a mixture of 5 percent Polysorbate 60 and 5 percent Polysorbate 80 in petrolatum; allergic reactions were shown by only 2 of the patients (< 0.2 percent). Several product formulations containing the Polysorbates have been tested for human skin sensitization on a total of 3481 subjects using a variety of testing methods; there were no reactions indicative of sensitization to any of the Polysorbates in these assays. Investigations with patients known to have skin disease revealed isolated instances of skin sensitization to Polysorbate 40 or 80. Intravenous injection of Polysorbate 80 produced hemodynamic changes in 5 patients. Studies involving exposure to ultraviolet light showed no instance of photocontact sensitization to the Polysorbates, although there were isolated instances of mild irritation following UV exposure when testing product formulations containing the Polysorbates.

PEGs Sorbitan/Sorbitol Fatty Acid Esters 2000 The PEGs Sorbitan/Sorbitol Fatty Acid Esters are ethoxylated sorbitan and sorbitol esters of fatty acids that function as surfactants in cosmetic formulations.2 These ingredients were used in a total of 81 cosmetic formulations in 1998. The Polysorbates, which are food additives, were used in 1418 formulations. They are formed by the esterification of sorbitol or sorbitan with a fatty acid, followed by the chemical addition of ethylene oxide. Typical impurities can include the free fatty acids, alcohol, peroxides, isosorbide ethoxylates, and other compounds; 1,4-dioxane and other water-soluble by- products are removed during the manufacturing process. Few data on the ingredients in this review were available; therefore, relevant data from the previous CIR safety assessments on the Polysorbates (other PEGs Sorbitan Fatty Acid Ester), PEGs, and Sorbitan Esters were included in this report as a further basis for assessing their safety in cosmetics. During feeding studies, the Polysorbates were absorbed and hydrolyzed by blood and pancreatic lipases. The fatty acid moiety was absorbed and metabolized as any other dietary fatty acid, and the PEG Sorbitan moiety was excreted mainly in the urine. The gastrointestinal absorption of PEGs was dependent on the molecular weight; the greater the molecular weight, the lesser the absorption that occurs. In oral and IV studies, the PEGs were not metabolized and were rapidly eliminated in the feces and urine. PEGs were readily absorbed through damaged skin. A number of cytotoxicity assays has been performed on the Polysorbates; they caused both membrane damage and reduced mitochondrial activity. A concentration of 5% PEG-20 Sorbitan Oleate in rats caused the "destruction" of the mitochondria of the epithelium of the small intestine of Wistar rats. The Polysorbate (concentration= 10%) caused a portion of the microvilli to disappear with flattening of the surfaces of the epithelial cells. PEG-20 Sorbitan Oleate had immunosuppressive effects in Balb/c mice that had been immunized with ovalbumin. PEG-20 Sorbitan Oleate was also a histamine-releasing agent, and increased recruitment of peritoneal macrophages without modifying phagocytic activity. PEG-20 Sorbitan Oleate (100 mg/ml) depressed cardiac potential in dogs and guinea pigs; the Polysorbate reduced mean arterial blood pressure and left ventricular dP/dt. The Polysorbates had low toxicity in both acute and longterm toxicity studies using animals. In rats, the LD50 values for these ingredients were >5 to >38.9 g/kg (oral), ~1.4 g/kg (IV), and 0.7 to >5 ml/kg (IP). When administered to rats by IP injection, 16% PEG-20 Sorbitan Laurate and 32% PEG-20 Sorbitan Oleate decreased locomotor activity. During an inhalation toxicity study, PEG-20 Sorbitan Oleate (7%; 0.1 to 0.2 ml) was relatively nontoxic. The Sorbitan Esters and PEGs also were relatively nontoxic to animals. During a 14-day feeding study of 3000 to 50,000 ppm PEG-20 Sorbitan Oleate, the high dose caused decreased body weight in male rats and mice, but no other clinical findings were reported. A vehicle containing 9% PEG-20 Sorbitan Oleate and 1% PEG-20 Sorbitan Laurate was mildly hepatotoxic to rabbits and, when given intraperitoneally, caused massive peritoneal fibrosis and degeneration of the kidneys in mice and rats. No adverse effects were observed in chicks fed Distributed for comment only -- do not cite or quote

2% to 5% PEG-20 Sorbitan Stearate for 7 weeks. Rats fed 10% of the Polysorbate for 8 weeks had diarrhea for the first few days of treatment, but no other signs of toxicity. Rats fed 1.5 ml PEG-20 Sorbitan Oleate (1%-4%) for 3 months had congestive and degenerative changes in the heart, liver, and kidneys. In 6-week studies using rats and monkeys, PEG-4 Sorbitan Stearate, PEG-20 Sorbitan Stearate, and PEG-5 Sorbitan Oleate produced no significant adverse effects. In dermal toxicity studies, the PEGs did not cause signs of toxicity other than transient, mild erythema. Evidence of systemic toxicity was only observed in rabbits that received repeated topical applications of a PEG-based cream to abraded skin. Rats fed 1% to 4% Sorbitan Laurate for 6 weeks had decreased growth rates, and hamsters fed 15% for 68 days had degenerative changes of the gastrointestinal tract, and other lesions. Similar changes were observed in rats fed 25% Sorbitan Laurate for 70 days. Rhesus monkeys fed 2 g/day had no signs of toxicity after 6 weeks of treatment. Growth retardation and diarrhea were noted in subchronic feeding studies of up to 1% PEG-20 Sorbitan Stearate using mice. Diarrhea in these and other studies was attributed to the high concentrations of the unabsorbed PEG Sorbitan moiety in the intestinal lumen. PEG-20 Sorbitan Oleate (up to 50,000 ppm) was nontoxic to rats and mice during a 13-week feed study. A concentration of 25% PEG-20 Sorbitan Laurate caused microscopic changes of the urinary bladder, spleen, kidneys, and gastrointestinal tract in rats during a 21-week study. The PEGs were nontoxic during a 90-day oral toxicity study using rats. Feeding of 10% to 25% Sorbitan Laurate for 90 days to 23 weeks caused decreased body and organ weights, diarrhea, and hepatic lesions in rats. During a chronic toxicity study using hamsters, 5% to 15% PEG-20 Sorbitan Laurate caused microscopic lesions of the urinary bladder, kidneys, spleen, and gastrointestinal tract. In monkeys, 1 g/day PEG-20 Sorbitan Laurate did not cause adverse effects after 17 months of treatment. Rats fed up to 2% PEG-20 Sorbitan Laurate for over 2 years had no signs of toxicity. PEG-20 Sorbitan Stearate, PEG-20 Sorbitan Oleate, and PEG-20 Sorbitan Tristearate at concentrations <20% were nontoxic in long-term feeding studies using mice, rats, dogs, and hamsters. At concentrations of 20%, these Polysorbates caused some growth retardation and diarrhea, and had minor effects on longevity and reproduction. Studies using 2% PEG-20 Sorbitan Palmitate and PEG-20 Sorbitan Trioleate were also negative. In chronic studies, dogs fed 2% PEG-8, PEG-32, or PEG-75 for 1 year had no adverse effects; rats fed 5% Sorbitan Laurate for 2 years had no signs of toxicity, but only 15% of the treated and control rats survived to the end of the study. The Polysorbates were nonirritating to mildly irritating in both in vivo and in vitro ocular irritation assays. The concentrations tested ranged from 1% to 100%. PEG-6 and PEG-75 did not cause corneal injuries when instilled into the conjunctival sac of rabbits, but 35% PEG-8 and 0.1 ml PEG-32 (melted in water bath) induced mild ocular irritation. Sorbitan Laurate (30%-100%) was not an ocular irritant in Draize ocular irritation tests using rabbits. The Polysorbates had little potential for rabbit and mouse skin irritation in acute studies. Moderate to strong sensitization to PEG-20 Sorbitan Laurate was observed in a Magnusson Kligman guinea pig maximization test; PEG-20 Sorbitan Oleate and PEG-20 Tristearate were not sensitizers. PEG-20 Sorbitan Laurate (1%) did not have comedogenic potential in rabbits. The Sorbitan Esters were generally mild skin irritants, but did not cause sensitization in animals. The PEGs were neither irritants nor sensitizers. In teratology studies of thalidomide, the PEG-20 Sorbitan Laurate vehicle (10 ml/kg) had no effect on the developing mouse embryo. In other studies, reproductive and developmental effects were seen primarily at exposure levels that were maternally toxic. PEG-20 Sorbitan Laurate caused dose-dependent malformations of offspring when administered to Swiss and NMRI mice via IP injections. In the Chernoff-Kavlock assay using Alpk/AP rats, 10 ml/kg/day PEG-20 Sorbitan Laurate reduced offspring litter size, survival, and weight gain when the Polysorbate was administered intraperitoneally, but the parameters did not differ from controls after dermal, oral, or subcutaneous administration. In another study using rats, PEG-20 Sorbitan Laurate had a maternal no-observable-effect level (NOEL) of 500 mg/kg/day, a maternal low effect level of 5000 mg/kg/day, and a developmental NOEL of > 5000 mg/kg/day. PEG -20 Sorbitan Laurate, PEG-20 Sorbitan Palmitate, PEG-20 Sorbitan Stearate, and PEG-20 Sorbitan Oleate caused serious developmental effects in sea urchin embryos when administered at concentrations as low as 0.004% in sea water. Mice fed 10% PEG-20 Sorbitan Stearate or PEG-20 Sorbitan Laurate during a multigeneration study had offspring with decreased weanling weights, significantly smaller litters, and delivered more dead fetuses than mice of the control group. PEG-20 Sorbitan Oleate was not teratogenic in a rat whole-embryo culture study. In in vivo studies using neonatal rats, PEG-20 Sorbitan Oleate (1%-10%, IP injection) accelerated maturation, prolonged the estrous cycle, and induced chronic estrogenic stimulation. The ovaries were without corpora lutea and had degenerative follicles, and the uterus had epithelial squamous cell metaplasia and cytological changes. PEG-20 Sorbitan Oleate (2500 mg/kg/day in one study; 1.25 ml/l drinking water in another) and PEG-20 Sorbitan Stearate (0.1%-10% in one study; 5200 mg/kg/day in another) did not cause developmental effects in rats and mice, but PEG-20 Sorbitan Oleate in drinking water increased locomotor activity and exploratory behavior of offspring of treated rats. The PEG monomer, ethylene glycol, and certain of its monoalkyl ethers are reproductive and developmental toxins. The CIR Expert Panel concluded that, as the PEGs Sorbitan and Sorbitol Esters are chemically different from the alkyl ethers of ethylene glycol and the alkyl ethers are not present as impurities, these ingredients pose no reproductive or developmental hazard. In subchronic and chronic oral toxicity studies, the PEGs did not cause adverse reproductive effects. The Polysorbates were nonmutagenic in a number of bacterial and mammalian systems, with the exception of PEG- 20 Sorbitan Stearate, which produced both positive and negative results in genotoxicity assays. In carcinogenicity studies, feeding of PEG-20 Sorbitan Oleate (up to 50,000 ppm) to rats and mice resulted in equivocal evidence of carcinogenicity; the male rats had an increased incidence of pheochromocytomas. The test compound Distributed for comment only -- do not cite or quote

was associated with inflammation and squamous hyperplasia of the nonglandular stomach in mice and with ulcers of the nonglandular stomach in female mice. PEG-20 Sorbitan Stearate did not increase the incidence of neoplasms in the nonglandular stomach and glandular stomach when administered with the carcinogens ENNG and MNNG. In general, the Polysorbates were not oral or dermal carcinogens, and were weak tumor promoters. PEG-20 Sorbitan Stearate and PEG-20 Sorbitan Oleate (0.002%) inhibited metabolic cooperation in V79 Chinese Hamster cells in vitro, which could result in tumor promotion. PEG-20 Sorbitan Stearate has been reported to have an in vivo promoter response, and the Polysorbate induced the cytoplasmic accumulation of proliferin transcripts in mouse fibroblasts; proliferin is an antagonistic regulator of muscle- specific transcription, and can promote morphological transformation. The Polysorbates also had antitumor activity in animal studies. PEG-8 was noncarcinogenic in studies using mice, rats, and guinea pigs. Sorbitan Laurate and Sorbitan Stearate were also noncarcinogenic. At concentrations ≥10%, Sorbitan Laurate was a tumor promoter in mouse skin. The Polysorbates were nontoxic by the oral route in clinical studies, but a Polysorbate vehicle (9% PEG-20 Sorbitan Oleate, 1% PEG-20 Sorbitan Laurate) for a neonatal parenteral supplement caused the deaths of 38 premature infants. The symptoms and lesions observed inc1uded pulmonary deterioration, hepatomegaly, metabolic acidosis, and renal failure. Investigators concluded that human infant membranes were more sensitive to the effects of the Polysorbates and could not efficiently metabolize the compounds. Oleic acid and PEG moieties released during in vivo hydrolysis of PEG-20 Sorbitan Oleate could have contributed to the pulmonary deterioration and renal failure, as could ethylene glycol formed from ethylene oxide moieties. The Polysorbates had little potential for human skin irritation, sensitization, and phototoxicity in extensive clinical studies. PEG-20 Sorbitan Oleate at a concentration of 100% was noncorrosive, and it and PEG-20 Sorbitan Laurate were not irritating to living skin equivalents. The PEGs were nonsensitizers, but cases of systemic toxicity and contact dermatitis were observed in burn patients that were treated with PEG-based topical ointments. The Sorbitan Esters had the potential to cause cutaneous irritation in humans, and could cause sensitization in patients with damaged skin. Sorbitan Stearate and Sorbitan Oleate were not photosensitizing; Sorbitan Laurate, Sorbitan Palmitate, Sorbitan Sesquioleate, and Sorbitan Trioleate did not absorb UVA or UVB light, suggesting that these compounds were not photosensitizers. In clinical ocular irritation studies, PEG-20 Sorbitan Laurate was nonirritating, but at a concentration of l %, it markedly increased the permeability of the corneal epithelium to fluorescein in the human eye. PEG-20 Sorbitan Oleate was classified as an ocular irritant, but further details were not available.

