Amended Safety Assessment of Butyl Polyoxyalkylene Ethers as Used in Cosmetics

Transcription

1 Amended Safety Assessment of Butyl Polyoxyalkylene Ethers as Used in Cosmetics Status: Draft Final Amended Report for Panel Review Release Date: March 17, 2017 Panel Meeting Date: April 10-11, 2017 The 2017 Cosmetic Ingredient Review Expert Panel members are: Chairman, 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 safety assessment was prepared by Monice M. Fiume, Assistant Director/Senior Scientific Analyst/Writer and Bart Heldreth, Ph.D., Chemist. Cosmetic Ingredient Review 1620 L Street, NW, Suite 1200 Washington, DC ph fax cirinfo@cir-safety.org

2 Commitment & Credibility since 1976 To: From: Memorandum CIR Expert Panel Members and Liaisons Monice M. Fiume MMF Assistant Director/Senior Scientific Analyst Date: March 17, 2017 Subject: Amended Safety Assessment of Butyl Polyoxyalkylene Ethers as Used in Cosmetics Enclosed is the Draft Final Amended Safety Assessment of Butyl Polyoxyalkylene Ethers as Used in Cosmetics. (It is identified as butype042017rep in the pdf document.) At its December 2016 meeting, the Panel issued a tentative amended report with a conclusion stating the butyl polyoxyalkylene ethers are safe in the present practices of use and concentration in cosmetics when formulated to be non-irritating. Updated (2017) FDA VCRP frequency of use data were received (butype042017fda), and this information has been incorporated in the draft final amended report. The frequency of use has increased for most of the ingredients, but no remarkable changes were noted. PPG-26-Buteth-26 continues to have the highest frequency of use; it was reported to be used in 1019 cosmetic formulations in 2016, and is now reported to be used in 1332 cosmetic formulations. One ingredient, PPG-20-Butyl-30, was not reported to be in use in 2016; according to 2017 VCRP data, it has 1 use in an eye make-up remover. At the December meeting, the Panel requested a restructuring of the format used for the read-across data. Please take a look at the new format to see if it matches the desired structure. Comments on the draft tentative and the tentative amended safety assessments (buty042017pcpc_1 and butype122016pcpc_2, respectively) were received from the Council. These comments have been addressed. The current version of the report includes summaries of the information from previous safety assessments. If you would like to access the original assessments, you can do so using the CIR website. ( Finally, the Panel should review the Discussion to ensure that it adequately addresses the deliberations of the Panel and be prepared to issue a final amended report L Street, NW, Suite 1200, Washington, DC (Main) (Fax) ( ) cirinfo@cir-safety.org (website)

3 RE-REVIEW FLOW CHART INGREDIENT/FAMILY Butylated Polyoxyalkylene Ethers MEETING April 2017 Public Comment CIR Expert Panel Re-Review Rpt Status announce 15 years since last review OR New Data; or request PRIORITY LIST Re-review to Panel June 2016 Are new data cause to reopen? YES NO New data = Combination of 2 previous reports (23 total ingredients). Also added 23 previously unreviewed ingredients. DAR Table DRAFT AMENDED REPORT* June 2016 Table IDA TAR Are new ingredients appropriate for inclusion/re-open? Yes No 60 day public comment period IDA Notice June 10, 2016 Draft TAR IDA DRAFT TENTATIVE AMENDED REPORT Dec 2016 RE-REVIEW SUMMARY Admin Book Table Table Tentative Amended Report Dec 15, 2016 Issue TAR 60 day Public comment period Draft FAR DRAFT FINAL AMENDED REPORT Apr 2017 Table Table Different Conclusion PUBLISH Final Amended Report Issue FAR

4 Butyl Polyoxyalkylene Ethers Butyl PPG Ethers 2001: The Panel published a safety assessment with the conclusion that PPG-2, -4, -5, -9, -12, -14, -15, -16, -17, -18, -20, -22, -24, -26, -30, -33, -40, -52, and -53 Butyl Ethers are safe for use in cosmetics when formulated to avoid irritation 1993: The Panel published a final report on PPG-40 Butyl Ether with a conclusion of insufficient data. Butyl PPG/PEG Ethers 2000: the Panel issued an Amended Final Report on PPG-12-Buteth-16, PPG-9-Buteth-12, PPG-26-Buteth-26, and PPG-28- Buteth-35 with a conclusion that all 4 ingredients are safe as used in cosmetic products; this superseded the conclusion that was published that year [2000: the Panel published the Final Report on the Safety Assessment of PPG-12-Buteth-16, PPG- 9-Buteth-12, PPG-26-Buteth-26, and PPG-28-Buteth-35 with a conclusion that stated PPG-26-Buteth-26 and PPG-28-Buteth- 35 are safe as used in cosmetic products, and that the data were insufficient to support the safety of PPG-12-Buteth-16 and PPG-9-Buteth-12 as used in cosmetics] 2015 Priorities Strategy Memo: the Panel agreed to combine the 2 sets of ingredients into one report, as a family named Butyl Polyoxyalkylene Ethers, and to add 22 previously unreviewed Butyl Polyoxyalkylene Ethers June 2016: Re-Review The re-review document was presented to Panel. IDA: June 10, 2016 The Panel noted that PPG-40 Butyl Ether is used at concentrations up to 60.5% in leave-on products, but sensitization test data at this concentration was not available. Therefore the Panel issued an IDA for sensitization data on PPG-40 Butyl Ether at the maximum concentration for leave-on use (i.e., 60.5%). The Panel added Propylene Glycol Butyl Ether to the list of ingredients included in the RR. Draft Tentative Amended Report: Dec 5-6, 2016 The Panel issued a tentative amended report for public comment with the conclusion that the 46 butyl polyoxyalkylene ethers are safe as used when formulated to be non-irritating.

5 Butyl Polyoxyalkylene Ethers - (new data only) Apr 2017 Monice Fiume Reported Use - current Method of Mfg Impurities Toxicokinetics Dermal Penetration Animal Tox Acute, Dermal Animal Tox Acute, Oral Animal Tox, Acute, Inhalation Animal Tox Rptd Dose, Dermal Animal Tox, Rptd Dose, Oral Animal Tox Rptd Dose, Inhalation Repro/Dev Toxicity Genotoxicity Carcinogenicity Dermal Irritation Dermal Sensitization Case Reports Ocular Irritation Mucous Membrane Irr general info- Butyl Polyoxyalkylene Ethers X X PPG-2-Buteth-1 PPG-2-Buteth-2 PPG-2-Buteth-3 PPG-3-Buteth-5 PPG-4-Buteth-4 PPG-5-Buteth- X PPG-5-Buteth-7 PPG-7-Buteth-4 X PPG-7-Buteth-10 X PPG-9-Buteth-12 X PPG-10-Buteth-9 PPG-12-Buteth-12 PPG-12-Buteth-16 X PPG-15-Buteth-20 X PPG-17-Buteth-17 X PPG-19-Buteth-19 PPG-20-Buteth-30 X PPG-24-Buteth-27 PPG-26-Buteth-26 X PPG-28-Buteth-35 X PPG-30-Buteth-30 PPG-33-Buteth-45 X PPG-36-Buteth-36 PPG-38-Buteth-37 X PPG-2 Butyl Ether X X PPG-3 Butyl Ether X PPG-4 Butyl Ether

6 Butyl Polyoxyalkylene Ethers - (new data only) Apr 2017 Monice Fiume Reported Use - current Method of Mfg Impurities Toxicokinetics Dermal Penetration Animal Tox Acute, Dermal Animal Tox Acute, Oral Animal Tox, Acute, Inhalation Animal Tox Rptd Dose, Dermal Animal Tox, Rptd Dose, Oral Animal Tox Rptd Dose, Inhalation Repro/Dev Toxicity Genotoxicity Carcinogenicity Dermal Irritation Dermal Sensitization Case Reports Ocular Irritation Mucous Membrane Irr PPG-5 Butyl Ether PPG-9 Butyl Ether PPG-12 Butyl Ether PPG-14 Butyl Ether X X PPG-15 Butyl Ether PPG-16 Butyl Ether PPG-17 Butyl Ether PPG-18 Butyl Ether PPG-20 Butyl Ether PPG-22 Butyl Ether PPG-24 Butyl Ether PPG-26 Butyl Ether PPG-30 Butyl Ether PPG-33 Butyl Ether X PPG-40 Butyl Ether X X PPG-52 Butyl Ether X PPG-53 Butyl Ether Propylene Glycol Butyl Ether X X X X X X X X X X X X Buteth-3 X X X X X X Read Across Ingredients [(Butoxymethylethoxy)methylethoxy]propan- 1-ol (aka tripropylene glycol-n-butyl ether) 1-(2-butoxy-1-methylethoxy)propan-2-ol (aka dipropylene glycol n-butyl ether) poly[oxy(methyl-1,2-ethanediyl)],α-butyl-ω- hydroxy- X X X X X x X X X X X X X X X X X x X X X X X X X

7 PREVIOUS REPORTS Method of Manufacture Impurities/Composition Toxicokinetics Dermal Absorption Animal Tox Acute, Dermal Animal Tox Acute, Oral Animal Tox, Acute, Inhal. Animal Tox Rptd Dose, Derm Animal Tox, Rptd Dose, Oral Animal Tox Rptd Dose, Inhal Repro/Dev Toxicity Genotoxicity Carcinogenicity Dermal Irr/Sens Ocular Irritation Mucous Membrane Irr Phototoxicity Amended Final Report on the Safety Assessment of PPG-40 Butyl Ether with an Addendum to Include PPG-2, etc PPG Butyl Ethers (not defined) X X X X PPG-2 Butyl Ether X X X X X X X PPG-4 Butyl Ether PPG-5 Butyl Ether X PPG-9 Butyl Ether X X X X X PPG-12 Butyl Ether PPG-14 Butyl Ether PPG-15 Butyl Ether X X X X PPG-16 Butyl Ether PPG-17 Butyl Ether PPG-18 Butyl Ether X X X X X PPG-20 Butyl Ether PPG-22 Butyl Ether X X PPG-24 Butyl Ether X PPG-26 Butyl Ether PPG-30 Butyl Ether PPG-33 Butyl Ether X X X X X X PPG-40 Butyl Ether X X X X PPG-52 Butyl Ether PPG-53 Butyl Ether X Final Report on the Safety Assessment of PPG-40 Butyl Ether PPG-40 Butyl Ether X

8 PREVIOUS REPORTS Method of Manufacture Impurities/Composition Toxicokinetics Dermal Absorption Animal Tox Acute, Dermal Animal Tox Acute, Oral Animal Tox, Acute, Inhal. Animal Tox Rptd Dose, Derm Animal Tox, Rptd Dose, Oral Animal Tox Rptd Dose, Inhal Repro/Dev Toxicity Genotoxicity Carcinogenicity Dermal Irr/Sens Ocular Irritation Mucous Membrane Irr Phototoxicity Amended Final Report of the Safety Assessment of PPG-9-Buteth-12, PPG-12-Buteth-16, PPG-26-Buteth-26, and PPG-28-Buteth-35(final 2000) General not defined X PPG-9-Buteth-12 PPG-12-Buteth-16 X X X X X X X X PPG-26-Buteth-26 X X X X X PPG-28-Buteth-35 PPG-7-Buteth-10 X X X X X PPG-20-Buteth-30 X X X X X PPG-24-Buteth-27 X X X X X PPG-33-Buteth-45 X X X X X X X Final Report of the Safety Assessment of PPG-9-Buteth-12, PPG-12-Buteth-16, PPG-26-Buteth-26, and PPG-28-Buteth-35 (published 2000) General - not defined X X PPG-9-Buteth-12 PPG-12-Buteth-16 X X X X X PPG-26-Buteth-26 X X X X PPG-28-Buteth-35 PPG-7-Buteth-10 X X X X X X PPG-20-Buteth-30 X X X X PPG-24-Buteth-27 X X X X X PPG-33-Buteth-45 X X X X X X X

9 PPG-26-Buteth-26 PPG-28-Buteth-35 PPG-12-Buteth-16 PPG-9-Buteth-12 Butyl Polyoxyalkylene Ethers CAS # Use InfoBase PubMed SciFinder ChemID NTIS FDA ECHA HPV IUCLID/ SIDS (generic) (generic) 0 hits 3 new hits 21CFR ; 21CFR ; 21CFR ; 21CFR ; 21CFR ; 21CFR ; 40CFR PPG-2 Butyl Ether (generic) yes PPG-3 Butyl Ether yes PPG-4 Butyl Ether (generic) PPG-5 Butyl Ether PPG-9 Butyl Ether PPG-12 Butyl Ether PPG-14 Butyl Ether PPG-15 Butyl Ether PPG-16 Butyl Ether PPG-17 Butyl Ether PPG-18 Butyl Ether PPG-20 Butyl Ether PPG-22 Butyl Ether PPG-24 Butyl Ether PPG-26 Butyl Ether PPG-30 Butyl Ether PPG-33 Butyl Ether PPG-40 Butyl Ether PPG-52 Butyl Ether PPG-53 Butyl Ether 21CFR CFR ; 21CFR ; 21CFR CFR ; 21CFR ; 21CFR ; 21CFR CFR ; 21CFR ; 21CFR ; 21CFR ; 21CFR CFR ; 21CFR ; 21CFR prer no Buteth-3 [ ] maybe PPG-2-Buteth CFR ; PPG-2-Buteth CFR ; PPG-2-Buteth-3 prer 21CFR ; (generic) PPG-3-Buteth-5 21CFR ; (generic) PPG-4-Buteth-4 21CFR ; CFR ; PPG-5-Buteth-5 no 40CFR PPG-5-Buteth-7 yes WHO/ JEFCA EU NICNAS Web

10 PPG-7-Buteth-4 PPG-7-Buteth-10 PPG-10-Buteth-9 PPG-12-Buteth-16 PPG-15-Buteth-20 PPG-17-Buteth-17 PPG-19-Buteth-19 PPG-20-Buteth-30 PPG-24-Buteth-27 PPG-30-Buteth-30 PPG-33-Buteth-45 PPG-36-Buteth-36 PPG-38-Buteth-37 Propylene Glycol Butyl Ether CAS # Use InfoBase PubMed SciFinder ChemID NTIS FDA ECHA HPV IUCLID/ SIDS ; ; no VCRP 88 hits/3 useful WHO/ JEFCA EU NICNAS Web 297 hits X no X no X no X (no R) no X PPG-40 Butyl Ether JACT 12(3): , 1993; IJT 20(S4): 39-52, 2001 PPG-12-Buteth-16, etc: IJT 19(S1): 47-67, 2000; Johnson 2000 (amended rpt; available on website) PubMed May 2, 2016: ((((( [EC/RN Number]) OR [EC/RN Number]) OR [EC/RN Number]) OR [EC/RN Number]) OR [EC/RN Number]) OR (PPG AND Buteth) OR (PPG AND Butyl AND Ether) OR buteth 88 hits; 0 useful June 20, 2016: (PROPYLENE AND GLYCOL AND BUTYL AND ETHER) OR (BUTOXYISOPROPANOL) OR ((( [EC/RN Number]) OR [EC/RN Number]) OR [EC/RN Number]) 41 hits/3 useful SciFinder May 2, 2016: ; ; ; ; ; Buteth hits June 22, 2016: ; ; ; Propylene Glycol Butyl Ether; Butoxyisopropanol 297 hits; 6 useful FDA Citations 21CFR Secondary Direct Food Additives Permitted In Food For Human Consumption; Specific Usage Additives; Boiler water additives 21CFR Secondary Direct Food Additives Permitted In Food For Human Consumption; Specific Usage Additives; Defoaming agents 21CFR Indirect Food Additive; Adhesives 21CFR Indirect Food Additive; Defoaming Agent Used in Coatings 21CFR Indirect Food Additive; Defoaming Agent Used in the Manufacture of Paper And Paperboard 21CFR Indirect Food Additive; Lubricants with Incidental Food Contact 21CFR Indirect Food Additive; Surface Lubricants Used In The Manufacture Of Metallic Articles

11 40CFR Polymers; exemptions from the requirement of a tolerance; Residues resulting from the use of the polymer as an inert ingredient in a pesticide chemical formulation, including antimicrobial pesticide chemical formulations, are exempted from the requirement of a tolerance under the Federal Food, Drug, and Cosmetic Act (FFDCA) section 408, if such use is in accordance with good agricultural or manufacturing practices.

12 BUTYL POLYOXYALKYLENE ETHERS FULL PANEL DEC 6, 2016 DR. BERGFELD:... And so we'll move on to the last item that we're going to be talking about, and that is the polyoxyalkylene ethers. Dr. Marks. DR. MARKS: So at the June meeting, the panel agreed to combine 23 previously reviewed butyl ethers from a four previous reports and 23 new butyl polyoxyalkylene ethers that had not been reviewed into a single safety assessment as a re review. We move a tentative amended report be issued with a safe conclusion for all 43 ingredients. DR. BELSITO: Second DR. BERGFELD: Any discussion? Paul. DR. SNYDER: Nonirritating DR. BERGFELD: Nonirritating, to be added to the conclusion. Is that acceptable? DR. MARKS: Yes DR. BERGFELD: Okay. Any other comments? DR. BELSITO: Yeah. Dan felt that several of the structures that we used for read across were not needed because we had sufficient data on the material themselves. And those were, Dan DR. MARKS: One of them was the methoxyisopropanol. Safe for nail products only. So we don't want to use that as a read across. DR. BELSITO: Dan, you want to mention the three? There were three, I believe. DR. LIEBLER: The one that I felt we could leave in was on PDF 36. I'm talking about Table 3, read across table. PDF 36, the top, which is that isomeric structure. That was okay. But then the one on PDF 38, which is the 1 (2 butoxy 1 methylethoxy) propan 2 ol (aka dipropylene glycol n butyl ether). That wasn't necessary. The PPG 3 methyl ether wasn't necessary and finally the methoxyisopropanol wasn't necessary. Again, this is just the principle of only put in read across when you have a gap as opposed to just adding more sauce to the sundae. DR. BERGFELD: Ron Hill wanted to make a DR. HLIL: I would vote to read in where it says 1 (2 butoxy 1 methylethoxy) propan 2 ol because it's produced as a four isomer mixture. Although I agree that the data isn't crucially needed, I don't think it hurts the case and I think it adds capture of the information to the body of the report. And my rationale was when you use epoxides, which is what they are, with propylene oxide and ethylene oxide, depending on the particular process conditions that are used, you're going to get mixtures of positional isomers that will happen and in one case the ingredient may be highly only one and in another case it may be highly only another. But this actually is a mixture four, it adds to the toxicology profile because we presumably picked up. So I think we should leave that data in. DR. LIEBLER: So, Ron, your argument then that this isomeric structure, cause it's different looking structure than some others, is representative of a contaminant that might be present in some of the other ingredients we're looking at? DR. HILL: Yes, and I have a background in this because I worked on butoxyethanol project and in fact, synthesized butoxyacidic acid is part of that work. And I feel like having that in there provides a comfort level that taking that data out loses. And I get your assertion about the direct data, but I don't see the downside in leaving it in. DR. LIEBLER: I see the merit in your point. And maybe this isn't the time to settle this. But I think we ought to adopt a pretty clear rule on when we use read across and when we don't. And this can be an exception, because we don't have a rule yet, you know, and I don't object to having it in the report at this point. But I think we haven't had a discussion as a full panel, and maybe we need to do that, in one of our first day sessions, or make this an agenda item, you know, in the administrative book. But to talk about what are the criteria that we feel we need to satisfy to invoke read across and when not to. Because eventually it's an issue for RIFM and I think we need to settle it here too. DR. HILL: I should mention in this case, this is a perspective metabolite. Because we know that some of the poly ethers do get chopped in vivo. We don't have clear information on this group of compounds in that regard but we do have information that some of these poly ethers get reduced in size by chopping off glycol units. DR. LIEBLER: It's true that it is a potential metabolite but then that doesn't really address the point that I'm making about when we use it and when we don't.

13 DR. HILL: No argument. I agree with everything you said. DR. LIEBLER: So post it for In 2017 we're gonna deal with read across. DR. BERGFELD: It's been added. DR. MARKS: I'd like to ask Bart, the PPG 3 butyl ether structure on page 36, how do we resolve this? DR. HLL: My assertion was that that can't be the correct structure. I think that's an error in the SCCS document. Because that's a hemiacetal, it would be highly unstable. It's certainly not a stale ingredient of any kind. It can't have possibly used that structure, that compound for testing. So I believe it's actually an error that second part of the report. DR. HELDRETH: I also thought that that it looked like he got the end unit that I have there in green is possibly a misnomer. I think that that was a possibility when I saw it myself. But even if we take as is, and we flip that to what we would expect, there's still the difference in the alpha beta DR. HLIL: My point is that actually these compounds have those patterns, both of those patterns in there, because of the way they're produced. And it's just our structures don't represent that we have these alternative possible patterns in the ingredients themselves. That in fact, it's an important issue to raise. Actually I think that should be discussed in the chemical composition. Because there's a lot of inferences that could be made by these sample structures that are added here. For example, it doesn't capture that we have alternating, depending on the process that's used, if you're just mixing ethylene oxide and propylene oxide in a certain molar ratio and doing the polymerization then you'll get random polymers, which is, I think, written in here. Whereas if you make a polymer of PPG to a certain length and then, with the butoxy on there and add the PEG group, you'll get a very different structure. So I think there's lots of ambiguities in the meaning and one of them is these positional isomers, because it would depend highly on what process is used, what temperature, what pressure, what equivalents. Whether it's a Lewis acid catalyst for example, or it's done uncatalyzed, all of those things. DR. HELDRETH: I agree with the possibilities of different insertion pattern. But the only information we have in front of us is what the dictionary has described. And they've described each one of these as having the substitution pattern that I've drawn in the tail. So you may very well be correct, or we don't have that information in front of us to describe them otherwise. DR. BERGFELD: Are you proposing to put this back to the dictionary committee to see about this structure? DR. HILL: So what you're saying is, when it says conforms generally to the structure above, I think that that needs to be revisited to the accuracy of that in the dictionary. DR. HELDRETH: That's certainly something for the dictionary folks, if you want to send a formal request from the panel for that. But what we have drawn here is what the dictionary shows. DR. HILL: I don't think we should brush that issue under the rug. In fact, maybe quite the contrary, I mean I like the beautiful structure that you put that points out clearly what the issue is. But I don't think we're really dealing with two different groups of compounds there. DR. HELDRETH: I can easily draft a letter and send it DR. HILL: That would be great. We might likely need some information from industry to put this to bed and it might be a year long, or longer process, in terms of that. You're right, you can only go by what's in the dictionary. But I feel like removing that information as being irrelevant may be not quite right here. DR. BERGFELD:DR. Marks, will you summarize where we are with this? DR. MARKS: It's been moved, I moved and seconded, I should say that Belsito seconded tentative amended report with a safe when formulated to be nonirritating conclusion for these 43 ingredients. DR. BERGFELD: Did that include their taking out of a few of the ingredients for the read across? DR. MARKS: No, the read across was general. To me that was that report. DR. BELSITO: No ingredients were removed. DR. BERGFELD: Okay. All right. I'm going to call the question. All those in favor of this safe conclusion. Unanimous. We've come to a, yes, I'm sorry. MS. FIUME: So after that discussion, the information that's in the table now as read across for the compound that was just discussed, stay in the table for read across? Or does it go DR. BELSITO: Yes

14 MS. FIUME: Okay. It doesn't go back into the DR. BELSITO: That's my understanding. And we'll have a discussion in 2017 as to what's appropriate. Not for this material, for read across in general. Belsito Team Dec 5, 2016 DR. BELSITO: Anything else? Okay. Okay, so then we're moving on to the polyoxyalkylene ethers. So, at the June meeting, we opened this rereview with a compilation of butyl polyoxyalkylene ethers that we previously reviewed in two reports and looked at adding in another 23 butyl polyoxyalkylene ethers that were not previously reviewed. We issued an insufficient data announcement requesting sensitization data on PPG 40 butyl ether at the maximum concentration of use in leave on products, which was reported to 60.5 percent at that meeting and is now reported to 71 percent. And the CIR was asking our guidance on whether data on ((butoxymethylethoxy)methylethoxy)propan 1 ol from the ECHA dossier could be included in the report. It has the same cast number but a different structure, so I defer that to Dan. So, we're looking at this report. What do you think, Dan, about DR. LIEBLER: I just returned from the land of the missing. Could you repeat the question, Don? DR. BELSITO: The question was whether data on ((butoxymethylethoxy)methylethoxy)propan 1 ol, which has the same cast number as that in the dictionary for PPG 3 butyl ether but a different structure, whether that could be appropriately used as a read across. DR. LIEBLER: Yes. So, this is PDF 36, table 3, top. Yeah, it's fine with me. It's actually interesting. These are like what they refer to as the alpha and beta isomers of propylene glycol, so they can be connected either through one alcohol or the other. And one is a primary alcohol and one is a secondary. And so, they have essentially, these molecules, the read across and the analog, the read across and the target have the same molecular weight, same everything except they're just arranged a little differently. So, they're isomeric structures. They would degrade to the same products. And they should have identical very similar physical properties. I would assume that their metabolism and physical properties essentially identical. So, I think there is a really good read across. MS. FIUME: So, it is read across, it's not the cosmetic ingredient. So, it's correct as captured. DR. LIEBLER: Yes, correct as captured. I'm sorry. That's great. MS. FIUME: Thank you. DR. LIEBLER: To the PPG butyl ether, right? Yeah. Yep. Don, did you get on to talking about the methoxyisopropanol as a read across? DR. BELSITO: I haven't even gotten DR. LIEBLER: Okay. DR. BELSITO: to open the document yet, so. Yes, it's a Dan et al. What do you think? DR. LIEBLER: Methoxyisopropanol, I just didn't know why we needed it. It really wasn't nearly as good a read across as the other example we just talked about. So, I didn't feel it was necessary. And I felt the same way about the PPG 3 methyl ether. You know, I scanned the data sets associated with both of these potential read across analogs. And I'm not sure it added much I mean, it added data, certainly, but it didn't add I don't think it added data where we had real gaps. DR. BELSITO: And where was that, Dan? I'm sorry. DR. LIEBLER: Well, I'm looking at the tables on page 43, PDF page 43 and 41. DR. BELSITO: Mm hmm. DR. LIEBLER: And the DR. BELSITO: So, like methoxyisopropanol, you would say no? DR. LIEBLER: Right. DR. BELSITO: Okay. DR. LIEBLER: And then the PPG 3 methyl ether, which is on PDF 41. And even though that they both had a nice collection of data associated with them, I'm not sure that were gaps that these were filling for us. So, unless you're filling gaps, I think there's no good justification for read across.

