amended safety assessment of butyl polyoxyalkylene ...2016/11/11 · 3 butyl ether in the june...

Amended Safety Assessment of Butyl Polyoxyalkylene Ethers as Used in Cosmetics

Status: Draft Tentative Amended Report for Panel Review Release Date: November 11, 2016 Panel Meeting Date: December 5-6, 2016 The 2016 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.

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Memorandum To: CIR Expert Panel Members and Liaisons From: Monice M. Fiume MMF Assistant Director/Senior Scientific Analyst Date: November 11, 2016 Subject: Amended Safety Assessment of Butyl Polyoxyalkylene Ethers as Used in Cosmetics Enclosed is the Draft Tentative Amended Safety Assessment of Butyl Polyoxyalkylene Ethers as Used in Cosmetics. (It is identified as butype122016rep in the pdf document). At the June meeting, the Panel agreed to combine 23 previously reviewed butyl ethers (from a total of 4 previous reports) and 23 butyl polyoxyalkylene ethers that have not yet been reviewed into a single safety assessment for re-review. During its deliberations, 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 were not available. Therefore, an insufficient data announce-ment (IDA) was issued requesting sensitization data on PPG-40 Butyl Ether at the maximum concentration for leave-on use. After the report was reviewed in June, industry submitted updated concentration of use data (butype062016data_1). The reported concentration of use for PPG-40 Butyl Ether increased; it is now reported to be used at a maximum leave-on concentration of 71% in a hair wax. Unpublished data were received in response to the IDA request. The following studies were submitted and have been incorporated into the report:

1. Dow Chemical Company. (1993) Summary of a repeated insult patch test study of PPG 14 Butyl Ether. (butype062016data_2); and

2. Essex Testing Clinic. (2011) Clinical safety evaluation repeated insult patch test (hair styling wax containing 71% PPG-40 Butyl Ether). (butype122016ddata_3)

Since the last meeting, a question arose among the CIR staff as to whether data that were included as test data on PPG-3 Butyl Ether in the June re-review document actually pertain to the cosmetic ingredient identified in the INCI Dictionary. The test data are part of the ECHA dossier on [(Butoxymethylethoxy)methylethoxy]propan-1-ol (CAS No. 55934-93-5). This is the same CAS No. as that given in the Dictionary for PPG-3 Butyl Ether, but there is a difference in the structure. For now, the information that had been included in the text of the June Panel document are now found as the first entry in Table 3 – Read Across data. Please take a look at the structures and provide guidance as to how that information should be used. Also, at the June meeting, the Panel determined that Propylene Glycol Butyl Ether should be included in this re-review; it is now listed as one of the 23 previously unreviewed ingredients included in this report. A memo from the Council stated that no uses of this ingredient were reported in response to a concentration of use survey. (butype122016data_4) The subsequent literature search on Propylene Glycol Butyl Ether resulted in a large volume of data, and this information is now incorporated in the draft Tentative Amended Report. Typically, data that are added to the report

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after your initial review are indicated in some manner, and that has been done up through the ADME section of the report (side bars). However, because there was such a substantial amount of new data added to the tables, please review all the data in the tables This applies to the information in the table on read-across as well. Also, in regard to read-across, a concern was raised at the June meeting as to whether Methoxyisopropanol is appropriate for inclusion. I don’t recall a final decision being made. Please provide guidance as to whether that information should remain in the report. The current version of the report includes summaries of the information from the previous safety assessments. If you would like to access the original assessments, you can do so using the CIR website. (http://www.cir-safety.org/ingredients) Comments on the draft amended safety assessment (butype122016pcpc) were received from the Council and have been addressed. Finally, the Panel should be prepared to formulate a tentative conclusion, provide the rationale to be described in the Discussion, and issue a Tentative Amended Report for public comment.

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


RE-REVIEW FLOW CHART INGREDIENT/FAMILY_____Butylated Polyoxyalkylene Ethers______________________________ MEETING _______ Dec 2016__________________________________________________________

Public Comment CIR Expert Panel Re-Review Rpt Status

announce OR

PRIORITY LIST

DAR

YES NO

Table IDA TAR Yes

No

60 day public comment period

IDA Notice June 10, 2016

Draft TAR

IDA

Admin Book

Table

Tentative Amended Report

60 day Public comment period

Draft FAR

Table Different Conclusion

PUBLISH

Final Amended Report

*If Draft Amended Report (DAR) is available, the Panel may choose to review; if not, CIR staff prepares DAR for Panel Review.