Sorbitan Beeswax, 2001 PEG-6, -8, and -20 Sorbitan Beeswax are ethoxylated derivatives of Beeswax that function as surfactants in cosmetic formulations.6 In 1998, PEG-20 Sorbitan Beeswax was reported used in 16 cosmetic formulations; PEG-6 and -8 Sorbitan Beeswax were not reported used. Data submitted by industry indicated that PEG-20 Sorbitan Beeswax was used at concentrations from 0.2% in make-up fixatives to 11% in blushers. In 1984, it was reported used at concentrations ≥10%. Few data were available on the PEGs Sorbitan Beeswax. Toxicology data on Beeswax, Synthetic Beeswax, Sorbitan Esters, PEGs, and Polysorbates were reviewed as a further basis for the assessment of safety. The ester link of the Polysorbate (PEG Sorbitan Fatty Acid Ester) molecule was hydrolyzed by blood and pancreatic lipases after oral administration. The fatty acid moiety was absorbed and metabolized as any other dietary fatty acid, and the PEG Sorbitan moiety was poorly absorbed from the GI tract. GI absorption of PEG was inversely related to the molecular weight of the compound. PEGs are readily absorbed through damaged skin. Sorbitan Stearate was hydrolyzed to the stearic acid and anhydrides of sorbitol, and did not accumulate in the fat stores of the rat. PEG-6 Sorbitan Beeswax was "practically nontoxic" when rats were treated with doses of 10.0 g/kg during acute IP studies. PEGs had low oral, dermal, and inhalation toxicity; greater molecular weight PEGs were less toxic than smaller molecular weight PEGs. The Polysorbates were not toxic during acute and long-term feeding studies, or during acute and short - term IV and IP injection studies. Formulations containing the Polysorbates produced no evidence of acute or subchronic percutaneous toxicity. Formulations containing up to 13% Beeswax (5 to 15 g/kg doses) were not toxic to rats. Undiluted Beeswax killed 2 of 10 rats within 2 days during an acute oral toxicity study. Ten rats fed 5 to 14.4 g/kg Synthetic Beeswax had chromorhinorrhea and chromodacryorrhea; rats fed 5 to 10.4 g/kg had diarrhea, ptosis, bulging eyes, and sniffling. Two rats died after ingestion of the high dose. The Sorbitan Esters (<10%) were relatively nontoxic via ingestion. The lowest LD50 (rats) reported was 31 g/kg Sorbitan Stearate. No adverse effects were observed when rats, mice, and dogs were fed 5% Sorbitans Laurate, Oleate, and Stearate for up to 2 years. In other studies, the feeding of 0.5%, 4%, and 10% Sorbitan Stearate to mice and rats resulted in depressed growth and renal and/or hepatic abnormalities. Undiluted PEG-6 Sorbitan Beeswax was nonirritating to the eyes of rabbits, and a 30% aqueous solution of PEG-20 Sorbitan Beeswax was minimally irritating (Draize score= 3.5/11 0). Eye makeup formulations containing 1.5% to 2.0% PEG-20 Sorbitan Beeswax were non- to minimally irritating to the eyes of rabbits. PEGs, Polysorbates, Sorbitan Esters, Beeswax, and Synthetic Beeswax were non- to mild ocular irritants. Undiluted PEG-6 Sorbitan Beeswax was nonirritating to the intact and abraded skin of rabbits. Cosmetic formulations containing 1.5% to 2.0% PEG-20 Sorbitan Beeswax were non- to minimal irritants to the skin of rabbits. The PEGs were not irritating to the skin of rabbits or guinea pigs, and PEG-75 was not a sensitizer. The Polysorbates had little potential for rabbit and mouse skin irritation during acute studies. Polysorbate 20 was a moderate to strong sensitizer in one study using guinea pigs, and Polysorbates 65 and 80 were nonsensitizers. Synthetic Beeswax (5 g in 1 ml corn oil) had Draize scores of 0 to 2.08 (out of 8.00) during primary irritation studies using rabbits. At a concentration of 50% in water, Synthetic Beeswax was nonsensitizing to guinea pigs. Sorbitan Esters (3% to 100%) were minimal to mild irritants. Distributed for comment only -- do not cite or quote

Ethylene glycol and certain of its monoalkyl ethers are reproductive and developmental toxins. As PEGs Sorbitan Beeswax are chemically different from these ethers, reproductive and developmental toxicity due to the ethers was not of concern. PEGs did not cause adverse reproductive effects during subchronic and chronic feeding studies. PEG-8 and -150 were not mutagenic in several genotoxicity assays. Polysorbate 80 was nonmutagenic in the Ames test. Sorbitan Stearate was not mutagenic in tests using bacteria, with or without metabolic activation, and did not transform hamster embryo cells in vitro. Sorbitan Oleate (0.01%) inhibited in vitro DNA repair. PEG-8 was not carcinogenic during oral, IP, or subcutaneous (SC) administration. The Polysorbates were generally noncarcinogenic, but enhanced the activity of some known chemical carcinogens. Sorbitan Stearate was not carcinogenic in mice during a feeding study, but Sorbitan Laurate was a tumor promoter during a mouse skin-painting study. Sorbitans Oleate and Trioleate were inactive as tumor promoters. In another study, undiluted Sorbitans Laurate and Trioleate were not cocarcinogens. In clinical studies, PEG-6 and -20 Sorbitan Beeswax were nonsensitizers. Formulations containing up to 3.0% PEG-20 Sorbitan Beeswax were mildly irritating and nonsensitizing during in-use, minicumulative, and RIPTs. Systemic toxicity and contact dermatitis were observed in burn patients treated with PEG-containing ointments, but PEGs were not sensitizing to normal skin. The Polysorbates and Sorbitan Esters were nontoxic after oral ingestion. Polysorbates, Beeswax, and Synthetic Beeswax did not cause irritation, sensitization, or photosensitization. The Sorbitan Esters were minimal to mild skin irritants in humans, but were nonsensitizing, nonphototoxic, and nonphotoallergenic.

CHEMISTRY Definition and Method of Manufacture The ingredients in this report (several of which are often referred to by the commercial trade name of Tween in the literature) are polyethoxylated sorbitan or sorbitol esters of fatty acids. Each ingredient has a common core structure of sorbitan or sorbitol, etherified with PEG chains, and esterified with fatty acids (Figure 1). Sorbitan is related to sorbitol as the simple dehydration product.

Figure 1. Polysorbates, sorbitan (“polysorbate-#” or “PEG-x sorbitan nomenclature) and sorbitol (“sorbeth-#” nomenclature) derivatives.

While those ingredients with the nomenclature “polysorbate-#” form sorbitan by dehydration of sorbitol during the above reactions (which is consequently ethoxylated and esterified), those ingredients herein with the nomenclature “PEG-x sorbitan fatty ester” are the product of the ethoxylation of a preformed sorbitan ester. Regardless of the nomenclature, the ingredients under these two nomenclature schemes are related as polyethoxylated sorbitan esters. The ingredients with the nomenclature “sorbeth-#” are not the product of dehydration, but are the ethoxylated and esterified products of sorbitol. While these ingredients are predominately either sorbitan derivatives or sorbitol derivatives, each may be mixtures resulting from some dehydration, isomerization, degree of ethoxylation, or degree of esterification. Accordingly, the ingredients in this report are closely related in that they have similar chemical structures and potential metabolism products (eg, via esterases know to be present in the skin). It should be noted that the number in ingredients with the nomenclature Distributed for comment only -- do not cite or quote

“polysorbate-#” has no relationship to the size of the molecule but to the associated fatty acid from which the ingredient is derived. Presented here are 2 possible routes for the synthesis of polysorbates.25 In the first, sorbitol is esterified with fatty acids or their anhydrides, which is typically performed with acid catalysis at 130-180˚C. At the temperature required for the esterification, water is eliminated from sorbitol to form 3 possible isomers of sorbitan and (with elimination of another water molecule) isosorbide. These dehydration products react with a fatty acid to form corresponding sorbitan esters. These products, which are known as “spans”, are ethoxylated to produce polysorbates. In the other common method of manufacture, sorbitol is reacted with ethylene oxide and a basic catalyst at 200- 250°C. Under these conditions, sorbitol is isomerized as above. Addition of ethylene oxide yields ethoxylated products, which are called carbowaxes, and which are subsequently esterified with fatty acids to produce oligomers of polyoxyethylene sorbitan esters (aka polysorbates).

Chemical and Physical Properties Polysorbates are amphiphilic molecules, which are fatty esters of polyoxyethylated sorbitan or sorbitol.25 The polysorbates are, for the most part, viscous liquids to waxy solids that range in color from yellow to orange to tan (Table 3).1 They possess a faint, characteristic odor and a warm, somewhat bitter taste. The reported physical and chemical properties of generic sorbitan monolaurate, ethoxylated and sorbitan monostearate, ethoxylated are provided in Table 4. Since the fatty acids used in the production of cosmetic ingredients frequently contain fatty acids other than the principal acid named (ie, a mixture), each of the polysorbates may contain a complex mixture of fatty acid moieties.1,26 Table 5 provides an example of the approximate ester content of polysorbate 20, 21, 40, 60, and 80. Polysorbate 21 is reported to be 30%-80% monoesters, <50% diesters, and <20% triesters.22 Sorbitan monolaurate is reported to be a mixture of esters of different lengths, with the highest percentage being C12, at 40%-60%.

Impurities During the manufacturing process, the polysorbates are steam-stripped to remove unwanted water-soluble by- products such as 1,4-dioxane.1 Since PEGs are the condensation products of ethylene oxide and water, with the chain length controlled by the number of moles of ethylene oxide that are polymerized, they may contain trace amounts of 1,4-dioxane, a by-product of ethoxylation. 1,4-Dioxane is a known animal carcinogen.27 The FDA has been periodically monitoring the levels of 1,4-dioxane in cosmetic products, and the cosmetic industry reported that it is aware that 1,4-dioxane may be an impurity in PEGs and, thus, uses additional purification steps to limit it in these ingredients before blending into cosmetic formulations.28,29

USE Cosmetic The Panel assesses the safety of cosmetic ingredients based on the expected use of these ingredients in cosmetics. The Panel reviews data received from the FDA and the cosmetics industry to determine the expected cosmetic use. The data received from the FDA are collected from manufacturers on the use of individual ingredients in cosmetics, by cosmetic product category, through the FDA VCRP, and the data from the cosmetic industry are submitted in response to a survey of the maximum reported use concentrations, by category, conducted by the Personal Care Products Council (Council). In 2015, the polysorbates included in this report with the highest number of uses reported were polysorbate 20 at 3013 (an increase from 770 in 1998), polysorbate 60 at 1589 (an increase from 332 in 1998), and polysorbate 80 at 932 (an increase from 231 in 1998; Table 6).1,2,5,6,14 Almost all of the previously reviewed ingredients had increases in the number of reported uses. All of the ingredients not previously reviewed had less than 15 reported uses (Tables 7). In the survey conducted by the Council in 2014 of the maximum use concentrations for ingredients in this group, the highest concentrations of use were reported for polysorbate 20 at 19.6% in bath soaps and detergents (a decrease from >50% in 1984), polysorbate 80 at 18.1% in paste masks and mud packs (a decrease from up to 25% in 1984), polysorbate 81 at 25.6% in skin cleansing products (an increase from up to 5% in 1984), and polysorbate 85 at 21.9% skin cleansing products (a decrease from >50% in 1984).1,2,30,31 The highest maximum concentration of use for leave-on products was 11.9% polysorbate 80 in perfumes. The Council is conducting a survey for PEG-4 sorbitan stearate. In the 2000 published report, the only concentration of use data that were provided was the following: “…PEG-60 sorbitan tetraoleate, PEG-40 sorbitan tetraoleate, and PEG-160 sorbitan triisostearate are used in cosmetics at concentrations of 0.5% to 10%...”.2 Since the data from the 2000 report are limited, the concentration of use data from the 1984 report were provided in Table 6 to give a better historical perspective. PEG-18 sorbitan trioleate is not listed as a cosmetic ingredient in the Dictionary.4 However, the VCRP reported 1 use in a moisturizer, which is a decrease from 10 uses reported in 1998.5 The VCRP also reported single uses for PEG-20 sorbitan laurate (used in 1 other personal cleanliness product) and PEG-20 sorbitan stearate (used in 1 night skin product).5 However, these names are not listed in the Dictionary as INCI (International Nomenclature of Cosmetic Ingredients) names or technical terms.4 The Council has reported that PEG-20 sorbitan laurate is another term for polysorbate 20 and PEG-20 sorbitan stearate is another term for polysorbate 60.32 Since it Distributed for comment only -- do not cite or quote

cannot be confirmed that the reporting companies intended to refer to polysorbate 20 and polysorbate 60, this use information on these 2 ingredients are reported separately. The 42 ingredients with no reported uses or concentrations of use are listed in Table 8. In some cases, reports of uses were received in the VCRP, but no concentration of use data were available.5,31 For example, PEG-3 sorbitan stearate was reported to be used in 3 formulations, but no use concentration data were reported. In other cases, no reported uses were received in the VCRP, however a use concentration was provided in the industry survey. For example, PEG-40 sorbitan laurate was not reported in the VCRP to be in use, but the industry survey indicated that it is used in leave-on formulations at up to 2% (skin care preparations) and rinse-off formulations up to 0.5% (shampoos and hair dyes and colors). It should be presumed that PEG-40 sorbitan laurate was used in at least 3 cosmetic formulations. Several of these polysorbate ingredients are used at concentrations up to 5.8% in cosmetic products that may be ingested, in cosmetics used around the eyes at concentrations up to 11%, or in baby products at concentrations up to 12.6%.30,31 Polysorbates were reported to be used in cosmetic sprays, including aerosol and pump hair sprays, spray deodorants, spray body and hand products, and spray moisturizing products, and could possibly be inhaled. The highest concentration of use was reported to be polysorbate 20 in spray deodorants up to 4%. In practice, 95% to 99% of the droplets/particles released from cosmetic sprays have aerodynamic equivalent diameters >10 µm, with propellant sprays yielding a greater fraction of droplets/particles below 10 µm compared with pump sprays.33-36 Therefore, most droplets/particles incidentally inhaled from cosmetic sprays would be deposited in the nasopharyngeal and bronchial regions and would not be respirable (ie, they would not enter the lungs) to any appreciable amount.33,35 There is some evidence indicating that deodorant spray products can release substantially larger fractions of particulates having aerodynamic equivalent diameters in the range considered to be respirable.33 However, the information is not sufficient to determine whether significantly greater lung exposures result from the use of deodorant sprays, compared to other cosmetic sprays. All of the polysorbates named in this report are listed in the European Union inventory of cosmetic ingredients.37

Non-Cosmetic The FDA reports that the total acceptable daily intake (ADI) for humans of all regulated polysorbates is 1500 mg/person/d.[21CFR172] The Joint Food and Agriculture Organization (FAO)/World Health Organization (WHO) Expert Committee on Food Additives (JECFA) estimated the acceptable daily intake for humans to be 0-25 mg/kg/d for total polyoxyethylene (20) sorbitan esters.38 The Science Committee on Food (SCF) issued a group ADI of 10 mg/kg/d for polysorbate 80, polyoxyethylene sorbitan mono-esters of lauric and palmitic acids and the mono- and the tri-ester of stearic acids.39 The largest food sources of polysorbates are confectionery, ices, desserts, fine bakery wares, milk analogues, emulsified sauces, chewing gums, and fat emulsions for baking.25 The polysorbates are used in the drug, food, and animal feed industries; several have been approved by the FDA as direct and indirect food additives for human consumption with certain restrictions (Table 9).

TOXICOKINETICS Following oral administration of polysorbate 20 to rats, the ester bond sites of polysorbates are hydrolyzed within the digestive tract by pancreatic lipase.24 Free fatty acids were absorbed from the digestive tract and oxidized and excreted, mainly as carbon dioxide in exhaled breath. No migration of the polyoxyethylene sorbitan into the thymus lymph nodes has been demonstrated. No sex difference has been detected in the disposition of polysorbates in rats. Following oral ingestion of polysorbate 20 in humans, 90% or more of the administered substance was excreted in the feces as metabolites, with the polyoxyethylene sorbitan structure maintained, and 2%-3% of these metabolites were excreted in the urine.24

Penetration Enhancement Polysorbate 20, polysorbate 65, and polysorbate 80 enhanced the dermal penetration of albuterol sulfate through mouse skin in assays using Franz cells (Table 10).40

TOXICOLOGICAL STUDIES Acute Toxicity Oral – Non-Human POLYSORBATE 81 23 The oral LD50 of polysorbate 81 was reported to be >20 000 mg/kg for rats (n=11).

Oral - Human SORBITAN MONOSTEARATE, ETHOXYLATED No toxic effects were observed in human subjects (n=6) orally administered sorbitan monostearate, ethoxylated (20g).24 The amount of gastric acid was slightly reduced. It was concluded that sorbitan monostearate, ethoxylated was not orally toxic to humans. Distributed for comment only -- do not cite or quote

Dermal – Non-Human SORBITAN MONOSTEARATE, ETHOXYLATED The acute dermal LD50 of sorbitan monostearate, ethoxylated in Wistar albino rats (n=10/sex) was reported to be >2000 mg/kg.24

Inhalation – Non-Human SORBITAN MONOLARUATE, ETHOXYLATED The inhalation LC50 was reported to be 5.1 mg/L air for sorbitan monolaurate, ethoxylated administered to Crl:Wl(Han) rats (n=5) for 4 h in a nose-only apparatus.22 No clinical signs of systemic toxicity were observed up to the end of the 14-day observation period. No abnormalities were observed at macroscopic post mortem examination of the rats.

Intravenous – Non-Human POLYSORBATE 20 22 The intravenous LD50 for polysorbate 20 in mice was reported to be 1420 mg/kg.

Repeated Dose Toxicity In a survey of 4 laboratories of the historical use of vehicles for in vivo experiments, the highest no-observed- adverse-effect levels (NOAEL) of various routes of administration were assembled (Table 11).41 The highest oral NOAELs for polysorbate 20 were 250 and 500 mg/kg/d for 1 month and 90 days in rats, respectively, and 10 mg/kg/d for 1 month in mice. For polysorbate 80, the highest oral NOAEL for 90 days in dogs was 5 mL/kg/d, and for 4 weeks in rats was 5 mL/kg/d. The NOAEL for intranasal administration of polysorbates 80 for 3 days to mice was 10 µL/nostril/d at 0.2%.

Oral – Non-Human POLYSORBATE 20 In a 22-month feeding study, the NOAEL of polysorbate 20 in male C57BL/6 Jax mice was 114285.71 mg/kg/d (10% in feed).24 Decreased hematologic values were observed but not specified. No characteristic morphologic anemia was observed. The test substance was administered in the feed at 5% or 10% polysorbate 20. No further details were provided.