15 DR. BELSITO: So, you're getting rid of methoxyisopropanol. And the other one was? DR. LIEBLER: Methyl ether. PPG 3 methyl ether. MS. FIUME: PDF page 41, Dr. Belsito. DR. BELSITO: Okay. I'm sorry. No wonder I'm not finding it. It was okay. DR. LIEBLER: So, it's not that they were inappropriate, they were just unnecessary. MS. FIUME: So, in the first version of the report going baseline cast number and not examining the differences between the two structures for that first ingredient you were talking about, those data were in the report, and they're now moved to the read across. So, that I can capture the language correctly for the discussion as to why they're appropriate for read across for the report and supporting safety, do you have any language written down, Dr. Liebler, or could you repeat it for me again as to what makes them so similar for read across, so I can capture it in discussion? DR. LIEBLER: Are you talking about the one that I did like? MS. FIUME: Yes. DR. LIEBLER: Okay. And you want to know what the justification for structural similarity or? MS. FIUME: Language that I can use in the discussion as to why that supports the safety of the did you say was isomeric or stereoisomer DR. LIEBLER: Right. Okay. MS. FIUME: (inaudible). DR. LIEBLER: Yeah. Yeah, I made some notes in my little Post it thing on the PDF. But it basically says orientation of the PPG unit differs in the two structures but the chemical properties, metabolism and physical properties, should be essentially identical. DR. BELSITO: And then I had the same comment on that, read across table, as I did on the prior data that we submitted. I think we can give it justification for the read across, a la an appendix that I thought I was able to get to Bart and Wilma and then put the appropriate data and the read across under the section headings. DR. LIEBLER: So, if you were in genotox, for example DR. BELSITO: Right. DR. LIEBLER: you would say they were no data available for compound, you know, ingredient A. But an appropriate read across material was identified with, you know, AMES studies and, you know, clastogenicity studies and a micronucleus test data. And then you present that there. And then at the end of the document, you have your read across justification explaining why they're similar, instead of imbedding all the argument for the similarity under the genotox section. MS. FIUME: So, the data are actually in the text and it's just the justification that's in the table. DR. LIEBLER: Exactly. MS. FIUME: Okay. DR. BELSITO: Right. MS. FIUME: Okay. I didn't understand that when we were talking format (inaudible). DR. LIEBLER: That turns out to be a really nice efficient formula because it doesn't get in the way. The read across justification per se doesn't get in the way of presenting the data on genotox or repro or, you know, inhalation or whatever. MS. FIUME: So then when we have multiple ingredient reports, and we have several ingredients under one main data point, say genotoxicity, if we have ingredient A, B, or C, we generally will name them as a subheading. If we have read across, how do you want us to handle that under say something for genotox? Do you want us to put it under the cosmetic ingredient being reviewed in the report and then give the information or do you want us to use DR. BELSITO: No, just MS. FIUME: title the read DR. BELSITO: The title should be the actual MS. FIUME: Ingredient.

16 DR. BELSITO: material that's looked at and say this is being used in the absence of whatever endpoint data, this is being used as a read across for this specific material. DR. LIEBLER: Based on. DR. BELSITO: Well, no, because that based on will be somewhere else in the document. Right. And, you know, you could say refer to whatever section for justification of use. But you wouldn't go into the justification there because then it would just confuse you. You would go into the data on that toxicity endpoint showing that whatever the effects of that read across DR. LIEBLER: Right, so DR. BELSITO: material was. DR. LIEBLER: To be sure I understand, Monice, if you have, let's say, genotox, and then you have chemical A, and you have genotox data on chemical A, you put that there. Then you have chemical B. And you don't have anything directly for chemical B, you just have read across. Now, what I would do, is I would probably put chemical B, parentheses, read across. MS. FIUME: Okay. DR. LIEBLER: Or you could put the name of the read across analog, parentheses, read across for, and the name of the cosmetic ingredient that's being reviewed, that we don't have genotox for. Does that make sense? MS. FIUME: Yes. DR. LIEBLER: Okay. DR. BELSITO: Okay. So, I thought we could go as safe as used when formulated to be nonirritating for this group of materials. So, I don't know what you thought. I had no other comments to make. DR. LORETZ: Could I add a comment? Since these are ethoxylated ingredients or a number of them are, should there be a mention of 1,4 dioxane and the DR. BELSITO: Well, we haven't gotten to discussion. DR. LORETZ: Okay. DR. BELSITO: I'm just giving the conclusion, then I think we can go to the discussion points unless other people have issues. DR. LIEBLER: So I agree with you. The formula as safe as used and nonirritating. DR. BELSITO: Right. Okay. So, yeah, discussion, minimize ethylene glycol and the new we don't have a propylene glycol boilerplate, right? That wasn't the one with Vern that was MS. FIUME: That was polyethylene glycol. DR. BELSITO: Polyethylene glycol, right. And then minimize dioxanes. That's what I had for discussion. Anything else that DR. LIEBLER: You know, strong weight of evidence for low systemic toxicity across the group. This is in my Post it note on the smaller molecules more rapidly absorbent, more potent in inhalation toxicity studies. That was the only toxicity where you've had the small molecules producing significant effects. DR. BELSITO: I'm sorry, Dan, what did you want in the discussion? I didn't follow that. DR. LIEBLER: Oh, I simply said strong weight of evidence for low systemic toxicity across the group, although smaller molecules are more rapidly absorbed and more potent in inhalation toxicity endpoints. DR. BELSITO: I'm still not following your reasoning there. So, low DR. LIEBLER: Low systemic toxicity across the group. Okay. DR. BELSITO: Okay. DR. LIEBLER: And smaller molecules more rapidly absorbed. DR. BELSITO: So, what you're saying is the smaller molecules in this group will be more rapidly absorbed but we're not concerned about that because of the low systemic toxicity across the group. Is that DR. LIEBLER: Yes. DR. BELSITO: Okay. Anything else?

17 MS. FIUME: Just so that I'm clear, we added propylene glycol butyl ether, but that fits perfectly in the group. I don't need to mention anything about that in the discussion, do I, about how it fits into the group? Just because its name looks different and the way it's described. DR. LIEBLER: But it's chemically MS. FIUME: The same. DR. LIEBLER: Analogous to the others in the group. Yeah. No, that's fine. DR. BELSITO: And that should go in the discussion or does it have to go in the discussion? DR. LIEBLER: I don't think it needs to. DR. BELSITO: Okay. So, in the discussion what I have is good manufacturing processes to minimize ethylene glycol and 1,4 dioxane. And low systemic toxicity across the group and, therefore, lack of concern that the smaller molecules may be more rapidly absorbed. Anything else? Okay. MS. FIUME: And the dermal irritation DR. BELSITO: Well, as formulated that's yeah, that they can be irritants, so. But the conclusion is safe as when formulated to be nonirritating. Marks Team Dec 5, 2016 DR. MARKS: Okay. The last one is butyl poly -- butyl polyoxyalkylene ethers. Are you sure there isn't an ester in one of these? DR. HILL: Well, if there is we're going to do something -- DR. MARKS: Polyalkylene ethers. So we have Monice again with a memo. At the June meeting the panel agreed to combine 23 previously reviewed butyl ethers from a total of four previous reports and 23 butyl polyoxyalkylene ethers that have not been yet reviewed into a single safety assessment for rereview. So this is not going to be just straightforward. This would be a tentative amended report, and I think the first question, of course, is we agreed to merge the two. ny questions or any problems with the ingredients as we look down the whole list? There's a whole bunch of them. And I'll get to the 33 butyl ether structure in a minute. So Ron, Ron, Tom, all the ingredients look okay? DR. SHANK: I think so. DR. MARKS: That would be 46 ingredients. Am I correct on that, Monice? MS. FIUME: Yes, that's correct. DR. MARKS: I hope I can add 23 and 23 DR. MARKS: Pardon? Okay. So all the ingredients look okay at this point to be in one report. We don't have an ester that snuck in there by chance. DR. HILL: Not that I can see. DR. MARKS: Okay. So let's first deal with that butyl -- the 33 butyl ether structure. Where was that in here Monice, on your memo? MS. FIUME: It's in the table of read-across. So that is -- DR. MARKS: Yeah, is this the one in your second question among the CIR staff as to whether the data that were included -- it's a test on PPG-3 butyl ether. In June we rereviewed a document that actually pertained to the cosmetic ingredient identified in the INCI dictionary. Please look at the structure and provide guidance So it's the PPG, not 33. So Ron Hill, what do you think? DR. HILL: Take me to that because there were two different places where we had structure -- apparent structure discrepancies that probably aren't but one of those structures is bogus. It has to be bogus.

18 DR. MARKS: Yeah, that's probably this one. MS. FIUME: PDF page 36. DR. HILL: All right, 36. There as one place where this was presented with highlights, wasn't there? Is this -- yeah, okay, I see. MS. FIUME: So just a little background. So you reviewed this report at the last meeting. Going by CAS number and some of the names, I thought the ingredient that was in the ECHA report was the same ingredient as our cosmetic ingredient. Further, looking at the structure, there's differences in structure. So just need guidance on how to handle the information. If it belongs in a read-across table or if it is actually the cosmetic ingredient and something is just wrong somewhere. DR. HILL: So that structure that goes with that CAS number cannot be correct. Somebody -- chemical abstracts doesn't make that many mistakes but there is no way that's the correct structure because you've got a hemiacetal there, and if it sees water walking down the street somewhere it's going to fall apart. MS. FIUME: It's the structure from the ECHA report. DR. HILL: Yeah, well, that can't be right. There's no way that's right. That would not be a stable compound. I'm not saying it couldn't be made in the lab briefly but it certainly wouldn't be stable enough to put in something, to study in something. It just can't be right. And I don't know how to resolve that. Is that a structure from Chemical Abstracts or is that based on the name that's given? MS. FIUME: The structure came from the ECHA report. DR. HILL: Okay. They've got -- can we look up that CAS number in SciFinder and see what structure they give there? I didn't do that, I'm sorry, because I didn't really see what you were talking about when I first reviewed this until I'm sitting on the airplane. I couldn't get behind my firewall anymore. DR. MARKS: Okay. So that's going to be DR. HILL: It's one of two issues. DR. MARKS: -- resolve the -- resolve the structure there. That shouldn't delay us in terms of coming to a conclusion because this is going to be a tentative amended report. And then there was an issue -- DR. HILL: There's another one. DR. MARKS: -- yeah, of the methoxyisopropanol read- across. MS. FIUME: My internet is not working very well, Dr. Hill. My signal is bad. DR. HILL: I haven't tried to even do there because -- DR. MARKS: There was -- in the June meeting there was an issue of whether or not we could use that as a readacross. There was a concern. I don't know whether Ron Hill in the minutes, had you brought that up? MS. FIUME: Actually -- DR. HILL: I wasn't the one that brought it up. No. MS. FIUME: -- Dr. Shank had requested taking it out when we were in the team meetings but it was never -- I realized afterwards it was never discussed in full panel, so I didn't want to pull information out not knowing if the other team relied on any of the information without first discussing it in a full meeting. So that's why I hadn't removed it yet and brought it back. So.

19 DR. HILL: Okay. So here's the deal. You're making these things from -- and Mr. Steinberg could be listening to me so that he can even chime in and correct further. You're reacting ethylene oxide and propylene oxide, so these are epoxides. And depending on the conditions that the reaction chemistry gets, Ron, the way in which those epoxide rings get open by, in this case butanol or any other alcohol, is going to depend on the conditions of temperature, concentration, pressure in the reaction vessel and whether there's a catalyst used, acid catalyst or not. So you would end up getting some mixture of alphas and betas and then I think the words "random linear polymer" are not necessarily reflected in the structures that are in there or the structures are there and maybe it's just not in neon lights enough to say random linear polymer. But exactly how that shakes out is going to depend again on the exact manufacturing conditions so that these ingredients have multiple meetings depending on what production person is making them and exactly what process they used to making them. So I think from that point of view read- across might be -- I mean, I've got a whole paragraph about some of this issue in terms of method of manufacture and so forth but that's the key thing. I have no problem with reading across because in that particular case they're actually testing it as a mixture of 4-isomers. Somewhere it explicitly says 4-isomers. I'm going to try searching on the text 4-isomers and see if I can find that language because I didn't capture that in my notes. Now, we don't exactly have information about what the percentages are. See if I remember right. It's so far stalling. DR. MARKS: So let's go back -- DR. HILL: Let me just search isomers. DR. MARKS: -- Ron, to sort of clarify the methoxyisopropanol for my -- that's not an ingredient in this. That's just used to support -- MS. FIUME: No. DR. HILL: Where are we? Maybe I'm looking at the wrong compound we're talking about. So where is that? In the text as read-across? Is that -- MS. FIUME: The -- DR. HILL: Okay, methoxyisopropanol you're talking about. I agree with him. DR. MARKS: Yeah. DR. HILL: I'm on that. I jumped ahead to the next compound. I'm sorry. I agree with him. DR. MARKS: Agree that -- DR. HILL: Not pertinent. DR. MARKS: So you -- DR. HILL: What did you say last time, Ron, again? I read this discussion before I came but -- DR. SHANK: I'd have to go back and make sure how I put it. S. FIUME: I believe it was because it was only safe as a nail product, in nail products. DR. HILL: That's it. DR. SHANK: Right. That's right. DR. HILL: That's it. That's it. DR. MARKS: Safe in nail products? MS. FIUME: That was the conclusion from CIR for methoxyisopropanol. Safe for use -- DR. HILL: That's it. Thank you. I jumped ahead.

20 MS. FIUME: -- in nail care products. DR. MARKS: Nail care products. DR. SHANK: We put a limit on it limiting the use. MS. FIUME: Right. DR. MARKS: Yeah. So -- so don't use methoxyisopropanol for read-across. DR. SHANK: Right. DR. HILL: I agree. Yeah. Yeah. I found it. His comments are on PDF pages 16 and 17. Sorry, I jumped ahead to that other issue. I was on the wrong one. DR. MARKS: Okay. So we'll delete that. So what needs do we have at this point with the combination of four previous reports and then these two new ingredients? Do we have any -- so we still have issues with what is the PPG-3 butyl ether structure? We don't know that for sure at this point. We'll get that clarified. MS. FIUME: Right. I believe the should be useful. It's just whether or not it's in the body of the report or in a read-across table. DR. MARKS: And then we're going to eliminate methoxyisopropanol read-across from this report. or comments, Ron, Ron, Tom? Other needs DR. HILL: Okay, I do. DR. MARKS: Monice, just while -- it looks like they're thinking -- were irritation and sensitization data from the 23 ingredients previously reviewed included in this report? MS. FIUME: I believe they're in the table. Let me go to the introduction. DR. MARKS: Because there's -- because I would have questioned like PPG-14 butyl ether. There's no sensitization and irritation data in that. And that's probably the highest -- no, it isn't. The highest concentration is actually the peg. PPG, not peg. PPG-40 butyl ether. And that's at 71 percent use. But we have that it's sensitization study, okay. DR. EISENMANN: And then you also got PPG-14 butyl ether. DR. MARKS: Oh, we do have a study? DR. EISENMANN: A sensitization study. Yes. DR. MARKS: Oh. And that was okay? DR. EISENMANN: Yes. DR. MARKS: Huh. How did I miss that? DR. EISENMANN: That was, I think, 100 percent. There were two studies. Well, in a couple of places it says - - it says 40 instead of 14. DR. HILL: Yeah, because if the 40 versus 14, do we really have data with 14? DR. EISENMANN: Yes. You really have a study of 14. DR. HILL: Okay.

21 DR. EISENMANN: Data provided a study with 14. DR. MARKS: Okay. Okay. DR. EISENMANN: Because it's a little smaller. DR. HILL: Yeah. Forty would -- DR. EISENMANN: It would be better. DR. MARKS: Yeah. DR. HILL: But 14 would be. Yeah. DR. MARKS: So we have -- DR. HILL: That makes me feel better. DR. MARKS: -- the data from 14 and okay sensitization? DR. EISENMANN: And then the product -- DR. MARKS: Okay. DR. EISENMANN: -- with 40. DR. MARKS: Good. How did I miss that? MS. FIUME: I think I had it captured incorrectly. DR. MARKS: Okay. Okay. So I think the sensitization irritation then is probably fine. The other 23 ingredients that were reviewed, is that -- is that in this table or a table in the report? I wasn't quite sure. I didn't go look up each one of those. And if not that can be captured as we go forward. Obviously, if they were felt to be safe before, they'll probably have adequate data. Tom, Ron, Ron, any systemic tox? Anything else? DR. SHANK: Not from me. DR. SLAGA: Not from me either. DR. MARKS: So it looks like we can move that a tentative amended report, safe for these ingredients? DR. SHANK: Yes. DR. HILL: I do have -- DR. MARKS: Without any restrictions? DR. SHANK: Right. DR. MARKS: Okay. And then Ron Hill, I see you are thinking there. DR. HILL: No, I mean, my needs according to my notes were all related to method of manufacture sorts of issues. I think part of it is the writing in the report because we need to make clear that these polymers are not a single compound. They're mixtures with a molecular weight range. And even that's not made very clear in the previous reports and you look and they have molecular weights given but those are intended to be, and I think in some cases well indicated to be averages or medians or modes or something. But they are ranges. And so they were discussed in the sense that they are impurities and they would not be impurities if they are lower molecular weight polymer species present. But then on the flip side, for example, we have information that the polymerization is butanol initiated but presumably there would be some kind of catalyst or some initiator added in many instances. I'm not

22 clear one way or another about that. Maybe not. So that goes to the question of residual impurities, which is really never addressed in the report. We don't really have anything on potential residual impurities. DR. MARKS: So it sounds like, again, going from where we are now to the next rendition when we actually see the tentative report, you would like to have that which I'm sure Monice can clarify and Ron, that would address your comments. Does that sound reasonable? DR. HILL: Yeah. And the other issue I wanted to raise with the toxicologists in particular is what -- were the skin painting studies done with -- I got the impression these were a high molecular weight and I wanted to make sure whether that was -- I mean, it's written though that's in fact the case. DR. SLAGA: Which page? DR. HILL: Do we know for sure -- I've got to plug in this computer. Do we know for sure -- (Discussion off the record.) DR. SHANK: Which study are you talking about? DR. SLAGA: The lifetime studies. The only really chronic talk we got on these. DR. HILL: Hang on. I'll find it. I thought I had a page number. Page 17 of the minutes. No, okay, hang on. It was talking about information in the old reports, where did they satisfy the chronic tox needs. So I was reading discussion on page 17 from '97 I think it was, or '98. DR. MARKS: Anything else? DR. HILL: Hang on. DR. GILL: The chronic -- DR. HILL: I'm looking at the minutes from DR. GILL: There's data from the chronic tox studies. That's on page 29. DR. MARKS: Okay. Anything else? DR. HILL: Hang on. DR. GILL: The chronic -- DR. HILL: I'm looking at the minutes fro -- DR. GILL: There's data from the chronic tox studies on page 29. DR. HILL: Page 29? DR. GILL: It's in the report. DR. HILL: Previous report? DR. GILL: Yeah. Previous report. DR. HILL: Page 29. Okay, here we go. DR. MARKS: Okay.

23 DR. HILL: Yeah, I think what bugged me was we were doing -- okay, so this one is PPG-7-buteth-10. I thought there was one that was dermal skin painting. That's where I'm looking at. Maybe I can search on it. With dermal dosing. It's not that one. I thought I had this clearly flagged where it was. MS. FIUME: Is it PDF page 30 in your carcinogenicity studies? DR. HILL: That might likely be it. DR. GILL: It's in the dermals. DR. HILL: Yeah, I know it's dermal. DR. MARKS: So actually, while you're looking that up, Lillian, may I ask you a question? DR. GILL: Sure. DR. MARKS: How is it handled when we combine these reports and they include ingredients that have been previously reported? If you were to do a data search would it send the searcher to both papers -- the paper which will come out of the totally combined amended report and -- DR. GILL: It should pull up when you search on the ingredient. It should pull up the reports that it's in. DR. MARKS: Okay. It should. Yeah, because -- DR. EISENMANN: On your site, yes. DR. MARKS: Yeah. DR. EISENMANN: Because that's how I put it in. DR. GILL: Yes. DR. MARKS: Okay. I just -- DR. SLAGA: I don't remember the details of it but I didn't have any problems with the skin study. MS. FIUME: They were from the previous report. DR. SLAGA: Right. MS. FIUME: And it was PPG-7-buteth-10 and PPG-33- buteth-45. Lifetime skin painting studies. DR. HILL: Yeah, I don't think I remember the 7 and 10. So I must have checked out whatever because I remember being bugged that one of them was the 33-buteth-45. Well, of course you're not getting any effects there because it's never going to get into the skin. But the 7, PPG-7-buteth-10 would. THE REPORTER: I just lost battery so that might mean we have to stop. DR. MARKS: Any other comments? SPEAKER: No. DR. MARKS: If not, we'll adjourn until tomorrow morning

24 FULL PANEL JUNE 7, 2016 DR. BERGFELD: So the last item or ingredient in this group is the ethers.dr. Marks. DR. MARKS: Well, we'll see whether our teams agree on one of these reopens. The polyoxyalkylene ethers. So this is an amended safety assessment of butyl polyoxyalkylene ethers. And, essentially, what is proposed was that we propose and move that we open the safety assessment, we issue a tentative amended report that combines the two reports, that from 2001 and the second one from 2000, with those ingredients and add 23 new ingredients including propylene glycol butyl ether with a conclusion safe when formulated to be nonirritating and insufficient for PPG 40 butyl ether. And the need is sensitization data since it's now being used at 60 percent on leave ons. In the original report there was a HRIPT, which was safe at seven percent. So it's now being used almost nine times the concentration it was in the original report. And we don't have safety data on the sensitization. So again, do you want me to repeat that motion? DR. BELSITO: I mean I'm fine with reopening and since we're reopening, I have I don't think our team has any problem with the request today. You're asking for sensitization data. If we don't get it, we'll see how we can handle it. DR. MARKS: Yeah, I think at this point it's insufficient unless we get it, so that's DR. BELSITO: Or we're just reopening it. DR. MARKS: Yeah. It's a DR. BELSITO: You're just pointing out this is one data need that you'd like to see. DR. MARKS: Yeah, I think although if we reopen it, we have to have a tentative report correctly with a conclusion. So that would be the conclusion, and then we can order that DR. BELSITO: No, at this point we're just deciding to reopen it. We don't have to DR. BERGFELD: The next time we would see the tentative report. DR. BELSITO: I mean it's a hint to industry if they want a slam dunk they'll get us the data, but. DR. GILL: Just to clarify, we are just going to announce it as being reopened, but it would be very helpful if you identify the needs, so that we can send that out as well. DR. BELSITO: So sensitization to that one. DR. MARKS: Correct. DR. BERGFELD: Do you want to repeat what you need? DR. MARKS: The only insufficient is for the PPG 40 butyl ether, and we need sensitization data at 60 percent, which is its (inaudible) concentration nail and leave-ons. DR. BERGFELD: Okay. DR. MARKS: The highest (inaudible). DR. BERGFELD: Any other needs? Ron Hill? DR. HILL: I'm just not clear that that is all of my needs just because this is a big category if we combine reports and look at the big picture. I wasn't sure in the time I had to digest the summed total and look at, especially, some of these low molecular weights, that I was clear on the totality of the need. So that's all. DR. BERGFELD: Well, we're going to reopen, and all of that can be examined. DR. HILL: Yep. DR. BERGFELD: All right. All those in favor of reopening please indicate and raise your hand. Unanimous. Belsito Team June 6, 2016 DR. BELSITO: We are returning. The next ingredient is the butyl polyoxyalkylene ethers. It's a re review. We've previously looked at the PPG ethers in 2000 and the PPG/PEG ethers in 2001 and so this is a re review that's looking at those as well as some additional ethers that we hadn't reviewed. And we had already decided to combine the PPG and PPG/PEG ether reports into one. They're hair conditioning agents and skin conditioning agents with some uses as surfactants, solvents, and also fragrance that we're not reviewing. The frequency hasn't changed much and for some of these however, PPG 26, Buteth 26 has increased from 13 to 1,091.

25 DR. BERGFELD: That's a big change. DR. BELSITO: That's a big change. So we have one big use change and we also are combining two reports. And the first question I had was to Dan. Are we okay with including Buteth 3? DR. LIEBLER: I was fine with it. DR. BELSITO: Okay, so I thought based if we can include Buteth 3 we could go with a safe as used conclusion for this entire group. DR. LIEBLER: I agree. DR. SNYDER: I agree. DR. BERGFELD: Just a conversation on the increase use of the one ingredient from double digit to quad double. DR. BELSITO: Yeah, but our you know, we certainly can comment on it, but there were, you know, nothing in the safety reports that would or in the data rather that would cause us to be of concern. I had a bunch of smaller comments, but just something under and this is a summary of what we had before. I realized that page 22 of the PDF, the fourth paragraph which you where you're just saying a chronic feeding study involving dogs. In the paragraph you didn't state that it was a two year study. You see it when you go back to the table. But I just thought in general, when we're talking about studies, we should also list DR. SNYDER: Agree. DR. BELSITO: in the text the duration of the study. I mean that would and everything else is even more minor than that. Anyone else with any count? DR. EISENMANN: The read across compounds, at least two of them we reviewed before which is Methoxyisopropanol and PPG 3 Methyl Ether. There was another one, Propylene Glycol Butyl Ether that somebody said was appropriate as a read across. That's also in the dictionary. So I wonder if you're going to use it as a read across if it should be in the report, but that's up to you. I mean, it has no uses, so, you know, in the VCRP, I have not surveyed it. So it would take some time to get the results for you if I surveyed it. But it seems to me that if it's appropriate for read across, is it appropriate for being in the report? DR. BELSITO: Well, I mean this is a DR. EISENMANN: That's just a general question. DR. BELSITO: This is a tentative final, so we certainly can include it, you know, and, you know, relook at it when we review the final. I mean I don't have a problem with that, but I'll throw that back to Dan as to DR. EISENMANN: I mean it's just a general question too. DR. BELSITO: Right. DR. EISENMANN: If it's appropriate for read across in general or do you add it to the report or? DR. LIEBLER: Yeah, I guess if I mean, if it's appropriate for read across it has enough structural and physiochemical similarity that justifies its inclusion, yeah. DR. BERGFELD: Would you think that would be a sort of, a policy or a guideline? DR. LIEBLER: You know, I don't know. I mean I think that one of the things that I think is important in a report is also its similarity of use context or continuity of use context. And what I don't know is whether the read across ingredients you mentioned were had very different use contexts that might influence some of the data that they were used. But it's probably okay, but I don't think a policy is a good substitute for judgment in this case. DR. BERGFELD: No, I know, DR. LIEBLER: Yep. DR. BERGFELD: but to consider it at least when they do a read across DR. LIEBLER: Yes. DR. BERGFELD: of a different chemical. DR. LIEBLER: Yep. DR. BERGFELD: Yeah. DR. BELSITO: Okay, so we're going to go safe as used, do the combination, and introduce the read across material. And it'll simply be part of our table and they'll be no listed uses and no listed concentration. But the assumption

26 would be that if it was used, it would be a similar use in a similar range of concentrations as we've always assumed. Everyone is fine with that? DR. LIEBLER: Yes. Marks Team June 6, 2016 DR. MARKS: Next ingredient is the poloxyalkylene ethers. Okay. So this is a re review of an amended safety assessment of the butyl polyoxyalkylene ethers. In 2001, that ingredient, with an addendum that it include PPG 2, 4, 5, 9, 12, 14, 15, 16, et cetera. up to 53 where safe for use in cosmetics when formulated to avoid irritation. Then in 2000 the year before a final report of PPG 12 buteth am I saying that correct? 16, 9, 12, and a couple more was amended and all these four ingredients were safe and now it's proposed to combine those two reports since they have a common structural motif of a butyl connected to a simple polyoxyalkylene and it includes 22 additional ethers. So, Ron, Ron, and Tom, do you like the idea of opening this, combining the two reports and adding 22 ingredients? And, if yes DR. SHANK: Yes. DR. MARKS: then which ingredients do we want? All of them, obviously. We don't want the ones that have already been reviewed and concluded unless there's been significant new data and then of the 22 adding those. I hear a yes in terms of reopening. That's what I had. Ron Shank, did you want to reopen and add the 22 reopen, combine the two reports and add the 22? Were you chemically happy with all the ingredients? DR. SHANK: It seemed more housekeeping to me than anything. I don't object to reopening it just to add DR. MARKS: The 22. DR. SHANK: the 22. DR. SLAGA: But it would be nice to combine them all together. DR. SHANK: Well, if you do, you know if you reopen it DR. SLAGA: You could do that. DR. SHANK: then you can combine the two and add the new ones. DR. SLAGA: Right. DR. HILL: Well, they're due for re review anyway. Isn't that at least some of them are? And then some of them have never been reviewed. Is that DR. MARKS: Yeah. That's correct. The 22 have not been reviewed before and then the ones up for re review. The PEG (inaudible) ethers and their group. So, I get the sense to open it. And we would be issuing a tentative amended report. I'll be moving for that. Monice, use and concentration table on page 30 31, I had some questions. And, let me see. Where was it? Oh, it was under the PPG 14 butyl ether. That's at the bottom of 30. And in the 2015 see at the top totals 0.05 to 7.5. Then under leave on, it has 1 to Was that just a typo? MS. FIUME: I do. I believe it's a typo. I'll double check the original. DR. MARKS: So it's 7.5 is probably the accurate number, you think? MS. FIUME: I'm thinking 17.5 is, but I will check the data right now. DR. MARKS: Oh, 17.5 is. MS. FIUME: PPG 14 butyl ether. Yes, let's use that 17.5 percent in a non spray deodorant. Sorry about that. DR. MARKS: Okay. So the top one should be MS. FIUME: DR. MARKS: point five. Okay. It doesn't change MS. FIUME: Thank you. DR. MARKS: oh, you're welcome. The other question I had was so I had a question. I wanted to get an HRIPT of sensitization study of PPG 40 butyl ether at 60 percent. That's the concentration of use now on page 31, if that's the correct percentages. Is that right, Monice?