DRAFT AMENDED REPORT* June 2016

DRAFT TENTATIVE AMENDED REPORT

Dec 2016

DRAFT FINAL AMENDED REPORT

Issue TAR

Issue FAR

Table

Table

Table

New Data; or request

Re-review to Panel

June 2016

Are new data cause to reopen?

15 years since last

review

Are new ingredients appropriate for

inclusion/re-open?

RE-REVIEW SUMMARY

New data = Combination of 2 previous reports (23 total ingredients).

Also added 23 previously unreviewed ingredients.

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

Distributed for comment only -- do not cite or quote

Butyl Polyoxyalkylene Ethers (new data only) – Dec 2016 – Monice Fiume Re

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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 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


Butyl Polyoxyalkylene Ethers (new data only) – Dec 2016 – Monice Fiume Re

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PPG-5 Butyl Ether PPG-9 Butyl Ether PPG-12 Butyl Ether PPG-14 Butyl Ether 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 PPG Butyl Ether, undefined X X X X X X Propylene Glycol Butyl Ether 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)

X X X X X X

1-(2-butoxy-1-methylethoxy)propan-2-ol (aka dipropylene glycol n-butyl ether)

X X X X X X X X X X X

Methoxyisopropanol X X X PPG-3 Methyl Ether X X X X X X X X X X


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Amended Final Report on the Safety Assessment of PPG-40 Butyl Ether with an Addendum to Include PPG-2 , etc - 2001

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


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PPG-40 Butyl Ether X 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


Butyl Polyoxyalkylene Ethers

CAS # Use InfoBase PubMed SciFinder ChemID NTIS FDA ECHA HPV IUCLID/ SIDS

WHO/ JEFCA

EU NICNAS Web

PPG-26-Buteth-26

9038-95-3 (generic) 9065-63-8 (generic)

0 hits 3 new hits

21CFR173.310; 21CFR173.340; 21CFR175.105; 21CFR176.210; 21CFR178.3570; 21CFR178.3910; 40CFR180.960

9038-95-3 – preR

9065-63-8 –

no

PPG-28-Buteth-35 PPG-12-Buteth-16 PPG-9-Buteth-12

PPG-2 Butyl Ether 9003-13-8 (generic) yes PPG-3 Butyl Ether 55934-93-5 yes PPG-4 Butyl Ether 9003-13-8 (generic)

yes

PPG-5 Butyl Ether PPG-9 Butyl Ether PPG-12 Butyl Ether PPG-14 Butyl Ether

21CFR178.3910

PPG-15 Butyl Ether PPG-16 Butyl Ether PPG-17 Butyl Ether PPG-18 Butyl Ether 21CFR175.105;

21CFR176.210; 21CFR178.3910

PPG-20 Butyl Ether

21CFR175.105; 21CFR176.200.; 21CFR176.210; 21CFR178.3910

PPG-22 Butyl Ether PPG-24 Butyl Ether PPG-26 Butyl Ether PPG-30 Butyl Ether PPG-33 Butyl Ether PPG-40 Butyl Ether 21CFR175.105;

21CFR176.200.; 21CFR176.210; 21CFR178.3570; 21CFR178.3910

PPG-52 Butyl Ether 21CFR176.200.; 21CFR178.3570; 21CFR178.3910

PPG-53 Butyl Ether

Buteth-3 [143-22-6] maybe PPG-2-Buteth-1

9038-95-3 (generic) 9065-63-8 (generic)

21CFR173.310; 21CFR173.340; 21CFR175.105; 21CFR176.210; 21CFR178.3570; 21CFR178.3910; 40CFR180.960

9038-95-3 – preR

9065-63-8 –

no

PPG-2-Buteth-2 PPG-2-Buteth-3 PPG-3-Buteth-5 PPG-4-Buteth-4 PPG-5-Buteth-5 PPG-5-Buteth-7