POLYSORBATE 20, 40, 60, and 80 There were no adverse effects or mortalities related to polysorbate 80 (0.005, 0.05, or 0.15 g/kg/d) when administered by gavage to Sprague-Dawley rats (n=5) for 5 days.42 There were no clinical signs and no significant findings at necropsy. There were decreased serum glucose and increased serum sodium at all concentrations, as well as decreases in uric acid in the mid- and high-dose groups. The high-dose group exhibited a modest reduction in serum calcium levels. There were no adverse effects or mortalities reported when Sprague-Dawley rats (n=6/sex) were orally administered polysorbate 80 (148, 740, or 3700 mg/kg/d in saline) for 28 days after 28 days of a high fat diet.43 It was not clear if the rats continued on the high fat diet during treatment with polysorbate 80. In the same study, there were no adverse effects or mortalities reported when C57BL/6J mice (n=6/sex) were orally administered polysorbates 80 (400, 1600, or 6400 mg/kg/d in saline) for 28 days after 28 days of a high fat diet. In additional studies, there were no adverse effects or mortalities reported when the same strain of mice (n=5/sex) were orally administered polysorbate 20, polysorbate 40, or polysorbate 60 (1600 mg/kg/d in saline) for 28 days also after 28 days of a high fat diet. It was not clear if the mice continued on the high fat diet during treatment with the polysorbates.43

REPRODUCTIVE AND DEVELOPMENTAL TOXICITY POLYSORBATE 60 The teratogenic and reproductive NOAEL was reported to be 7693 mg/kg/d when polysorbate 60 (0, 0.1%, 1.0% or 10% in feed; 0, 99 mg/kg, 960 mg/kg, 7693 mg/kg) was administered to pregnant Wistar rats on gestations days 7-14.24 There were no effects by polysorbate 60 on the number, sex ratio, and body weights of live fetuses. There were no differences between the polysorbate 60-treated and control groups observed in the numbers of resorptions, dead fetuses and live fetuses per litter, the sex ratio of live fetuses, and the fetal body weight of both sexes. External, skeletal, and internal examinations of the fetuses revealed no evidence of teratogenesis. It was concluded that polysorbate 60 had no harmful effects on the prenatal development of the rat offspring.

POLYSORBATE 80 In a reproductive and developmental study where polysorbate 80 (500 and 5000 mg/kg/d in distilled water; 5 mL) was administered by gavage to Crl:CD BR VAF/PlusTM outbred albino rats (n=25) on gestation days 6-15, the maternal and the developmental NOAELs were reported to be >5000 mg/kg/d.23 The control group was administered 5 mL/kg distilled water. No maternal mortalities or treatment-related clinical signs of toxicity were observed. There were no effects on weight gain, organ weights (except non-adverse increased relative liver weights), and feed and water consumption observed. There were no differences in the number of corpora lutea per dam, number of implantations per litter, percent preimplantation loss Distributed for comment only -- do not cite or quote

per litter, percent resorptions per litter, and percent litters with resorptions. No adverse fetal effects were observed, including growth, viability, or development of the fetuses. There were no observed differences in malformations between treatment groups and controls.23

GENOTOXICITY In Vitro POLYSORBATE 20 After conducting the series of assays of the cyto/genotoxicity of polysorbate 20 described below, and examining the data all together, the authors concluded that this ingredient can interact with DNA in treated cells to cause DNA damage and fragmentation, thereby inducing apoptosis in human umbilical vein endothelial cells (HUVEC) and A549 lung cancer cells.44 Therefore, they concluded that polysorbate 20 inhibits the growth of both normal and cancer cell lines by inducing apoptosis via chromatin and DNA fragmentation. In an MTT (3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide) assay, there was a dose- and time- dependent reduction in cell growth for both the HUVEC and A549 cells with IC50s of approximately 0.3 and 0.4 µL/mL polysorbate 20, respectively. There was >90% cell death observed after treatment with 2 µL/mL, and the greatest cell death was observed in the highest test group. For the assay, the cells were incubated with various concentrations of polysorbate 20 (2, 4, 6, 8, or 10 µL/mL) for 24, 48, and 72 h, and then washed. In a DAPI (4',6-diamidino-2-phenylindole) staining assay, morphological changes and fragmentation in the chromatin and DNA rings within the nucleus were observed in the polysorbate-treated cells of both cell lines, but morphology was unaltered in untreated cells. Polysorbate 20-treated cells showed chromatin and DNA fragmentation as high as the positive control of 5% dimethyl sulfoxide (DMSO). For the assay, the cells were treated with polysorbates 20 (4 µL/mL) for various durations (not provided), then fixed and stained with DAPI. In a DNA fragmentation assay analyzed by agarose gel electrophoresis, polysorbate 20 (concentration not clear) induced apoptosis by DNA fragmentation after incubation for 24 h. The gel showed the formation of DNA ladders of both treated cell lines. An alkaline comet assay showed that polysorbate 20 (2 µL/mL)-treated A549 cells exhibited increased DNA cleavages compared to untreated cells and similar DNA cleavages to the positive control, hydrogen peroxide (200 mM)- treated cells. Only A549 cells were used in this assay; HUVEC cells were not used. When polysorbate 20 (2 µL/mL)-treated A549 cells were analyzed with a fluorescein isothiocyanate (FITC)-labeled annexin V apoptosis assay and flow cytometry analysis was used to estimate early and late apoptosis, the results were similar to the results of the DAPI staining assay. Almost all of the treated cells were in early and late stages of apoptosis after 24 h; less than half of DMSO-treated control cells were in early and late stages of apoptosis for the same period of exposure. Only A549 cells were used in this assay; HUVEC cells were not used.44

POLYSORBATE 80 Polysorbate 80 was not genotoxic to Salmonella typhimurium (strains TA98, TA100, TA1535, and TA1537) at up to 10 000 µg/plate (in distilled water) with and without metabolic activation.23 The controls had the expected results. Polysorbate 80 was not genotoxic to S. typhimurium (strains TA1535, TA1537, TA98 and TA100) and Escherichia coli (strain WP2 uvr A) at up to 5000 µg/plate (in ethanol) with and without metabolic activation.23 The controls had the expected results.

SORBITAN MONOLAURATE, ETHOXYLATED Sorbitan monolaurate, ethoxylated was not mutagenic, with or without metabolic activation, in an Ames assay using S. typhimurium (strains TA98, TA100, TA1535, and TA1537) and E. coli (strain WP2 uvr A) in 3 separate experiments.22 In experiment 1, S. typhimurium (strains TA98, TA1535, TA1537) was tested at 10-3330 µg/plate in ethanol; and S. typhimurium (strain TA100) and E. coli were also tested at 3 and 5000 µg/plate with and without metabolic activation. In experiment 2, S. typhimurium (strains TA98 and TA1535) was tested at 33-5000 µg/plate in ethanol with and without metabolic activation. In experiment 3, all strains were tested again at 33-5000 µg/plate in ethanol with and without metabolic activation. Controls had the expected results. In a chromosomal aberration assay using human lymphocytes, sorbitan monolaurate, ethoxylated was not genotoxic up to 100 µg/mL in ethanol, with and without metabolic activation, but was cytotoxic at 300 µg/mL.22 Assays were run for 3, 24, and 48h. Controls had the expected results. In 2 mammalian cell gene mutation assays using mouse lymphoma L5178Y cells, sorbitan monolaurate, ethoxylated was not found to be genotoxic.22 In the first experiment, the cells were tested for 3 h at 0.3-275 μg/mL without metabolic activation and at 0.3-300 μg/mL with metabolic activation in ethanol. In the second experiment, the cells were tested for 3 h at: 0.3-150 µg/mL without metabolic activation and at 0.3-350 μg/mL with metabolic activation in ethanol. Controls had the expected results.

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SORBITAN MONOOLEATE, ETHOXYLATED Sorbitan monooleate, ethoxylated produced ambiguous results in a chromosome aberration assay using Chinese hamster ovary (CHO; CHO-W-B1) cells.23 The number and percentages of aberrations did not change in a concentration- dependent manner. Sorbitan monooleate, ethoxylated was tested at 300-1600 µg/mL without metabolic activation and 100- 1000 µg/mL in DMSO. The positive controls were mitomycin and cyclophosphamide, which had the expected results. Sorbitan monooleate, ethoxylated was not genotoxic in a chromosome aberration assay using CHO (CHO-W-B1) cells.45 Sorbitan monooleate, ethoxylated was tested at 300-1600 µg/mL without metabolic activation and 16-500 µg/mL in DMSO. The positive controls were mitomycin and cyclophosphamide. The controls had the expected results.

SORBITAN MONOSTEARATE, ETHOXYLATED Sorbitan monostearate, ethoxylated (concentration and vehicle were not specified) was not mutagenic in a bacterial gene mutation assay using S. typhimurium (strain TA 98) with metabolic activation.24

CARCINOGENICITY No new carcinogenicity data on polysorbates were found in the published literature nor were unpublished data provided.

IRRITATION AND SENSITIZATION Irritation Dermal – Non-Human Polysorbate 60 was a moderate irritant at 5% and skin necrosis occurred at 10% when administered to rabbits for 30 days (Table 12).24 In another study, polysorbate 60 was not an irritant at 15% but a mild irritant in rabbits at 100%. Local inflammation was observed in mouse skin when polysorbate 60 was administered in a long-term study. Sorbitan monolaurate, ethoxylated (100%; 0.5mL) had a Draize score of 0.89 out of 4 when administered to rabbits (Table 12).22 When sorbitan monostearate, ethoxylated was dermally administered to rabbits for 30 days, the test substance caused necrosis of the skin at 10% but only moderate irritation at 5% (Table 12).24 Administration of sorbitan monostearate, ethoxylated (100%) for 60 days did not cause irritation in rabbits. Sorbitan monostearate, ethoxylated (100%) did not produce any skin reaction when administered to the shaved backs of rabbits.

Dermal – Human In human irritation studies, polysorbate 60 (1%), polysorbate 80 (100%), and sorbitan monostearate, ethoxylated (25%) were not dermally irritating (Table 12).24,46-48 Polysorbate 60 (100%) caused uticaria on the foreheads of subjects but not to the dorsal and arm skin.

Ocular – Non-Human Tests of polysorbate 20 (10%) and polysorbate 81 (up to 100%) showed that these ingredients were not ocular irritants in rabbits (Table 13).49-51 Sorbitan monostearate, ethoxylated (0.1 g in water) and sorbitan monolaurate, ethoxylated (100%; 0.1 mL) were not ocular irritants to rabbits.22,23

Ocular – In Vitro POLYSORBATE 20 In vitro ocular irritation tests of polysorbate 20 had mixed results. EpiOcular tests, a red blood cell hemolysis assay, and a k562 cell assay predicted polysorbate 20 to be a non- or minimal ocular irritant at 2% and 100% (Table 13).52,53 Polysorbate 20 was predicted to be an ocular irritant in a short time exposure (STE) assay using SIRC cells, Hen’s Egg test- Chorioallantoic Membrane (HET-CAM) assays, and Bovine Corneal Opacity and Permeability (BCOP) assay.52

Sensitization Non-Human POLYSORBATE 81 Polysorbate 81 (2% and 4% in corn oil) was not sensitizing to female Dunkin-Hartley guinea pigs (n=10) when the guinea pigs were challenged at 100% (0.5 mL). 22,23 The induction was a single intradermal injection followed 48 h later with an epicutaneous induction; the epicutaneous challenge was administered 21 days after second induction. There were no signs of sensitization up to 72 h after the challenge. The positive control, α-hexyl cinnamic acid (20%), had the expected results.

SORBITAN MONOLAURATES, ETHOXYLATED In a local lymph node assay of sorbitan monolaurates, ethoxylated (25%, 50% and 100% in acetone/olive oil [4:1 v/v]; 25 µL) using female CBA mice (n=5), the stimulation indexes (SI) were calculated to be 1.9, 6.0 and 5.0, respectively. The test substance was considered sensitizing.22 The authors noted that the response of the 100% group did not follow the Distributed for comment only -- do not cite or quote

expected dose-response relationship, which they also noted was common in this kind of study. The response might be less severe due to differences in skin penetration (no vehicle present) or viscosity. The estimated concentration of polysorbates that would give an SI of 3 was calculated to be 34%. The positive control, hexyl cinnamic aldehyde, had the expected results.

Human POLYSORBATE 81 In a human patch test (n=50), polysorbate 81 (100%) was not sensitizing.23 There were no signs of irritation or sensitization observed in any subject. The test material was administered under a single occluded patch for 3 days. After 7 days, challenge patches were administered for 72 h. In a human patch test (n=10), polysorbate 81 (100%) was not sensitizing.23 There were no signs of irritation or sensitization observed in any subject. The test material was administered under a single occluded patch for 5 days. After 10 days, challenge patches were administered for 48 h. In a human patch test (n=10), polysorbate 81 (12%; vehicle not specified) was not sensitizing.23 There were no signs of irritation or sensitization observed in any subject. The test material was administered under a single occluded patch 5 days. After 10 days, challenge patches were administered for 48 h.

SUMMARY OF NEW DATA This is a re-review of the safety of polysorbates as used in cosmetics. Safety assessments of various polysorbates were published in 1984, 2000, and 2001 with conclusions of safe as used. These safety assessments have been combined, and additional polysorbate ingredients have been identified and included, in this assessment for a total of 80 ingredients. All of these polysorbate ingredients are related in that they have a common core structure of sorbitan or sorbitol etherified with PEG chains. The highest number of uses were reported for polysorbate 20 at 3013 (an increase from 770 in 1998), polysorbate 60 at 1589 (an increase from 332 in 1998), and polysorbates 80 at 932 (an increase from 231 in 1998). Almost all of the previously reviewed ingredients had increases in the number of reported uses. The highest maximum concentrations of use were reported for polysorbate 20 at 19.6% (a decrease from >50% in 1984), polysorbate 80 at 18.1% (a decrease from up to 25% in 1984), polysorbate 81 at 25.6% (an increase from up to 5% in 1984), and polysorbate 85 at 21.9% (a decrease from >50% in 1984) in rinse-off products. The highest maximum concentration of use for leave-on products was 11.9% polysorbate 80 in perfumes. Polysorbate 20, polysorbate 65, and polysorbate 80 enhanced the dermal penetration of albuterol sulfate through mouse skin. The oral LD50 of polysorbate 81 was reported to be >20 000 mg/kg for rats. The acute dermal LD50 of sorbitan monostearate, ethoxylated in rats was reported to be >2000 mg/kg. The inhalation LC50 was reported to be 5.1 mg/L air for sorbitan monolaurate, ethoxylated administered to rats for 4 h. The intravenous LD50 for mice was reported to be 1420 mg/kg for polysorbate 20. In a survey of 4 laboratories of the historical use of vehicles for in vivo experiments, the highest NOAEL of various routes of administration were assembled. The highest oral NOAELs for polysorbate 20 were 250 and 500 mg/kg/d for 1 month and 90 days in rats, respectively, and 10 mg/kg/d for 1 month in mice. For polysorbate 80, the highest oral NOAEL for 90 days in dogs was 5 mL/kg/d, and for 4 weeks in rats was 5 mL/kg/d. The NOAEL for intranasal administration of polysorbates 80 for 3 days to mice was 10 µL/nostril/d at 0.2%. There were no adverse effects or mortalities related to polysorbate 80 (up to 0.15 g/kg) when administered by gavage to rats for 5 days or in rats orally administered polysorbate 80 (up to 3700 mg/kg/d) for 28 days. There were no adverse effects observed in mice orally administered polysorbate 80 (up to 6400 mg/kg/d), or polysorbate 20, polysorbate 40, or polysorbate 60 (1600 mg/kg/d) for 28 days. The teratogenic and reproductive NOAEL of polysorbate 60 was reported to be 7693 mg/kg/d (ie, the highest dose tested) when administered to pregnant rats on gestations days 7-14 in feed. In a reproductive and developmental study where polysorbate 80 was administered by gavage to rats on gestation days 6-15, the maternal and the developmental NOAELs were reported to be >5000 mg/kg/d. Polysorbate 80 was not genotoxic to S. typhimurium, up to 10 000 µg/plate, and E. coli, up to 5000 µg/plate, with and without metabolic activation. Sorbitan monolaurate, ethoxylated was not mutagenic in an Ames assay using S. typhimurium up to 5000 µg/plate. In a chromosomal aberration assay using human lymphocytes, sorbitan monolaurate, ethoxylated was not genotoxic up to 100 µg/mL but was cytotoxic at 300 µg/mL. In 2 mammalian cell gene mutation assays using mouse lymphoma L5178Y cells, sorbitan monolaurate, ethoxylated was not found to be genotoxic up to 275 μg/mL without metabolic activation and up to 300 μg/mL with metabolic activation. Sorbitan monooleate, ethoxylated produced ambiguous results in a chromosome aberration assay using CHO cells, but was not genotoxic in a second chromosome aberration assay also using CHO cells. The combined results of MTT, DAPI, DNA fragmentation, alkaline comet, and FITC-labeled annexin V apoptosis assays led to the authors to conclude that polysorbate 20 can interact with DNA in treated cells to cause DNA damage and fragmentation inducing apoptosis in HUVEC and A549 lung cancer cells. Distributed for comment only -- do not cite or quote

In a 30-day skin-painting study of polysorbate 60 in rabbits, there was moderate irritation observed at 5% and skin necrosis at 10%. In a study in rabbits, there were no dermal effects from a 15% aqueous solution of polysorbate 60 administered for 60 consecutive days; there was mild irritation after administration of an undiluted solution. Local inflammation also occurred after long-term (time not specified) administration of an undiluted polysorbate 60 solution to mouse skin. Sorbitan monolaurate, ethoxylated at 100% had a Draize score of 0.89 out of 4 when administered to rabbits. When sorbitan monostearate, ethoxylated was dermally administered to rabbits for 30 days, the test substance caused necrosis of the skin at 10% but only moderate irritation at 5%. Administration of sorbitan monostearate, ethoxylated at 100% for 60 days did not cause irritation in rabbits. Sorbitan monostearate, ethoxylated at 100% did not produce any skin reaction when administered to the shaved backs of rabbits. In a clinical test, polysorbate 60 at 100%, polysorbate 80 at 100%, and sorbitan monostearate, ethoxylated at 25% were not dermally irritating. In vivo tests of polysorbate 20 (10%) and polysorbate 81 (up to 100%) showed that these ingredients were not ocular irritants. In vitro predictions tests had mixed results. EpiOcular tests, a red blood cell hemolysis assay, and a k562 cell assay predicted that polysorbate 20 to be a non- or minimal ocular irritant at 2% and 100%. STE at 5%, HET-CAM at 100%, and BCOP at 100% predicted that polysorbate 20 would be a mild to severe ocular irritant. Polysorbate 81 up to 4% was not sensitizing to guinea pigs when challenged at 100% 21 days. Polysorbate 81 at 100% was not sensitizing in human patch tests.