27 MS. FIUME: I'm sorry, if what is the DR. MARKS: PPG 40 butyl ether. It's now being used at 60 percent on a leave on? MS. FIUME: Yes. It's used at 60.5 percent in a tonic, dressing, and other hair grooming aid. DR. MARKS: Yeah. And in in the previous report I went and looked it up on page 54, we have an HRIPT of percent. So I didn't feel we could comfortably say safe for only the PPG 40 butyl ether because it's now being used at concentration almost 10 times what had been reported previously as safe. And that HRIPT from the previous report was page 54. You look under clinical assessment of safety on the right hand column, the second paragraph. It says in clinical test of 112 subjects (inaudible) approximately.2 milliliters of seven percent PPG 40 butyl ether was applied. I'm sure I picked that out because the present use is so high I wanted to confirm that's what had been done before. So, to me, it would be we reopen and we combine the two reports as previously. We add the 22 ingredients. But my conclusion would be in this tentative amended report, safe when formulated to be nonirritating. That covers what was done before. Insufficient for PPG 40 butyl ether because we need an HRIPT or some sensitization at 60 percent. MR. ANSELL: And that's not an add on, that's one of the materials in the original report. DR. MARKS: Right. MR. ANSELL: Yeah. DR. SHANK: In that table, it says leave on up to DR. MARKS: Yeah. DR. SHANK: But if you look in the next section below that DR. MARKS: That's page DR. SHANK: that 60.5 is the hair color hair product MS. FIUME: It's a hair tonic. DR. SHANK: tonic. And that's considered leave on. DR. MARKS: And I could see that in a tonic. It probably not just putting in on the hair, but there is getting a lot of scalp. That's how I interpret it. A lot would be left on the scalp. It's not rinsed off after you put this on. So that that's how I would DR. SHANK: So has that use gone concentration gone up DR. MARKS: Yes. It's gone up. DR. SHANK: since we reviewed it last time. DR. MARKS: I assume so since we only had HRIPT of seven percent and safety. I didn't look at the use concentration. MS. FIUME: We didn't have use concentration at that time. DR. MARKS: No. Okay. That's that's so, team, does that sound let me see. DR. SLAGA: Yup. DR. MARKS: I'll be moving so open tentative amended report, safe when formulated to be nonirritating and insufficient for PPG40 butyl ether. We need sensitization either animal or human. DR. SHANK: At 60 percent. DR. MARKS: Sensitization at 60 percent. Okay. Any other comments about these? If not DR. SHANK: Is that nothing. Sorry. DR. MARKS: No. Go ahead. DR. SHANK: I answered my own question. DR. MARKS: Okay. Any other comments? This is the last ingredient I had. Anything else that we need to discuss, team? If not DR. SHANK: Well, actually, there is DR. MARKS: oh, okay.

28 DR. SHANK: SPEAKER: It's too early. DR. SHANK: On page 23. if we're going to go that far. DR. MARKS: And this is on the butyl polyoxyalkylene? DR. SHANK: No. This is going to have to do with reading across. At the top of page 23, above the paragraph above genotoxicity studies. It looks like we use methyloxyisopropanol for read across. It's mentioned several places in the report. And if you go back to that original report, that was a compound that was regarded as safe for nail exposure only. Highly restricted. So I don't think that's a very good sample for read across. But what do we do 15 years later? DR. MARKS: Well, we're reopening it, so we could put in now the question comes DR. SHANK: So then we have to look at it without find another one for read across. Because I don't think that's a very good one to pick for read across, when we concluded it was safe only for use on nails. DR. SLAGA: Good point. DR. SHANK: And that DR. MARKS: So now we're DR. SHANK: that messes it up, I'm afraid. DR. MARKS: well, no. We want to be safe. So tentative amended report. Now, we're into insufficient period. MS. FIUME: Well, that was ECHA's that was a read across compound that ECHA used. So I can delete it. That's an inhalation carcinogenicity study. There were skin painting studies in the original reports for PPG7 butyl 10 and PPG33 butyl 45 that were lifetime skin painting studies that you already have. DR. SHANK: Okay. MS. FIUME: So if the inhalation carcinogenicity is not needed. We can just delete those two studies. DR. SHANK: I think I would delete those, but we can discuss that tomorrow. It gives support for it's not carcinogenic. These compounds are not likely to be carcinogenic, but it's a bad choice for read across. DR. MARKS: Okay. DR. SHANK: Because we were highly restrictive for that particular compound. And also you shouldn't use NOEL's for carcinogens. DR. MARKS: So, I DR. SHANK: But they did, so that's it. DR. MARKS: so, Ron Shank, when asks for comments, do you want to comment or do you want me to mention? DR. SHANK: If you want me to say a few words, I will. DR. MARKS: I think so since you want to delete those and that's data that we have. Yeah, so, if you don't mind, Ron Shank, that would be good. Shank, comments. DR. SHANK: Okay. DR. MARKS: Okay. We have that and that. Good. DR. HILL: Of course, there's the issue with those dermal skin painting studies lifetime not withstanding that they're not going to be penetrable based on molecular weight. So if you want to read down to something lower molecular weight, not done very well with that either. DR. SHANK: Right. DR. MARKS: Okay. So tomorrow I'm going to move that we open this report from 2001 and then the second report from 2000, combining the ingredients of those reports and adding 22 more ingredients. It will be a tentative amended report with a conclusion of safe when formulated to be nonirritating, insufficient for PPG40 butyl ether since we need sensitization data to confirm it's safe at 60 percent. And, Ron, I'll ask you for to make those comments. MS. FIUME: And, Dr. Marks, Carol had brought this up earlier. One of the ingredients ECHA used as read across and is in this report is propylene glycol butyl ether. It's an INCO ingredient with no VCRP uses, but her question was if it's appropriate for read across in the report, should it just be added to the report?

29 DR. HILL: My answer to that would be yes. DR. MARKS: Again, which one is that? So that would make adding 23 because that's not previously been reviewed. MS. FIUME: Correct. DR. MARKS: So 23 ingredients. Tom and Ron, does that sound if you use it for read across, chemically it's in the same family, obviously. So there's no was there a reason why that wasn't included to begin with? DR. SHANK: Which one is this? MS. FIUME: Propylene glycol butyl ether. DR. SHANK: Okay. DR. HILL: It's not a polypropylene glycol. So maybe it was originally excluded on that basis. DR. MARKS: Propylene glycol butyl ether, you said? MS. FIUME: Yes. DR. MARKS: PPG. MS. FIUME: It's in there as I believe it's in I'm trying to find (inaudible). DR. MARKS: Ron Hill, chemically, you're fine with adding it? DR. HILL: I am. MS. FIUME: I know it was used. It should be in this table on developmental reproductive toxicity and genotoxicity. DR. MARKS: Propylene butyl glycol. MS. FIUME: Propylene glycol butyl ether. DR. MARKS: Oh. DR. HILL: Okay. It's under the DART study is on page wait a minute. What page is it? I can't see it on page 22. Actually, it starts at the very bottom of page 21. MS. FIUME: And I think that's just the summary. It's in the table the DART table, which page 38 and 37. And then it's in the genotoxicity table that follows. DR. MARKS: Okay. So, Ron Shank, Tom, you're fine with adding the propylene glycol butyl ether? DR. SHANK: Yup. DR. MARKS: So that'll be then we have 23 ingredients that will be added to these two combined reports. Okay. Any other comments? Thanks, Monice, for bringing that up.

30 ORIGINAL DELIBERATIONS PPG BUTYL ETHERS (PPG-2, -4, -5, -9, -12, -14, -15, -16, -17, -18, , -24, -26, -30, -33, -52, and -53 Butyl Ether) (Addendum to PPG-40 Butyl Ether Report) May 18-19, 1998 Dr. Schroeter noted that his Team concluded that these ingredients are safe as used, but that concern in the area of genotoxicity was expressed during the Team review, which should be discussed. Dr. Belsito said that his Team concluded that these ingredients are safe for use when formulated to avoid skin irritation. Dr. Schroeter agreed with the Belsito Team=s amendment of the safe as used conclusion that was proposed. Dr. Shank noted that neither the methods of manufacture, impurities data, nor genotoxicity data were made available on the PPG Butyl Ethers. He indicated that two genotoxicity assays on PPG-2 Butyl Ether are needed. Dr. Shank wanted to know how the Belsito Team addressed the issue of genotoxicity. Dr. Belsito noted that his Team considered that the PPG Butyl Ethers would be broken down to propylene glycol and butanol. Dr. Shank said that it is not the breakdown of the PPG Butyl Ethers that is of concern. Specifically, he noted that the manufacturing process may yield some byproduct that has not been anticipated, and that the Panel does not have data to indicate otherwise. Dr. Belsito stated that the Panel received a report from Union Carbide indicating that the potential for PPG Butyl Ether-induced skin cancer is low. He also noted that PPG Butyl Ether 800, fed to rats at a concentration of 0.26% of the diet, was not carcinogenic after two years of dosing.dr. Belsito noted that his Team is comfortable with these data. Dr. Belsito added that it was clarified that the PPG Butyl Ethers are produced from n-butyl alcohol. With this in mind, he said that in addition to the Schroeter Team=s request to delete references to the brake-coating fluid study that was done using an unknown concentration of PPG Butyl Ether, his Team requested that the references to t-butyl alcohol be deleted as well. Dr. Belsito wanted to know the method by which PPG-40 Butyl Ether can be incorporated into the present document such that the Panel=s conclusion on PPG Butyl Ethers that will be generated today will be applicable.dr. Belsito recalled that the Panel previously issued an insufficient data conclusion on PPG-40 Butyl Ether, published in Dr. Andersen said that PPG-40 Butyl Ether could be added to the title of the current report on PPG Butyl Ethers, and that the public could be alerted to the fact that the current conclusion amends the Panel=s previous conclusion on PPG-40 Butyl Ether. The Panel voted unanimously in favor of issuing a Tentative Report with the following conclusion: Based on the available data, the CIR Expert Panel concludes that PPG-2, -4, -5, -9, -12, -14, -15, -16, -17, -18, -20, -22, -24, -26, - 30, -33, -40, -52, and -53 Butyl Ether are safe for use in cosmetics when formulated to avoid irritation. (Note: This tentative conclusion would amend the conclusion previously reached for PPG-40 Butyl Ether.) December 2-3, 1998 Dr. Belsito noted that the Panel issued a Tentative Report with the following conclusion at the May 18-19, 1998 Panel meeting: Based on the available data, the CIR Expert Panel concludes that PPG-2, -4, -5, -9, -12, -14, -15, - 16, -17, -18, -20, -22, -24, -26, -30, -33, -40, -52, and -53 Butyl Ether are safe for use in cosmetics when formulated to avoid irritation. (Note: This tentative conclusion would amend the conclusion previously reached for PPG-40 Butyl Ether.) Dr. Belsito also recalled that the Panel had previously reviewed a significant amount of data that was received just prior to the May Panel meeting as well as additional new data that were received. He noted that these data have been incorporated into the CIR report and do not warrant any change in the Panel s tentative conclusion. The Panel voted unanimously in favor of issuing a Final Report with the conclusion stated in the first paragraph of this section.

31

32 ORIGINAL DELIBERATIONS PPG BUTETHS (PPG-12-Buteth-16, PPG-9-Buteth-12, PPG-26-Buteth-26, and PPG-28-Buteth-35) December 11-12, 1995 The Panel voted unanimously in favor of issuing an Insufficient Data Announcement on the PPG Buteths, with the following data requests: (1) Percutaneous absorption data, preferably on the lowest molecular weight PPG Buteth that is being used in cosmetics (PPG-9-Buteth-12); if absorption occurs, then a dermal teratogenicity study may be needed (2) Skin irritation and sensitization data on PPG-9-Buteth-12, preferably involving human subjects (3) UV spectral analysis on PPG-9-Buteth-12; if there is absorption in the UVA or UVB range, then photosensitization data will be requested. June 3-4, 1996 Dr. Schroeter noted that neither of the following studies requested in the Insufficient Data Announcement issued at the December 11-12, 1995 Panel meeting has been received: (1) Percutaneous absorption data, preferably on the lowest molecular weight PPG Buteth that is being used in cosmetics (PPG-9-Buteth-12); if absorption occurs, then a dermal teratogenicity study may be needed; (2) Skin irritation and sensitization data on PPG-9-Buteth-12, preferably involving human subjects; and (3) UV spectral analysis on PPG-9-Buteth-12; if there is absorption in the UVA or UVB range, then photosensitization data will be requested.dr. Schroeter then proposed that the Panel approve the issuance of a Tentative Report with an insufficient data conclusion and a discussion section that includes the preceding data requests. DR. Belsito said that his Team determined that the Panel=s data needs could be met by requesting one of the following three items: (1) dermal absorption, assuming that this would be low or negligible, or (2) teratogenicity of n-butyl alcohol, or (3) the amount of n-butyl alcohol impurity in the finished product. He also said that if either of the three was found to be negative (i.e., no dermal absorption, n-butyl alcohol not teratogenic, or no significant amount of n-butyl alcohol contaminating the finished product), his Team would be able to rule on the safety of the PPG Buteths. Dr. Bergfeld confirmed that Dr. Belsito=s Team also agreed that the UV spectral analysis and skin irritation and sensitization study included in the Insufficient Data Announcement are not needed. Dr. Belsito noted that deletion of the request for skin irritation and sensitization data is based on the observation that, historically, PPG Buteths have not been recognized as sensitizers under use conditions, along with data from an earlier CIR Report indicating that n-butyl alcohol was not a sensitizer at test concentrations of 2 to 3%. He acknowledged that though significantly higher amounts of n-butyl alcohol are conjugated with the PPG=s, it is not believed that 2 to 3% n-butyl alcohol will actually be released into the skin. Dr. Schroeter noted that the Panel does not have any data to support either his or Dr.Belsito=s assumption that the PPG Buteths are not sensitizers, and recommended that the Panel=s request for skin irritation and sensitization data remain. Given the large number of inhalation toxicity studies included in the Tentative Report draft, Dr. Belsito requested clarification of the reason why these studies were performed. He wanted to know whether there was some concern relating to pulmonary toxicity. Dr. Andersen noted that the report on PPG Buteths has been updated to include the following studies on PPG-26- Buteth-26 that were received from industry: acute oral toxicity, acute dermal toxicity, skin irritation, and ocular irritation. It was also noted that these studies do not address any of the Panel=s current concerns relating to the safety of PPG Buteths in cosmetics. Dr. McEwen noted that there had been a discussion in Teams relating to the possibility of adding more PPG Buteths to the current report. He also recalled that the Panel had requested that PPG-9-Buteth-12 be tested in the skin irritation and sensitization and percutaneous absorption studies listed in the Insufficient Data Announcement that was issued. With this in mind, Dr. McEwen wanted to know whether it would be appropriate to discuss using the lowest molecular weight PPG Buteth (PPG-2-Buteth-2) that is listed for use in cosmetics in the International

33 Cosmetic Ingredient Dictionary for these tests. He also wanted to know if other PPG Buteths listed in the dictionary that are not reported to FDA as being used should be added to the current report. Dr. Andersen said that such a discussion, as proposed by Dr. McEwen above, holds the potential for two things: (1) If the data were provided, then the basic insufficiencies could be satisfied; and (2) if the data were provided on the lowest molecular weight PPG Buteth, the Panel would be on record as saying that this would support expanding the group of ingredients reviewed in the present report to include the range encompassing PPG-2-Buteth-2 (lowest molecular weight) up to PPG-38-Buteth-37 (highest molecular weight). In response to Dr. Bergfeld=s question, the Panel agreed that data on the lowest molecular weight PPG Buteth (PPG- 2-Buteth-2) would satisfy the Panel=s request for skin irritation and sensitization and percutaneous absorption data. Dr. Andersen recommended that it be indicated in the report discussion that the results of studies involving PPG-2- Buteth-2 may serve as the basis for expanding the group of PPG Buteths reviewed in the present report to include all PPG Buteths listed in the International Cosmetic Ingredient Dictionary. The Expert Panel concluded that the available data are insufficient to support the safety of PPG-12-Buteth-16, PPG- 9-Buteth-12, PPG-26-Buteth-26, and PPG-28-Buteth-35 as used in cosmetics, and voted unanimously in favor of issuing a Tentative Report. Based on today=s discussion, the data needed in order for the Panel to complete its safety assessment will be included in the discussion section of the Tentative Report as follows:

34 (1) Dermal absorption of lowest molecular weight PPG Buteth in this group*; alternatively, data on n-butyl alcohol teratology or the amount of n-butyl alcohol as an impurity in the finished product could be provided (2) Human dermal irritation and sensitization* *Studies on the lowest molecular weight PPG Buteth listed in the International Cosmetic Ingredient Dictionary (PPG-2- Buteth-2) are acceptable and may provide a basis for expanding this family of ingredients to include all of the PPG Buteths. December 16-17, 1996 Dr. Schroeter noted that a Tentative Report with an insufficient data conclusion was issued at the June 3-4, 1996 Panel meeting. However, since this Panel meeting, data on human skin irritation and sensitization data and an impurities analysis, all on PPG-26-Buteth-26, were received. In recognition of the new study results on PPG-26-Buteth-26, Dr. Schroeter said that his Team concluded that PPG-26-Buteth-26 and PPG-28-Buteth-35 are safe as used. It was also concluded that the available data are insufficient for arriving at a conclusion on the safety of PPG-12-Buteth-16 and PPG-9-Buteth-12 in cosmetics. The data needed for completion of the safety assessment of these two ingredients were stated as follows: (1) Human dermal irritation and sensitization; (2) Dermal absorption of the lowest molecular weight PPG Buteth in this group; and (3) n-butyl alcohol impurities in the finished compounds. Dr. Shank noted that the Panel does not have data on the toxicity of the lower molecular weight PPG Buteths, and, furthermore, lower molecular weight compounds usually have a higher biological activity than higher molecular weight compounds. Dr. Belsito noted that the Panel received data indicating that the PPG Buteths do not contain n-butyl alcohol as an impurity, and requested that data from the CIR Final Report on n-butyl alcohol be deleted from the present report on PPG Buteths. Dr. Belsito also said that based on the Panel=s prior review of PPG=s and other PPG-containing compounds, the existing report probably could be broadened to include additional PPG Buteths listed in the International Cosmetic Ingredient Dictionary. Dr. Klaassen said that he would not suspect that there would be any tremendous differences in absorption between PPG-12- Buteth-16, PPG-9-Buteth-12, PPG-26-Buteth-26, and PPG-28-Buteth-35, based on molecular weights. He also noted that the Panel is quite knowledgeable of the PPG=s. With this in mind, he said that additional lower molecular weight PPG Buteths from the International Cosmetic Ingredient Dictionary could probably be grouped together for review. Dr. McEwen brought to the Panel=s attention that data on a representative low molecular weight PPG Buteth (compared to the four ingredients being reviewed) are included in the present review: acute oral toxicity, chronic oral toxicity, intravenous toxicity, and dermal carcinogenicity studies on PPG-7-Buteth-10. Dr. Shank noted that the exact number of mice tested in the carcinogenicity study on PPG-7-Buteth-10 was not stated. In response to Dr. McEwen=s question regarding additional data needed to complete the present safety assessment, Dr. Shank noted that very minimal impurities data are available and that there are no skin irritation or sensitization data on the lower molecular weight compounds. He reiterated that lower molecular weight compounds usually have more biological activity than higher molecular weight compounds, and the extent of penetration into the skin may be greater for lower molecular weight compounds. Dr. Shank said that his concerns about the lower molecular weight PPG Buteths relate to dermal effects, not systemic effects. He expressed interest in knowing the changes that occur when the lower molecular weight compounds are applied to the skin. Dr. Belsito recalled that the Panel has approved Propylene Glycol and Polypropylene Glycols (PPG=s) for use in cosmetics. In response to Dr. Belsito=s comments, Dr. Shank noted that the PPG Buteths are different compounds with, perhaps, different impurities. The Panel voted in favor of issuing the following conclusion on PPG Buteths: The CIR Expert Panel concluded that PPG-26- Buteth-26 and PPG-28-Buteth-35 are safe as used in cosmetic products, and that the available data are insufficient to support the safety of PPG-12-Buteth-16 and PPG-9-Buteth-12 as used in cosmetics. There was one abstention, Dr. Belsito. The Panel also determined that the following data are needed in order to complete the safety assessment of PPG-9-Buteth-12 and PPG-12-Buteth-16, and, possibly, to evaluate the safety of even lower molecular weight PPG Buteths: (1) Dermal absorption of PPG-9-Buteth-12*

35 (2) Human dermal irritation and sensitization of PPG-9-Buteth-12* * Studies on the lowest molecular weight PPG Buteth listed in the International Cosmetic Ingredient Dictionary (PPG-2- Buteth-2) are acceptable and could provide a basis for expanding this family of ingredients to include all of the PPG Buteths. The preceding data requests will be included in the report discussion. Dr. Andersen noted that because the conclusion reached at the present meeting is substantially different from the one included in the Tentative Report, the current document will be re-issued as a Tentative Report with the new conclusion that was approved today. Announcement of the Tentative Report will be followed by a 90-day comment period. The Panel had previously issued a tentative insufficient data conclusion on PPG-12-Buteth-16, PPG-9-Buteth-12, PPG-26-Buteth-26, and PPG-28-Buteth-35. June 5-6, 1997 Dr. Schroeter noted that a Tentative Report with the following conclusion was issued at the December 16-17, 1997 Panel meeting: The CIR Expert Panel concluded that PPG-26-Buteth-26 and PPG-28-Buteth-35 are safe as used in cosmetic products, and that the available data are insufficient to support the safety of PPG-12-Buteth-16 and PPG-9-Buteth-12 in cosmetics. The data needed in order for the Panel to complete its safety assessment of PPG-12-Buteth-16 and PPG-9-Buteth-12 were stated as follows: (1) Dermal absorption of PPG-9-Buteth-12* (2) Human dermal irritation and sensitization of PPG-9-Buteth-12* *Studies on the lowest molecular weight PPG Buteth listed in the International Cosmetic Ingredient Dictionary (PPG-2- Buteth-2) are acceptable and could provide a basis for expanding this family of ingredients to include all of the PPG Buteths. Dr. Schroeter noted that no information was received in response to the Panel=s data requests on PPG-12-Buteth-16 and PPG- 9-Buteth-12. The Panel voted unanimously in favor of issuing a Final Report with the conclusion and data requests (in report discussion) stated above. May 18-19, 2000 Dr. Schroeter recalled that a Final Report with the following conclusions was issued in 1997: The CIR Expert Panel concluded that PPG-26-Buteth-26 and PPG-28-Buteth-35 are safe as used in cosmetic products, and that the available data are insufficient to support the safety of PPG-12-Buteth-16 and PPG-9-Buteth-12 as used in cosmetics. He noted that the Panel has identified the following data that are still needed in order to complete the safety assessment of PPG-9-Buteth-12 and PPG-12-Buteth-16 (and possibly, to evaluate the safety of even lower molecular weight PPG Buteths): (1) Dermal absorption of PPG-9-Buteth 121 (2) Human dermal irritation and sensitization of PPG-9-Buteth Studies on the lowest molecular weight PPG Buteth listed in the International Cosmetic Ingredient Dictionary (PPG-2- Buteth-2) are acceptable and could provide a basis for expanding this family of ingredients to include all of the PPG Buteths. Dr. Schroeter indicated that the Panel recently received negative repeated insult patch test data on PPG-12-Buteth-16, which was tested at a concentration of 0.75%, and that these data are acceptable. However, he said that his Team noted that the question relating to the dermal absorption of PPG-9-Buteth-12 remains and that these data are still needed. Dr. Schroeter also requested confirmation that the carcinogencity study on PPG-7-Buteth-10 is a skin-painting study, because the reference for this study is indicative of oral toxicity testing. He said that if the study is a skin-painting study, then the Panel would have good documentation that the lower and higher molecular weight PPG Buteths are safe.dr. Schroeter requested that review of the Final Report be tabled until the September 2000 Panel meeting, pending confirmation of the route of administration of PPG-7-Buteth-10 in the carcinogenicity study. Dr. Belsito noted that his Team agreed that a Final Report with a safe as used conclusion on the two lower molecular weight PPG Buteths should be issued at this meeting, assuming that the carcinogenicity study is a skin-painting study and that this will be verified.dr. Belsito also said that if it is determined that the study is not a dermal carcinogenicity study, then further discussion of the report by the Panel would be necessary.

36 Dr. Andersen said that if it is determined that the carcinogenicity study is a dermal carcinogenicity study, then the Final Report will be revised and issued as a Tentative Amended Final Report. He added that if further consideration of the study is required, then a Draft Report along with the carcinogenicity study will be provided for consideration at the September 11-12, 2000 Panel meeting. The Panel voted unanimously in favor of issuing a Tentative Amended Final Conclusion on PPG-9-Buteth-12, PPG-12- Buteth-16, PPG-26-Buteth-26, and PPG-28-Buteth-35 indicating that these ingredients are safe as used in cosmetic formulations, with the caveat that the study on PPG-7-Buteth-10 is reexamined and found to be a robust evaluation of longterm, chronic toxicity. Dr. Bailey asked who would be making the determination that is referred to in the caveat. Dr. Andersen said that the chair, Panel members designated by the chair, or the entire Panel could make the determination. Dr. Bergfeld said that the study could be submitted to toxicologists on the Panel for review and comment, and that any concerns raised would result in the report being tabled for review at the September Panel meeting.