CAS # Use InfoBase PubMed SciFinder ChemID NTIS FDA ECHA HPV IUCLID/ SIDS

WHO/ JEFCA

EU NICNAS Web

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

15821-83-7; 29387-86-8; 5131-66-8

no VCRP 88 hits/3 useful

297 hits X no X no X no X (no R) no X

PPG-40 Butyl Ether JACT 12(3): 257-59, 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: (((((9038-95-3[EC/RN Number]) OR 9065-63-8[EC/RN Number]) OR 9003-13-8[EC/RN Number]) OR 55934-93-5[EC/RN Number]) OR 143-22-6[EC/RN Num-ber]) 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 (((15821-83-7[EC/RN Number]) OR 29387-86-8[EC/RN Number]) OR 5131-66-8[EC/RN Number]) – 41 hits/3 useful SciFinder May 2, 2016: 9038-95-3; 9065-63-8; 9003-13-8; 55934-93-5; 143-22-6; Buteth-3 – 602 hits June 22, 2016: 15821-83-7; 29387-86-8 ; 5131-66-8; Propylene Glycol Butyl Ether; Butoxyisopropanol – 297 hits; 6 useful FDA Citations 21CFR173.310 - Secondary Direct Food Additives Permitted In Food For Human Consumption; Specific Usage Additives; Boiler water additives 21CFR173.340 - Secondary Direct Food Additives Permitted In Food For Human Consumption; Specific Usage Additives; Defoaming agents 21CFR175.105 – Indirect Food Additive; Adhesives 21CFR176.200 – Indirect Food Additive; Defoaming Agent Used in Coatings 21CFR176.210 – Indirect Food Additive; Defoaming Agent Used in the Manufacture of Paper And Paperboard 21CFR178.3570 – Indirect Food Additive; Lubricants with Incidental Food Contact 21CFR178.3910 – Indirect Food Additive; Surface Lubricants Used In The Manufacture Of Metallic Articles


40CFR180.960 - Polymers; exemptions from the requirement of a tolerance; Residues resulting from the use of the polymer as an inert ingredient in a pesticide chemical formula-tion, 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.


RE-REVIEW - BUTYL POLYOXYALKYLENE ETHERS 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.

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 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 17.5. 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: 17.5.

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?

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 60.5.

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.

DR. SHANK: if we're going to go that far.

SPEAKER: It's too early.

DR. SHANK: On page 23.

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?

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.


ORIGINAL DELIBERATIONS – PPG BUTYL ETHERS (PPG-2, -4, -5, -9, -12, -14, -15, -16, -17, -18, -20 -22, -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 1993.

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.


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 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:

(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*

(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-121

1 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.

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 long-term, 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.


Amended Safety Assessment of Butyl Polyoxyalkylene Ethers as Used in Cosmetics

Status: Draft Tentative Amended Report for Panel Review Release Date: November 11, 2016 Panel Meeting Date: December 5-6, 2016 The 2016 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.

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ABSTRACT

The Cosmetic Ingredient Review (CIR) Expert Panel (Panel) assessed the safety of 46 butyl polyoxyalkylene ethers that all share a common structural motif, namely a butyl chain (4 carbon alkyl chain) connected 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 among all the ingredients are hair conditioning agent and skin conditioning agent; additionally, all but one of the butyl PPG/PEG ethers function as fragrance ingredients. Upon review of relevant new data, including frequency and concentration of use, and consideration of data from previous CIR reports, the Panel concluded that these ingredients [to be determined].

INTRODUCTION

The Cosmetic Ingredient Review (CIR) Expert Panel (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 2001.1 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-35.3 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 on the ingredients named above have been issued. Because the ingredients included in the reports on the butyl PPG ethers and the butyl PPG/PEG ethers all share a common structural motif, namely a butyl chain (4 carbon alkyl chain) connected 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 several 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 is a compilation of the 23 butyl polyoxyalkylene ethers named in those two reports, as well as an additional 23 butyl polyoxyalkylene ethers (listed above) that were not previously 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. 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. 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. (http://www.cir-safety.org/ingredients)