DISCUSSION This is a re-review of polysorbates from 3 previous safety assessments that have been combined, along with similar polysorbates that have not been reviewed, into one report. The Panel agreed that grouping these ingredients together was appropriate because of the common core structure of sorbitan or sorbitol, etherified with PEG chains, and esterified with fatty acids. The Panel recognizes that there are data gaps regarding use and concentration of these ingredients. However, the overall information available on the types of products in which these ingredients are used, concentrations of use and the similar pattern of use raise no safety concerns. The Panel cautioned that polysorbate 20, polysorbate 65, and polysorbate 80 were shown to enhance dermal drug absorption. The Panel cautions that care should be taken in formulating cosmetic products that may contain these ingredients in combination with any ingredients whose safety was based on their lack of dermal absorption data, or when dermal absorption was a concern. Especially, care should be taken when creating formulations intended for use on infants. To address the possible presence of 1,4-dioxane and ethylene oxide impurities in these ingredients, the Panel stressed that the cosmetics industry should continue to use the necessary procedures to limit these impurities from the PEG ingredients before blending them into cosmetic formulations. The Panel expressed concern about pesticide residues and heavy metals that may be present in botanical (ie, coconut-derived) ingredients. They stressed that the cosmetics industry should continue to use current good manufacturing practices (cGMPs) to limit impurities. Data from the 1984 safety assessment suggested that polysorbates caused a slight enhancement of tumor development caused by 7, 12-dimethyl-benz[a]antracene (DMBA) and N-methyl-N’-nitro-N-nitrosoquanidine (MNNG). However the data were not consistent. For other compounds, the tumorigenic properties of 3-methyl-chloanthrene (MCA) and 3,4-benz[a]-pyrene (BP) were not enhanced by polysorbates. Overall, since tumor enhancement was not consistently demonstrated, the Panel was not concerned. Because some studies showed minimal irritation at concentrations that are used in cosmetics, the Panel cautioned that products containing these ingredients should be formulated to be non-irritating. It was noted that at the time of the 2001 safety assessment on sorbeth beeswaxes, the Panel had recommended that cosmetic formulations containing PEGs not be used on damaged skin. Since then, PEGs have been re-reviewed and the Panel has removed the caveat that PEGs should not be used on damaged skin. The Panel discussed the issue of incidental inhalation exposure from including aerosol and pump hair sprays, spray deodorants, spray body and hand products, and spray moisturizing products. The limited acute exposure data available from 1 new inhalation study and 1 historical tracheal study suggest little potential for respiratory effects at relevant doses. The Expert Panel believes that the sizes of a substantial majority of the particles of these ingredients, as manufactured, are larger than the respirable range and/or aggregate and agglomerate to form much larger particles in formulation. These ingredients are reportedly used at concentrations up to 4% in cosmetic products that may be aerosolized. The Panel noted that 95%-99% of droplets/particles would not be respirable to any appreciable amount. Coupled with the small actual exposure in the breathing zone and the concentrations at which the ingredients are used, the available information indicates that incidental inhalation would not be a significant route of exposure that might lead to local respiratory or systemic effects. The Panel considered other data available to characterize the potential for polysorbates to cause systemic toxicity, irritation, sensitization, reproductive and developmental toxicity, and genotoxicity. They noted the lack of systemic toxicity at low and moderate doses in several acute and repeated dose oral exposure studies and low toxicity at high does; little or no irritation or sensitization in multiple tests of dermal and ocular exposure; the absence of genotoxicity in multiple Ames tests and chromosome aberration tests, and minimal irritation and lack of sensitization in tests of dermal exposure at concentration of Distributed for comment only -- do not cite or quote

use. A detailed discussion and summary of the Panel’s approach to evaluating incidental inhalation exposures to ingredients in cosmetic products is available at http://www.cir-safety.org/cir-findings.

CONCLUSION The CIR Expert Panel concluded that polysorbates are safe in cosmetics when formulated to be non-irritating. This conclusion supersedes the conclusion reached in the 1984, 2000, and 2001 safety assessments.

Polysorbate 20 PEG-40 sorbitan Sorbeth-2 hexaoleate* Polysorbate 21 perisostearate* Sorbeth-40 hexaoleate* Polysorbate 40 PEG-40 sorbitan peroleate Sorbeth-50 hexaoleate* Polysorbate 60 PEG-3 sorbitan stearate Sorbeth-6 hexastearate* Polysorbate 61 PEG-4 sorbitan stearate* Sorbeth-150 hexastearate* Polysorbate 65 PEG-6 sorbitan stearate Sorbeth-3 isostearate* Polysorbate 80 PEG-40 sorbitan stearate Sorbeth-6 laurate* Polysorbate 81 PEG-60 sorbitan stearate* Sorbeth-2/oleate/dimer Polysorbate 85 PEG-30 sorbitan tetraoleate dilinoleate crosspolymer* PEG-30 sorbitan beeswax PEG-40 sorbitan tetraoleate Sorbeth-20 pentaisostearate* PEG-20 sorbitan cocoate PEG-60 sorbitan tetraoleate Sorbeth-30 pentaisostearate* PEG-40 sorbitan diisostearate PEG-60 sorbitan tetrastearate* Sorbeth-40 pentaisostearate* PEG-2 sorbitan isostearate* PEG-4 sorbitan triisostearate* Sorbeth-50 pentaisostearate* PEG-5 sorbitan isostearate* PEG-20 sorbitan triisostearate* Sorbeth-40 pentaoleate* PEG-20 sorbitan isostearate PEG-160 sorbitan triisostearate Sorbeth-20 tetraisostearate* PEG-40 sorbitan lanolate PEG-2 sorbitan trioleate* Sorbeth-30 tetraisostearate PEG-75 sorbitan lanolate* PEG-18 sorbitan trioleate Sorbeth-40 tetraisostearate* PEG-10 sorbitan laurate PEG-3 sorbitan tristearate* Sorbeth-50 tetraisostearate* PEG-40 sorbitan laurate Sorbeth-2 beeswax* Sorbeth-4 tetraoleate PEG-44 sorbitan laurate Sorbeth-6 beeswax Sorbeth-6 tetraoleate PEG-75 sorbitan laurate Sorbeth-8 beeswax* Sorbeth-30 tetraoleate PEG-80 sorbitan laurate Sorbeth-20 beeswax Sorbeth-40 tetraoleate PEG-3 sorbitan oleate Sorbeth-2 cocoate* Sorbeth-60 tetraoleate PEG-6 sorbitan oleate Sorbeth-2 Sorbeth-30 tetraoleate laurate* PEG-20 sorbitan oleate* hexacaprylate/caprate* Sorbeth-60 tetrastearate* PEG-40 sorbitan oleate* Sorbeth-12 hexacocoate* Sorbeth-3 tristearate* PEG-80 sorbitan palmitate* Sorbeth-2 hexaisostearate* Sorbeth-160 tristearate* Sorbeth-2 hexalaurate* Sorbeth-450 tristearate*

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

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TABLES AND FIGURES

Table 1. The Definitions and Functions of the Polysorbates in This Safety Assessment.4 [Bracketed entries are the work product of CIR staff] Ingredient and CAS No. Definition Function

Polysorbate Monoesters Sorbitan derivatives Polysorbate 21 A mixture of laurate esters of sorbitol and sorbitol anhydrides, consisting predominantly of the monoester, Fragrance 9005-64-5 (generic) condensed with approximately 4 moles of ethylene oxide. It conforms generally to the formula: ingredient; surfactant- emulsifying agent

[ ]

where w + x + y + z has an average value of 4. PEG-10 sorbitan PEG-10 Sorbitan Laurate is an ethoxylated sorbitan ester of lauric acid with an average of 10 moles of Fragrance laurate ethylene oxide. ingredient; 9005-64-5 (generic) surfactant- cleansing agent; surfactant- solubilizing agent

[ ] where w + x + y + z has an average value of 10. Polysorbate 20 A mixture of laurate esters of sorbitol and sorbitol anhydrides, consisting predominantly of the monoester, Fragrance 9005-64-5 (generic) condensed with approximately 20 moles of ethylene oxide. It conforms generally to the formula: ingredient; surfactant- emulsifying agent; surfactant- solubilizing agent []

where w + x + y + z has an average value of 20. PEG-40 sorbitan An ethoxylated sorbitan ester of lauric acid with an average of 40 moles of ethylene oxide. Fragrance laurate ingredient; 9005-64-5 (generic) surfactant- cleansing agent; surfactant- solubilizing agent

[ ] where w + x + y + z has an average value of 40. PEG-44 sorbitan An ethoxylated sorbitan ester of lauric acid with an average of 44 moles of ethylene oxide. Fragrance laurate ingredient; 9005-64-5 (generic) surfactant- cleansing agent; surfactant- solubilizing agent [ ] where w + x + y + z has an average value of 44. Distributed for comment only -- do not cite or quote

Table 1. The Definitions and Functions of the Polysorbates in This Safety Assessment.4 [Bracketed entries are the work product of CIR staff] Ingredient and CAS No. Definition Function PEG-75 sorbitan An ethoxylated sorbitan ester of lauric acid with an average of 75 moles of ethylene oxide. Fragrance laurate ingredient; 9005-64-5 (generic) surfactant- cleansing agent; surfactant- solubilizing agent

[ ] where w + x + y + z has an average value of 75. PEG-80 sorbitan An ethoxylated sorbitan ester of lauric acid with an average of 80 moles of ethylene oxide. Fragrance laurate ingredient; 68154-33-6 (generic) surfactant- 9005-64-5 (generic) cleansing agent; surfactant- solubilizing agent

[ ] where w + x + y + z has an average value of 80. Polysorbate 40 A mixture of palmitate esters of sorbitol and sorbitol anhydrides, consisting predominantly of the Surfactant- 9005-66-7 monoester, condensed with approximately 20 moles of ethylene oxide. It conforms generally to the formula: emulsifying agent; surfactant- solubilizing agent

[ ]

where w + x + y + z has an average value of 20. PEG-80 sorbitan An ethoxylated sorbitan monoester of palmitic acid with an average of 80 moles of ethylene oxide. Surfactant- palmitate cleansing agent; 9005-66-7 (generic) surfactant solubilizing agent

[ ] where w + x + y + z has an average value of 80. PEG-2 sorbitan An ethoxylated sorbitan monoester of isostearic acid with an average of 2 moles of ethylene oxide. Surfactant- isostearate emulsifying 66794-58-9 (generic) agent

[ (one example of an “iso”) ] where w + x + y + z has an average value of 2. PEG-5 sorbitan An ethoxylated sorbitan monoester of isostearic acid with an average of 5 moles of ethylene oxide. Surfactant- isostearate emulsifying 66794-58-9 (generic) agent

[ (one example of an “iso”) ] where w + x + y + z has an average value of 5. Distributed for comment only -- do not cite or quote

Table 1. The Definitions and Functions of the Polysorbates in This Safety Assessment.4 [Bracketed entries are the work product of CIR staff] Ingredient and CAS No. Definition Function PEG-20 sorbitan An ethoxylated sorbitan monoester of isostearic acid with an average of 20 moles of ethylene oxide. Surfactant- isostearate cleansing agent; 66794-58-9 (generic) surfactant- emulsifying agent; surfactant solubilizing agent

[ (one example of an “iso”) ] where w + x + y + z has an average value of 20. PEG-3 sorbitan An ethoxylated sorbitan monoester of stearic acid with an average of 3 moles of ethylene oxide. Fragrance stearate ingredient; 9005-67-8 (generic) surfactant- emulsifying agent

[ (one example of an “iso”) ] where w + x + y + z has an average value of 3. PEG-4 sorbitan An ethoxylated sorbitan monoester of stearic acid with an average of 4 moles of ethylene oxide. Fragrance stearate ingredient; 9005-67-8 (generic) surfactant- emulsifying agent

[ (one example of an “iso”) ] where w + x + y + z has an average value of 4. Polysorbate 61 A mixture of stearate esters of sorbitol and sorbitol anhydrides, consisting predominantly of the monoester, Fragrance 9005-67-8 (generic) condensed with approximately 4 moles of ethylene oxide. It conforms generally to the formula: ingredient; surfactant- emulsifying agent

[]

where w + x + y + z has an average value of 4. PEG-6 sorbitan An ethoxylated sorbitan monoester of stearic acid with an average of 6 moles of ethylene oxide. Fragrance stearate ingredient; 9005-67-8 (generic) surfactant- emulsifying agent

[ ] wherein w + x + y + z has an average value of 6. Polysorbate 60 A mixture of stearate esters of sorbitol and sorbitol anhydrides, consisting predominantly of the monoester, Fragrance 9005-67-8 (generic) condensed with approximately 20 moles of ethylene oxide. It conforms generally to the formula: ingredient; surfactant- emulsifying agent; surfactant- solubilizing agent []

where w + x + y + z has an average value of 20. Distributed for comment only -- do not cite or quote

Table 1. The Definitions and Functions of the Polysorbates in This Safety Assessment.4 [Bracketed entries are the work product of CIR staff] Ingredient and CAS No. Definition Function Polysorbate 65 A mixture of stearate esters of sorbitol and sorbitol anhydrides, consisting predominantly of the triester, Surfactant- 9005-71-4 condensed with approximately 20 moles of ethylene oxide. It conforms generally to the formula: emulsifying agent

[]

where w + x + y + z has an average value of 20. PEG-40 sorbitan An ethoxylated sorbitan ester of stearic acid with an average of 40 moles of ethylene oxide. Fragrance stearate ingredient; 9005-67-8 (generic) surfactant- cleansing agent; surfactant- solubilizing agent

[ ] where w + x + y + z has an average value of 40. PEG-60 sorbitan An ethoxylated sorbitan ester of stearic acid with an average of 60 moles of ethylene oxide. Fragrance stearate ingredient; 9005-67-8 (generic) surfactant- cleansing agent; surfactant- solubilizing agent

[ ] where w + x + y + z has an average value of 60. PEG-3 sorbitan oleate An ethoxylated sorbitan ester of oleic acid with an average of 3 moles of ethylene oxide. Fragrance 9005-65-6 (generic) ingredient; surfactant- emulsifying agent