37 Amended Safety Assessment of Butyl Polyoxyalkylene Ethers as Used in Cosmetics Status: Draft Final Amended Report for Panel Review Release Date: March 17, 2017 Panel Meeting Date: April 10-11, 2017 The 2017 Cosmetic Ingredient Review Expert Panel members are: Chairman, 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 safety assessment was prepared by Monice M. Fiume, Assistant Director/Senior Scientific Analyst/Writer and Bart Heldreth, Ph.D., Chemist. Cosmetic Ingredient Review 1620 L Street, NW, Suite 1200 Washington, DC ph fax cirinfo@cir-safety.org

38 ABSTRACT The Cosmetic Ingredient Review (CIR) Expert Panel (Panel) assessed the safety of 46 butyl polyoxyalkylene ethers that share a common structural motif, namely a butyl chain (4 carbon alkyl chain) bound to a polyoxyalkylene (PPG, PEG, or both); 23 of these ethers were previously reviewed by the Panel, and 23 are reviewed for the first time. Most of the butyl polyoxyalkylene ethers have several functions in cosmetics, but the most common functions include hair conditioning agent and skin conditioning agent, and many function as fragrance ingredients. Upon review of new data, including frequency and concentration of use, and data from previous CIR reports and on read-across analogs, the Panel concluded that these ingredients are safe in the present practices of use and concentration in cosmetics when formulated to be non-irritating. INTRODUCTION The CIR Expert Panel published the Amended Final Report on the Safety Assessment of PPG-40 Butyl Ether with an Addendum to Include PPG-2, -4, -5, -9, -12, -14, -15, -16, -17, -18, -20, -22, -24, -26, -30, -33, -52, and -53 Butyl Ethers in Based on the available data, the Panel concluded that these butyl PPG ethers were safe for use in cosmetics when formulated to avoid irritation. This was a revised conclusion for PPG-40 Butyl Ether; in 1993, the Panel concluded that the safety of PPG-40 Butyl Ether was not documented or substantiated. 2 In 2000, the Panel published the Final Report on the Safety Assessment of PPG-12-Buteth-16, PPG-9-Buteth-12, PPG-26- Buteth-26, and PPG-28-Buteth Based on the information included in that published report, the Panel concluded that PPG-26-Buteth-26 and PPG-28-Buteth-35 are safe as used in cosmetic products, and that the data were insufficient to support the safety of PPG-12-Buteth-16 and PPG-9-Buteth-12 as used in cosmetics. However, that same year, the Panel issued an Amended Final Report on these butyl PPG/PEG ethers, and concluded that all four ingredients are safe as used in cosmetic products. 4 CIR usually evaluates the conclusions of previously-issued reports every 15 years, and it has been at least 15 years since the last assessments have been issued on the ingredients named above. Because the ingredients included in the reports on the butyl PPG ethers and the butyl PPG/PEG ethers share a common structural motif, namely a butyl chain (4 carbon alkyl chain) bound to a polyoxyalkylene (PPG, PEG, or both), the Panel determined that the butyl PPG ethers and butyl PPG/PEG ethers could be re-reviewed together in one report; this family is referred to as the butyl polyoxyalkylene ethers. Included in this assessment are butyl polyoxyalkylene ethers named in the International Cosmetic Ingredient Dictionary and Handbook (Dictionary) that have not yet been reviewed: Buteth-3 PPG-3 Butyl Ether PPG-2-Buteth-1 PPG-2-Buteth-2 PPG-2-Buteth-3 PPG-3-Buteth-5 PPG-4-Buteth-4 PPG-5-Buteth-5 PPG-5-Buteth-7 PPG-7-Buteth-4 PPG-7-Buteth-10 PPG-10-Buteth-9 PPG-12-Buteth-12 PPG-15-Buteth-20 PPG-17-Buteth-17 PPG-19-Buteth-19 PPG-20-Buteth-30 PPG-24-Buteth-27 PPG-30-Buteth-30 PPG-33-Buteth-45 PPG-36-Buteth-36 PPG-38-Buteth-37 Propylene Glycol Butyl Ether Therefore, this safety assessment includes 23 butyl polyoxyalkylene ethers that were evaluated in two previous reports and 23 butyl polyoxyalkylene ethers that were not yet reviewed by the Panel. A list of all 46 ingredients included in this review is provided in Table 1. The two groups of ingredients that are being combined in this report have similar functions in cosmetics. According to the Dictionary, both the butyl PPG/PEG ethers and the butyl PPG ethers are reported to function as hair conditioning agents and skin conditioning agents (Table 2). 5 Other functions for some butyl PPG/PEG ethers include fragrance ingredients, surfactants, or solvents. Buteth-3 is reported to function as a solvent. The Panel has reviewed similar groups of ingredients. Previously, the Panel concluded alkyl PEG ethers (reaction products of an alkyl alcohol and one or more equivalents of ethylene oxide) are safe in the present practices of use and concentration (as described in the safety assessment) when formulated to be non-irritating. 6 The Panel also found the alkyl PEG/PPG ethers (reaction products of an alkyl alcohol and one or more equivalents each of ethylene oxide and propylene oxide) safe in the present practices of use and concentration (as described in the safety assessment) when formulated to be non-irritating. 7 These reports are available on the CIR website. (

39 Distributed for comment only -- do not cite or quote Much of the new data included in this safety assessment was found on the European Chemicals Agency (ECHA) website8 and in an Organisation for Economic Co-operation and Development (OECD) Screening Information Data Set (SIDS).9 ECHA dossiers10,11 and the SIDS document9 also provided information that is useful for read-across. The justifications for the use of information on (butoxymethylethoxy)methylethoxy]propan-1-ol, poly[oxy(methyl-1,2-ethanediyl)],α-butyl-ωhydroxy-, and 1-(2-butoxy-1-methylethoxy)-propan-2-ol for read across are provided in Table 3; test data on these compounds are included in the body of the report. Excerpts from the summaries of previous reports (issued in 2000 and 2001) on butyl PPG/PEG ethers and the butyl PPG ethers are disseminated throughout the text of this re-review document, as appropriate, and are identified by italicized text. (This information is not included in the tables or the summary section.) CHEMISTRY Definition and Structure The definitions and structures of the butyl polyoxyalkylene ethers are provided in Table 2. The butyl polyoxyalkylene ethers in this report share a common core structure comprising a linear, four carbon alkyl chain (butyl) connected, through an ether linkage, to a polyether chain comprising a polyethylene glycol (PEG, or an eth suffix), polypropylene glycol (PPG), or both. These polyether chains vary in length from just 1 repeat unit (i.e. Propylene Glycol Butyl Ether, MW= g/mol) to 75 repeat units (i.e. PPG-38-Buteth-37, mean MW= g/mol). Accordingly, the butyl polyoxyalkylene ethers may be represented generically as a butyl terminated polyether, as shown in Figure 1. wherein x may be any integer from 0 to 53 and y may be any integer from 0 to 45 Figure 1. Generic and specific butyl polyoxyalkylene ether structures Propylene Glycol Butyl Ether represents the smallest ingredient in this report, and is simply the ether of butanol and one propylene glycol residue.12 While the Dictionary recites the structures of all of the other propylene glycol containing ingredients in this report as the β-isomers (terminal alcohol is primary (1o)), as shown in Figure 1, Propylene Glycol Butyl Ether is recited as the α-isomer (terminal alcohol is secondary (2o)). Figure 2. Propylene Glycol Butyl Ether Physical and Chemical Properties Propylene Glycol Butyl Ether13,14 and PPG-3 Butyl Ether,10 a hydrophobic glycol ether,15 are colorless liquids (Table 4). Also described in Table 4 are physical and chemical properties of Buteth-3, a water-soluble crystalline compound with low volatility,16 and those of an undefined polypropylene glycol butyl ether. Methods of Manufacture PPG-12-Buteth-16 and other ethylene oxide/propylene oxide polymers of this series, are butanol-initiated, random linear copolymers that are produced from equal amounts (by weight) of ethylene and propylene oxide.4 The PPG Butyl Ethers are produced by the reaction of excess propylene glycol with n-butyl alcohol.1 Generally, propylene glycol ethers are prepared commercially by reacting propylene oxide with an alcohol in the presence of a catalyst17 in a closed continuous system.9 This reaction can produce glycol ethers of varying chain lengths that depend on

40 the stoichiometric ratio of reactants and the temperatures and pressures used in the reaction. Milder conditions and lower stoichiometric ratios of propylene oxide to alcohol yields the monopropylene glycol ethers, while using more propylene oxide and higher temperatures and pressures produces the di-, tri-, and poly-propylene glycol, mono-alkyl ethers. The products are purified by distillation. The α-isomer and a β-isomer are usually formed during the synthesis of Propylene Glycol Butyl Ether. A technical product generally comprises 95-99% of the α-isomer and only traces of the β-isomer. (The α-isomer is a secondary alcohol, and the β-isomer is a primary alcohol). 17 Impurities The concentration of residual ethylene oxide and propylene oxide in PPG-33-Buteth-45 is less than 1 ppm. 4 The PPG Butyl Ethers can contain propylene oxide. 1 It was reported (by two suppliers in 2010) that a maximum of 10 ppm propylene oxide was present in PPGs used to make finished products. 18 A tradename mixture containing PPG-26-Buteth-26 contained<5 ppm dioxane and <1 ppm ethylene oxide. 3 Some of the butyl polyoxyalkylene ethers are ethoxylated and therefore may contain trace amounts of 1,4-dioxane, which is a by-product of ethoxylation and a known animal carcinogen. 19 USE Cosmetic The safety of the cosmetic ingredients addressed in this assessment is evaluated based on data received from the U.S. Food and Drug Administration (FDA) and the cosmetics industry on the expected use of these ingredients in cosmetics. Use frequencies of individual ingredients in cosmetics are collected from manufacturers and reported by cosmetic product category in FDA s Voluntary Cosmetic Registration Program (VCRP) database. Use concentration data are submitted by the cosmetic industry in response to a survey, conducted by the Personal Care Products Council (Council), of maximum reported use concentrations by product category. According to information from the VCRP and the Council, 18 of the 46 ingredients assessed in this report are in use PPG-26-Buteth-26 has the highest frequency of use; according to the 2017 VCRP data, it is used in 1332 cosmetic formulations. 20 Buteth-3 and PPG-12-Buteth-16 have the next highest frequency of use, with 446 and 436 reported uses, respectively. (Table 5, Table 6) The results of the concentration of use survey conducted by the Council in 2015 indicate that PPG-40 Butyl Ether has the highest maximum use concentration in both leave-on (71% in a hair wax listed under tonics, dressings, and other hair grooming aids) and rinse-off formulations (73.5% in hair tints) 23 PPG-14 Butyl Ether has the greatest maximum leave-on concentration of use that results in dermal exposure; it is used at up to 17.5% in deodorants. (Table 5, Table 6). Approximately half of the in-use ingredients have been reviewed previously by the Panel. 3,4 The current frequency of use for the majority of these ingredients is similar to that reported at the time of the original review. However, there has been a large increase in the frequency of use of PPG-26-Buteth-26; in 1997, this ingredient was reported to be used in 13 formulations, and it is now used in 1332 formulations. Concentrations of use were not reported by the FDA at the time of the previous safety assessments, so it is not known if the concentrations of use have changed. The 28 butyl polyoxyalkylene ethers not currently reported to be in use according to VCRP data and industry survey are listed in Table 7. In some cases, reports of uses were received from the VCRP, but no concentration of use data were provided. For example, PPG-28-Buteth-35 is reported to be used in 9 formulations, but no use concentration data were submitted. In other cases, no uses were reported to the VCRP, but a maximum use concentration was provided in the industry survey. For example, PPG-52 Butyl Ether was not reported to be in use in the VCRP database, but the industry survey indicated that it is used in at least 2 hair product categories; it should be presumed that PPG-52 Butyl Ether is used in at least one cosmetic formulation in each category. A few of the butyl polyoxyalkylene ethers are used in products that can be used near the eye (e.g., 3.6% PPG-26-Buteth-26 in eyeliner and eye shadow) or come in contact with mucous membranes (e.g. 2% PPG-26-Buteth-26 in bath soaps and detergents). Additionally, some of these ingredients are used in cosmetic sprays and could possibly be inhaled; for example, PPG-40 Butyl Ether is reported to be used at a maximum concentration of 10% in hair sprays. 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 <10 µm compared with pump sprays. 24,25 Therefore, most droplets/particles incidentally inhaled from cosmetic sprays would be deposited in the nasopharyngeal and thoracic regions of the respiratory tract and would not be respirable (i.e., they would not enter the lungs) to any appreciable amount. 26,27 PPG-26-Butth-26 has reported use in spray deodorant at a concentration of 0.099%. 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. 27 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.

41 The butyl polyoxyalkylene ethers described in this safety assessment are not restricted from use in any way under the rules governing cosmetic products in the European Union (EU). 28 Non-Cosmetic Most of the butyl polyoxyalkylene ethers are approved for use as secondary direct food additives or as indirect food additives. (Table 8) Propylene glycol ethers are coalescing, coupling and dispersing agents. 17 These ethers are used in solvents and have a wide range of applications. For example, they are used in paints, lacquers, resins, surface coatings, dyes, and other related products. Propylene Glycol Butyl Ether Propylene Glycol Butyl Ether is used as a coupling agent and solvent due to its high solvency, oil solubility, high formulating flexibility, and low viscosity. 29 It has been used in household and commercial degreasers and hard surface cleaners. PPG-3 Butyl Ether PPG-3 Butyl Ether is a solvent and coalescing agent used in architectural and industrial coatings, and in indoor decorative paints. 30 It is also used as a solvent in heavy-duty cleaning formulations, oven cleaners, inks for ball-point and felt-tip pens and stamp pads, and in textile printing pastes. Buteth-3 Buteth-3 is used as a component of hydraulic brake fluid, as a solvent in paint stripping formulations, and as a dye carrier for textile dye processes. 16 TOXICOKINETICS STUDIES Dermal Penetration Buteth-3 The dermal penetration of Buteth-3 through human skin was measured in vitro. 31 Epidermal samples were mounted in a glass diffusion apparatus; the exposure area was 2.54 cm 2. (The identification of the receptor fluid was not provided.) Undiluted Buteth-3 (99.9% pure) was placed in contact with the epidermis for 12 h; 5 runs were performed. Tritiated water was used as a control. The diffusion rate was 22 µg/cm 2 /h. Additionally, the epidermal damage caused by exposure to Buteth-3 was examined by measuring the increase in tritiated water diffusion following exposure. Buteth-3 had no significant effect on skin barrier function; the damage ratio (i.e., the ratio of permeability constants determined from tritiated water diffusion after chemical exposure compared to before exposure) was Absorption, Distribution, Metabolism, and Excretion (ADME) In rats dosed orally with 14 C-PPG-7-Buteth-10, most of the administered radioactivity was excreted (urine, feces, and expired CO 2 ) within seven days post-dosing. Similar observations were reported for rats dosed orally with 14 C-PPG-33-Buteth-45; however, radioactivity was not detected in expired CO 2. 4 Absorption of the PPGs Butyl Ether was inversely proportional to the molecular weight; typical gastric absorption values ranged from 2% to 100%, depending upon the chain length. PPG BE800 (PPG BE refers to the molecular weight of the substance; PPG BE800 is ~PPG- 13 Butyl Ether) penetrated rabbit skin slowly, if at all, and passed poorly through internal tissue barriers. Once absorbed, the butyl group was removed and oxidized, then was partly or completely excreted as CO 2 by the lungs. The chains were apparently split into random length fragments and eliminated in urine as weak acids after oxidation of the terminal hydroxyls to carboxyl groups. 1 Propylene Glycol Butyl Ether As a class, the propylene glycol ethers are rapidly absorbed and distributed throughout the body following oral and inhalation exposure. 9 The primary routes of excretion are via the urine and expired air; a small amount is excreted in the feces. Absorption via the dermal route is slower, but subsequent distribution is rapid. 9 Additionally, Propylene Glycol Butyl Ether (a monoglycol ether) is expected to be absorbed more rapidly than diglycol and triglycol ethers. 12 However, diglycol and triglycol ethers may be present on the skin much longer than monoglycol ethers because of lower vapor pressures. Animal Oral 1-(2-Butoxy-1-methylethoxy)-propan-2-ol (read-across for PPG-n Butyl Ethers) ADME data were not available for the PPG Butyl Ethers. But an appropriate read across material was identified; an ADME study was conducted in accord with OECD Guideline 417 with 1-(2-butoxy-1-methylethoxy)-propan-2-ol. 9 Groups of four male Fischer 344 rats were given a single dose by gavage of 0.4 or 4.4 mmol/kg bw [ 14 C]1-(2-butoxy-1-methylethoxy)- propan-2-ol in 1% methylcellulose. Urine, feces, expired air, blood and tissues were collected for 48 h and analyzed for total 14 C-activity. In the low dose group, 42% of the dose was excreted in urine, 4% in the feces, and 42% as 14 CO 2 ; the tissues, carcass and skin retained 11% of the radioactivity. In the high-dose group, 51% of the dose was excreted in urine, 11% in the feces, and 35% as 14 CO 2 ; the tissues, carcass and skin retained 7% of the dose. Peak blood levels of 14 C-activity

42 occurred 0.5 h after dosing in the low dose group and 4 h after dosing in the high dose group. The distribution of 14 C-activity in tissues was similar between dose groups, with liver, bone marrow, and kidneys retaining the greatest percentage of 14 C. Urinary metabolites included propylene glycol n-butyl ether, dipropylene glycol, propylene glycol, and the sulfate conjugate of 1-(2-butoxy-1-methylethoxy)-propan-2-ol. The parent material was present in the urine. Human Inhalation Propylene Glycol Butyl Ether A cleaning solution containing 3.5% Propylene Glycol Butyl Ether was applied in a simulated cleaning procedure in 7 offices where 8 individuals were employed. 12 The office floor spaces ranged from 41 to 55 m 2 and the room volumes ranged from 33 to 50 m 3. Each office contained wooden furnishings and linoleum flooring and was naturally ventilated. The furniture was wetted with 40 ml of undiluted cleaning solution in the morning; application of the cleaner resulted in a Propylene Glycol Butyl Ether concentration of 0.55 ppm (average; standard deviation 0.17 ppm) in the office air. Seven of the subjects were exposed for approximately 8 h, and one was exposed for approximately 5 h. Subjects collected daily urine the day before, the day of, and the day after exposure. Urine samples were collected by unexposed individuals and analyzed to determine background levels of glycol ether metabolites. 2-Butoxypropionic acid, a metabolite of Propylene Glycol Butyl Ether, could not be quantified in control urine samples. In all test subjects, the concentration of 2-butoxypropionic acid in the urine was below the limit of quantification (LOQ; 0.01 ppm) the day before exposure; it was present at an average concentration of 0.06 ppm (standard deviation 0.9 ppm) in samples collected on the day of exposure. In three subjects, 2-butoxypropionic acid was detected in the urine samples collected on the day after exposure at concentrations slightly above the LOQ ( ppm). TOXICOLOGICAL STUDIES Acute Toxicity Studies Mortality rates for rabbits dosed with PPG Buteths (dose = 21 g/kg) in acute dermal toxicity studies are summarized as follows: 1 of 4 rabbits (PPG-12-Buteth-16); 1 of 4 rabbits (PPG-20-Buteth-30); and 1 of 4 rabbits (PPG-33-Buteth-45). In another acute dermal toxicity study, no deaths occurred in groups of rabbits dosed with PPG-24-Buteth-27 (2, 4, 8, and 16 ml/kg). Erythema, edema, ecchymosis, and desquamation were noted in this study. Pulmonary lesions were noted at necropsy. In New Zealand Albino rabbits dosed with PPG-26- Buteth-26, the acute cutaneous LD 50 was not achieved at a dose of 2.0 g/kg (1.89 ml/kg). 4 An LD 50 of 18.3 g/kg for PPG-12-Buteth-16 was reported in an acute oral toxicity study involving rats. Acute oral LD 50 s ranging from 4.49 to 8.57 ml/kg have been reported for PPG-7-Buteth-10 in studies involving rats. Oral LD 50 s of 7.46 ml/kg (mice) and ml/kg (rabbits) for PPG-7- Buteth-10 also have been reported. The oral LD 50 for PPG-20-Buteth-30 in rats was 20.6 g/kg, and,> 16 ml/kg, in rats dosed with PPG-24-Buteth-27. An oral LD 50 of >5.01 g/kg (4. 72 ml/kg) was reported for PPG-26-Buteth-26 in Long Evans rats. Similar results were reported for Sprague-Dawley rats dosed with a solubilizing system containing PPG-26-Buteth-26 (concentration not stated); the LD 50 was greater than 5.0 g/kg (4.81 ml/kg). In acute oral toxicity studies on PPG-33-Buteth-45 using rats and mice, LD 50 s of 45.2 ml/kg and 49.4 ml/kg, respectively, were reported. In studies using rabbits, an LD 50 of 15.8 ml/kg was reported for PPG-33-Buteth-45. Acute inhalation LC 50 values for PPG Buteths that have been reported for rats are as follows: 4670 mg/m 3 and > 5230 mg/m 3 for males and females, respectively (PPG-12-Buteth-16); 4.77 mg/m 3 (males and females) for PPG-7-Buteth-10; 330 mg/m 3 (males and females) for PPG-20-Buteth-30; and 14 7 mg/m 3 for PPG-33-Buteth-45. LC 50 values of 17 4 mg/m 3 (mice); 511 mg/m 3 (hamsters); and 293 mg/m 3 (guinea pigs) have also been reported for PPG-33-Buteth-45 in other acute inhalation toxicity studies. In general, the lethality of the PPG Butyl Ethers decreased as the molecular weight increased. In rats, the acute oral LD 50 values of the PPG butyl ethers ranged from ml/kg (PPG-2 Butyl Ether) to 48.7 ml/kg (PPG-40 Butyl Ether). For rabbits, the cutaneous LD 50 values were ml/kg (PPG-2 Butyl Ether) to > 20 ml/kg (PPG-40 Butyl Ether). 1 PPG-2 Butyl Ether vapors were non- toxic by the inhalation route. A room-temperature mist of PPG-33 Butyl Ether was nontoxic when inhaled by rats, but when the mist was evolved at 170 C, the ether was moderately toxic. Rats that were exposed to mist and oxidation products from cooling PPG-9, -18, and -24 Butyl Ether vapors for 1 hour died, but none were killed during a 15-minute exposure period. The acute dermal, oral, and inhalation toxicity studies summarized below are described in Table 9. No acute toxicity data were available for PPG-3 Butyl Ether or PPG Butyl Ethers in general. But appropriate read across materials were identified for dermal, oral, and inhalation acute toxicity testing, and those data are included in this table. In rats, the dermal LD 50 was 3.5 g/kg for Buteth-3 16 and >2 g/kg for Propylene Glycol Butyl Ether, 9,13,32 [(butoxymethylethoxy)methylethoxy]-propan-1-ol, 10 poly[oxy(methyl-1,2-ethanediyl)],α-butyl-ω-hydroxy-, 11 and 1-(2-butoxy-1-methylethoxy)-propan-2-ol. 9 In rabbits, the dermal LD 50 was 1.4 g/kg for Propylene Glycol Butyl Ether 13 and >2 g/kg for [(butoxymethylethoxy)methylethoxy]-propan-1-ol. 10 In rats, the oral LD 50 was 6.6 g/kg for Buteth-3, 16 >2 g/kg for Propylene Glycol Butyl Ether, 13 [(butoxymethylethoxy)- methylethoxy]-propan-1-ol, 10 and 1-(2-butoxy-1-methylethoxy)-propan-2-ol, and between g/kg poly[oxy(methyl-1,2-

43 ethanediyl)],α-butyl-ω-hydroxy-. 11 In rats, inhalation LC 50 s were >3251 mg/m 3 Propylene Glycol Butyl Ether 10,11,16 and >328 mg/m 3 1-(2-butoxy-1-methylethoxy)-propan-2-ol. 9 Short-Term, Subchronic and Chronic Toxicity Studies The subchronic (3 months) oral toxicity of PPG-24-Buteth-27 in rats was evaluated at concentrations of 0.01 to 1.25% in the diet. Acute pneumonia was the primary cause of death in one of the two rats (highest exposure group) that died. Lesions were observed in the livers and kidneys of rats from the 0.05, 0.25, or 1.25% treatment groups. The changes observed in the 0.05% treatment group were regarded as transitory, and tissues from rats in the 0.01% group differed little from those of the control group. 4 Hepatic and renal lesions were also observed in another subchronic study (90 days) in which groups of rats were fed PPG-33-Buteth-45 at dietary doses of 0.7 and 4.0 g/kg/day for 90 days. These lesions were not observed in rats fed lower doses (0.03 or 0.15 g/kg/day). In a 2-yr feeding study involving rats, no statistically significant differences were found in the incidence of neoplasms and other lesions (20 tissues) between rats fed PPG-7-Buteth-10 (0.004, 0.02, 0.1, and 0.5 g/kg/day) and control groups. Similar results were reported for PPG-33-Buteth-45, following administration to groups of rats at dietary concentrations of 0.02, 0.1, and 0.5 g/kg/day, respectively. In a chronic 2-yr feeding study involving dogs, no statistically significant differences in the incidence of gross or microscopic lesions (18 tissues) between groups of animals fed PPG-7-Buteth-10 (0.004, 0.02, 0.1, and 0.5 g/kg/day) and control groups were observed. Similar results were reported for PPG-33-Buteth-45, following administration to groups of dogs at dietary doses of 0.023, 0.11, and 0.61 g/kg/day. PPG-2 Butyl Ether at a dose of 0.40 g/kg/day was nontoxic to rats during a 14-day feeding study. In 90-day feeding studies, the noobserved effect levels (NOELs) of PPG BE400, 800, 910, and 1020 were g/kg/day, 0.16 to 0.67 g/kg/day, 0.25% of the diet, and % of the diet, respectively. When rats were treated topically with PPG-2 Butyl Ether 5 days/week for 13 weeks, the dermal NOEL was 0.1 ml/kg/day, which was equivalent to a dose of 91 mg/kg/day. Doses of 0.25 g/kg/day 80% PPG- 40 Butyl Ether, 2.0 g/kg/day 80% PPG-33 Butyl Ether, and 1.0 ml/kg/day PPG BE800 had no effect on mortality, weight change, or microscopic findings when applied to the skin of rabbits 5 days/week for 6 weeks, but the 30-day dermal NOEL for PPG BE400 was <0.1 ml/kg/day. When dogs and rats were fed PPG BE800 and 910 for up to two years, the NOELs were up to 0.5 g/kg/day. 1 The short-term and subchronic toxicity studies summarized below are described in Table 10. No repeated-dose dermal, oral, or inhalation toxicity data were available for PPG-3 Butyl Ether or PPG Butyl Ethers in general. Appropriate read-across materials were identified for dermal subchronic toxicity, oral short-term and subchronic toxicity, and short-term inhalation toxicity testing, and those data are included in this table. In dermal studies, effects on rabbit skin were reported in a 21-day toxicity study of Buteth-3 (1000 mg/kg, occlusive application), 31 in 28-day (at concentrations of 5.69%, open applications) 33,34 and 13-wk (NOEL of 1.76 mg/kg bw/day) studies of Propylene Glycol Butyl Ether, 9,35 and in a 13-wk study of 1-(2-butoxy-1-methylethoxy)-propan-2-ol ( 91 mg/kg bw/day). Clinical signs of toxicity generally were not observed. Irritation was also observed in a 13-wk study of Propylene Glycol Butyl Ether in rats ( 88 mg/kg). 9,13,36 In short-term oral toxicity studies in rats, a no-observed adverse effect level (NOAEL) of 400 mg/kg was reported in 14-day gavage studies of Propylene Glycol Butyl Ether 9,13,37 and 1-(2-butoxy-1-methylethoxy)-propan-2-ol, 9 and of 1000 mg/kg in a 28-day gavage study with [(butoxymethylethoxy)methylethoxy]-propan-1-ol. 10 In oral combined repeated dose toxicity studies with the reproduction/developmental toxicity screening test in rats, the NOEL was 100 mg/kg bw/day in rats exposed to either poly[oxy(methyl-1,2-ethanediyl)],α-butyl-ω-hydroxy- 11 or 1-(2-butoxy-1-methylethoxy)-propan-2-ol. 10 In subchronic (13-wk) drinking water studies in rats, both Propylene Glycol Butyl Ether 9,13 and PPG-3 Butyl Ether 30 had a NOAEL of 350 mg/kg, and [(butoxymethylethoxy)methylethoxy]-propan-1-ol had a NOAEL of 1000 mg/kg. 10 A NOAEL of 450 mg/kg was reported in rats fed a diet containing 1-(2-butoxy-1-methylethoxy)-propan-2-ol for 13 wks. 9 In short-term inhalation studies (nine 6-h exposures) in rats, the NOAEL for Propylene Glycol Butyl Ether was 3785 mg/m 3 9,13,38 and for 1-(2-butoxy-1-methylethoxy)-propan-2-ol was 200 mg/m 3. 9 DEVELOPMENTAL AND REPRODUCTIVE TOXICITY STUDIES PPG-2 Butyl Ether when dermally applied was nontoxic to pregnant rats and was non-teratogenic at doses up to 1.0 ml/kg/ day. 1 The developmental and reproductive toxicity (DART) studies summarized below are described in Table 11. No DART studies were available for PPG Butyl Ethers; appropriate read-across materials were identified for dermal and oral DART testing, and those data are included in this table. Dermal application of PPG-2 Butyl Ether to rats during days 6-16 of gestation produced local skin reactions, but not reproductive or teratogenic effects (NOEL > 1 ml/kg). 17 Dermally applied Propylene Glycol Butyl Ether was not embryotoxic or teratogenic to rats ( 1.0 ml/kg bw/day applied on days 6-16 of gestation) 9,11,17 or rabbits ( 100 mg/kg bw/day applied on days 7-18 of gestation). 9,10,17 Dermal application of up to 910 mg/kg bw/day 1-(2-butoxy-1-methylethoxy)-propan-2-ol was not embryotoxic, fetotoxic, or teratogenic in rats No test-article related adverse developmental or reproductive effects were observed in rats dosed by gavage (days 7-16 of gestation) with up to 1000 mg/kg Buteth No effects on reproduction were observed in rats dosed orally prior to and

44 during mating with up to 500 mg/kg bw/day poly[oxy(methyl-1,2-ethanediyl)],α-butyl-ω-hydroxy- 11 or up to 1000 mg/kg bw/day 1-(2-butoxy-1-methylethoxy)-propan-2-ol. 10 GENOTOXICITY STUDIES The genotoxicity studies summarized below are described in Table 12. No genotoxicity data were available for PPG-3 Butyl Ether or PPG Butyl Ethers in general. Appropriate read-across materials were identified for which Ames tests, mammalian chromosomal aberration assays, and a mammalian cell mutation assay were conducted in vitro and micronucleus tests were conducted in vivo. Those data are included in this table. Propylene Glycol Butyl Ether, 39 [(butoxymethylethoxy)methylethoxy]-propan-1-ol, 10 poly[oxy(methyl-1,2-ethanediyl)],αbutyl-ω-hydroxy-, 11 and 1-(2-butoxy-1-methylethoxy)-propan-2-ol 9 were not mutagenic in Ames tests. Propylene Glycol Butyl Ether was not mutagenic in numerous other genotoxicity studies, including mammalian chromosomal aberration assays in Chinese hamster ovary (CHO) cells ( 6000 µg/ml), 9,13,40 mouse lymphoma cell assays in T5178Y TK+/- lymphoma cells ( 6000 µg/ml), 9,41 and unscheduled DNA synthesis (UDS) assays in primary rat hepatocytes ( 6000 µg/ml). 42 Poly[oxy- (methyl-1,2-ethanediyl)],α-butyl-ω-hydroxy-was not genotoxic in a mammalian chromosomal assay in rat lymphocytes ( 5000 µg/ml), or a mammalian cell mutation assay in CHO cells ( 2500 µg/ml) (2-Butoxy-1-methylethoxy)-propan-2- ol was positive, with chromatid and chromosome gaps and breaks, in chromosomal aberration assays in CHO-K1,S1B cells but not in CHO-K1,CCL61 cells or CHO cells. 9 Gaps and breaks were also reported in negative controls in the tests using CHO-K1, S1B cells. Both [(butoxymethylethoxy)methylethoxy]-propan-1-ol and 1-(2-butoxy-1-methylethoxy)-propan-2-ol were negative in vivo in the mouse micronucleus assay following a single oral dose of 1875 mg/kg bw 10 and 2500 mg/kg bw, 9 respectively. CARCINOGENICITY STUDIES In two lifetime skin painting studies, PPG-7-Buteth-10 and PPG-33-Buteth-45, respectively, did not induce papillomas or carcinomas in mice. When administered following either one or two initiator doses of dimethylbenzanthracene (DMBA), 70% PPG-24-Buteth-27 acted as a tumor promoter; however, 5% PPG-24-Buteth-27 did not act as a tumor promoter. 4 PPG BE800 at concentrations of 0.001% to 0.26% in feed was non-carcinogenic to rats after 2 years of treatment. 1 DERMAL IRRITATION AND SENSITIZATION STUDIES In a skin irritation test of PPG-12-Buteth-16, PPG-20-Buteth-30, and PPG-33-Buteth-45, capillary injection was observed in rabbits only after the application of PPG-12-Buteth-16. The results of another study indicated that PPG-24-Buteth-27 induced minor erythema and moderate edema in rabbits. Reactions were not observed after day 2 post-application. PPG-26-Buteth-26 induced very slight to slight skin irritation in New Zealand albino rabbits. A solubilizing system containing PPG-26-Buteth-26 (concentration not stated) was classified as a mild skin irritant in New Zealand White rabbits. 4 An RIPT study in 109 subjects found no irritation or sensitization associated with the application of 0.75% PPG-12-Buteth-16 under semiocclusive patches. Aftershave formulations containing 2.5% PPG-26-Buteth-26 were not skin irritants or sensitizers when evaluated in two 21-day home use tests. The skin irritation and/or sensitization use test and the skin irritation use test involved 52 and 54 subjects, respectively. In a 4-hour occlusive patch test using rabbits, PPG-2 Butyl Ether caused minor, transient erythema and desquamation, but not edema. PPG-33 Butyl Ether was nonirritating in a vesicant, 4-hour irritation, and 3-day repeated application tests. Undiluted PPG-40 Butyl Ether was minimally irritating to the skin of rabbits. Rabbits treated with PPG BE800 had minimal capillary injection during a 3-day repeated application test, and PPG-40 Butyl Ether was slightly less irritating than PPG BE400 (caused erythema) in a 4-hour belly irritation test. PPG-9 and -18 Butyl Ethers caused capillary injection, whereas PPG-15, -33, and ~9-15 Butyl Ethers caused no response during a rabbit belly vesicant test. 1 In clinical studies, PPG BE800 was nonirritating and non-sensitizing to the skin when tested using 200 subjects. PPG-40 Butyl Ether was neither an irritant nor a sensitizer in a repeat insult patch test using 112 subjects. The dermal irritation and sensitization studies summarized below are described in Table 13. No dermal irritation or sensitization data were available for PPG-3 Butyl Ether or PPG Butyl Ethers in general. Studies on appropriate read-across materials were identified for in vitro irritation testing, irritation and sensitization testing in animals, and sensitization testing in humans. Those data are included in this table. Poly[oxy(methyl-1,2-ethanediyl)],α-butyl-ω-hydroxy- was classified as non-corrosive based on the results of an EpiDerm TM test. 11 In rabbits, Propylene Glycol Butyl Ether was slightly irritating at a concentration of 50% 9,13,43 and was generally irritating when applied undiluted. 9,13,44 In guinea pigs, undiluted Propylene Glycol Butyl Ether was a minimal irritant in one study; 9 however, it was not irritating or sensitizing in a Buehler test (three induction patches with 80% and a challenge with 40%). 9,13,45 Undiluted [(butoxymethylethoxy)methylethoxy]-propan-1-ol was not irritating to rabbit skin and was not a sensitizer in guinea pigs in a Buehler test (2-Butoxy-1-methylethoxy)-propan-2-ol produced some slight irritation in rabbit skin, but was not irritating according to EU classification criteria; also, it was not a sensitizer in guinea pigs (three induction patches with 80% and a challenge with 40%). 9

45 In human repeated insult patch tests (HRIPT), undiluted PPG-14 Butyl Ether, 46 hair styling wax containing 71% PPG-40 Butyl Ether (applied neat), 47 and 1-(2-butoxy-1-methylethoxy)-propan-2-ol 9 were not sensitizers. OCULAR IRRITATION STUDIES Buteth-27 induced iritis and minor to moderate conjunctival irritation. All reactions had cleared by day 2 post-instillation. PPG-26-Buteth- 26 did not induce ocular irritation in New Zealand albino rabbits. Mild ocular irritation was induced in New Zealand White rabbits tested with a solubilizing system containing PPG-26-Buteth-26 (concentration not stated). 4 Rabbits treated with 0.1 ml PPG-2 Butyl Ether had minor corneal injury (opacity), iritis, and moderate conjunctival irritation; rabbits treated with 0.01 ml of the ether had iritis and minor to moderate conjunctival irritation. In an ocular toxicity study, PPG-15 Butyl Ether produced traces of diffuse corneal necrosis in four of five rabbits and PPG-33 Butyl Ether was not irritating. PPG-9, ~9-15, -15,-18,-22, and -33 Butyl Ethers caused minor injury to the eyes of rabbits. 1 The ocular irritation studies summarized below are described in Table 14. No ocular irritation data were available for PPG-3 Butyl Ether or PPG Butyl Ethers in general. Ocular irritation studies in rabbits for appropriate read-across materials were identified, and those data are included in this table. The classification of undiluted Propylene Glycol Butyl Ether in rabbit eyes ranged from not irritating (according to criteria established by the EU) to moderately irritating (according the Draize scores). 9,13,48 Undiluted [(butoxymethylethoxy)methylethoxy]-propan-1-ol 10 and 1-(2-butoxy-1-methylethoxy)-propan-2-ol 9 were not irritating and slightly irritating to rabbit eyes, respectively. SUMMARY The Panel has previously issued final reports on the safety of 19 butyl PPG ethers (2001; safe for use in cosmetics when formulated to avoid irritation) and four butyl PPG/PEG ethers (2000; safe as used in cosmetic products). The ingredients that were reviewed in those two reports share a common structural motif, namely a butyl chain (4 carbon alkyl chain) bound to a polyoxyalkylene (PPG, PEG, or both). This safety assessment combines the 23 butyl polyoxyalkylene ethers named in those two reports with 23 butyl polyoxyalkylene ethers that were not previously reviewed by the Panel. Most of the ingredients included in this safety assessment are reported to function as hair conditioning agents and skin conditioning agents and several are also reported to function as fragrance ingredients, surfactants, or solvents. Eighteen of the 46 ingredients assessed in this report are currently reported as used in cosmetic formulations. According to 2017 VCRP data, PPG-26-Buteth-26 has the highest frequency of use, with 1332 reported uses. Buteth-3 and PPG-12- Buteth-16 have the next highest frequency of use, with 446 and 436 reported uses, respectively. PPG-40 Butyl Ether has the highest maximum use concentration in both leave-on (71% in tonics, dressings, and other hair grooming aids) and rinse-off formulations (73.5% in hair tints). Approximately half of the ingredients that are in use have been reviewed previously by the Panel, and for the majority of these ingredients, the frequency of use has not changed. However, there has been a large increase in the frequency of use of PPG-26-Buteth-26, from 13 reported uses in 1997 to 1332 uses reported in Most of the butyl polyoxyalkylene ethers are approved for use as secondary direct food additives or as indirect food additives. The in vitro diffusion rate of Buteth-3 through human skin samples following a 12-h exposure was 22 µg/cm 2 /h. Buteth-3 did not have a significant effect on skin barrier function. Small propylene glycol ethers are rapidly absorbed and distributed throughout the body following oral and inhalation exposures. Excretion is primarily via the urine and expired air; a small amount is excreted in the feces. Absorption via the dermal route is slower, but subsequent distribution is rapid. Additionally, Propylene Glycol Butyl Ether (a monoglycol ether) is absorbed through the skin better than diglycol and triglycol ethers. However, diglycol and triglycol ethers may be present on the skin much longer than monoglycol ethers because of their lower vapor pressures. Following a single oral dose of [ 14 C]1-(2-butoxy-1-methylethoxy)-propan-2-ol in 1% methylcellulose in rats, 42-51% of the dose was excreted in the urine and 42-35% in CO 2 (0.4 or 4.4 mmol/kg bw, respectively) within 48 h. Metabolites and the parent compound were present in the urine. 2-Butoxypropionic acid, a metabolite of Propylene Glycol Butyl Ether, appeared in the urine (at a concentration of 0.06 ppm) of 6 subjects who were exposed to vapors from a cleaning solution containing 3.5% Propylene Glycol Butyl Ether. The day after the exposure, 2-butoxypropionic acid was detected in the urine samples of 3 subjects at slightly over the LOQ ( ppm). In rats, the dermal LD 50 was 3.5 g/kg for Buteth-3 and >2 g/kg for Propylene Glycol Butyl Ether, [(butoxymethylethoxy)- methylethoxy]-propan-1-ol, poly[oxy(methyl-1,2-ethanediyl)],α-butyl-ω-hydroxy-, and 1-(2-butoxy-1-methylethoxy)-propan-2-ol. In rabbits, the dermal LD 50 was 1.4 g/kg for Propylene Glycol Butyl Ether and >2 g/kg for [(butoxymethylethoxy)methylethoxy]-propan-1-ol.

46 In rats, the oral LD 50 was 6.6 g/kg Buteth-3, >2 g/kg for Propylene Glycol Butyl Ether, [(butoxymethylethoxy)methylethoxy]-propan-1-ol, and 1-(2-butoxy-1-methylethoxy)-propan-2-ol, and between g/kg poly[oxy(methyl-1,2-ethanediyl)],α-butyl-ω-hydroxy-. In rats, inhalation LC 50 s were >3251 mg/m 3 Propylene Glycol Butyl Ether and >328 mg/m 3 1-(2- butoxy-1-methylethoxy)-propan-2-ol. In dermal studies, effects on rabbit skin were reported in a 21-day toxicity study of Buteth-3 (1000 mg/kg, occlusive application), in 28-day (at concentrations of 5.69%, open applications) and 13-wk (NOEL of 1.76 mg/kg bw/day) studies of Propylene Glycol Butyl Ether, and in a 13-wk study of 1-(2-butoxy-1-methylethoxy)-propan-2-ol ( 91 mg/kg bw/day). Clinical signs of toxicity generally were not observed. Irritation was also observed in a 13-wk study of Propylene Glycol Butyl Ether in rats ( 88 mg/kg). In short-term oral toxicity studies in rats, a NOAEL of 400 mg/kg was reported in 14-day gavage studies of Propylene Glycol Butyl Ether and 1-(2-butoxy-1-methylethoxy)-propan-2-ol, and of 1000 mg/kg in a 28-day gavage study with [(butoxymethylethoxy)methylethoxy]-propan-1-ol. In oral combined repeated dose toxicity studies with the reproduction/ developmental toxicity screening test, the NOEL was 100 mg/kg bw/day in rats exposed to either poly[oxy(methyl-1,2- ethanediyl)],α-butyl-ω-hydroxy- or 1-(2-butoxy-1-methylethoxy)-propan-2-ol. In subchronic (13-wk) drinking water studies in rats, both Propylene Glycol Butyl Ether and PPG-3 Butyl Ether 30 had a NOAEL of 350 mg/kg, and [(butoxymethylethoxy)methylethoxy]-propan-1-ol had a NOAEL of 1000 mg/kg. A NOAEL of 450 mg/kg was reported in rats fed a diet containing 1-(2-butoxy-1-methylethoxy)-propan-2-ol. In short-term inhalation studies (nine 6-h exposures) in rats, the NOAEL for Propylene Glycol Butyl Ether was 3785 mg/m 3 and for 1-(2-butoxy-1-methylethoxy)-propan-2-ol was 200 mg/m 3. Dermal application of PPG-2 Butyl Ether to rats during days 6-16 of gestation produced local skin reactions, but it did not produce reproductive or teratogenic effects (NOEL > 1 ml/kg). Dermally applied Propylene Glycol Butyl Ether was not embryotoxic or teratogenic to rats ( 1.0 ml/kg bw/day applied on days 6-16 of gestation) or rabbits ( 100 mg/kg bw/day applied on days 7-18 of gestation). Dermal application of up to 910 mg/kg bw/day 1-(2-butoxy-1-methylethoxy)-propan-2-ol was not embryotoxic, fetotoxic, or teratogenic in rats. No test-article related adverse developmental or reproductive effects were observed in rats dosed by gavage (days 7-16 of gestation) with up to 1000 mg/kg Buteth-3. No effects on reproduction were observed in rats dosed orally prior to and during mating with up to 500 mg/kg bw/day poly[oxy(methyl-1,2-ethanediyl)],α-butyl-ω-hydroxy- or up to 1000 mg/kg bw/day 1- (2-butoxy-1-methylethoxy)-propan-2-ol. Propylene Glycol Butyl Ether, [(butoxymethylethoxy)methylethoxy]-propan-1-ol, poly[oxy(methyl-1,2-ethanediyl)],α-butylω-hydroxy-, and 1-(2-butoxy-1-methylethoxy)-propan-2-ol were not mutagenic in Ames tests. Propylene Glycol Butyl Ether was not mutagenic in numerous other genotoxicity studies, including mammalian chromosomal aberration assays in CHO cells ( 6000 µg/ml), mouse lymphoma cell assays in T5178Y TK+/- lymphoma cells ( 6000 µg/ml), and UDS assays in primary rat hepatocytes ( 6000 µg/ml). Poly[oxy(methyl-1,2-ethanediyl)],α-butyl-ω-hydroxy-was not genotoxic in a mammalian chromosomal assay in rat lymphocytes ( 5000 µg/ml), or a mammalian cell mutation assay in CHO cells ( 2500 µg/ml). 1-(2-Butoxy-1-methylethoxy)-propan-2-ol was positive, with chromatid and chromosome gaps and breaks, in chromosomal aberration assays in CHO-K1,S1B cells but not in CHO-K1,CCL61 cells or CHO cells. Gaps and breaks were also reported in negative controls in the tests using CHO-K1, S1B cells. Both [(butoxymethylethoxy)methylethoxy]-propan-1-ol and 1-(2-butoxy-1-methylethoxy)-propan-2-ol were negative in the mouse micronucleus assay following a single oral dose of 1875 mg/kg bw and 2500 mg/kg bw, respectively. Poly[oxy(methyl-1,2-ethanediyl)],α-butyl-ω-hydroxy- was classified as non-corrosive in an EpiDerm TM study. In rabbits, Propylene Glycol Butyl Ether was slightly irritating at a concentration of 50% and was generally irritating when applied undiluted. In guinea pigs, undiluted Propylene Glycol Butyl Ether was a minimal irritant in one study; it was not irritating or sensitizing in a Buehler test (three induction patches with 80% and a challenge with 40%). Undiluted [(butoxymethylethoxy)- methylethoxy]-propan-1-ol was not irritating to rabbit skin, and was not a sensitizer in guinea pigs in a Buehler test. 1-(2- Butoxy-1-methylethoxy)-propan-2-ol produced some slight irritation in rabbit skin, but was not irritating according to the EU classification, and it was not a sensitizer in guinea pigs (three induction patches with 80% and a challenge with 40%). In HRIPTs, undiluted PPG-14 Butyl Ether, hair styling wax containing 71% PPG-40 Butyl Ether (applied neat), and 1-(2- butoxy-1-methylethoxy)-propan-2-ol were not sensitizers. The classification of undiluted Propylene Glycol Butyl Ether in rabbit eyes ranged from not irritating (according to criteria established by the EU) to moderately irritating (according the Draize scores). Undiluted [(butoxymethylethoxy)methylethoxy]-propan-1-ol and 1-(2-butoxy-1-methylethoxy)-propan-2-ol were not irritating and slightly irritating to rabbit eyes, respectively. DISCUSSION The Panel has previously issued final reports on the safety of 19 butyl PPG ethers (2001; safe for use in cosmetics when formulated to avoid irritation) and four butyl PPG/PEG ethers (2000; safe as used in cosmetic products). In accordance with its Procedures, CIR evaluates the conclusions of previously-issued reports every 15 years to determine whether the conclusion should be reaffirmed. Because the ingredients included in the reports on the butyl PPG ethers and the butyl PPG/ PEG ethers share a common structural motif, the Panel determined that the butyl PPG ethers and butyl PPG/PEG ethers should be

47 combined in one report for the re-review. Additionally, the Panel determined that it was appropriate to include 23 butyl polyoxyalkylene ethers that have not yet been reviewed, because these ingredients also share the same structural motif. The Panel addressed the use of chemicals for read-across, and determined that information reported for [(butoxymethylethoxy)methylethoxy]propan-1-ol, poly[oxy(methyl-1,2-ethanediyl)],α-butyl-ω-hydroxy-, and 1-(2-butoxy-1-methylethoxy)- propan-2-ol is appropriate for read-across. [(Butoxymethylethoxy)methylethoxy]propan-1-ol and PPG-3 Butyl Ether are positional isomers. The Panel stated that, because the chemical and physical properties and metabolism of these two compounds should be essentially identical, the information on [(butoxymethylethoxy)methylethoxy]propan-1-ol is useful for evaluating the safety of ingredients included in this assessment. Poly[oxy(methyl-1,2-ethanediyl)],α-butyl-ω-hydroxycontains the common core structure of the butyl polyoxyalkylene ethers; therefore, the information on this chemical supports the safety of the butyl PPG ethers named in this report. 1-(2-Butoxy-1-methylethoxy)-propan-2-ol is a potential metabolite of the butyl PPG ethers; accordingly, data on this ingredient are included to strengthen the toxicity profile. For many of the ingredients included in this report, the frequency of use has increased somewhat since the Panel s original review. However, there has been a large increase in the frequency of use of PPG-26-Buteth-26, from 13 reported uses in 1997 to the 1332 uses reported in Additionally, at the time of the original review, concentrations of use were not reported; it is now known that the maximum use concentrations for PPG-40-Butyl Ether are up to 71% for leave-on formulations (in a hair wax) and 73.5% in rinse-off formulations (hair tint). The Panel noted that the smaller compounds are more rapidly absorbed than the larger compounds in the group. However, because there is a strong weight of evidence for low systemic toxicity across the group, the Panel was generally not concerned about the use of these ingredients in cosmetics. Because some of these ingredients are ethoxylated, the Panel was concerned about the possible presence of 1,4-dioxane and ethylene oxide impurities. The Panel stressed that the cosmetics industry should continue to use the necessary procedures to limit these impurities from the butyl polyoxyalkylene ethers before blending them into cosmetic formulations. The Panel was also concerned that the potential exists for dermal irritation with the use of products formulated with butyl polyoxyalkylene ethers. Therefore, the Panel specified that products containing these ingredients must be formulated to be non-irritating. Finally, the Panel discussed the issue of incidental inhalation exposure, as some of the butyl polyoxyalkylene ethers are used in cosmetic sprays and could possibly be inhaled. For example, PPG-40 Butyl Ether is reported to be used at a maximum concentration of 10% in hair sprays. The inhalation study data included in the safety assessment did not concern the Panel. Additionally, the Panel noted that droplets/particles from spray cosmetic products would not be respirable to any appreciable amount. Furthermore, droplets/particles deposited in the nasopharyngeal or bronchial regions of the respiratory tract present no toxicological concerns based on the chemical and biological properties of these ingredients. 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. A detailed discussion and summary of the Panel s approach to evaluating incidental inhalation exposures to ingredients in cosmetic products is available at CONCLUSION The CIR Expert Panel concluded that the following butyl polyoxyalkylene ethers safe in the present practices of use and concentration in cosmetics when formulated to be non-irritating: Buteth-3 PPG-2-Buteth-1* PPG-2-Buteth-2* PPG-2-Buteth-3* PPG-3-Buteth-5* PPG-4-Buteth-4* PPG-5-Buteth-5 PPG-5-Buteth-7* PPG-7-Buteth-4 PPG-7-Buteth-10 PPG-9-Buteth-12 PPG-10-Buteth-9* PPG-12-Buteth-12* PPG-12-Buteth-16 PPG-15-Buteth-20 PPG-17-Buteth-17 PPG-19-Buteth-19* PPG-20-Buteth-30 PPG-24-Buteth-27* PPG-26-Buteth-26 PPG-28-Buteth-35 PPG-30-Buteth-30* PPG-33-Buteth-45 PPG-36-Buteth-36* PPG-38-Buteth-37 PPG-2 Butyl Ether PPG-3 Butyl Ether* PPG-4 Butyl Ether* PPG-5 Butyl Ether* PPG-9 Butyl Ether* PPG-12 Butyl Ether* PPG-14 Butyl Ether PPG-15 Butyl Ether* PPG-16 Butyl Ether* PPG-17 Butyl Ether* PPG-18 Butyl Ether* PPG-20 Butyl Ether* PPG-22 Butyl Ether*

48 PPG-24 Butyl Ether* PPG-26 Butyl Ether* PPG-30 Butyl Ether* PPG-33 Butyl Ether PPG-40 Butyl Ether PPG-52 Butyl Ether PPG-53 Butyl Ether* Propylene Glycol Butyl Ether* *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.