[ ] where w + x + y + z has an average value of 3. Polysorbate 81 A mixture of oleate esters of sorbitol and sorbitol anhydrides, consisting predominantly of the monoester, Fragrance 9005-65-6 (generic) condensed with approximately 5 moles of ethylene oxide. It conforms generally to the formula: ingredient; surfactant- emulsifying agent

[]

where w + x + y + z has an average value of 5. PEG-6 sorbitan oleate An ethoxylated sorbitan ester of oleic acid with an average of 6 moles of ethylene oxide. Fragrance 9005-65-6 (generic) ingredient; surfactant- emulsifying agent

[ ] where w + x + y + z has an average value of 6. Distributed for comment only -- do not cite or quote

Table 1. The Definitions and Functions of the Polysorbates in This Safety Assessment.4 [Bracketed entries are the work product of CIR staff] Ingredient and CAS No. Definition Function PEG-20 sorbitan An ethoxylated sorbitan ester of oleic acid with an average of 20 moles of ethylene oxide. Surfactant- oleate cleansing agent; surfactant- emulsifying agent; surfactant solubilizing agent

[ ] where w + x + y + z has an average value of 20. Polysorbate 80 A mixture of oleate esters of sorbitol and sorbitol anhydrides, consisting predominantly of the monoester, Denaturant; 9005-65-6 (generic) condensed with approximately 20 moles of ethylene oxide. It conforms generally to the formula: fragrance ingredient; surfactant- emulsifying agent; surfactant solubilizing [] agent

where w + x + y + z has an average value of 20. PEG-30 sorbitan [Not listed as a cosmetic ingredient in the Dictionary. [1 use in beeswax An ethoxylated sorbitan ester of beeswax acid with an average of 30 moles of ethylene oxide.] VCRP54]

where CH3(CH2)vC(O)- represents the fatty acids derived from beeswax and w + x + y + z has an average value of 30. The composition of beeswax is a variable mixture of glycerides and fatty acids containing 24 to 36 carbons in alkyl chain [ 18 ] length (beeswax acid). PEG-40 sorbitan An ethoxylated sorbitan ester of oleic acid with an average of 40 moles of ethylene oxide. Surfactant- oleate cleansing agent; surfactant- emulsifying agent; surfactant solubilizing agent [ ] where w + x + y + z has an average value of 40. PEG-20 sorbitan An ethoxylated sorbitan ester of coconut acid with an average of 20 moles of ethylene oxide. Surfactant- cocoate cleansing agent; surfactant- solubilizing agent

where CH3(CH2)vC(O)- represents the fatty acids derived from cocos nucifera (coconut) oil and w + x + y + z has an average value of 20. The fatty acid distribution of coconut oil is 0-1% caproic, 5-9% caprylic, 6-10% capric, 44-52% lauric, 13-19% myristic, 0-1% palmitoleic, 1-3% stearic, 5-8% oleic, and trace-2.5% [ 55 ] linoleic acid. Distributed for comment only -- do not cite or quote

Table 1. The Definitions and Functions of the Polysorbates in This Safety Assessment.4 [Bracketed entries are the work product of CIR staff] Ingredient and CAS No. Definition Function PEG-40 sorbitan An ethoxylated sorbitan derivative of lanolin acid with an average of 40 moles of ethylene oxide. Surfactant- lanolate cleansing agent; 8036-77-9 surfactant solubilizing agent

where CH3(CH2)vC(O)- represents the fatty acids derived from lanolin acid and w + x + y + z has an average value of 40. The length of the lanolin fatty acid chain varies from 7 to 41 carbon atoms. The main fatty acids are palmitic (C16), stearic [ 12 ] (C18) and longer molecules (C20 to C 32). PEG-75 sorbitan An ethoxylated sorbitan derivative of lanolin acid with an average of 75 moles of ethylene oxide. Surfactant- lanolate cleansing agent; 8051-13-6 surfactant solubilizing agent

where CH3(CH2)vC(O)- represents the fatty acids derived from lanolin acid and w + x + y + z has an average value of 75. The length of the lanolin fatty acid chain varies from 7 to 41 carbon atoms. The main fatty acids are palmitic (C16), stearic [ 12 ] (C18) and longer molecules (C20 to C 32).

Polysorbate Monoesters Sorbitol derivatives Sorbeth-6 laurate The ester of lauric acid and a polyethylene glycol ether of sorbitol containing an average of 6 moles of Surfactant- [66686-72-4] ethylene oxide. emulsifying agent; surfactant- solubilizing agent

[ ] where u + v + w + x + y + z has an average value of 6. Sorbeth-3 isostearate The ester of isostearic acid and a polyethylene glycol ether of sorbitol containing an average of 3 moles of Surfactant- ethylene oxide. emulsifying agent

[ (one example of an “iso”) ] where u + v + w + x + y + z has an average value of 3. Sorbeth-2 cocoate The ester of the fatty acids derived from cocos nucifera (coconut) oil and a polyethylene glycol ether of Surfactant- Sorbitol containing an average of 2 moles of ethylene oxide. emulsifying agent

where CH3(CH2)tC(O)- represents the fatty acids derived from cocos nucifera (coconut) oil and u + v + w + x + y + z has an average value of 2. The fatty acid distribution of coconut oil is 0-1% caproic, 5-9% caprylic, 6-10% capric, 44-52% lauric, 13-19% myristic, 0-1% palmitoleic, 1-3% stearic, 5-8% oleic, and trace-2.5% [ 55 ] linoleic acid. Distributed for comment only -- do not cite or quote

Table 1. The Definitions and Functions of the Polysorbates in This Safety Assessment.4 [Bracketed entries are the work product of CIR staff] Ingredient and CAS No. Definition Function Sorbeth-2 beeswax An ethoxylated sorbitan derivative of beeswax with an average of 2 moles of ethylene oxide. Surfactant- emulsifying agent

where CH3(CH2)tC(O)- represents the fatty acids derived from beeswax and u + v + w + x + y + z has an average value of 2. The composition of beeswax is a variable mixture of glycerides and fatty acids containing 24 to 36 carbons in alkyl chain [ 18 ] length (beeswax acid). Sorbeth-6 beeswax An ethoxylated sorbitan derivative of beeswax with an average of 6 moles of ethylene oxide. Surfactant- 8051-15-8 emulsifying agent

where CH3(CH2)tC(O)- represents the fatty acids derived from beeswax and u + v + w + x + y + z has an average value of 6. The composition of beeswax is a variable mixture of glycerides and fatty acids containing 24 to 36 carbons in alkyl chain [ 18 ] length (beeswax acid). Sorbeth-8 beeswax An ethoxylated sorbitan derivative of beeswax with an average of 8 moles of ethylene oxide. Surfactant- emulsifying agent

where CH3(CH2)tC(O)- represents the fatty acids derived from beeswax and u + v + w + x + y + z has an average value of 8. The composition of beeswax is a variable mixture of glycerides and fatty acids containing 24 to 36 carbons in alkyl chain [ 18 ] length (beeswax acid). Sorbeth-20 beeswax An ethoxylated sorbitan derivative of beeswax with an average of 20 moles of ethylene oxide. Surfactant- emulsifying agent; surfactant- solubilizing agent

where CH3(CH2)tC(O)- represents the fatty acids derived from beeswax and u + v + w + x + y + z has an average value of 20. The composition of beeswax is a variable mixture of glycerides and fatty acids containing 24 to 36 carbons in alkyl chain [ 18 ] length (beeswax acid).

Polysorbate Diester Sorbitan Derivative PEG-40 sorbitan An ethoxylated sorbitan diester of isostearic acid with an average of 40 moles of ethylene oxide. Surfactant- diisostearate emulsifying agent; surfactant solubilizing agent

[ (one example of an “iso”; one example of a diester) ] where w + x + y + z has an average value of 40. Distributed for comment only -- do not cite or quote

Table 1. The Definitions and Functions of the Polysorbates in This Safety Assessment.4 [Bracketed entries are the work product of CIR staff] Ingredient and CAS No. Definition Function

Polysorbate Triesters Sorbitan Derivatives PEG-4 sorbitan The triester of isostearic acid and a polyethylene glycol ether of sorbitol with an average of 4 moles of Surfactant- triisostearate ethylene oxide. emulsifying agent

[ (one example of an “iso”; one example of a triester) ] where w + x + y + z has an average value of 4. PEG-20 sorbitan The triester of isostearic acid and a polyethylene glycol ether of sorbitol with an average of 20 moles of Surfactant- triisostearate ethylene oxide. emulsifying agent

[ (one example of an “iso”; one example of a triester) ] where w + x + y + z has an average value of 20. PEG-160 sorbitan The triester of isostearic acid and a polyethylene glycol ether of sorbitol with an average of 160 moles of Surfactant- triisostearate ethylene oxide. cleansing agent; surfactant- solubilizing agent

[ (one example of an “iso”; one example of a triester) ] where w + x + y + z has an average value of 160. PEG-3 sorbitan The triester of stearic acid and a polyethylene glycol ether of sorbitol with an average of 3 moles of ethylene Skin- tristearate oxide. conditioning agent-emollient

[ (one example of a triester) ] where w + x + y + z has an average value of 3. Distributed for comment only -- do not cite or quote

[ (one example of a triester) ] where w + x + y + z has an average value of 2. PEG-18 sorbitan [No longer listed as a cosmetic ingredient in the Dictionary. [1 use in trioleate A triester of oleic acid and a polyethylene glycol ether of sorbitol with an average of 18 moles of ethylene VCRP54] oxide.]

[ (one example of a triester) ] where w + x + y + z has an average value of 18. Polysorbate 85 A mixture of oleate esters of sorbitol and sorbitol anhydrides, consisting predominantly of the triester, Surfactant- 9005-70-3 condensed with approximately 20 moles of ethylene oxide. It conforms generally to the formula: dispersing agent; surfactant- emulsifying agent

[]

where w + x + y + z has an average value of 20.

Polysorbate Triesters Sorbitol Derivatives Sorbeth-3 tristearate The triester of stearic acid and a polyethylene glycol ether of sorbitol containing an average of 3 moles of Surfactant- ethylene oxide. emulsifying agent

[ (one example of a triester) ] where u + v + w + x + y + z has an average value of 3. Distributed for comment only -- do not cite or quote

[ (one example of a triester) ] where u + v + w + x + y + z has an average value of 160. Sorbeth-450 The triester of stearic acid and a polyethylene glycol ether of sorbitol with an average of 450 moles of Surfactant- tristearate ethylene oxide. dispersing agent; surfactant - emulsifying agent; surfactant – foam booster; viscosity increasing agent – aqueous

[ (one example of a triester) ] where u + v + w + x + y + z has an average value of 450.

Polysorbate Tetraesters Sorbitan Derivatives PEG-60 sorbitan The tetraester of stearic acid and a polyethylene glycol ether of sorbitol, with an average of 60 moles of Surfactant- tetrastearate ethylene oxide. emulsifying agent

[ (one example of a tetraester) ] where w + x + y + z has an average value of 60. PEG-30 sorbitan The tetraester of oleic acid and a polyethylene glycol ether of sorbitol, with an average of 30 moles of Surfactant- tetraoleate ethylene oxide. emulsifying agent [ ] where w + x + y + z has an average value of 30. Distributed for comment only -- do not cite or quote

Table 1. The Definitions and Functions of the Polysorbates in This Safety Assessment.4 [Bracketed entries are the work product of CIR staff] Ingredient and CAS No. Definition Function PEG-40 sorbitan The tetraester of oleic acid and a polyethylene glycol ether of sorbitol, with an average of 40 moles of Surfactant- tetraoleate ethylene oxide. emulsifying agent [ ] where w + x + y + z has an average value of 40. PEG-60 sorbitan The tetraester of oleic acid and a polyethylene glycol ether of sorbitol, with an average of 60 moles of Surfactant- tetraoleate ethylene oxide. emulsifying agent

[where w + x + y + z has an average value of 60.]

Polysorbate Esters - mixtures Sorbitan Derivatives PEG-40 sorbitan A mixture of isostearic acid esters of sorbitol condensed with an average of 40 moles of ethylene oxide. Surfactant- perisostearate emulsifying agent

(one example of a perester) [ where each R is hydrogen or isostearate, and w + x + y + z has an average ] value of 40. PEG-40 sorbitan A mixture of oleic acid esters of sorbitol condensed with an average of 40 moles of ethylene oxide. Surfactant- peroleate emulsifying agent; surfactant solubilizing agent

(one example of a perester) [ where each R is hydrogen or oleate, and w + x + y + z has an average value ] of 40.

Polysorbate Tetraesters Sorbitol Derivatives Sorbeth-20 The tetraester of isostearic acid and a polyethylene glycol ether of sorbitol containing an average of 20 Surfactant- tetraisostearate moles of ethylene oxide. emulsifying agent

[ (one example of an “iso”; one example of a tetraester) ] where u + v + w + x + y + z has an average value of 20. Distributed for comment only -- do not cite or quote

[ (one example of an “iso”; one example of a tetraester) ] where u + v + w + x + y + z has an average value of 30. Sorbeth-40 The tetraester of isostearic acid and a polyethylene glycol ether of sorbitol containing an average of 40 Surfactant- tetraisostearate moles of ethylene oxide. emulsifying agent

[ (one example of an “iso”; on example of a tetraester) ] where u + v + w + x + y + z has an average value of 40. Sorbeth-50 The tetraester of isostearic acid and a polyethylene glycol ether of sorbitol containing an average of 50 Surfactant- tetraisostearate moles of ethylene oxide. emulsifying agent

[ (one example of an “iso”; one example of a tetraester) ] where u + v + w + x + y + z has an average value of 50. Sorbeth-60 The tetraester of stearic acid and a polyethylene glycol ether of sorbitol containing an average of 60 moles Surfactant- tetrastearate of ethylene oxide. emulsifying agent

[ (one example of an “iso”; one example of a tetraester) ] where u + v + w + x + y + z has an average value of 60. Distributed for comment only -- do not cite or quote

[ (one example of a tetraester) ] where w + x + y + z has an average value of 4. Sorbeth-6 tetraoleate The tetraester of oleic acid and a polyethylene glycol ether of sorbitol containing an average of 6 moles of Surfactant- ethylene oxide. emulsifying agent

[ (one example of a tetraester) ] where w + x + y + z has an average value of 6. Sorbeth-30 The tetraester of oleic acid and a polyethylene glycol ether of sorbitol containing an average of 30 moles of Surfactant- tetraoleate ethylene oxide. emulsifying agent

[ (one example of a tetraester) ] where w + x + y + z has an average value of 30. Sorbeth-40 The tetraester of oleic acid and a polyethylene glycol ether of sorbitol with an average of 40 moles of Surfactant- tetraoleate ethylene oxide. emulsifying agent

[ (one example of a tetraester) ] where w + x + y + z has an average value of 40. Distributed for comment only -- do not cite or quote

[ (one example of a tetraester) ] where w + x + y + z has an average value of 60.

Polysorbate Pentaesters Sorbitol Derivatives Sorbeth-20 The pentaester of isostearic acid and a polyethylene glycol ether of sorbitol containing an average of 20 Surfactant- pentaisostearate moles of ethylene oxide. emulsifying agent

[ (one example of an “iso”; one example of a pentaester) ] where u + v + w + x + y + z has an average value of 20. Sorbeth-30 The pentaester of isostearic acid and a polyethylene glycol ether of sorbitol containing an average of 30 Surfactant- pentaisostearate moles of ethylene oxide. emulsifying agent

[ (one example of an “iso”; one example of a pentaester) ] where u + v + w + x + y + z has an average value of 30. Sorbeth-40 The pentaester of isostearic acid and a polyethylene glycol ether of sorbitol containing an average of 40 Surfactant- pentaisostearate moles of ethylene oxide. emulsifying agent

[ (one example of an “iso”; one example of a pentaester) ] where u + v + w + x + y + z has an average value of 40. Distributed for comment only -- do not cite or quote

[ (one example of an “iso”; one example of a pentaester) ] where u + v + w + x + y + z has an average value of 50. Sorbeth-40 The pentaester of oleic acid and a polyethylene glycol ether of sorbitol containing an average of 40 moles of Surfactant- pentaoleate ethylene oxide. emulsifying agent

[ (one example of a pentaester) ] where u + v + w + x + y + z has an average value of 40. Sorbeth-30 The oleic acid tetraester and lauric acid ester of sorbitol ethoxylated with an average of 30 moles of ethylene Surfactant- tetraoleate laurate oxide. emulsifying agent

[ (one example of an “iso”; one example of a pentaester) ] where u + v + w + x + y + z has an average value of 30.