49 Table 1. Butyl polyoxyalkylene ethers included in this report Buteth-3 PPG-2-Buteth-1 PPG-2-Buteth-2 PPG-2-Buteth-3 PPG-3-Buteth-5 PPG-4-Buteth-4 PPG-5-Buteth-5 PPG-5-Buteth-7 PPG-7-Buteth-4 PPG-7-Buteth-10 PPG-9-Buteth-12 PPG-10-Buteth-9 PPG-12-Buteth-12 PPG-12-Buteth-16 PPG-15-Buteth-20 PPG-17-Buteth-17 PPG-19-Buteth-19 PPG-20-Buteth-30 PPG-24-Buteth-27 PPG-26-Buteth-26 PPG-28-Buteth-35 PPG-30-Buteth-30 PPG-33-Buteth-45 PPG-36-Buteth-36 PPG-38-Buteth-37 PPG-2 Butyl Ether PPG-3 Butyl Ether PPG-4 Butyl Ether PPG-5 Butyl Ether PPG-9 Butyl Ether PPG-12 Butyl Ether PPG-14 Butyl Ether Note: ingredients that were reviewed previously are indicated in blue TABLES PPG-15 Butyl Ether PPG-16 Butyl Ether PPG-17 Butyl Ether PPG-18 Butyl Ether PPG-20 Butyl Ether PPG-22 Butyl Ether PPG-24 Butyl Ether PPG-26 Butyl Ether PPG-30 Butyl Ether PPG-33 Butyl Ether PPG-40 Butyl Ether PPG-52 Butyl Ether PPG-53 Butyl Ether Propylene Glycol Butyl Ether (5; CIR Staff) Table 2. Definitions, structures, and functions of butyl polyoxyalkylene ethers Ingredient CAS No. Definition & Structure Function Butyl Propylene Glycol Ether Propylene Glycol Butyl Ether (mixture); (α-isomer); (β-isomer) 9 Propylene Glycol Butyl Ether is the propylene glycol ether of n-butyl alcohol that conforms to the formula: fragrance ingredient; solvent Butyl PPG Ethers the butyl PPG ethers included in this report all conform generally to the formula: PPG-2 Butyl Ether (generic) PPG-3 Butyl Ether PPG-4 Butyl Ether (generic) PPG-5 Butyl Ether (generic) PPG-9 Butyl Ether (generic) PPG-12 Butyl Ether (generic) PPG-14 Butyl Ether (generic) PPG-15 Butyl Ether (generic) PPG-16 Butyl Ether (generic) PPG-17 Butyl Ether (generic) PPG-18 Butyl Ether (generic) PPG-20 Butyl Ether (generic) PPG-22 Butyl Ether (generic) the value of n varies for each ingredient, and this value is specified with each definition PPG-2 Butyl Ether is the polypropylene glycol ether of butyl alcohol that conforms generally to the formula depicted above, where n has an average value of 2 PPG-3 Butyl Ether is the polypropylene glycol ether of butyl alcohol that conforms generally to the formula depicted above, where n has an average value of 3 PPG-4 Butyl Ether is the polypropylene glycol ether of butyl alcohol that conforms generally to the formula depicted above, where n has an average value of 4 PPG-5 Butyl Ether is the polypropylene glycol ether of butyl alcohol that conforms generally to the formula depicted above, where n has an average value of 5 PPG-9 Butyl Ether is the polypropylene glycol ether of butyl alcohol that conforms generally to the formula depicted above, where n has an average value of 9 PPG-12 Butyl Ether is the polypropylene glycol ether of butyl alcohol that conforms generally to the formula depicted above, where n has an average value of 12 PPG-14 Butyl Ether is the polypropylene glycol ether of butyl alcohol that conforms generally to the formula depicted above, where n has an average value of 14 PPG-15 Butyl Ether is the polypropylene glycol ether of butyl alcohol that conforms generally to the formula depicted above, where n has an average value of 15 PPG-16 Butyl Ether is the polypropylene glycol ether of butyl alcohol that conforms generally to the formula depicted above, where n has an average value of 16 PPG-17 Butyl Ether is the polypropylene glycol ether of butyl alcohol conforms generally to the formula depicted above, where n has an average value of 17 PPG-18 Butyl Ether is the polypropylene glycol ether of butyl alcohol that conforms generally to the formula depicted above, where n has an average value of 18 PPG-20 Butyl Ether is the polypropylene glycol ether of butyl alcohol that conforms generally to the formula depicted above, where n has an average value of 20 PPG-22 Butyl Ether is the polypropylene glycol ether of butyl alcohol that conforms generally to the formula depicted above, where n has an average value of 22 hair conditioning agent; skinconditioning agent misc; solvent hair conditioning agent; skin-conditioning agent misc; solvent hair conditioning agent; skin-conditioning agent misc hair conditioning agent; skin-conditioning agent misc hair conditioning agent; skin-conditioning agent misc hair conditioning agent; skin-conditioning agent misc hair conditioning agent; skin-conditioning agent misc hair conditioning agent; skin-conditioning agent misc hair conditioning agent; skin-conditioning agent misc hair conditioning agent; skin-conditioning agent misc hair conditioning agent; skin-conditioning agent misc hair conditioning agent; skin-conditioning agent misc hair conditioning agent; skin-conditioning agent misc

50 (5; CIR Staff) Table 2. Definitions, structures, and functions of butyl polyoxyalkylene ethers Ingredient CAS No. Definition & Structure Function PPG-24 Butyl Ether (generic) PPG-24 Butyl Ether is the polypropylene glycol ether of butyl alcohol that conforms generally to the formula depicted above, where n has an average value of 24 hair conditioning agent; skin-conditioning agent misc PPG-26 Butyl Ether (generic) PPG-26 Butyl Ether is the polypropylene glycol ether of butyl alcohol that conforms generally to the formula depicted above, where n has an average value of 26 hair conditioning agent; skin-conditioning agent misc PPG-30 Butyl Ether (generic) PPG-30 Butyl Ether is the polypropylene glycol ether of butyl alcohol that conforms generally to the formula depicted above, where n has an average value of 30 hair conditioning agent; skin-conditioning agent misc PPG-33 Butyl Ether (generic) PPG-33 Butyl Ether is the polypropylene glycol ether of butyl alcohol conforms generally to the formula depicted above, where n has an average value of 33 hair conditioning agent; skin-conditioning agent misc PPG-40 Butyl Ether (generic) PPG-40 Butyl Ether is the polypropylene glycol ether of butyl alcohol that conforms generally to the formula depicted above, where n has an average value of 40 hair conditioning agent; skin-conditioning agent misc PPG-52 Butyl Ether (generic) PPG-52 Butyl Ether is the polypropylene glycol ether of butyl alcohol that conforms generally to the formula depicted above, where n has an average value of 52 hair conditioning agent; skin-conditioning agent misc PPG-53 Butyl Ether (generic) PPG-53 Butyl Ether is the polypropylene glycol ether of butyl alcohol that conforms generally to the formula depicted above, where n has an average value of 53 hair conditioning agent; skin-conditioning agent misc Butyl PPG/PEG Ethers the butyl PPG/PEG ethers included in this report all conform generally to the formula: PPG-2-Buteth (generic) (generic) PPG-2-Buteth (generic) (generic) PPG-2-Buteth (generic) (generic) PPG-3-Buteth (generic) (generic) PPG-4-Buteth (generic) (generic) PPG-5-Buteth (generic) (generic) PPG-5-Buteth (generic) (generic) PPG-7-Buteth (generic) (generic) PPG-7-Buteth (generic) (generic) PPG-9-Buteth (generic) (generic) PPG-10-Buteth (generic) (generic) PPG-12-Buteth (generic) (generic) PPG-12-Buteth (generic) (generic) the value of x and y varies for each ingredient, and these values are specified with each definition PPG-2-Buteth-1 is the polyoxypropylene, polyoxyethylene ether of butyl alcohol that conforms generally to the formula depicted above, where x has an average value of 2 and y has an average value of 1 PPG-2-Buteth-2 is the polyoxypropylene, polyoxyethylene ether of butyl alcohol that conforms generally to the formula depicted above, where x has an average value of 2 and y has an average value of 2 PPG-2-Buteth-3 is the polyoxypropylene, polyoxyethylene ether of butyl alcohol that conforms generally to the formula depicted above, where x has an average value of 2 and y has an average value of 3 PPG-3-Buteth-5 is the polyoxypropylene, polyoxyethylene ether of butyl alcohol that conforms generally to the formula depicted above, where x has an average value of 3 and y has as average value of 5 PPG-4-Buteth-4 is the polyoxypropylene, polyoxyethylene ether of butyl alcohol that conforms generally to the formula depicted above, where x has an average value of 4 and y has an average value of 4 PPG-5-Buteth-5 is the polyoxypropylene, polyoxyethylene ether of butyl alcohol that conforms generally to the formula depicted above, where x has an average value of 5 and y has an average value of 5 PPG-5-Buteth-7 is the polyoxypropylene, polyoxyethylene ether of butyl alcohol that conforms generally to the formula depicted above, where x has an average value of 5 and y has an average value of 7 PPG-7-Buteth-4 is the polyoxypropylene, polyoxyethylene ether of butyl alcohol that conforms generally to the formula depicted above, where x has an average value of 7 and y has an average value of 4 PPG-7-Buteth-10 is the polyoxypropylene, polyoxyethylene ether of butyl alcohol that conforms generally to the formula depicted above, where x has an average value of 7 and y has an average value of 10 PPG-9-Buteth-12 is the polyoxypropylene, polyoxyethylene ether of butyl alcohol that conforms generally to the formula depicted above, where x has an average value of 9 and y has an average value of 12 PPG-10-Buteth-9 is the polyoxypropylene, polyoxyethylene ether of butyl alcohol that conforms generally to the formula depicted above, where x has an average value of 10 and y has an average value of 9 PPG-12-Buteth-12 is the polyoxypropylene, polyoxyethylene ether of butyl alcohol that conforms generally to the formula depicted above, where x has an average value of 12 and y has an average value of 12 PPG-12-Buteth-16 is the polyoxypropylene, polyoxyethylene ether of butyl alcohol that conforms generally to the formula depicted above, where x has an average value of 12 and y has an average value of 16 hair conditioning agent; skinconditioning agent - misc fragrance ingredient; hair conditioning agent; skin-conditioning agent misc; surfactant emulsifying agent fragrance ingredient; hair conditioning agent; skin-conditioning agent misc; solvent fragrance ingredient; hair conditioning agent; skin-conditioning agent misc; solvent fragrance ingredient; hair conditioning agent; skin-conditioning agent misc; surfactant emulsifying agent fragrance ingredient; hair conditioning agent; skin-conditioning agent misc; surfactant emulsifying agent fragrance ingredient; hair conditioning agent; skin-conditioning agent misc; solvent fragrance ingredient; hair conditioning agent; skin-conditioning agent misc; solvent; surfactant emulsifying agent fragrance ingredient; hair conditioning agent; skin-conditioning agent misc; solvent; surfactant emulsifying agent fragrance ingredient; hair conditioning agent; skin-conditioning agent - misc; surfactant - emulsifying agent fragrance ingredient; hair conditioning agent; skin-conditioning agent misc; surfactant emulsifying agent fragrance ingredient; hair conditioning agent; skin-conditioning agent misc; surfactant emulsifying agent fragrance ingredient; hair conditioning agent; skin-conditioning agent - misc; solvent; surfactant - emulsifying agent

51 (5; CIR Staff) Table 2. Definitions, structures, and functions of butyl polyoxyalkylene ethers Ingredient CAS No. Definition & Structure Function PPG-15-Buteth (generic) (generic) PPG-15-Buteth-20 is the polyoxypropylene, polyoxyethylene ether of butyl alcohol that conforms generally to the formula depicted above, where x has an average value of 15 and y has an average value of 20 fragrance ingredient; hair conditioning agent; skin-conditioning agent misc; solvent; surfactant emulsifying agent PPG-17-Buteth (generic) (generic) PPG-19-Buteth (generic) (generic) PPG-20-Buteth (generic) (generic) PPG-24-Buteth (generic) (generic) PPG-26-Buteth (generic) (generic) PPG-28-Buteth (generic) (generic) PPG-30-Buteth (generic) (generic) PPG-33-Buteth (generic) (generic) PPG-36-Buteth (generic) (generic) PPG-38-Buteth (generic) (generic) PPG-17-Buteth-17 is the polyoxypropylene, polyoxyethylene ether of butyl alcohol that conforms generally to the formula depicted above, where x has an average value of 17 and y has an average value of 17 PPG-19-Buteth-19 is the polyoxypropylene, polyoxyethylene ether of butyl alcohol that conforms generally to the formula depicted above, where x has an average value of 19 and y has an average value of 19 PPG-20-Buteth-30 is the polyoxypropylene, polyoxyethylene ether of butyl alcohol that conforms generally to the formula depicted above, where x has an average value of 20 and y has an average value of 30 PPG-24-Buteth-27 is the polyoxypropylene, polyoxyethylene ether of butyl alcohol that conforms generally to the formula depicted above, where x has an average value of 24 and y has an average value of 27 PPG-26-Buteth-26 is the polyoxypropylene, polyoxyethylene ether of butyl alcohol that conforms generally to the formula depicted above, where x has an average value of 26 and y has an average value of 26 PPG-28-Buteth-35 is the polyoxypropylene, polyoxyethylene ether of butyl alcohol that conforms generally to the formula depicted above, where x has an average value of 28 and y has an average value of 35 PPG-30-Buteth-30 is the polyoxypropylene, polyoxyethylene ether of butyl alcohol that conforms generally to the formula depicted above, where x has an average value of 30 and y has an average value of 30 PPG-33-Buteth-45 is the polyoxypropylene, polyoxyethylene ether of butyl alcohol that conforms generally to the formula depicted above, where x has an average value of 33 and y has an average value of 45 PPG-36-Buteth-36 is the polyoxypropylene, polyoxyethylene ether of butyl alcohol that conforms generally to the formula depicted above, where x has an average value of 36 and y has an average value of 36 PPG-38-Buteth-37 is the polyoxypropylene, polyoxyethylene ether of butyl alcohol that conforms generally to the formula depicted above, where x has an average value of 38 and y has an average value of 37 fragrance ingredient; hair conditioning agent; skin-conditioning agent misc; surfactant emulsifying agent fragrance ingredient; hair conditioning agent; skin-conditioning agent misc; surfactant emulsifying agent fragrance ingredient; hair conditioning agent; skin-conditioning agent misc; solvent; surfactant emulsifying agent fragrance ingredient; hair conditioning agent; skin-conditioning agent misc; surfactant emulsifying agent fragrance ingredient; hair conditioning agent; skin-conditioning agent misc; surfactant - emulsifying agent fragrance ingredient; hair conditioning agent; skin-conditioning agent - misc; surfactant - emulsifying agent fragrance ingredient; hair conditioning agent; skin-conditioning agent misc; surfactant cleansing agent; surfactant solubilizing agent fragrance ingredient; hair conditioning agent; skin-conditioning agent misc fragrance ingredient; hair conditioning agent; skin-conditioning agent misc; surfactant cleansing agent; surfactant solubilizing agent fragrance ingredient; hair conditioning agent; skin-conditioning agent misc; surfactant cleansing agent; surfactant solubilizing agent Butyl PEG Ether Buteth-3 [ ] Buteth-3 is the polyethylene glycol ether of butyl alcohol that conforms generally to the formula: solvent

52 Distributed for comment only -- do not cite or quote Table 3. Read across justification Name CAS No. Structure read-across endpoints justification Name CAS No. Structure read-across endpoints justification Name CAS No. Structure Target Material PPG-3 Butyl Ether Read-Across Material [(Butoxymethylethoxy)methylethoxy]propan-1-ol acute toxicity; dermal, oral short-term toxicity oral subchronic toxicity; oral genotoxicity; in vitro, in vivo dermal irritation; animal dermal sensitization; animal ocular irritation; animal chemical properties, physical properties and metabolism are expected to be essentially identical for these two positional isomers PPG-n Butyl Ether (generic) the butyl PPG ethers included in this report all conform generally to the formula: Poly[oxy(methyl-1,2-ethanediyl)],α-butyl-ω-hydroxy the value of n varies for each ingredient, as specified in each definition acute toxicity; dermal, oral short-term; oral DART genotoxicity; in vitro dermal irritation; in vitro the common core structure (butoxy) and the polyol repeat units (propylene glycol residues) of the butyl PPG ethers are identical to those of α-butyl-ω-hydroxy-poly[oxy(methyl-1,2-ethanediyl)] 1-(2-Butoxy-1-methylethoxy)-propan-2-ol9 PPG-n Butyl Ether (generic) the butyl PPG ethers included in this report all conform generally to the formula: (produced as a 4-isomer mixture) mol. wt (avg) read-across endpoints justification the value of n varies for each ingredient, as specified in each definition potential metabolite of positional isomers of the butyl PPG ethers ADME acute toxicity; dermal, oral; inhalation short-term toxicity oral; inhalation subchronic toxicity; dermal, oral DART genotoxicity; in vitro, in vivo dermal irritation; animal dermal sensitization; animal, human ocular irritation; animal

53 Table 4. Physical and Chemical Properties Property Value Reference Propylene Glycol Butyl Ether Physical Form clear liquid 13,14 Color colorless 13,14 Molecular Wt Density (20ºC) 0.88 g/cm 3 13 (25ºC) 0.87 g/cm 3 Relative Density (water =1; 25ºC) Viscosity (25ºC) 2.9 mm 2 /s 14 Vapor Pressure 0.6 mm Hg (20 C) 1.40 mm Hg (25ºC) Relative Vapor Density (air = 1) Melting Point below -75 C 14 Boiling Point 171 C 14 Solubility 6 g/100 ml water (moderate) 14 log P ow 1.2 (experimental) 1.15 (calculated) PPG-3 Butyl Ether Physical Form liquid 10,15 Color colorless 10,15 Odor practically none mild Molecular Wt g/mol 15 Density (20ºC) g/cm 3 15 (25ºC) g/cm 3 Specific Gravity (25/25ºC) Viscosity (mm 2 25ºC) 7 15 Vapor Pressure (20ºC extrapolated) <0.01 mm Hg 15 Vapor Density (air = 1) >6 15 Boiling Point (760 mm Hg) 275ºC 10,15 Water Solubility (25ºC) 40.2 g/l 15 log P ow ,15 Buteth-3 Physical Form clear crystalline substance 16 Vapor Pressure (25ºC) mm Hg 16 Solubility water soluble 16 Poly[oxy(methyl-1,2-ethanediyl)],α-butyl-ω-hydroxy- Physical Form liquid 11 Color brown 11 Density (20ºC) g/cm 3 11 Viscosity (20ºC) 19 mpa s 11 (40ºC) 16 mpa s Vapor Pressure (20ºC) mm Hg 11 Melting Point < -20ºC 11 Boiling Point ( ~760 mm Hg) 306ºC 11 Solubility (solvent in 25ºC) 42.3 g/l; very soluble 11 log P ow (28 C)

54 Table 5. Frequency and concentration of use of previously reviewed butyl polyoxyalkylene ethers according to duration and exposure # of Uses Max Conc of Use (%) # of Uses Max Conc of Use (%) PPG-9-Buteth-12 PPG-12-Buteth ; 1999 # ; 1999 # Totals* 2 2 NR NR Duration of Use Leave-On 0 0 NR NR Rinse-Off 0 0 NR NR Diluted for (Bath) Use 2 2 NR NR Exposure Type Eye Area NR NR NR NR 0 1 NR NR Incidental Ingestion NR NR NR NR 0 NR NR NR Incidental Inhalation-Spray NR NR NR NR 1; 4 a 10 a ; 1 b 0.53; 0.5 a a Incidental Inhalation-Powder NR NR NR NR NR 1 b NR 1 Dermal Contact 2 2 NR NR Deodorant (underarm) NR NR NR NR NR NR NR NR Hair - Non-Coloring NR NR NR NR Hair-Coloring NR NR NR NR 2 NR 0.05 NR Nail NR NR NR NR NR 1 NR NR Mucous Membrane 2 2 NR NR Baby Products NR NR NR NR NR 1 NR NR PPG-26-Buteth-26 PPG-28-Buteth ; 1999 # ; 1999 # Totals* NR 9 10 NR 1 Duration of Use Leave-On NR 6 1 NR NR Rinse-Off NR 3 9 NR 1 Diluted for (Bath) Use NR NR NR NR NR Exposure Type Eye Area 27 NR NR NR NR NR NR Incidental Ingestion 1 NR NR NR NR NR NR NR Incidental Inhalation-Spray 448; 93 a ; 112 b 5 a ; 1 b ; NR 5 a NR NR NR a Incidental Inhalation-Powder 112 b ; 1 c NR 8 c NR NR NR NR NR Dermal Contact NR 4 3 NR NR Deodorant (underarm) 7 a 1 a spray: NR 1 a NR NR NR Hair - Non-Coloring 107 NR NR 5 7 NR 1 Hair-Coloring 3 NR NR NR NR NR NR Nail NR NR NR NR NR NR NR NR Mucous Membrane NR NR 1 NR NR Baby Products 3 NR 0.9 NR NR NR NR NR PPG-2 Butyl Ether PPG-14 Butyl Ether Totals* ** ** Duration of Use Leave-On ** ** Rinse-Off 6 NR 3-8 ** ** Diluted for (Bath) Use NR NR NR ** NR NR NR ** Exposure Type Eye Area 1 NR NR ** 1 NR 1.9 ** Incidental Ingestion NR NR NR ** NR NR NR ** Incidental Inhalation-Spray NR NR NR ** 6; 2 a ; 5 b 9; 4 a ; 1 b 1-10 ** Incidental Inhalation-Powder NR NR NR ** 5 b 1 b c ** Dermal Contact 5 NR 2-8 ** ** Deodorant (underarm) NR NR NR ** 13 a 2 a ** Hair - Non-Coloring NR NR NR ** NR NR ** Hair-Coloring 2 NR 5 ** NR NR NR ** Nail NR 1 NR ** NR NR NR ** Mucous Membrane 4 NR NR ** 1 29 NR ** Baby Products NR NR NR ** NR NR 0.05 **

55 Table 5. Frequency and concentration of use of previously reviewed butyl polyoxyalkylene ethers according to duration and exposure # of Uses Max Conc of Use (%) # of Uses Max Conc of Use (%) PPG-16-Butyl Ether PPG-18 Butyl Ether Totals* NR 1 NR ** NR 1 NR ** Duration of Use Leave-On NR NR NR ** NR NR NR ** Rinse-Off NR 1 NR ** NR 1 NR ** Diluted for (Bath) Use NR NR NR ** NR NR NR ** Exposure Type Eye Area NR NR NR ** NR NR NR ** Incidental Ingestion NR NR NR ** NR NR NR ** Incidental Inhalation-Spray NR NR NR ** NR NR NR ** Incidental Inhalation-Powder NR NR NR ** NR NR NR ** Dermal Contact NR 1 NR ** NR 1 NR ** Deodorant (underarm) NR NR NR ** NR NR NR ** Hair - Non-Coloring NR NR NR ** NR NR NR ** Hair-Coloring NR NR NR ** NR NR NR ** Nail NR NR NR ** NR NR NR ** Mucous Membrane NR NR NR ** NR NR NR ** Baby Products NR NR NR ** NR NR NR ** PPG-33 Butyl Ether PPG-40 Butyl Ether Totals* ** ** Duration of Use Leave-On ** ** Rinse-Off 1 NR NR ** ** Diluted for (Bath) Use NR NR NR ** NR NR NR ** Exposure Type Eye Area NR NR NR ** NR NR NR ** Incidental Ingestion NR NR NR ** NR NR NR ** Incidental Inhalation-Spray 1 5; 1 a 2-2.1; 10 a ** 6 a 6 a ; 7-23 a ** Incidental Inhalation-Powder NR NR NR ** NR NR NR ** Dermal Contact ** NR 1 NR ** Deodorant (underarm) NR NR NR ** NR NR NR ** Hair - Non-Coloring NR NR 10 ** ** Hair-Coloring NR NR NR ** NR ** Nail NR NR NR ** NR NR NR ** Mucous Membrane NR NR NR ** NR NR NR ** Baby Products NR NR NR ** NR NR NR ** PPG-52 Butyl Ether Totals* NR NR 3-23 ** Duration of Use Leave-On NR NR 23 ** Rinse-Off NR NR 3 ** Diluted for (Bath) Use NR NR NR ** Exposure Type Eye Area NR NR NR ** Incidental Ingestion NR NR NR ** Incidental Inhalation-Spray NR NR 23 a ** Incidental Inhalation-Powder NR NR NR ** Dermal Contact NR NR NR ** Deodorant (underarm) NR NR NR ** Hair - Non-Coloring NR NR 3-23 ** Hair-Coloring NR NR NR ** Nail NR NR NR ** Mucous Membrane NR NR NR ** Baby Products NR NR NR ** 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. **at the time of the original safety assessment, concentration of use data were not reported by the FDA. # some concentration of use data were reported at that time a It is possible these products are sprays, but it is not specified whether the reported uses are sprays.. b 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 c It is possible these products are powders, but it is not specified whether the reported uses are powders NR no reported use

56 Table 6. Frequency (2017) and concentration of use (2015) of previously unreviewed butyl polyoxyalkylene ethers # of Uses 20 Max Conc of Use (%) 23 # of Uses 20 Max Conc of Use (%) 23 # of Uses 20 Max Conc of Use (%) 23 PPG-5-Buteth-5 PPG-7-Buteth-4 PPG-7-Buteth-10 Totals* NR NR Duration of Use Leave-On NR NR NR Rinse-Off NR NR NR NR Diluted for (Bath) Use NR NR NR NR NR NR Exposure Type Eye Area NR NR NR NR NR NR Incidental Ingestion NR NR NR NR NR NR Incidental Inhalation-Spray NR 0.05; 0.5 a NR NR NR NR Incidental Inhalation-Powder NR 0.05 b NR NR NR NR Dermal Contact NR 0.05 NR 4 NR NR Deodorant (underarm) NR NR NR NR NR NR Hair - Non-Coloring NR NR Hair-Coloring NR NR NR NR NR NR Nail NR NR NR NR NR NR Mucous Membrane NR NR NR NR NR NR Baby Products NR NR NR NR NR NR PPG-15-Buteth-20 PPG-17-Buteth-17 PPG-20-Buteth-30 Totals* NR NR Duration of Use Leave-On NR 2 NR NR Rinse Off NR 2 NR NR Diluted for (Bath) Use NR NR NR NR NR NR Exposure Type Eye Area NR NR NR NR 1 NR Incidental Ingestion NR NR NR NR NR NR Incidental Inhalation-Spray 1 a NR NR 2 NR NR Incidental Inhalation-Powder NR 6.2 b NR NR NR NR Dermal Contact NR NR Deodorant (underarm) NR NR NR NR NR NR Hair - Non-Coloring NR NR NR 2 NR NR Hair-Coloring NR NR NR NR NR NR Nail NR NR NR NR NR NR Mucous Membrane NR NR NR NR NR NR Baby Products NR NR NR NR NR NR PPG-33-Buteth-45 PPG-38-Buteth-37 Buteth-3 Totals* Duration of Use Leave-On NR NR NR Rinse-Off Diluted for (Bath) Use NR NR NR NR Exposure Type Eye Area NR NR NR NR NR NR Incidental Ingestion NR NR NR NR NR NR Incidental Inhalation-Spray NR NR NR NR 6; 32 a ; 9 c ; a Incidental Inhalation-Powder NR NR NR NR 1 b 9 c b Dermal Contact NR NR 2 NR Deodorant (underarm) NR NR NR NR NR NR Hair - Non-Coloring NR Hair-Coloring NR NR Nail NR NR NR NR Mucous Membrane NR NR NR NR Baby Products NR NR NR NR 1 NR *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 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 NR no reported use

57 Table 7. Ingredients not reported to be in use PPG-2-Buteth-1 PPG-2-Buteth-2 PPG-2-Buteth-3 PPG-3-Buteth-5 PPG-4-Buteth-4 PPG-5-Buteth-7 PPG-10-Buteth-9 PPG-12-Buteth-12 PPG-19-Buteth-19 PPG-24-Buteth-27 PPG-30-Buteth-30 PPG-36-Buteth-36 PPG-3 Butyl Ether PPG-4 Butyl Ether PPG-5 Butyl Ether PPG-9 Butyl Ether PPG-12 Butyl Ether PPG-15 Butyl Ether PPG-16 Butyl Ether PPG-17 Butyl Ether PPG-18 Butyl Ether PPG-20 Butyl Ether PPG-22 Butyl Ether PPG-24 Butyl Ether PPG-26 Butyl Ether PPG-30 Butyl Ether PPG-53 Butyl Ether Propylene Glycol Butyl Ether Table 8. Food additive use status Substance as named in the CFR Status CFR Citation monobutyl ethers of polyethylene-polypropylene glycol produced by random condensation of a 1:1 mixture by wt of ethylene oxide and propylene oxide with butanol; minimum mol. wt. of 1500 Da secondary direct food additives permitted in food for human consumption when used as boiler water additives 21CFR n-butoxypoly(oxyethylene)-poly(oxypropylene)glycol; viscosity range of secondary direct food additive permitted in food for human consumption when used as a defoaming agent in processing beet sugar 21CFR butoxy polyethylene polypropylene glycol; mol. wt Da indirect food additive permitted in adhesives 21CFR polyoxybutylene-polyoxypropylene-polyoxyethylene glycol; indirect food additive permitted as a defoaming agent used in 21CFR minimum mol. wt coatings butoxy polyethylene polypropylene glycol; mol. wt Da indirect food additive permitted as a defoaming agent used in the 21CFR manufacture of paper and paperboard [alpha]-butyl-omega-hydroxypoly(oxyethylene) poly(oxypropylene) produced by random condensation of a 1:1 mixture by wt of ethylene oxide and propylene oxide with butanol; minimum mol. wt Da (CAS No ) indirect food additive permitted for use in surface lubricants with incidental food contact; addition to food not to exceed 10 ppm 21CFR [alpha]-butyl-omega-hydroxypoly(oxypropylene); minimum mol. wt Da (CAS No ) [alpha]-butyl-[omega]-hydroxypoly (oxyethylene)-poly (oxypropylene) (CAS No ), produced by random condensation of a 1:1 mixture by weight of ethylene oxide and propylene oxide with butanol; minimum mol. wt. of 1000 Da oxirane, methyl-, polymer with oxirane, monobutyl ether Abbreviations: FFDCA - Federal Food, Drug, and Cosmetic Act ; mol. wt. molecular weight indirect food additive permitted for use in surface lubricants used in the manufacture of metallic articles. residues resulting from the use of the polymer as an inert ingredient in a pesticide chemical formulation, including antimicrobial pesticide chemical formulations, are exempted from the requirement of a tolerance under FFDCA section 408, if such use is in accordance with good agricultural or manufacturing practices 21CFR CFR

58 Table 9. Acute Toxicity Studies Ingredient Animals No./Group Vehicle Concentration/Dose/Procedure Results Reference DERMAL Propylene Glycol Butyl Ether Wistar rats 5/sex none in accord with OECD Guideline 402; 24-h semi-occlusive patch 2 g/kg bw LD 50 >2 g/kg 9,13,32 Propylene Glycol Butyl Ether NZW rabbits 4 males none in accord with OECD Guideline LD g/kg ; 24-h occlusive patch (estimated) Propylene Glycol Butyl Ether NZW rabbits 4 males none in accord with OECD Guideline 402; 24-h occlusive patch LD g/kg (estimated) 13 [(butoxymethylethoxy)methylethoxy]propan-1-ol (read across to PPG-3 Butyl Ether) (99% pure) Wistar rats 5/sex none in accord with OECD Guideline 402; 25-h semi-occlusive patch 2 g/kg LD50 >2 g/kg 10 [(butoxymethylethoxy)methylethoxy]propan-1-ol (read across to PPG-3 Butyl Ether) (85% pure) poly[oxy(methyl-1,2-ethanediyl)],α-butylω-hydroxy- (read across for PPG-n Butyl Ether) 1-(2-butoxy-1-methylethoxy)-propan-2-ol (read across for PPG-n Butyl Ether) NZW rabbits 2 males none in accord with OECD Guideline 402; 24-h patch; type of coverage not stated 2 g/kg Fischer 344 rats 5/sex none in accord with OECD guideline 402; 24-h application using an occlusive 2 x 3 patch (10% of body area) 2 g/kg Wistar rats 5/sex none in accord with OECD Guideline 402; 24-h semi-occlusive patch to intact skin 2 g/kg Buteth-3 rats not specified not specified details not provided ORAL Propylene Glycol Butyl Ether Wistar rats 5/sex none in accord with OECD Guideline 401; single dose by gavage 1.8, 2.4, 3.2 g/kg bw Propylene Glycol Butyl Ether Wistar rats 5/sex none in accord with OECD Guideline 401; single dose by gavage Propylene Glycol Butyl Ether Wistar rats 6/sex CMC in accord with OECD Guideline 401; single dose by gavage 2 g/kg [(butoxymethylethoxy)methylethoxy]propan-1-ol Fischer rats 3 females none in accord with OECD Guideline (read across to PPG-3 Butyl Ether) 401; single dose by gavage (85% pure) 2 g/kg [(butoxymethylethoxy)methylethoxy]propan-1-ol (read across to PPG-3 Butyl Ether) [(butoxymethylethoxy)methylethoxy]propan-1-ol (read across to PPG-3 Butyl Ether) (99% pure) [(butoxymethylethoxy)methylethoxy]propan-1-ol (read across to PPG-3 Butyl Ether) (99% pure) poly[oxy(methyl-1,2-ethanediyl)],α-butylω-hydroxy- (read across for PPG-n Butyl Ether) 1-(2-butoxy-1-methylethoxy)-propan-2-ol (read across for PPG-n Butyl Ether) Wistar rats 6/sex CMC in accord with OECD Guideline 423; single dose by gavage 2 g/kg Wistar rats 1/sex none 2.5, 4, and 5 mg/kg bw in accord with OECD Guideline 401; single dose by gavage Wistar rats 5/sex none in accord with OECD Guideline 401; single dose by gavage 2.4, 3.2, and 4.2 g/kg Fisher rats 3 female none in accord with OECD Guideline 423 gavage study 0.3 (2 groups) or 2.0 g/kg bw CD-1 mice 4 males none in accord with OECD guideline 401; 0.1, 0.316, 1.0, and 10 ml LD50 >2 g/kg no dermal effects LD 50 >2 g/kg bw; no animals died; no signs of gross toxicity, dermal irritation, adverse toxicological effects, or abnormal behavior LD 50 >2 mg/kg bw LD g/kg LD g/kg (calculated) 1 female of the mid dose group, and 4 females and 1 male of the high dose group, died LD g/kg (estimated) LD 50 >2 g/kg >2 g/kg 1 animal died >2 g/kg 1 female died both animals of the 4 and 5 g/kg group died within 24 h of dosing LD 50 ~2.8 mg/kg bw (combined) 3.1 g/kg bw (males) 2.6 g/kg bw (females) 3, 6, and 10 animals of the low, mid- and high-dose died LD 50 between 0.3 and 2 g/kg bw 2/3 high dose animals died; 0/6 low dose animals died LD mg/kg bw (calculated) ,

59 Table 9. Acute Toxicity Studies Ingredient Animals No./Group Vehicle Concentration/Dose/Procedure Results Reference 1-(2-butoxy-1-methylethoxy)-propan-2-ol 9 (read across for PPG-n Butyl Ether) Wistar rats 5/sex none in accord with OECD guideline 401; single dose by gavage 3200, 4200, or 5600 mg/kg LD 50 combined 4000 mg/kg LD50 males 4400 mg/kg LD50 females 3700 mg/kg 1-(2-butoxy-1-methylethoxy)-propan-2-ol rats not none in feed; dose not specified LD mg/kg bw 9 (read across for PPG-n Butyl Ether) specified Buteth-3 rats not specified not specified details not provided LD g/kg 16 INHALATION Propylene Glycol Butyl Ether Fischer 344 5/sex none in accord with OECD Guideline LC 50 >3251 mg/m 3 9,13 rats 403; 4-h whole-body exposure 3251 mg/m 3 Propylene Glycol Butyl Ether rats 6 none in accord with OECD Guideline 403; 8-h whole-body exposure saturated vapor no mortality 13 1-(2-butoxy-1-methylethoxy)-propan-2-ol (read across for PPG-n Butyl Ether) (99.33% pure) Fischer 344 rats 5/sex none in accord with OECD guideline 403; 4 h whole body exposure 328 mg/m 3 LC 50>328 mg/m 3 9 Abbreviations: CMC carboxymethylcellulose; NZW New Zealand White; OECD Organisation for Economic Co-operation and Development

60 Table 10. Short-Term and Subchronic Toxicity Studies Ingredient Animals/Group Study Duration Vehicle Dose/Concentration Procedure Results Reference SHORT-TERM TOXICITY STUDIES Dermal Propylene Glycol Butyl Ether Propylene Glycol Butyl Ether Buteth-3 (99.9% pure) Propylene Glycol Butyl Ether Propylene Glycol Butyl Ether [(butoxymethyleth- oxy)methylethoxy]- propan-1-ol (read across to PPG-3 Butyl Ether) purity % 5 NZW rabbits/sex 5 NZW rabbits/sex 5 NZW rabbits/sex 2 Sprague- Dawley rats/sex 6 Sprague- Dawley rats/sex 5 Fischer 344 rats/sex 4 wks 50/50 ethanol/ water 0, 0.569, 5.69, and 56.9%; 2 ml/kg open 7-h applications 5 days/wk for 4 wks to clipped abraded skin; collars were used to prevent ingestion 28 days distilled water 0, 50, and 100%; 2 ml/kg open 7-h applications 5 days/wk for 4 wks to clipped abraded skin; collars were used to prevent ingestion 21 days none 0 (water) or 1000 mg/kg/day 6-h occlusive application to a shaved area of the back 1x/day, 5 days/wk; collars used to prevent ingestion during dosing; test sites were rinsed following dosing animals were killed within 1 day of termination of dosing 8 days propylene glycol 14 days propylene glycol 0, 200, 500, and 1000 mg/kg bw 0, 100, 200, and 400 mg/kg bw 28 days corn oil 0, 100, 350, or 1000 mg/kg bw Oral in accord with OECD Guideline 407 dosed by gavage 1x daily in accord with OECD Guideline 407 dosed by gavage 1x daily in accord with OECD Guideline 407 dosed 1x/day, 5 days/wk by gavage -the mid-dose produced slight erythema (6 animals), the high-dose resulted in moderate erythema and desquamation (n=10), slight edema (n=9) and atonia (n=5), and slight (n=6) to moderate (n=4) fissuring -no clinical signs of toxicity, and no changes in body, liver, or kidney wts -no clinical, gross, or microscopic signs of toxicity - slight to moderate (low dose group) and slight to severe (high dose group) erythema, slight atonia, and slight desquamation; no edema, fissuring, eschar, or exfoliation -no clinical signs of toxicity; no effect on body wt gain; no mortality -slight erythema and edema on day 6 and day 7 respectively; both were reported in all test animals as of day 11; desquamation in 1-8 animals on days 10-17; fissuring in 3-5 animals on days 8-16; no signs of irritation in controls -no treatment-related effects on hematology or clinical chemistry parameters -no gross lesions at necropsy; a statistically significant increase in brain wts was not considered treatment-related; other organ wts were comparable to controls -microscopic examination of skin from the test site found trace acanthosis and moderate dermatitis 1 mid-dose male and 1 high-dose female died NOAEL and LOAEL 400 mg/kg bw -no signs of toxicity; no effect of body weights, organ weights, hematology or clinical chemistry NOAEL 1000 mg/kg bw -no treatment-related effects on body wt, hematology parameters -statistically significant increase in absolute and relative liver wts for mid-and high-dose animals, with increased hepatocellular size and altered staining of the cytoplasm in high dose animals ,13,37 10

61 Table 10. Short-Term and Subchronic Toxicity Studies Ingredient Animals/Group Study Duration Vehicle Dose/Concentration Procedure Results Reference poly[oxy(methyl-1,2- ethanediyl)],α-butylω-hydroxy- (read across for PPG-n Butyl Ether) 12 Crj: CD(SD rats/sex 46 day, males 53 days, females CMC 0, 20, 100, or 500 mg/kg bw/day 11 1-(2-butoxy-1- methylethoxy)-propan-2-ol (read across for PPG-n Butyl Ether) 1-(2-butoxy-1- methylethoxy)-propan-2-ol (read across for PPG-n Butyl Ether) 1-(2-butoxy-1- methylethoxy)-propan-2-ol (read across for PPG-n Butyl Ether) (99.34% pure) Propylene Glycol Butyl Ether (98.8% pure) 6 Sprague- Dawley rats/sex 5 Sprague- Dawley rats/sex 12 Crl:CD (SD) rats/sex main study: 10 Fischer 344 and 5 Sprague-Dawley rats/sex recovery: additional 10 sex/ strain control and high dose 2 wks propylene glycol in accord with OECD Guideline 422 (combined repeated dose toxicity study with the reproduction /developmental toxicity screening test) - males dosed by gavage 1x/day for 14 days prior to and throughout mating, for 32 days - females dosed 1x/day for 14 days prior to mating and continuing through breeding (2 wks), gestation (3 wks), and lactation (4 days) 0, 100, 200, or 400 mg/kg bw in accord with OECD guideline 407; by gavage 2-wk in feed 0, 250, 500, or 750 mg/kg bw in accord with OECD guideline 407; feed study 43 days (males) 53 days (females) 0.5% methylcellulose 0, 100, 300, or 1000 mg/kg bw/day in accord with OECD guideline 422 -males dosed by gavage 1x/day for 14 days prior to and during, mating; males were killed on day 29 -females were dosed 1x/day for 14 days prior to breeding, and continuing through mating, gestation, and 4 days of lactation; females were killed 5 days after parturition (53 total days) Inhalation 11 days none 0, 540, 1622, and 3244 in accord with OECD Guideline 412 mg/m 3 9 whole body exposure; 6 h/day, 5 days/wk; a 4-wk recovery group was used with each strain hematologic, clinical chemistry, and urinalysis parameters were examined NOEL 100 mg/kg bw/day, for clinical observations, higher absolute and relative liver wts, and increased incidence of liver and thyroid gland hypertrophy 500 mg/kg/day: treatment-related transient clinical observations in males and females during all phases of the study, including perioral soiling (all animals), muscle twitches (6/12 males, 11/12 females), uncoordinated gait (0/12 males, 6/12 females) and decreased activity (0/12 males, 3/12 females); all effects resolved within 1 h of dosing - no significant effects on body wt or body wt gain, feed consumption, hematology, clinical chemistry, urinalysis NOAEL 400 mg/kg NOAEL >750 mg/kg NOAEL for systemic toxicity mg/kg/day, based on very slight to slight hepatocellular hypertrophy with no corresponding increases in liver weights in low-dose males - treatment-related increases in the incidence of hepatocellular hypertrophy in males of all dose groups and in mid- and high-dose females, correlated with increased liver weights in midand high-dose males and high dose females; considered to be adaptive changes associated with increased hepatic metabolism - treatment-related increases in absolute and relative kidney weights in high-dose animals; hyaline droplet formation in the proximal renal tubules in mid- and high-dose males; histopathologic correlation with the higher kidney weights not evident in females NOAEL 3244 mg/m 3 Fischer 344 rats: statistically significant increase in absolute and relative liver (to body and to brain) weights (3244 mg/m 3 males) and relative liver to body weights (244 mg/m 3 females) without microscopic changes; low incidence of mild eye lesions 1622 and 3244 mg/m 3 groups) Sprague Dawley rats: no exposure-related effects ,49

62 Table 10. Short-Term and Subchronic Toxicity Studies Ingredient Animals/Group Study Duration Vehicle Dose/Concentration Procedure Results Reference Propylene Glycol 5 Fischer 344 9,13,38 Butyl Ether rats/sex 1-(2-butoxy-1- methylethoxy)-propan-2-ol (read across for PPG-n Butyl Ether) 1-(2-butoxy-1- methylethoxy)-propan-2-ol (read across for PPG-n Butyl Ether) Propylene Glycol Butyl Ether Propylene Glycol Butyl Ether Propylene Glycol Butyl Ether Propylene Glycol Butyl Ether 1-(2-butoxy-1- methylethoxy)-propan-2-ol (read across for PPG-n Butyl Ether) 5 Fischer 344 rats/sex 5 Fischer 344 rats/sex 2 wks none 0, 270, 1081, and 3785 in accord with OECD Guideline 412 mg/m 3 9 whole body exposure; 6 h/day, 5 days/wk 2 wks none 0, 160, 320 mg/m 3 in accord with OECD guideline 412; 9 6/h nose-only exposures 2 wks none 0, 200, 810,or 2010 mg/m 3 in accord with OECD guideline 412; 9 6/h nose-only exposures SUBCHRONIC TOXICITY STUDIES Dermal 10 Wistar rats/sex 13 wks propylene glycol 0, 88, 264, 880 mg/kg in accord with OECD Guideline open 24-h application/day, 5 days/wk; collars were used to prevent grooming 5 NZW rabbits/sex 5 NZW rabbits/sex 5 NZW rabbits/sex 91 days water 2 ml/kg bw in accord with OECD Guideline open 7-h application/day, 5 days/wk; collars were used to prevent grooming 13 wks 50/50 ethanol/ water 13 wks 50/50 ethanol/ water 0, 10, 100, or 1000 mg/kg bw/day; 2 ml/kg bw 0, 0.569, 5.69, and ml/kg 10 Wistar rats/sex 13 wks propylene glycol 0, 91, 273, or 910 mg/kg bw/day in accord with OECD Guideline h application/day, 5 days/wk; collars were used to prevent grooming open 7-h applications to intact skin of the back, 5 days/wk for 13 wks; collars were used to prevent grooming in accord with OECD guideline 411; 5 open applications/wk; animals wore collars to prevent ingestion NOAEL and LOAEL >3785 mg/m 3 -slightly increased relative liver weight in high dose males and females without microscopic effects NOAEL 320 mg/m 3 9 NOAEL 200 mg/m 3 LOAEL 810 mg/m 3 NOAEL 880 mg/kg bw -irritation at all application sites, including controls; focal necrosis of the epidermis, crust formation, mild inflammatory changes and acanthosis; difference in severity between treated and control animals was not significant -no clinical, gross, or microscopic signs of toxicity NOEL 1.76 mg/kg bw/day -mild to moderate irritation at the application site -no clinical signs of toxicity NOAEL/local skin irritation 10 mg/kg bw/day LOAEL/local skin irritation 100 mg/kg bw/day NOAEL/systemic toxicity 1000 mg/kg bw/day -dermal irritation in the mid and high dose groups; in the high dose group, severe erythema, slight to moderate edema, slight to moderate atonia, moderate desquamation, and slight to moderate fissuring. skin lesions were considered to be a direct, local effect from the solvents and the clipping procedure. -no clinical signs of toxicity - slight erythema and severe erythema in the midand high-dose groups, respectively - no significant differences in body wt parameters or absolute organ or relative organ wts of the test animals compared to the vehicle control group NOAEL 91 mg/kg/day LOAEL 273 mg/kg/day (based on body weight - changes and increased neutrophil count) -skin irritation at all test sites (including controls) 9 9,13,

63 Table 10. Short-Term and Subchronic Toxicity Studies Ingredient Animals/Group Study Duration Vehicle Dose/Concentration Procedure Results Reference Oral Propylene Glycol Butyl Ether (99.4% pure) 10 Fischer 344 rats/sex 9,13 PPG-3 Butyl Ether 10 Fischer 344 rats/sex [(butoxymethyleth- oxy)methylethoxy]- propan-1-ol (read across to PPG-3 Butyl Ether) ( 97.7% pure) 1-(2-butoxy-1- methylethoxy)-propan-2-ol (read across for PPG-n Butyl Ether) 10 Fischer 344 rats/sex 20 Sprague- Dawley rats/sex; additional 5 for interim sacrifice 13 wks none 0, 100, 350, and 1000 mg/kg bw recovery groups: 0 and 1000 mg/kg bw in accord with OECD Guideline 408 administered in drinking water recovery groups given untreated water for 4 wks following dosing NOAEL 350 mg/kg bw; LOAEL 1000 mg/kg - absolute and relative liver weights increased in high dose males ad absolute and relative kidney weights increased in high dose females with no accompanying histopathology - no changes in organs selected for examination, including the testes 13 wks none 0, 100, 350, or 1000 mg/kg bw administered in drinking water NOAEL 350 mg/kg bw; LOAEL 1000 mg/kg bw -histopathological and organ weight alterations of liver and kidney (males) and liver (females) (details not provided) 13 wks none 0, 100, 350, or 1000 mg/kg bw; 0 and 1000 mg/kg (recovery group) in accord with OECD Guideline day study administered in drinking water 13 wks in feed 0, 200, 450, or 1000 mg/kg bw in accord with OECD guideline 408; feed study NOAEL 1000 mg/kg bw -no clinical signs of toxicity; statistically significant changes included: decrease in body wts and feed consumption of high dose animals; treatmentrelated increases in absolute and relative liver weights in males of all dose groups and females of the mid- and high-dose groups; absolute and relative kidney weights were increased in high-dose males mid- and high-dose females -changes in hematology, clinical chemistry, and urinalysis parameters not considered toxicologically significant NOAEL 450 mg/kg LOAEL 1000 mg/kg -high-dose males: slight but statistically significant decrease in body wts, enlarged livers with histopathological changes, increased absolute and relative liver weights; some changes in clinical chemistry corroborated liver changes -high-dose females: absolute and relative kidney weights were increased in high dose females with no accompanying histopathology. Abbreviations: CMC carboxymethylcellulose; LOAEL lowest-observed adverse effect level; NOAEL no-observed adverse effect level; NOEL no-observed effect level; NZW New Zealand White

64 Table 11. Developmental and Reproductive Toxicity Studies Test Article Animals/Group Vehicle Dose/Concentration Procedure Results Reference Dermal Propylene Glycol Butyl Ether (>98% pure) 9,11,17 Propylene Glycol Butyl Ether (100% pure) 25 gravid Wistar rats propylene glycol (test article was provided as 2 mixtures in vehicle at ratios 12:60 [sic] and 40:60) gravid NZW rabbits; 19/test group, 17 control water 0, 0.3 and 1.0 ml/kg bw/day (equivalent to 0, 264, and 880 mg/kg bw/day) 0, 10, 40, and 100 mg/kg bw/day in accord with OECD Guideline 414 open applications (20 cm 2 ) on days 6-16 of gestation; collars were used to prevent ingestion; animals were killed on day 21 of gestation in accord with OECD Guideline h applications to a 10 cm x 20cm shaved area of the dorsal trunk on days 7-18 of gestation; collars were used to prevent ingestion; animals were killed on day 29 of gestation PPG-2 Butyl Ether 20 gravid Wistar rats not stated 0, 0.3, 1 ml/kg the test substance was applied dermally on days 6-16 of gestation; details were not provided 1-(2-butoxy-1-methylethoxy)-propan-2-ol (read across for PPG-n Butyl Ether) poly[oxy(methyl-1,2- ethanediyl)],α-butyl-ωhydroxy- (read across for PPG-n Butyl Ether) 1-(2-butoxy-1-methylethoxy)-propan-2-ol (read across for PPG-n Butyl Ether) (99.34% pure) 22 (control), 21 (lowdose), and 25 (highdose) gravid Wistar rats propylene glycol 0, 0.3 or 1.0 ml/kg bw/day (0, 273, or 910 mg/kg bw/day, respectively) applied volumes of 1.5 ml (control), 1.8 ml, and 2.5 ml test solution/kg bw, respectively 12 Crj: CD(SD) rats/sex CMC 0, 20, 100, or 500 mg/kg bw/day 12 Crl:CD(SD) rats/sex 0.5% methylcellulose 0, 100, 300, or 1000 mg/kg bw/day in accord with OECD guideline 414 open applications (20 cm 2 ) on days 6-15 of gestation; collars were used to prevent ingestion; animals were killed on day 21 of gestation Oral combined repeated dose toxicity study with the reproduction/developmental toxicity screening test (described previously in Table 10) combined repeated dose toxicity study with the reproduction/developmental toxicity screening test (described previously in Table 10 Buteth-3 10 gravid rats/group water 0, 250, or 1000 mg/kg animals dosed by gavage on days 7-16 of gestation NOAEL for maternal toxicity, embryotoxicity, and teratogenicity 880 mg/kg/day -not embryotoxic, fetotoxic, or teratogenic -minor skin reactions not considered toxicologically relevant -no clinical signs of toxicity; no mortality; no statistically significant differences in body weight, feed consumption, -ovaries, uterus, kidneys and liver wts comparable for test and control groups. -no test-article related visceral and skeletal malformations, anomalies or variants developmental NOEL - >100 mg/kg bw/day -no maternal toxicity -no embryotoxic or teratogenic effects -mild erythema in the high dose group occurred at a greater incidence and severity compared to other groups maternal and developmental NOEL - > 1 ml/kg -local skin reactions observed in all treated animals; no signs of maternal toxicity -no reproductive or teratogenic effects - minor skin reactions were not considered toxicologically relevant; no clinical signs of toxicity; no mortality; organ weights comparable for test and control groups - pre- and post-implantation loss, number of viable fetuses, and fetal weights and lengths comparable between treatment and control groups, no signs of developmental toxicity - not embryotoxic, fetotoxic, or teratogenic NOEL for reproductive effects mg/kg/ day no indication of reproductive toxicity at any dose; no adverse effects on prenatal/early neonatal growth and survival of the offspring. NOEL for reproductive effects mg/kg/day - no treatment-related effects on any reproductive parameters -no clinical signs of toxicity or effects on maternal body wts -no developmental or reproductive toxicity -no effect on number of live pups, mean pup body wts, or mean pup body wt gains on day 1 and day 5 post-partum Abbreviations: CMC carboxymethylcellulose; LOAEL lowest-observable adverse effect level; NOAEL no-observed adverse effect level; NOEL no-observed-effect level; NZW New Zealand White; OECD Organisation for Economic Co-operation and Development; PND post-natal day 9,10,

65 Table 12. Genotoxicity studies Test Article Concentration/Vehicle Procedure Test System Results Reference In Vitro Propylene Glycol Butyl Ether µl/plate in DMSO Ames test Salmonella typhimurium strains TA98, TA100, TA1535, TA1537, TA1538; solvent and appropriate positive controls were used Propylene Glycol Butyl Ether µg/ml with and of µg/ml without metabolic activation in culture medium Propylene Glycol Butyl Ether 500, 1667, and 5000 µg/ml with and without metabolic activation in culture medium Propylene Glycol Butyl Ether dose-range finding study: µl/ml in 50% solution of 95% ethanol mammalian chromosome aberration assay, in accord with OECD Guideline 473 mammalian chromosome aberration assay, in accord with OECD Guideline 473 mouse lymphoma cell assay, with and without metabolic activation main study: µl/ ml in 50% solution of 95% ethanol Propylene Glycol Butyl Ether µg/ml mouse lymphoma cell assay, with and without metabolic activation, in accord with OECD Propylene Glycol Butyl Ether Propylene Glycol Butyl Ether [(butoxymethylethoxy)methylethoxy]propan-1-ol (read across to PPG-3 Butyl Ether) (96.12% pure) poly[oxy(methyl-1,2-ethanediyl)],α-butyl-ω-hydroxy- (read across for PPG-n Butyl Ether) poly[oxy(methyl-1,2-ethanediyl)],α-butyl-ω-hydroxy- (read across for PPG-n Butyl Ether) poly[oxy(methyl-1,2-ethanediyl)],α-butyl-ω-hydroxy- (read across for PPG-n Butyl Ether) 1-(2-butoxy-1-methylethoxy)-propan-2-ol (read across for PPG-n Butyl Ether) µl/ml in ethanol/water (50:50) µg/ml in culture medium µg/plate, +/- metabolic activation in DMSO Guideline 476 UDS assay; appropriate negative and positive controls were used UDS assay, with and without metabolic activation, in accord with OECD Guideline 482 in accord with OECD Guideline 471 Ames test, with and without metabolic activation negative and positive controls were included µg/plate in accord with OECD guideline 471 Ames test, negative and positive controls were included µg/ml with, µg/ml without, metabolic activation µg/ml +/- activation (initial assay) µg/ml with and µg/ml without activation µg/ml in DMSO in accord with OECD guideline 473 mammalian chromosomal aberration assay (4 h exposure) ; negative and positive controls in accord with OECD guideline 476 mammalian cell mutation assay; negative and positive controls in accord with OECD guideline 471, Ames test, with and without metabolic activation CHO cells CHO cells T5178Y TK+/- lymphoma cells T5178Y TK+/- lymphoma cells primary rat hepatocytes primary rat hepatocytes S. typhimurium TA1535, TA1537, TA98, TA100 S. typhimurium TA1535, TA1537, TA98, TA100 Escherichia coli WP2 uvr A rat lymphocytes CHO cells S. typhimurium TA98, TA100, TA1535, TA1527, TA1538 negative negative negative dose-range finding study: no growth with 5.0 µl/ml main study: negative results negative negative doses >0.65 µl/ml were too toxic to score negative negative controls gave expected results negative controls gave expected results negative controls gave expected results negative controls gave expected results negative 39 9,