Polysorbate Hexaesters Sorbitol Deriviatives Sorbeth-2 hexalaurate The hexaester of lauric acid and a polyethylene glycol ether of sorbitol containing an average 2 moles of Skin- ethylene oxide. conditioning agent-emollient

[ (one example of a pentaester) ] where u + v + w + x + y + z has an average value of 2. Distributed for comment only -- do not cite or quote

[ (one example of a pentaester) ] where u + v + w + x + y + z has an average value of 2. Sorbeth-6 The hexaester of stearic acid and a polyethylene glycol ether of sorbitol containing an average of 6 moles of Surfactant- hexastearate ethylene oxide. emulsifying agent

[ ] where u + v + w + x + y + z has an average value of 6. Sorbeth-150 The hexaester of stearic acid and a polyethylene glycol ether of sorbitol containing an average of 150 moles Viscosity hexastearate of ethylene oxide. increasing agent-aqueous

[ ] where u + v + w + x + y + z has an average value of 150. Distributed for comment only -- do not cite or quote

[ ] where u + v + w + x + y + z has an average value of 2. Sorbeth-40 The hexaester of oleic acid and sorbeth-40. Surfactant- hexaoleate emulsifying agent

[ ] where u + v + w + x + y + z has an average value of 40. Sorbeth-50 The hexaester of oleic acid with a polyethylene glycol ether of sorbitol containing an average of 50 moles of Surfactant- hexaoleate ethylene oxide. emulsifying agent

[ ] where u + v + w + x + y + z has an average value of 50. Distributed for comment only -- do not cite or quote

Table 1. The Definitions and Functions of the Polysorbates in This Safety Assessment.4 [Bracketed entries are the work product of CIR staff] Ingredient and CAS No. Definition Function Sorbeth-2 The hexaester of a mixture of caprylic and capric acids with a polyethylene glycol ether of sorbitol Skin- hexacaprylate/ containing an average of 2 moles of ethylene oxide. conditioning caprate agent-emollient

[ where n is in each case 6 or 8, and u + v + w + x + y + z has an average value of ] 2. Sorbeth-12 The hexaester of coconut acid with a polyethylene glycol ether of sorbitol containing an average of 12 moles Skin- hexacocoate of ethylene oxide. conditioning agent-emollient

where CH3(CH2)n C(O)- represents the fatty acids derived from cocos nucifera (coconut) oil and u + v + w + x + y + z has an average value of 12. The fatty acid distribution of coconut oil is 0-1% caproic, 5-9% caprylic, 6-10% capric, 44-52% lauric, 13-19% myristic, 0-1% palmitoleic, 1-3% stearic, 5-8% oleic, [ 55 ] and trace-2.5% linoleic acid.

Other Sorbeth-2/oleate/ The crosslinked polymer of a 2-mole ethoxylate of sorbitol, oleic acid, and dilinoleic acid. Skin- dimer dilinoleate conditioning crosspolymer agent – emollient

[ where R is hydrogen, oleate, or dimer dilinoleate, and u + v + w + x + y + z has an ] average value of 2.

Distributed for comment only -- do not cite or quote

Table 2. Previous safety assessment of polysorbates and component moieties of the ingredients in this safety assessment. Maximum concentration Ingredients Conclusion in report Reference Previous safety assessment of polysorbates Polysorbates – polysorbate 20, 21, 40, 60, 61, 65, 80, 81, 85 Safe as used. >50% 1 Polysorbates – PEG-20 sorbitan cocoate, PEG-40 sorbitan diisostearate, PEG-2 sorbitan Safe as used. 10% 2 isostearate, PEG-5 sorbitan isostearate, 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, PEG-3 sorbitan oleate, PEG-6 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, PEG-30 sorbitan tetraoleate, PEG-40 sorbitan tetraoleate, PEG-60 sorbitan tetraoleate, PEG-60 sorbitan tetrastearate, PEG-20 sorbitan triisostearate, PEG-160 sorbitan triisostearate, PEG-40 sorbitol hexaoleate (currently sorbeth-40 hexaoleate), PEG-50 sorbitol hexaoleate(currently sorbeth-50 hexaoleate), PEG-30 sorbitol tetraoleate laurate (currently sorbeth-30 tetraoleate laurate), PEG-60 sorbitol tetrastearate (currently sorbeth-60 tetrastearate) Sorbeth-6 beeswax, Sorbeth-8 beeswax, Sorbeth-20 beeswax Safe for use as cosmetic 11% 6 ingredients under the present practices of use. The Expert Panel recommends that cosmetic formulations containing PEG-6, PEG-20, or PEG- 75 not be used on damaged skin.* Safety assessments of components Beeswax, candelilla wax, carnauba wax, and Japan wax Safe as used. 56% 8,14 Coconut oil, acid and related ingredients Safe as used 100% 8,10,11,56 Isostearic acid Safe as used. 26% 8,13 Lanolin acid Safe as used 65% 8,12 Oleic acid, lauric acid, myristic acid, stearic acid Safe in the present > 50%; 43% 9,16 practices of use and concentration. Polyethylene glycols (PEG) - triethylene glycol and polyethylene (PEGs) -4, -6, -7, -8, -9, Safe in the present 85% 7,17 -10, -12, -14, -16, -18, -20, -32, -33, -40, -45, -55, -60, -75, -80, -90, -100, -135, -150, practices of use and -180, -200, -220, -240, -350, -400, -450, -500, -800, -2M, -5M, -7M, -9M, -14M, -20M, concentration.* -23M, -25M, -45M, -65M, -90M, -115M, -160M, and -180M and any PEG >= 4 Sorbitan esters - sorbitan caprylate, sorbitan cocoate, sorbitan diisostearate, sorbitan Safe as used. 9.1% 19-21 dioleate, sorbitan distearate, sorbitan isostearate, sorbitan laurate, sorbitan oleate, sorbitan olivate, sorbitan palmitate, sorbitan sesquiisosotearate, sorbitan stearate, sorbitan sesquioleate, sorbitan triisostearate, sorbitan trioleate, and sorbitan tristearate Stearates - butyl stearate, cetyl stearate, isobutyl stearate, isocetyl stearate, isopropyl Safe as used. 87% 8,15 stearate, myristyl stearate, and octyl stearate Alkyl Esters Safe as used 78% 18 * In 2010, the Panel concluded that PEGs were safe as used and removed the caveat that PEGs should not be used on damaged skin.7

Table 3. Chemical and physical properties of some polysorbates. Property Value Reference Polysorbate 21 Physical Form Liquid/Oily liquid 22 Molecular Weight g/mol 390.5 22 PEG-10 sorbitan laurate Physical Form Unctuous liquid 57 Color Clear yellow 57 Odor Mild 57 Water Solubility Soluble 57 Other Solubility Acetone Soluble 57 Ethyl acetate Soluble 57 Mineral oil Insoluble 57 Distributed for comment only -- do not cite or quote

Table 3. Chemical and physical properties of some polysorbates. Property Value Reference Polysorbate 20 Physical Form Liquid 22,58 Oily liquid 59 Color Lemon-amber 22,58,59 Odor Characteristic 22,58 Molecular Weight g/mol ~1228 58 Density/Specific Gravity @ 25oC 1.095 22,58 Water Solubility Soluble 57,58 Other Solubility Ethanol Soluble 57,58 Ethyl acetate Soluble 57,58 Mineral oil Insoluble 59 Polysorbate 40 Physical Form Oily liquid or Vaseline- 60-63 like Color Lemon-orange 64 Odor Characteristic 2,57,64 Density/Specific Gravity 1.05 63 Water Solubility Soluble 57,64 Other Solubility Methanol Soluble 57,64 Ethanol Soluble 57,64 Mineral oil Insoluble 57,64 Polysorbate 61 Physical Form Waxy solid 57,60,65 Color Tan 57 Water Solubility Dispersable 66 Other Solubility Ethylene glycol Insoluble 66 Propylene glycol Insoluble 66 Polysorbate 60 Physical Form Oily liquid 60,67 Semigel 67,68 Wax 69 Color Lemon yellow 57 Yellow-orange 67 Odor Characteristic 67 Water Solubility Soluble 67 Other solubility Ethyl acetate Soluble 67 Tolulene Soluble 67 Vegetable and mineral oil insoluble 67 Polysorbate 65 Physical Form Waxy solid 60,61,70 Color Tan 57,70 Odor Faint, characteristic 57,70 Water Solubility Dispersible 57 Other Solubility Acetone Soluble 70 Ethanol Soluble 57 Methanol Soluble 57 Vegetable and mineral oil Soluble 57 Distributed for comment only -- do not cite or quote

Table 3. Chemical and physical properties of some polysorbates. Property Value Reference Polysorbate 81 Physical Form Liquid 23 May gel at room 61 temperature Color Clear 23 Odor Faint 57 Density/Specific Gravity @ 20oC 1.0356 23 @ 25 oC 1.032 23 @ 20 oC 10299 23 @ 25 oC 1.0264 23 Viscosity kg/(s m) @ 20oC 0.672 23 0.84 23 @ 25oC 0.328 23 0.383 23 Vapor pressure mmHg 0.002 23 Melting Point oC -33.9 23 -32.7 23 Water Solubility g/L ~0.100 23 ~0.035 23 @ 20oC & pH 8.29-9.39 >0.500 23 Other Solubility Ether Dispersible 57 Ethylene glycol Dispersible 57 Ethanol Soluble 57 PEG-20 sorbitan oleate Density/Specific Gravity 1.1/1.064 2 Other Solubility Dimethyl sulfoxide Soluble 57 Ethanol Soluble 57 Mineral oil Soluble 57 Toluene Soluble 57 Polysorbate 80 Physical Form Viscous, oily liquid 60,62,63,68,69,71-73 Color Lemon to orange/amber 57,73,74 Odor Characteristic 57,73 Density/Specific Gravity 1.08 71 1.06-1.10 72,74 1.07-1.09 63 Viscosity kg/(s m) 0.3-0.5 74 Water Solubility Soluble 57 Other Solubility Ethanol Soluble 73 Methanol Soluble 73 Toluene Soluble 73 Mineral oil Insoluble 73 Petroleum ether Insoluble 73 PEG-40 sorbitan lanolate Physical Form Soft paste 66 Water Solubility @ 65oC Soluble 66 Other Solubility @ 65oC Dioxane Soluble 66 Carbon tetrachloride Soluble 66 Sorbeth-6 beeswax Physical Form Waxy solid 75 Color Tan 75 Odor Fatty 75 Water Solubility Insoluble 75 Other Solubility Corn oil Soluble 75 Ethylene glycol Insoluble 75 Mineral oil Insoluble 75 Sorbeth-20 beeswax Physical Form Waxy solid 75 Color Tan 75 Odor Mild, fatty 75 Water Solubility Insoluble 75 Other Solubility 75 Warm corn oil Soluble Mineral oil Dispersible Distributed for comment only -- do not cite or quote

Table 3. Chemical and physical properties of some polysorbates. Property Value Reference Polysorbate 85 Physical Form Liquid 60,62 May gel at room 57,61 temperature Color Clear amber 57 Odor Characteristic 57 Water Solubility Dispersible 57 Other Solubility Vegetable and mineral oils Soluble 57 PEG-40 sorbitan peroleate Physical Form Viscous, oily liquid 66 Color Clear yellow 66 Odor Faint characteristic 66 Water Solubility Dispersible 66 Other Solubility 66 Mineral oil Soluble

Table 4. Chemical and physical properties of generic Sorbitan monolaurate, ethoxylated ingredients. Property Value Reference Sorbitan monolaurate, ethoxylated Physical Form Liquid 22

Water Solubility g/L @ 20 oC & pH 6.3 and 7.9 <2.0 22 Sorbitan monostearate, ethoxylated Physical Form Solid (wax) 24 Color Colorless 24 Odor Odorless 24 Density/Specific Gravity @ 23oC 1.007 24 @ 25oC 1.07 24 Vapor pressure mmHg @ 20oC <0. 0.75 24 @ 20oC <0.1 24 Melting Point oC 45-50 24 39.6 24 Boiling Point oC 90.4 24 Water Solubility g/L @ 23oC 0.300 24 Other Solubility g/L Petroleum ether @ 23oC 1.800 24 Methanol @ 23oC 0.200 24 o 24 log Kow @ 23 C & pH 6.4 0.03 Disassociation constants pKa @ 23oC 0.199 x 10-9 24

Table 5. The approximate ester content of some polysorbates.22,26 Ingredient Laurate (%) Myristate (%) Palmitate (%) Stearate (%) Oleate (%) Other esters (%) Polysorbate 20 39±2 26±1 12±1 12±2 ND 11±2 Polysorbate 21 40-60 14-25 6-15 0-7 0-11 0-24 Polysorbate 40 <1 2 87±2 10±1 ND <1 Polysorbate 60 2±1 4±1 43±1 51±2 ND <1 Polysorbate 80 <1 2 22±2 11±2 66±1 <1 ND=none detected

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Table 6. Current and historical frequency and concentration of use of polysorbates according to duration and exposure.1,2,5,6,14,31 # of Uses Max Conc of Use (%) # of Uses Max Conc of Use (%) 2015 1998** 2014 1981*** 2015 1998 2014 1981 Polysorbate 20 Polysorbate 21 Totals* 3013 770 0.00001-19.6 0.09->50 55 4 0.33-8 0.1-1 Duration of Use Leave-On 1639 446 0.00001-9.1 0.09->50 17 4 0.33-2 0.1-1 Rinse-Off 1275 297 0.0006-19.6 0.09-25 38 NR 0.5-8 NR Diluted for (Bath) Use 99 27 0.0097-8.9 0.1-50 NR NR NR NR Exposure Type Eye Area 226 39 0.00015-3.5 0.1-10 4 NR 0.5 NR Incidental Ingestion 32 12 0.01-5.8 0.09-5 NR NR NR NR 0.00001-3d; 0.09-1; 35; 546a; 22; 169a; Incidental Inhalation-Spray 0.0019-3a; <0.1->50a; 6a 4a 0.33g 0.1-1a 397c 50c 0.76-2c 0.09-5c 0.00075-3; 0.1-1; Incidental Inhalation-Powder 52; 5b; 397c 43; 50c 0.0006-9.1b; NR NR 0.38b NR 0.09-5c 0.76-2c Dermal Contact 2299 493 0.00001-19.6 0.09-5 14 4 0.38-2 NR 0.00018-4e; Deodorant (underarm) 9a 3a 0.1-5a NR NR NR NR 0.00082-3f Hair - Non-Coloring 555 205 0.006-12.6 0.09-25 14 NR 0.33-8 NR Hair-Coloring 92 50 0.4-3.8 0.09-5 24 NR 2.4 NR Nail 11 6 0.000041-3.3 0.09-5 NR NR NR NR Mucous Membrane 822 66 0.0006-19.6 0.09->50 3 NR NR NR Baby Products 32 3 0.00078-12.6 0.1-25 NR NR NR NR

2015 1998 2014 1981 2014 1998 2014 1981 Polysorbate 40 Polysorbate 60 Totals* 80 32 0.008-5 0.09-10 1589 332 0.0000001-6 0.09-25 Duration of Use Leave-On 65 24 0.008-5 0.09-10 1228 255 0.00009-4 0.09-25 Rinse-Off 15 8 1.5-3 0.09-5 358 77 0.0000001-6 0.09-5 Diluted for (Bath) Use NR NR NR NR 3 NR 0.0015-0.06 0.1-10 Exposure Type Eye Area 12 1 0.015-3.75 1-5 75 35 0.0021-3.8 0.09-10 Incidental Ingestion 1 NR NR NR 13 NR 0.2-0.4 0.09-5 0.0025-0.8h; 0.1-10a; 2; 635a; Incidental Inhalation-Spray 24a; 21c 13a; 3c 0.5-2.5a 93a; 59c 0.0005-4a; 0.1-10a 0.1-5c 338c 2.4c 0.053; 7; 10b; Incidental Inhalation-Powder 21c 3c 0.019-5b 0.1-5c 59c 0.018-3.7b; 0.09-5 338c 2.4c Dermal Contact 76 29 0.008-5 0.09-10 1302 297 0.00009-6 0.09-10 Deodorant (underarm) NR NR NR NR 1a NR 0.02f NR Hair - Non-Coloring 1 2 0.8-2.5 0.09-5 156 22 0.0000001-5 0.1-25 Hair-Coloring NR NR NR NR 107 1 0.002-2.5 1-5 Nail NR 1 NR 0.1-5 2 5 3.5 0.1-5 Mucous Membrane 4 NR 3 NR 52 NR 0.0008-2 0.09-10 Baby Products NR NR NR NR 11 3 0.00009-1.5 NR

Distributed for comment only -- do not cite or quote

Table 6. Current and historical frequency and concentration of use of polysorbates according to duration and exposure.1,2,5,6,14,31 # of Uses Max Conc of Use (%) # of Uses Max Conc of Use (%) 2015 1998 2014 1981 2015 1998 2014 1981 Polysorbate 61 Polysorbate 65 Totals* 16 8 1-1.8 0.1-5 24 2 0.0003-3 1-5 Duration of Use Leave-On 16 8 1-1.8 0.1-5 21 NR 0.0003-3 NR Rinse-Off NR NR NR 0.1-5 3 2 0.002-0.15 1-5 Diluted for (Bath) Use NR NR NR NR NR NR NR NR Exposure Type Eye Area NR NR NR NR 5 NR 0.5 NR Incidental Ingestion NR NR NR NR NR NR NR NR Incidental Inhalation-Spray 9a; 5c 4c NR 1-5a; 0.1-1c 7a; 8c NR NR NR Incidental Inhalation-Powder 1b; 5c 3b; 4c 1.8b 1-5b; 0.1-1c 8c NR 0.003-3b NR Dermal Contact 16 8 1-1.8 0.1-5 24 1 0.0003-3 1-5 Deodorant (underarm) NR NR NR NR NR NR 0.0003f NR Hair - Non-Coloring NR NR NR NR NR 1 NR NR Hair-Coloring NR NR NR NR NR NR NR NR Nail NR NR NR NR NR NR 0.002-0.003 NR Mucous Membrane NR NR NR NR NR NR NR NR Baby Products 1 4 NR 1-5 NR NR NR NR

2015 1998 2014 1981 2015 1998 2014 1981 Polysorbate 80 Polysorbate 81 Totals* 932 231 0.00031-18.1 0.01-25 NR 4 0.4-25.6 0.1-5 Duration of Use Leave-On 759 132 0.00031-11.9 0.01-10 NR 4 0.5-7.5 0.1-5 Rinse-Off 166 89 0.0038-18.1 0.09-10 NR NR 0.4-25.6 0.1-5 Diluted for (Bath) Use 7 10 NR 0.1-25 NR NR 5-7.5 NR Exposure Type Eye Area 114 16 0.0024-11 0.09-5 NR NR 0.5 NR Incidental Ingestion 45 15 0.00031-1.5 0.09-1 NR NR NR NR 0.1-1; 15; 315a; 16; 71a; 0.02-11.9i; 0.1-5a; Incidental Inhalation-Spray 0.09-10a; NR 1a 5 196c 13c 0.0038-2a 0.1-1c 0.09-10c 1-10; 18;2b; 0.42-2; Incidental Inhalation-Powder 7; 13c 0.09-10b; NR NR 5b 0.1-1c 196c 0.005-2c 0.09-10c Dermal Contact 731 122 0.00075-18.1 0.01-25 NR 3 0.5-25.6 0.1-1 Deodorant (underarm) 1a NR NR 0.09-1a NR NR NR NR Hair - Non-Coloring 118 80 0.02-10 0.09-10 NR 1 0.4 0.1-5 Hair-Coloring 25 10 0.36 NR NR NR NR NR Nail 7 2 NR 0.1-1 NR NR 7.5 NR Mucous Membrane 75 29 0.00031-1.5 0.09-25 NR NR 5-7.5 NR Baby Products 4 4 10 0.1-10 NR NR NR NR

2015 1998 2014 1981 2015 1998 2014 1998 Polysorbate 85 PEG-20 sorbitan isostearate Totals* 51 35 0.03-21.9 0.01->50 3 2 0.3 NR Duration of Use Leave-On 23 28 0.03-6 0.01-10 3 2 0.3 NR Rinse-Off 15 7 5.5-21.9 0.09->50 NR NR NR NR Diluted for (Bath) Use 13 NR 0.03-0.055 NR NR NR NR NR Exposure Type Eye Area 4 5 NR 0.09-5 NR NR NR NR Incidental Ingestion NR NR NR NR NR NR NR NR 0.01-10a; Incidental Inhalation-Spray 1; 6a; 5c NR NR 1a; 2c 1a NR NR 0.1-1c 0.01-1b; Incidental Inhalation-Powder 1; 5c NR 0.06-0.54b 2c NR 0.3b NR 0.1-1c Dermal Contact 51 30 0.03-21.9 0.01-10 3 NR 0.3 NR Deodorant (underarm) NR NR NR NR NR NR NR NR Hair - Non-Coloring NR 4 NR 0.01-5 NR NR NR NR Hair-Coloring NR 1 NR >50 NR NR NR NR Nail NR NR NR NR NR 1 NR NR Mucous Membrane 14 NR 0.03-0.55 NR NR NR NR NR Baby Products NR NR NR NR NR NR NR NR

Distributed for comment only -- do not cite or quote

Table 6. Current and historical frequency and concentration of use of polysorbates according to duration and exposure.1,2,5,6,14,31 # of Uses Max Conc of Use (%) # of Uses Max Conc of Use (%) 2014 1998 2014 1998 2015 1998 2014 1998 PEG-40 sorbitan lanolate PEG-10 sorbitan laurate Totals* NR 7 NR NR 2 2 NR NR Duration of Use Leave-On NR 4 NR NR 1 NR NR NR Rinse-Off NR 3 NR NR 1 2 NR NR Diluted for (Bath) Use NR NR NR NR NR NR NR NR Exposure Type Eye Area NR NR NR NR NR NR NR NR Incidental Ingestion NR NR NR NR NR NR NR NR Incidental Inhalation-Spray NR 1a NR NR 1a NR NR NR Incidental Inhalation-Powder NR NR NR NR NR NR NR NR Dermal Contact NR NR NR NR 2 NR NR NR Deodorant (underarm) NR NR NR NR NR NR NR NR Hair - Non-Coloring NR 5 NR NR NR 1 NR NR Hair-Coloring NR 2 NR NR NR NR NR NR Nail NR NR NR NR NR 1 NR NR Mucous Membrane NR NR NR NR NR NR NR NR Baby Products NR NR NR NR NR NR NR NR

2015 1998 2014 1998 2015 1998 2014 1998 PEG-44 sorbitan laurate PEG-80 sorbitan laurate Totals* 3 8 0.5-2 NR 93 34 0.0002-4.2 NR Duration of Use Leave-On 1 6 2 NR 20 6 0.0002-0.059 NR Rinse-Off 2 2 0.5 NR 60 28 2-4.2 NR Diluted for (Bath) Use NR NR NR NR 13 NR 2.5 NR Exposure Type Eye Area NR NR NR NR NR NR NR NR Incidental Ingestion NR NR NR NR 1 NR 0.059 NR Incidental Inhalation-Spray 1a 1a NR NR NR NR NR NR Incidental Inhalation-Powder NR NR NR NR NR NR 0.0002-0.0098b NR Dermal Contact 3 8 2 NR 70 14 0.0002-4.2 NR Deodorant (underarm) NR NR NR NR NR NR NR NR Hair - Non-Coloring NR NR 0.5 NR 22 20 4.2 NR Hair-Coloring NR NR NR NR NR NR NR NR Nail NR NR NR NR NR NR NR NR Mucous Membrane NR NR NR NR 36 2 0.059-4.2 NR Baby Products NR NR NR NR 33 15 4.2 NR

2015 1998 2014 1998 2015 1998 2014 1998 PEG-3 sorbitan oleate PEG-40 sorbitan peroleate Totals* 1 4 NR NR 53 13 0.16-4 NR Duration of Use Leave-On 1 4 NR NR 51 8 0.16-4 NR Rinse-Off NR NR NR NR 2 NR NR NR Diluted for (Bath) Use NR NR NR NR NR 5 NR NR Exposure Type Eye Area NR NR NR NR 8 NR NR NR Incidental Ingestion NR NR NR NR NR NR NR NR Incidental Inhalation-Spray 1a 1a NR NR 14a; 13c 6a; 1c 4a NR Incidental Inhalation-Powder NR NR NR NR 13c 1; 1c 0.3-0.9b NR Dermal Contact 1 3 NR NR 50 13 0.16-1 NR Deodorant (underarm) NR NR NR NR NR NR NR NR Hair - Non-Coloring NR 1 NR NR 3 NR 4 NR Hair-Coloring NR NR NR NR NR NR NR NR Nail NR NR NR NR NR NR NR NR Mucous Membrane NR NR NR NR NR 5 NR NR Baby Products NR NR NR NR NR NR NR NR

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Table 6. Current and historical frequency and concentration of use of polysorbates according to duration and exposure.1,2,5,6,14,31 # of Uses Max Conc of Use (%) # of Uses Max Conc of Use (%) 2015 1998 2014 1998 2015 1998 2014 1998 PEG-40 sorbitan stearate PEG-40 sorbitan tetraoleate Totals* 1 1 NR NR 1 1 NR NR Duration of Use Leave-On 1 NR NR NR 1 1 NR NR Rinse-Off NR 1 NR NR NR NR NR NR Diluted for (Bath) Use NR NR NR NR NR NR NR NR Exposure Type Eye Area NR NR NR NR NR NR NR NR Incidental Ingestion NR NR NR NR NR NR NR NR Incidental Inhalation-Spray NR NR NR NR 1c 1c NR NR Incidental Inhalation-Powder 1a NR NR NR 1c 1c NR NR Dermal Contact 1 1 NR NR 1 1 NR NR Deodorant (underarm) NR NR NR NR NR NR NR NR Hair - Non-Coloring NR NR NR NR NR NR NR NR Hair-Coloring NR NR NR NR NR NR NR NR Nail NR NR NR NR NR NR NR NR Mucous Membrane NR NR NR NR NR NR NR NR Baby Products 1 NR NR NR NR NR NR NR

2015 1998 2014 1999 Sorbeth-20 beeswax Totals* 9 16 0.5-2.8 0.5-2.8 Duration of Use Leave-On 9 1 0.5-2.8 NR Rinse-Off NR NR NR NR Diluted for (Bath) Use NR NR NR NR Exposure Type Eye Area 7 11 2.8 2.8 Incidental Ingestion 1 4 2.5 2.5 Incidental Inhalation-Spray NR NR NR NR Incidental Inhalation-Powder NR NR 0.5-1b NR Dermal Contact 1 4 0.5-1 0.5-1 Deodorant (underarm) NR NR NR NR Hair - Non-Coloring NR NR NR NR Hair-Coloring NR NR NR NR Nail NR NR NR NR Mucous Membrane 1 4 2.5 2.5 Baby Products NR NR NR NR NR – no reported use * Because each ingredient may be used in cosmetics with multiple exposure types, the sum of all exposure types may not equal the sum of total uses. ** The year that the Council survey was conducted in the previous report. In the report published in 2000, the only concentration of use data that were provided was the following: “…PEG-60 sorbitan tetratoleate, PEG-40 sorbitan tetraoleate, and PEG-160 sorbitan Triisostearate are used in cosmetics at concentrations of 0.5% to 10%...” in 1998. Since the data from the 2000 report is limited, the concentration of use data from the 1984 report are provided here to give a better historical perspective. *** At the time of the 1984 safety assessment, concentration of use data were not reported by the FDA; 1981 data were presented. These data were presented in ranges so the limits of the ranges are represented here. a It is possible these products are sprays, but it is not specified whether the reported uses are sprays. b It is possible these products are powders, but it is not specified whether the reported uses are powders. c Not specified whether a spray or a powder, but it is possible the use can be as a spray or a powder, therefore the information is captured in both categories. d Aerosol hair spray 0.027%-3%; pump hair spray 0.4%-1%; spray body and hand products 0.00001%-1.2%; spray moisturizing products 0.1%. e Spray deodorants. f Not spray deodorants. g Aerosol hair spray. h Spray body and hand products 0.083%-0.8%. i Aerosol hair spray 0.078%-1.6%; pump hair spray 0.02%-0.2%; spray face and neck products 0.39%.

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PEG-40 sorbitan laurate PEG-75 sorbitan laurate PEG-6 sorbitan oleate PEG-3 sorbitan stearate Total/range NR 0.25-2 NR 0.5-2 NR 0.43 3 NR Duration of use Leave-on NR 2 NR NR NR 0.43 2 NR Rinse-off NR 0.25-0.5 NR 0.5-2 NR NR 1 NR Diluted for (bath) NR NR NR NR NR NR NR NR use Exposure type Eye area NR NR NR NR NR NR NR NR Incidental NR NR NR NR NR NR NR NR ingestion Incidental NR NR NR NR NR NR NR NR Inhalation-sprays Incidental NR NR NR NR NR NR NR NR inhalation-powders Dermal contact NR 2 NR 2 NR 0.43 3 NR Deodorant NR NR NR NR NR NR NR NR (underarm) Hair-noncoloring NR 0.5 NR 0.5 NR NR NR NR Hair-coloring NR 0.25 NR NR NR NR NR NR Nail NR NR NR NR NR NR NR NR Mucous NR NR NR NR NR NR NR NR Membrane Baby NR NR NR NR NR NR NR NR

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PEG-6 sorbitan stearate stearate tetraoleate tetraoleate Total/range 2 3.4 1 NS 1 10 NR 0.5-0.9 Duration of use Leave-on NR NR 1 NS NR NR NR 0.5-0.9 Rinse-off 2 3.4 NR NS 1 10 NR NR Diluted for (bath) NR NR NR NS NR NR NR NR use Exposure type Eye area NR NR NR NS NR NR NR NR Incidental NR NR NR NS NR NR NR NR ingestion Incidental NR NR NR NS NR NR NR 0.5-0.8a Inhalation-sprays Incidental NR NR NR NS NR NR NR 0.9c inhalation-powders Dermal contact 2 3.4 1 NS 1 10 NR 0.8-0.9 Deodorant NR NR NR NS NR NR NR NR (underarm) Hair-noncoloring NR NR NR NS NR NR NR 0.5 Hair-coloring NR NR NR NS NR NR NR NR Nail NR NR NR NS NR NR NR NR Mucous NR NR NR NS NR NR NR NR Membrane Baby NR NR NR NS NR NR NR NR

PEG-160 sorbitan Sorbeth-30

triisostearate Sorbeth-6 beeswax tetraisostearate Sorbeth-4 tetraoleate Total/range 4 NR 7 2 1 NR 4 NR Duration of use Leave-on NR NR 7 2 1 NR 4 NR Rinse-off 4 NR NR NR NR NR NR NR Diluted for (bath) NR NR NR NR NR NR NR NR use Exposure type Eye area NR NR 3 NR NR NR NR NR Incidental NR NR NR NR NR NR NR NR ingestion Incidental NR NR NR NR 1c NR NR NR Inhalation-sprays Incidental NR NR NR NR 1c NR NR NR inhalation-powders Dermal contact 1 NR 7 2 1 NR 4 NR Deodorant NR NR NR NR NR NR NR NR (underarm) Hair-noncoloring 3 NR NR NR NR NR NR NR Hair-coloring NR NR NR NR NR NR NR NR Nail NR NR NR NR NR NR NR NR Mucous 1 NR NR NR NR NR NR NR Membrane Baby NR NR NR NR NR NR NR NR

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Table 7. Frequency of use according to duration and exposure of polysorbates that are reviewed for the first time in this safety assessment.5,31 Maximum Maximum Maximum Maximum Concentration Concentration Concentration Concentration Use type Uses (%) Uses (%) Uses (%) Uses (%) Sorbeth-6 tetraoleate Sorbeth-30 tetraoleate Sorbeth-40 tetraoleate Sorbeth-60 tetraoleate Total/range NR 0.21 10 0.11-10.8 2 0.5 1 NR Duration of use Leave-on NR 0.21 4 NR 1 0.5 1 NR Rinse-off NR NR 6 0.11-10.8 1 NR NR NR Diluted for (bath) NR NR NR NR NR NR NR NR use Exposure type Eye area NR NR NR NR NR NR NR NR Incidental NR NR NR NR NR NR NR NR ingestion Incidental NR NR NR NR 1b NR 1a NR Inhalation-sprays Incidental inhalation- NR 0.21 NR NR 1b 0.5c NR NR powders Dermal contact NR 0.21 10 0.11-10.8 2 0.5 1 NR Deodorant NR NR NR NR NR NR NR NR (underarm) Hair-noncoloring NR NR NR NR NR NR NR NR Hair-coloring NR NR NR NR NR NR NR NR Nail NR NR NR NR NR NR NR NR Mucous NR NR NR NR NR NR NR NR Membrane Baby NR NR NR NR NR NR NR NR NR = Not Reported; NS = Not Surveyed; Totals = Rinse-off + Leave-on Product Uses. Note: Because each ingredient may be used in cosmetics with multiple exposure types, the sum of all exposure type uses may not equal the sum total uses. *Because each ingredient may be used in cosmetics with multiple exposure types, the sum of all exposure types may not equal the sum of total uses. a It is possible these products may be sprays, but it is not specified whether the reported uses are sprays. b Not specified whether a powder or a spray, so this information is captured for both categories of incidental inhalation. c It is possible these products may be powders, but it is not specified whether the reported uses are powders.