66 Table 12. Genotoxicity studies Test Article Concentration/Vehicle Procedure Test System Results Reference 1-(2-butoxy-1-methylethoxy)-propan-2-ol (read across for PPG-n Butyl Ether) in accord with OECD guideline 473, chromosomal aberration assay CHO-K1, S1B cells 9 1-(2-butoxy-1-methylethoxy)-propan-2-ol (read across for PPG-n Butyl Ether) 1-(2-butoxy-1-methylethoxy)-propan-2-ol (read across for PPG-n Butyl Ether) 1-(2-butoxy-1-methylethoxy)-propan-2-ol (read across for PPG-n Butyl Ether) 1-(2-butoxy-1-methylethoxy)-propan-2-ol (read across for PPG-n Butyl Ether) 1-(2-butoxy-1-methylethoxy)-propan-2-ol (read across for PPG-n Butyl Ether) (98.97% pure) [(butoxymethylethoxy)methylethoxy]propan-1-ol (read across to PPG-3 Butyl Ether) (96.12% pure) 1-(2-butoxy-1-methylethoxy)-propan-2-ol (read across for PPG-n Butyl Ether) 0, 333, 1000, or 3333 µg/ml with and 0, 1000, 2000, 3000, and 4000 µg/ml without activation in culture medium 0 and 3500 µg/ml with and 0 and 4500 µg/ml without activation in culture medium 0, 500, 1000, 2000, and 3000 µg/ml with and 0, 500, 1000, 2000, 3500, and 5000 µg/ml without activation in culture medium 0, 500, 1667, and 5000 µg in culture medium 0, 500, 1667, and 5000 µg in culture medium µg/ml in DMSO 0, 187.5, 625, and 1875 mg/kg bw in corn oil 0, 250, 833, and 2500 mg/kg bw in accord with OECD guideline 473, chromosomal aberration assay in accord with OECD guideline 473, chromosomal aberration assay in accord with OECD guideline 473, chromosomal aberration assay with and without metabolic activation in accord with OECD guideline 473, chromosomal aberration assay with and without metabolic activation in accord with OECD guideline 476; mammalian CHO/HGPRT forward mutation assay with and without metabolic activation In Vivo in accord with OECD Guideline 474 mammalian erythrocyte micronucleus test animals were given a single dose by gavage solvent and positive controls were used in accord with OECD guideline 475, micronucleus assay; single dose by gavage CHO-K1, S1B cells CHO-K1, S1B cells CHO-K1, CCL61cells CHO-K1, S1B cells CHO cells positive chromatid and chromosome gaps and breaks and fragments detected in all groups, including negative control; the frequency of these aberrations increased significantly in some of the treated groups at the 9 and 13-hour incubation (fixation) times positive chromatid and chromosome gaps and breaks and fragments detected in all groups, including negative control; treated groups showed increased frequencies in these aberrations and occasional exchanges and pulverized chromosomes positive chromatid and chromosome gaps and breaks and fragments detected in all groups, including negative controls, in cells with activation; a dose-response increase was not evident without activation, a more pronounced increase observed in cells, significant to a higher p value at the highest dose; but a dose-response still was not apparent negative negative negative 5 CD-1 mice/sex/group negative controls gave expected results 5 CD-1 mice/sex negative Abbreviations: CHO Chinese hamster ovary; DMSO dimethyl sulfoxide; OECD Organisation for Economic Co-operation and Development; UDS unscheduled DNA synthesis ,

67 Table 13. Dermal irritation and sensitization studies Test Article Concentration/Dose Test Population Procedure Results Reference poly[oxy(methyl-1,2-ethane- diyl)],α-butyl-ω-hydroxy- (read across for PPG-n Butyl Ether) Propylene Glycol Butyl Ether 25, 50, and 75% in water; 0.5 ml IN VITRO EpiDerm TM study to evaluate skin corrosivity ANIMAL Irritation 3 female NZW rabbits in accord with OECD Guideline 404 semi-occlusive 4 h patch to 6 cm 2 area of clipped unabraded skin Propylene Glycol Butyl Ether undiluted; 0.5 ml 3 female NZW rabbits in accord with OECD Guideline 404 semi-occlusive 4 h patch to 6 cm 2 area of clipped unabraded skin Propylene Glycol Butyl Ether undiluted; 0.5 ml 3 NZW rabbits in accord with OECD Guideline 404, EU Method B.4, and EPA OPPTS semi-occlusive 4 h patch to 2.5 cm 2 area of clipped unabraded skin Propylene Glycol Butyl Ether undiluted; 0.01 ml 5 albino rabbits in accord with OECD Guideline 404 open 24 h application to clipped skin Propylene Glycol Butyl Ether undiluted; 0.01 ml 5 albino rabbits in accord with OECD Guideline 404 open 24 h application to clipped skin Propylene Glycol Butyl Ether 100%, 5, 10, and Hartley guinea pigs, # (purity >98%) 50% in propylene not stated [(butoxymethylethoxy)methylethoxy]propan-1-ol (read across to PPG-3 Butyl Ether) [(butoxymethylethoxy)methylethoxy]propan-1-ol (read across to PPG-3 Butyl Ether) (99% pure) [(butoxymethylethoxy)methylethoxy]propan-1-ol (read across to PPG-3 Butyl Ether) (85% pure) glycol not provided 3 NZW rabbits in accord with OECD Guideline h semi-occlusive patch 0.5 ml 3 female NZW rabbits in accord with OECD Guideline h semi-occlusive patch to shaved skin 0.5 ml (semi-occlusive application) 0.1 ml (open applications) classified as non-corrosive; mean tissue viability following the 3 min and 1 h exposure periods was 89.2% and 92.6%, respectively 25%: non-irritating; PDII - 0 no significant irritation 50%: slightly irritating; PDII 0.8 very slight erythema in 3 animals, edema in 1 animal; all resolved by day 7 75%: moderately irritating; PDII 2.5 well-defined erythema in 2 animals; eschar in 1 animal; very slight edema in 3 animals; all resolved by day 7 moderately irritating; PDII 4; erythema/eschar 2.66, edema 1.33 on day 1, eschar formation in 1 animal that mostly resolved on day 14; well defined erythema and slight edema in 2 rabbits with some scaliness (days 2 and 3) resolved by day 14 not irritating mean h erythema score 1.6/4 erythema scores of 2 in all animals at 1 and 24 h, 2 in 2 animals and 1 in 1 animal at 48 h, 1 in all animals at 72 h, 0 in all animals on day 8 edema was not observed in any of the animals irritating PDII 2/10 irritating PDII 3/10 preliminary dose-range finding study for a sensitization test minimal irritation with undiluted material; no irritation at lower concentrations 1 male NZW rabbit in accord with OECD Guideline h semi-occlusive patches to intact and abraded skin of the abdomen; 3 applications to abraded skin and 5 to intact skin 5 daily open applications to intact skin on the medial surface of the left ear pinna not irritating mean erythema score of 1.6; erythema scores of 1-2 reported in all animals, and erythema extended beyond the application area in 1 animal; fully reversible within 9 days; no edema not irritating; PII = 1.2 slight erythema (score = 1) in all animals; slight edema (score = 0.7) in 1 animal; fully reversible in 1 wk not irritating repeated contact resulted in very slight to slight erythema and exfoliation 11 9,13,43 9,13,

68 Table 13. Dermal irritation and sensitization studies Test Article Concentration/Dose Test Population Procedure Results Reference 1-(2-butoxy-1-methylethoxy)- propan-2-ol (read across for PPG-n Butyl Ether) Propylene Glycol Butyl Ether (purity >98%) [(butoxymethylethoxy)methylethoxy]propan-1-ol (read across to PPG-3 Butyl Ether) (98.47% pure) 1-(2-butoxy-1-methylethoxy)- propan-2-ol (read across for PPG-n Butyl Ether) 0.5 ml 3 female NZW rabbits 4-h semi-occlusive patch PDII 2; slightly irritating EU classification - not irritating induction: 80% challenge: 40% 0.3 ml vehicle propylene glycol undiluted in petrolatum; 0.5% (w/w); dose volume not provided 80% for induction; 40% for at challenge vehicle propylene glycol Hartley guinea pigs 10/sex - test and 5/sex - control female Hartley guinea pigs; 20 test, 10 control Sensitization in accord with OECD Guideline 406 Buehler test; occlusive patches induction: 3, 6-h occlusive patches over 3 wks challenge: 1, 6-h application after a 10-day non-treatment period in accord with OECD Guideline 406 Buehler test; epicutaneous induction and challenge induction: 9, 6-h applications over 3 wks challenge: 1, 6-h application after a 10-day non-treatment period 10 guinea pigs/sex in accord with OECD guideline 406; 3, 6-h induction applications (1/wk); 6 h challenge patch applied after a 12- day non-treatment period HUMAN Sensitization PPG-14 Butyl Ether undiluted; 0.2 ml 199 subjects RIPT; nine 24-h occlusive patches (2 cm 2 ) applied over a 3 wk period for induction - challenge was performed after a 2-wk non-treatment period at a previously unpatched site hair styling wax containing 71% PPG-40 Butyl Ether 1-(2-butoxy-1-methylethoxy)- propan-2-ol (read across for PPG-n Butyl Ether) applied neat; g ~25-38 µg/cm 2 48 subjects RIPT; nine 24-h semi-occlusive patches (2 cm 2 ) applied over a 3 wk period for induction - challenge was performed after a 2-wk non-treatment period at a previously unpatched site non-sensitizing and non-irritating not sensitizing not a sensitizer not a sensitizer 0.4 ml 82 human subjects RIPT; 24 h patches not a sensitizer not an irritant or a sensitizer no reactions during induction or at challenge Abbreviations: EPA Environmental Protection Agency; NZW New Zealand White; OECD Organisation for Economic Co-operation and Development; OPPTS Office of Prevention, Pesticides and Toxic Substances; PDII primary dermal irritation index; RIPT repeat insult patch test 9 9,13,

69 Table 14. Ocular irritation studies Test Article Concentration/Dose Test Population Procedure Results Reference Propylene Glycol Butyl Ether undiluted; 0.1 ml 3 NZW rabbits in accord with OECD Guideline 405, EU Method B.5, and EPA OPPTS eyes scored after 24 h contralateral eye served as a control irritating at 24 h, mean scores: 1/4 for corneal opacity; 0.9/2 for effects on the iris; 2.7/3 for conjunctival redness; 0.7/4 for chemosis. -only chemosis was fully reversible by day 7 13 Propylene Glycol Butyl Ether undiluted; 0.1 ml 3 female NZW rabbits in accord with OECD Guideline 405 eyes were not rinsed contralateral eye served as a control Propylene Glycol Butyl Ether undiluted; 0.1 ml 3 female NZW rabbits in accord with OECD Guideline 405 eyes were not rinsed contralateral eye served as a control Propylene Glycol Butyl Ether undiluted; 0.1 ml rabbits; # not specified in accord with OECD Guideline 405 eyes were not rinsed [(butoxymethylethoxy)methylethoxy]propan-1-ol undiluted; 0.1 ml 3 female NZW rabbits in accord with OECD guideline 405 (read across eyes were not rinsed to PPG-3 Butyl Ether) contralateral eye served as a control (99% pure) [(butoxymethylethoxy)methylethoxy]propan-1-ol (read across to PPG-3 Butyl Ether) [(butoxymethylethoxy)methylethoxy]propan-1-ol (read across to PPG-3 Butyl Ether) (85% pure) 1-(2-butoxy-1-methylethoxy)- propan-2-ol (read across for PPG-n Butyl Ether) undiluted; 0.1 ml 3 NZW rabbits in accord with OECD guideline 405 eyes were not rinsed contralateral eye served as a control undiluted; 0.1 ml 1 NZW rabbits in accord with OECD guideline 405 test instilled into both eyes; one eye was rinsed after 30 sec, the other after 1 h undiluted; 0.1 ml 3 female NZW rabbits in accord with OECD guideline 405; eyes were not rinsed Abbreviations: NZW New Zealand White; OECD Organisation for Economic Co-operation and Development not irritating according to EU criteria mean h scores: 0.3 for corneal opacity; 0.2 for effects on the iris; 2.2 for conjunctival redness ;1 for chemosis -all fully reversible by day 7 moderately irritating; 1-h Draize score 34/110; classifiable as an eye irritant according to European criteria mean h scores: 0 for corneal opacity; 0.2 for iridial damage; 2.2 for conjunctival redness ;1 for chemosis -all effects were fully reversible by day 7 not irritating according to EU criteria corneal opacity was 7/10 not irritating; Draize score = 12 (60 min) slight conjunctival redness and obvious to moderate chemosis; 1 animal with slight injection of the iris after 24 h; no adverse effects on the cornea, except for epithelial damage in 2 animals visualized with fluorescein not irritating no corneal or iridial irritation; conjunctival redness (score = 2) was reversible within 48 h not irritating moderate conjunctival redness and swelling, and slight to moderate reddening of the iris; corneal effects included very slight, transient haziness and moderate corneal injury Draize score (1 h) 12.7/110, slightly irritating (EC classification not irritating) 13 9,

70 REFERENCES 1. Andersen FA. Amended Final Report on the Safety Assessment of PPG-40 Butyl Ether with an Addendum to Include PPG-2, -4, -5, -9, -12, -14, -15, -16, -17, -18, -20, -22, -24, -26, -30, -33, -52, and -53 Butyl Ethers. Int J Toxicol. 2001;20(Suppl 4): Andersen FA. Final Report on the Safety Assessment of PPG-40 Butyl Ether. J Am Coll Toxicol. 1993;12(3): Andersen FA. Final Report on the Safety Assessment of PPG-12-Buteth-16, PPG-9-Buteth-12, PPG-26-Buteth-26, and PPG-28- Buteth-35. Int J Toxicol. 2000;19(Suppl 1): Johnson WJ Jr. Amended Final Report on the Safety Asssessment of PPG-9-Buteth-12, PPG-12-Buteth-16, PPG-26-Buteth-26, and PPG-28-Buteth This report is avialbleon the CIR website 5. Nikitakis J and Lange B. International Cosmetic Ingredient Dictionary and Handbook. 16 ed. Washington, D.C.: Personal Care Products Council, Fiume MM, Heldreth B, Bergfeld WF, Belsito DV, Hill RA, Klaassen CD, Liebler DC, Marks JG Jr, Shank RC, Slaga TJ, Snyder PW, and Andersen FA. Safety Assessment of Alkyl PEG Ethers as Used in Cosmetics. Int J Toxicol. 2012;31(Supple 2): Fiume MM, Heldreth B, Bergfeld WF, Andersen FA, Hill RA, Klaassen CD, Liebler DC, Marks JG Jr, Shank RC, Slaga TJ, Snyder PW, and Gill LJ. Safety Assessment of Alkyl PEG/PPG Ethers as Used in Cosmetics Final report available from CIR 8. European Chemicals Agency (ECHA). Information on Chemicals [pamphlet] Organisation for Economic Co-operation and Development (OECD). Propylene Glycol Ethers; Screening Information Data Set (SIDS) Initial Assessment Report for SAIM Last Updated Date Accessed European Chemicals Agency (ECHA). [(Butoxymethylethoxy)methylethoxy]propan-1-ol (CAS No ; EC No ). Last Updated Date Accessed European Chemicals Agency (ECHA). Poly[oxy(methyl-1,2-ethanediyl)],α-butyl-ω-hydroxy- (CAS No ; EC no ). Last Updated Date Accessed Fromme H., Nitschke L., Boehmer S., Kiranoglu M., and Goeen T. Exposure of German residents to ethylene and propylene glycol ethers in general and after cleaning scenarios. Chemosphere. 2013;90(11): European Chemicals Agency (ECHA). 1-Butoxypropan-2-ol (CAS No ; Propylene Glycol Butyl Ether). Last Updated Date Accessed National Institute for Occupational Health and Safety (NIOSH). International Chemical Safety Card (ICSC) 1614: Propylene Glycol n-butyl Ether. Last Updated Date Accessed Dow. Technical Data Sheet: Dowanol TPnB (PPG-3 Butyl Ether). nts/pdfs/noreg/ pdf&frompage=getdoc. Last Updated Date Accessed Environmental Protection Agency (EPA). Triethylene glycol monobutyl ether (CASRN ). Last Updated Date Accessed Spencer PJ. New toxicity data for the propylene glycol ethers - a commitment to public health and safety. Toxicology Letters. 2005;156(1):

71 18. Fiume MM, Bergfeld WF, Belsito DV, Hill RA, Klaassen CD, Liebler DC, Marks JG Jr, Shank RC, Slaga TJ, Snyder PW, and Andersen FA. Safety assessment of propylene glycol, tripropylene glycol, and PPGs as used in cosmetics. Int J Toxicol. 2012;31(Suppl 2):245S-260S. 19. Kociba RJ, McCollister SB, Park C, Torkelson TR, and Gehring PJ. 1,4-Dioxane. I. Results of a 2-year ingestion study in rats. Toxicol Appl Pharmacol. 1974;30: Food and Drug Administration (FDA). Frequency of use of cosmetic ingredients. FDA Database Personal Care Products Council Concentration of Use: Propylene Glycol Butyl Ether. Unpublished data submitted by Personal Care Products Council. 22. Personal Care Products Council Updated Concentration of Use by FDA Product Category: Butyl Polyoxyalkylene Ethers. Unpublished data submitted by Personal Care Products Council. 23. Personal Care Products Council Updated Concentration of Use by FDA Product Category: Butyl Polyoxyalkylene Ethers. butyl polyoxyalkylene ethers. 24. Johnsen MA. The influence of particle size. Spray Technol Marketing. 2004;14(11): Rothe H. Special Aspects of Cosmetic Spray Evalulation Unpublished data presented at the 26 September CIR Expert Panel meeting. Washington, D.C. 26. Rothe H, Fautz R, Gerber E, Neumann L, Rettinger K, Schuh W, and Gronewold C. Special aspects of cosmetic spray safety evaluations: Principles on inhalation risk assessment. Toxicol Lett. 2011;205(2): Bremmer HJ, Prud'homme de Lodder LCH, and Engelen JGM. Cosmetics Fact Sheet: To assess the risks for the consumer; Updated version for ConsExpo Report No. RIVM /2006. pp European Commission. CosIng database; following Cosmetic Regulation No. 1223/ Last Updated Date Accessed HERA. Human & Environmental Risk Assessment (HERA) on ingredients of household cleaning products. Propylene Glycol n- Butyl Ether (CAS No ; ). Last Updated Date Accessed Anonymous. Draft Interim REL: Tripropylene Glycol n-butyl Ether (TPnB; CAS # ). Last Updated Date Accessed Leber AP, Scott RC, Hodge MCE, Johnson D, and Krasavage WJ. Triethylene glycol ethers: evaluations of in vitro absorption through human epidermis, 21-day dermal toxicity in rabbits, and a developmental toxicity screen in rats. Journal of the American College of Toxicology. 1990;9(5): NOTOX. Evaluation of the acute dermal toxicity of Dowanol-PnB (Propylene Glycol n-butyl Ether) in the rat Date Accessed NTIS OTS Hazleton Laboratories America, Inc. 28-Day subchronic percutaneous toxicity test of substance B (CAS No ) Date Accessed NTIS OTS Hazleton Laboratories America, Inc. Final Report: 28-day Subchronic Percutanous Toxicity Study in Rabbits with (CAS No ) Date Accessed Report No. HLA Study No, NTIS document OTS Hazleton Laboratories America, Inc. 91-Day subchronic percutaneous toxicity study (CAS No ) Date Accessed NTIS OTS Civo Institutes TNO. Subchronic (13 wk) dermal toxicity study with Propylene Glycol n-butyl Ether in rats Date Accessed Report No. Study No NTIS OTS NOTOX. Assessment of the oral toxicity, including the haemolytic activity, of Dowanol-PnB (Propylene Glycol n-butyl Ether) in the rat 14-day study NTIS OTS Dow Chemical Company. Propylene Glycol n-butyl Ether: Two-week vapor inhalation study with Fischer 344 rats Date Accessed NTIS OTS

72 39. Microbiological Associates. Salmonella/mammalian microsome mutagenesis assay of test substance B (1-butoxy-2- propanol; ) Date Accessed Report No. Study No. T NTIS OTS Dow Chemical Company. Evaluation of Propylene Glycol-n-Butyl Ether in an in vitro chromosomal assay utilizing Chinese hamster ovary (CHO) cells Date Accessed NTIS OTS Sitek Research Laboratories. Test for chemical induction of mutation in mammalian cells in culture; the L5178Y +/- mouse lymphoma cells for test substance B (butoxypropanol, CAS No ) Date Accessed Report No. Study no NTIS OTS Sitek Research Laboratories. Test for chemical induction of unscheduled DNA synthesis in primary cultures of rat hepatocytes (by autoradiography) of test substance (1-butoyx-2-propanol; CAS No ) Date Accessed Report No. Study No NTIS OTS NOTOX. Assessment of primary skin irritation/corrosion by Dowanol PbN (Propylene Glycol n-butyl Ether) diluted to 75%, 50%, and 25% (w/w) om the rabbit Date Accessed Report No. 0482/748. NTIS OTS NOTOX. Assessment of primary skin irritation/corrosion by Dowanol-PnB (Propylene Glycol n-butyl Ether) in the rabbit Date Accessed NTIS OTS S.C.K. - C.E.N. Guinea pig sensitization study, modified Buehler method, of Propylene Glcyol n-butyl Ether Date Accessed Report No. SS87BO1. NTIS OTS Dow Chemical Company Summary of a repeated insult patch test study of PPG-14 Butyl Ether. Unpublished data submitted by Personal Care Products Council. 47. Essex Testing Clinic Inc Clinical safety evaluation repeated insult patch test (hair styling wax containing 71% PPG-40 Butyl Ether). Unpublished data submitted by Personal Care Products Council. 48. NOTOX. Assessment of acute eye irritation/corrosion of Dowanol-PnB (Propylene Glycol n-butyl Ether) in the rabbit Date Accessed NTIS OTS Bushy Run Research Center. Propasol Solvent B: Nine-day vapor inhalation study on rats Date Accessed Report No. BRRC Project No ; Project Report NTIS Document; OTS ; pdf pages

73 BUTETH B - Baby Lotions, Oils, Powders, and Creams BUTETH A - Bath Oils, Tablets, and Salts BUTETH B - Bubble Baths BUTETH D - Other Bath Preparations BUTETH A - Cologne and Toilet waters BUTETH E - Other Fragrance Preparation BUTETH A - Hair Conditioner BUTETH F - Shampoos (non-coloring) BUTETH G - Tonics, Dressings, and Other Hair Grooming Aids BUTETH A - Hair Dyes and Colors (all types requiring caution statements and patch tests) BUTETH G - Other Manicuring Preparations BUTETH A - Bath Soaps and Detergents BUTETH E - Other Personal Cleanliness Products BUTETH A - Cleansing BUTETH C - Face and Neck (exc shave) BUTETH D - Body and Hand (exc shave) BUTETH F - Moisturizing BUTETH J - Other Skin Care Preps PPG-7-BUTETH I - Other Hair Preparations PPG-9-BUTETH D - Other Bath Preparations PPG-12-BUTETH B - Bubble Baths PPG-12-BUTETH B - Hair Spray (aerosol fixatives) PPG-12-BUTETH F - Shampoos (non-coloring) PPG-12-BUTETH G - Tonics, Dressings, and Other Hair Grooming Aids PPG-12-BUTETH H - Other Hair Coloring Preparation PPG-12-BUTETH A - Bath Soaps and Detergents PPG-12-BUTETH E - Other Personal Cleanliness Products PPG-12-BUTETH A - Cleansing PPG-12-BUTETH I - Skin Fresheners PPG-12-BUTETH J - Other Skin Care Preps PPG-12-BUTETH B - Indoor Tanning Preparations PPG-15-BUTETH F - Moisturizing PPG-20-BUTETH E - Eye Makeup Remover PPG-26-BUTETH B - Baby Lotions, Oils, Powders, and Creams PPG-26-BUTETH C - Other Baby Products PPG-26-BUTETH B - Bubble Baths PPG-26-BUTETH D - Other Bath Preparations PPG-26-BUTETH B - Eyeliner PPG-26-BUTETH C - Eye Shadow PPG-26-BUTETH D - Eye Lotion PPG-26-BUTETH E - Eye Makeup Remover PPG-26-BUTETH F - Mascara PPG-26-BUTETH G - Other Eye Makeup Preparations PPG-26-BUTETH A - Cologne and Toilet waters PPG-26-BUTETH B - Perfumes PPG-26-BUTETH E - Other Fragrance Preparation PPG-26-BUTETH A - Hair Conditioner PPG-26-BUTETH B - Hair Spray (aerosol fixatives) PPG-26-BUTETH F - Shampoos (non-coloring) PPG-26-BUTETH G - Tonics, Dressings, and Other Hair Grooming Aids PPG-26-BUTETH H - Wave Sets PPG-26-BUTETH I - Other Hair Preparations PPG-26-BUTETH D - Hair Shampoos (coloring) PPG-26-BUTETH C - Foundations PPG-26-BUTETH E - Lipstick PPG-26-BUTETH H - Makeup Fixatives PPG-26-BUTETH A - Bath Soaps and Detergents

74 PPG-26-BUTETH B - Deodorants (underarm) PPG-26-BUTETH E - Other Personal Cleanliness Products PPG-26-BUTETH A - Aftershave Lotion PPG-26-BUTETH G - Other Shaving Preparation Products PPG-26-BUTETH A - Cleansing PPG-26-BUTETH C - Face and Neck (exc shave) PPG-26-BUTETH D - Body and Hand (exc shave) PPG-26-BUTETH E - Foot Powders and Sprays PPG-26-BUTETH F - Moisturizing PPG-26-BUTETH G - Night PPG-26-BUTETH H - Paste Masks (mud packs) PPG-26-BUTETH I - Skin Fresheners PPG-26-BUTETH J - Other Skin Care Preps PPG-26-BUTETH B - Indoor Tanning Preparations PPG-28-BUTETH G - Tonics, Dressings, and Other Hair Grooming Aids PPG-28-BUTETH B - Deodorants (underarm) PPG-28-BUTETH A - Cleansing PPG-33-BUTETH F - Shampoos (non-coloring) PPG-38-BUTETH A - Hair Dyes and Colors (all types requiring caution statements and patch tests) PPG-38-BUTETH H - Other Hair Coloring Preparation PPG-38-BUTETH A - Cleansing PPG-2 BUTYL ETHER 1 03B - Eyeliner PPG-2 BUTYL ETHER 2 06A - Hair Dyes and Colors (all types requiring caution statements and patch tests) PPG-2 BUTYL ETHER 2 10A - Bath Soaps and Detergents PPG-2 BUTYL ETHER 2 10E - Other Personal Cleanliness Products PPG-14 BUTYL ETHER 1 03G - Other Eye Makeup Preparations PPG-14 BUTYL ETHER 5 04A - Cologne and Toilet waters PPG-14 BUTYL ETHER 1 04E - Other Fragrance Preparation PPG-14 BUTYL ETHER 13 10B - Deodorants (underarm) PPG-14 BUTYL ETHER 1 10E - Other Personal Cleanliness Products PPG-14 BUTYL ETHER 4 12C - Face and Neck (exc shave) PPG-14 BUTYL ETHER 1 12D - Body and Hand (exc shave) PPG-14 BUTYL ETHER 2 12F - Moisturizing PPG-14 BUTYL ETHER 1 12J - Other Skin Care Preps PPG-33 BUTYL ETHER 1 04A - Cologne and Toilet waters PPG-33 BUTYL ETHER 1 12A - Cleansing PPG-40 BUTYL ETHER 6 05G - Tonics, Dressings, and Other Hair Grooming Aids

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