Table 8. Ingredients for which there were no reported current or historic uses from the VCRP or the Council.5,31 PEG-2 sorbitan isostearate Sorbeth-2 hexaoleate PEG-5 sorbitan isostearate Sorbeth-40 hexaoleate PEG-75 sorbitan lanolate Sorbeth-50 hexaoleate PEG-20 sorbitan oleate Sorbeth-6 hexastearate PEG-40 sorbitan oleate Sorbeth-150 hexastearate PEG-80 sorbitan palmitate Sorbeth-3 isostearate PEG-40 sorbitan perisostearate Sorbeth-6 laurate PEG-4 sorbitan stearate* Sorbeth-2/oleate/dimer dilinoleate crosspolymer PEG-60 sorbitan stearate Sorbeth-20 pentaisostearate PEG-60 sorbitan tetrastearate Sorbeth-30 pentaisostearate PEG-4 sorbitan triisostearate Sorbeth-40 pentaisostearate PEG-20 sorbitan triisostearate Sorbeth-50 pentaisostearate PEG-2 sorbitan trioleate Sorbeth-40 pentaoleate PEG-3 sorbitan tristearate Sorbeth-20 tetraisostearate Sorbeth-2 beeswax Sorbeth-40 tetraisostearate Sorbeth-8 beeswax Sorbeth-50 tetraisostearate Sorbeth-2 cocoate Sorbeth-30 tetraoleate laurate Sorbeth-2 hexacaprylate/caprate Sorbeth-60 tetrastearate Sorbeth-12 hexacocoate Sorbeth-3 tristearate Sorbeth-2 hexaisostearate Sorbeth-160 tristearate Sorbeth-2 hexalaurate Sorbeth-450 tristearate * The Council has not completed the survey for concentration of use data.

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Table 9. U. S. regulations controlling the use of polysorbates. Ingredient Regulation Citation Polysorbate 20, 60, 65, and 80 Approved as diluents in color additives for drug use. 21CFR73.1; 21CFR73.1001 Polysorbates 20, 60, and 80 Approved for direct use in all food types as synthetic flavorings. 21CFR172.623 Polysorbate 80 Approved to be used with carrageenan to make chewing gum bases and related 21CFR172.623 substances. Polysorbate 60, 65, and 80 Approved as multipurpose additives. 21CFR172.836; 21CFR172.838; 21CFR172.840 Polysorbate 20 Permitted as a secondary direct food additive for human consumption. 21CFR173.310 Polysorbate 60, 65, and 80 Approved as defoaming agents in food for human consumption. 21CFR173.340 Polysorbate 20, 40, 60, and 80; PEG-3 sorbitan Approved for indirect addition to all food types as components of adhesives. 21 CFR 175.105 stearate; and PEG-3 sorbitan oleate PEG-40 sorbitan laurate, PEG-6 sorbitan stearate, May be used as indirect food additives as a defoaming agent in the manufacture 12CFR176.210 PEG-40 sorbitan stearate, PEG-6 sorbitan oleate, of paper and paperboard. PEG-40 sorbitan tetraoleate, and PEG-40 sorbitan peroleate Polysorbate 20, 40, 60, 65, 80, and 85, and PEG-3 Approved for indirect addition to all food types as emulsifiers and/or surfactants. 21CFR178.3400 sorbitan oleate PEG-3 sorbitan oleate May be used as a component of paper and paperboard in contact with dry food. 21CFR180 Polysorbate 80 Approved as an ophthalmic demulcent. 21CFR349.12 Polysorbate 60 and 80 Approved for use in animal feed and drinking water. 21CFR573.840; 21CFR573.860 Polysorbate 80 May be used to denature spirits. 27CFR21.68; 27CFR21.151

Table 10. Penetration enhancement studies of some polysorbates. 40 Ingredient Chemical/drug tested Results; notes Polysorbate 20 Albuterol sulfate ER compared to control (saline buffer)=3.43±0.52; ER compared to vehicle (5%) (ethanol)=1.26±0.32. Thawed, hairless mouse skin pretreated with test substance using Franz cells. Polysorbate 65 Albuterol sulfate ER compared to control (saline buffer)=4.74±0.23; ER compared to vehicle (5%) (ethanol)=1.75±0.29. Thawed, hairless mouse skin pretreated with test substance using Franz cells. Polysorbate 80 Albuterol sulfate ER compared to control (saline buffer)=2.95±0.45; ER compared to vehicle (5%) (ethanol)=1.09±0.17. Thawed, hairless mouse skin pretreated with test substance using Franz cells. ER=Enhancement ratio

Table 11. Highest reported historic NOAELs for polysorbate 20 and polysorbate 80 reported in a survey of 4 research laboratories.41 Animal Route Duration Dose Comments Polysorbate 20 Rat Oral 1 month 250 mg/kg Well tolerated Oral 90 days 500 mg/kg Diarrhea Mouse Oral 1 month 10 mg/kg Well tolerated Polysorbate 80 Dog Oral 90 days 5 mL/kg As 1% of formulation; well tolerated Rat Oral Not reported 350 mg/kg Well tolerated Oral 4 weeks 5 mL/kg 1%; well tolerated Oral 7 days 10 mL/kg 1%; well tolerated Intravenous Not reported 100 mg/kg Well tolerated Mouse Intraperitoneal 1 month 10 mL/kg 2%; well tolerated Intranasal 3 days 10 µL/nostril 0.2%; well tolerated Primate Oral Efficacy 5 mL/kg 1%; well tolerated

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Table 12. In vivo animal and human irritation studies of some polysorbates. Ingredient (concentration) Assay Results; notes Reference Animal studies Polysorbate 60 (5% and 10% Daily skin-painting study for 30 days on Moderate irritation observed at 5%; skin necrosis occurred at 24 aqueous) rabbits 10%. Polysorbate 60 (15% aqueous) Daily skin-painting study for 60 days on No dermal effects at 15%; mild irritation at 100%. 24 rabbits Polysorbate 60 (100%) Long-term (time not specified) dermal Local inflammation. 24 administration on mice Sorbitan monolaurate, Draize test using New Zealand White Draize score of 0.89. Scaliness was observed in all 3 animals 22 ethoxylated (100%; 0.5mL) Rabbits (n=3). The test sites were at 72 h after exposure and in 1 rabbit at 7 days after observed at 1, 24, 48, and 72 h and 7 exposure. days. Sorbitan monostearate, Dermally administered to rabbits (n not Necrosis of the skin at 10%. Necrosis was reversible after 24 ethoxylated (5% and 10% specified) for 30 days. stopping treatment. Moderate irritation was observed at 5%. aqueous) Sorbitan monostearate, Dermally administered to rabbits (n not Did not cause irritation. 24 ethoxylated (100%) specified) for 60 days. Sorbitan monostearate, Dermally administered to the shaved Did not produce any skin reaction. The irritation score was 24 ethoxylated (100%; 0.5 g) backs (approximately 6 cm2) of New 0.8 out of 8. Zealand white rabbits (n=3) for 4 h under occlusion. The test site was observed for 14 days after removal. Human studies Polysorbate 60 (concentration Administered to the forehead, dorsal, and Urticaria observed at application sites at 20 min caused by 24 not specified in a cream or arm skin. Amount and n not specified. both polysorbate 60-based cream and polysorbate 60. There 100%) was no effect of either the polysorbate 60 or the cream on the dorsal and arm skin Polysorbate 60 (1% in Human patch test scored according to Irritation score=0.4 out of 4. 47 DMEM) ICDRG. Patches were in place for 2 days in Haye’s chambers. n=30. Polysorbate 80 (100%) Test substance administered for 1 positive reaction. Control of 20% sodium dodecyl sulfate 46 increasing time periods: 15 min-4 h and exhibited 24 of 29 reactions. observed at 24, 48, and 72 h. n=29 Polysorbate 80 (100%) Test substance administered for 1 positive reaction. Control of 20% sodium dodecyl sulfate 48 increasing time periods to the upper outer exhibited 8 of 27 reactions. arm in a 25 mm Hill Top Chamber: 15 min-4 h and observed at 24, 48, and 72 h. n=24 Sorbitan monostearate, 10 drops of the solution administered to Irritation score 1 out of 68. Mild redness observed in 1 24 ethoxylated (25% aqueous) the scalp twice/d for 16 weeks. n=68 subject. Not irritating. DMEM – Dulbecco’s minimal essential medium

Table 13. Ocular irritation assays of some polysorbates. Ingredient (concentration) Assay Results; notes Reference Non-human Polysorbate 20 (10%) Draize test using New Zealand White rabbits (n=3) Maximal average score=0.7; 24-h 50, 51 average score=0.0 Polysorbate 81 (10% in light Draize test using New Zealand White Rabbits (n=9) Irritation score=0 out of 4; not 23 mineral oil) irritating. Polysorbate 81 (100%) Draize test using New Zealand White Rabbits (n=9). Irritation score=0 out of 4; not 23 Eyes were washed 2 sec after administration in 3 irritating. rabbits. Eyes were observed at 1, 24, 48, 72 h and 7 days. Sorbitan monostearate, ethoxylated Draize test using New Zealand White Rabbits (n=3) Irritation score-0 out of 110; not 24 (0.1 g in water) irritating. Did not produce any eye irritation or any eye discharge throughout the 72-h observation period. No lesions such as pannus or staining were observed. Sorbitan monolaurate, ethoxylated Draize test using New Zealand White rabbits (n=9). Irritation score=0 out of 4; not 22 (100%; 0.1 mL) Eyes were washed 2 sec after administration in 3 irritating. rabbits. Distributed for comment only -- do not cite or quote

Table 13. Ocular irritation assays of some polysorbates. Ingredient (concentration) Assay Results; notes Reference In vitro Polysorbate 20 (not provided) EpiOcular test over 7 laboratories Not predicted to be an ocular irritant. 53 Average mean cell viability 97.40±6.49% of distilled water control. Polysorbate 20 (2%) Red blood cell hemolysis assay Predicted to be a minimal ocular 49 irritant. Polysorbate 20 (2%) K562 cell assay Predicted to be a minimal ocular 49 irritant. Polysorbate 20 (5% in saline; 200 STE using SIRC cells (CCL-60). Exposure for 5 Predicted to be an irritant. 52 µL) min. Polysorbate 20 (100%; 50 µL) EpiOcular assay Predicted to be a non-irritant. 52 Polysorbate 20 (100%; 200 µL) HET-CAM assay (Fertilized chicken eggs (white Predicted to be an irritant. 52 leghorn breed) with microscopic evaluation of hemorrhage, lysis, and coagulation at 0.5, 2, and 5 min. Polysorbate 20 (100%) HET-CAM assay (Same as above but evaluation of Predicted to be a severe irritant. 52 time to hemorrhage, lysis, and coagulation) Polysorbate 20 (100%) BCOP assay Predicted to be a mild irritant. 52 BCOP=Bovine Corneal Opacity and Permeability assay; DMEM= Dulbecco's modified Eagle's medium; HET-CAM=Hen’s Egg Test- Chorioallantoic Membrane assay; ICDRG=International Contact Dermatitis Research Group; STE=Short Time Exposure test.

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Distributed for comment only -- do not cite or quote

Memorandum

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

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

DATE: April 9, 2015

SUBJECT: Comments on the Tentative Report: Safety Assessment of Polysorbates as Used in Cosmetics

Key Issues Introduction, Tables 1, 6 and 7 - PEG-20 sorbitan laurate is another name for Polysorbate 20 and PEG-20 sorbitan stearate is another name for Polysorbate-60. Therefore, it is not correct to state that these ingredients are not listed in the Dictionary. These two ingredients are in the Dictionary under different names. The VCRP information for PEG-20 sorbitan laurate should be combined with Polysorbate 20 and the VCRP information for PEG-20 sorbitan stearate should be combined with Polysorbate-60. The other names used in the VCRP could also be mentioned in Table 1 as alternative names. Presenting Information from Previous CIR Reports - There does not appear to be a consistent protocol for presenting information from previous reports. Republishing the summaries of previous safety assessments, especially when there are multiple summaries that are repetitive is not helpful. Summarizing the studies from the old reports in a table would be helpful, or summarizing the relevant information in the relevant section (which has been done in other re-reviews) would also be useful. For this report, if a study was presented in all three previous reports, it should be presented once in this report (either in a table or in the appropriate section) associated with three references. Non-cosmetic Use - What organization determined the ADI of 10 mg/kg for polysorbates? It is cited to reference 26 (Abrar and Trathnigg, 2009), implying they determined the ADI. It would be helpful to state if it was the FDA, JEFCA or another regulatory body that determined the ADI and to cite the ADI to the primary reference. As stated in the comments for the draft report for the March meeting, the penetration enhancement study (reference 38) was completed in hairless mice, not hairless rats as stated in the text (Penetration Enhancement section) and in Table 10. The complete study is available at: http://210.101.116.28/W_files/kiss10/81600753_pv.pdf Distributed for comment only -- do not cite or quote

Genotoxicity, Summary - Please ask the CIR Expert Panel if studies concerning apoptosis should be in the Genotoxicity section. These studies maybe more appropriate in a cytotoxicity section. Substances can result in apoptosis without directly interacting with DNA. Apoptosis is a process of cell death in which the DNA is fragmented, so the statement that “polysorbate 20 induced apoptosis by DNA fragmentation” is misleading. The statement in the Summary “inducing apoptosis via chromatin and DNA fragmentation” also needs to be corrected.

Additional Comments Summary 1984 Report - It is understood that the summaries are taken word for word from the original reports, but the following sentence is meaningless and should not be published again. “As expected, the Polysorbates are active at levels of biological structure and function from basic biochemical pathways to the cardiovascular and immune systems.” Previous report summaries - These summaries are not helpful if they do not include the concentrations/doses of the ingredients tested. Definition and Method of Manufacture - Please correct “by like chemical structures” Cosmetic Use, Table 1 - Was PEG-18 sorbitan trioleate ever listed? If it was never in the Dictionary, “no longer listed” needs to be revised to “not listed”.

The use section should note the ingredients for which the Council has not completed a concentration of use survey.

Please update the check of the Cosing database as Sorbeth-450 Tristearate is now included. Repeated Dose Exposure - The last paragraph is about a study in mice. Therefore, the last sentences that states: “...not clear if the rats continued...” needs to be revised. Reproductive and Developmental Toxicity, Polysorbate 80 - The following is not a complete sentence: “No effects on weight gain, organ weights (except non-adverse increased relative liver weights), and feed and water consumption.” Discussion - Please revise the following sentence: “Especially, care should be taken when creating formulations especially those products intended for use on infants.” Table 1 - If the ingredients are ordered by the number of moles of ethylene oxide, Polysorbate 20 needs to be moved before PEG-40 Sorbitan Laurate.

PEG-20 Sorbitan Isostearate - The number of moles of ethylene oxide in the definition needs to be corrected from “5" to “20".

If PEG-18 sorbitan oleate is included in Table 1, the other ingredient in the report that is not in the Dictionary (PEG-30 sorbitan beeswax) should also be added to Table 1.

Sorbeth-2/Oleate/Dimer Dilinoleate Crosspolymer - The definition from the Dictionary says “2-mole ethoxylate” while the staff added information says “u+v+w+x+y+z has an average value of 12" - 12 should be 2.

Page 2 of 3 Distributed for comment only -- do not cite or quote

Table 54 - Please check the CTFA specifications again (reference 54) as they do not include specifications for Polysorbate 21 and Sorbeth-6 Laurate which are included in Table 3 and listed with reference 54. Table 9 - The heading of this table should indicate that these are US regulations. Table 13 - Please indicate the species used in the first three studies. References - It is not clear why the first names of the authors are written out for some of the references while initials for first names are used for other references.

Reference 54 - Please correct: “Washingtonm”

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