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 found it appropriate to read-across data from similar ingredients to those named in this report. The read-across data provided by ECHA, as well as other studies that were found in the literature on these compounds, are provided in Table 3; test data for all toxicological data categories considered by CIR are included. The Panel has reviewed the safety of two of the ingredients used for read-across by ECHA. In 2008, the Panel concluded that Methoxyisopropanol is safe for use in nail care products in the practices of use and concentration (it was only reported to be used in nail products),10 and, in 2009, that PPG-3 Methyl Ether is safe as cosmetic ingredients in the practices of use and concentration.11

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=132.20 g/mol) up to 75 repeat units (i.e. PPG-38-Buteth-37, MW=3911.12 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 PPG-3 Butyl Ether, a hydrophobic glycol ether,14 is a colorless liquid (Table 4). Also described in Table 4 are physical and chemical properties of Buteth-3, a water-soluble crystalline compound with low volatility,15 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

Propylene glycol ethers, in general, are prepared commercially by reacting propylene oxide with an alcohol in the presence of a catalyst13 in a closed continuous system.9 This reaction can produce glycol ethers of varying chain length depending on the molar ratio of reactants and the temperatures and pressures used in the reaction. Milder conditions and lower molar ratios of


propylene oxide to alcohol will produce 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.

In the synthesis of Propylene Glycol Butyl Ether, an α-isomer and a β-isomer are usually formed. 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).13

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

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 this ingredient 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 that received from the Council, 17 of the 45 ingredients assessed in this report are in use.16-18 PPG-26-Buteth-26 has the highest frequency of use; according to the 2016 VCRP data, it is used in 1091 cosmetic formulations.16 Buteth-3 has the next highest frequency of use, with 433 reported uses (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)19 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 remarkable 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 1091 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 29 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 in the VCRP database to be in use, 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 for 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.20,21 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.22,23 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.23 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.

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).24

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.13 These ethers are used in solvents and have a wide range of applications; for example, they are used in pains, lacquers, resins, surface coatings, dyes, and other related products.

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.25 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.15

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.26 It has been used in household and commercial degreasers and hard surface cleaners.

TOXICOKINETICS STUDIES

Dermal Penetration

Buteth-3 The dermal penetration of Buteth-3 through human skin was measured in vitro.27 Epidermal samples were mounted in a glass diffusion apparatus; the exposure area was 2.54 cm2. 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/cm2/h. The epidermal damage caused by exposure to Buteth-3 was also 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., ratio of permeability constants determined from tritiated water diffusion after chemical exposure compared to before exposure) was 1.26.

Absorption, Distribution, Metabolism, and Excretion In rats dosed orally with 14C-PPG-7-Buteth-10, most of the administered radioactivity was excreted (urine, feces, and expired CO2) within seven days post-dosing. Similar observations were reported for rats dosed orally with 14C-PPG-33-Buteth-45; however, radioactivity was not detected in expired CO2.4

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 C02 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 Small 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 dermal route is slower, but subsequent distribution is rapid.9 Additionally, Propylene Glycol Butyl Ether (a monoglycol ether) is expected to be absorbed better 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.

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 with floor space of 41-55 m2 and a room volume of 33-50 m3.12 The room contained wooden furnishings and linoleum floor-ing and was naturally ventilated. The furniture was wetted with 40 ml of undiluted cleaning solution in the morning; applica-tion of the cleaner resulted in a Propylene Glycol Butyl Ether concentration of 3.0 mg/m3 (average; standard deviation of 0.9 mg/m3) in the office air. Eight test subjects worked in the offices; seven of the subjects were exposed for approximately 8 h and one for approximately 5 h.

Subjects collected daily urine the day before, the day of, and the day after exposure. Urine samples were collected by unex-posed individuals and analyzed to determine normal 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 con-centration of 2-butoxypropionic acid in the urine was below the limit of quantification (LOQ; 0.01 mg/l) the day before expo-sure; it was present at an average concentration of 0.06 mg/l standard deviation of 0.9 mg/l) on the day of exposure. In three subjects, 2-butoxypropionic acid was detected in the urine samples at slightly over the LOQ (0.012 – 0.014 mg/l) on the day after exposure.


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 LD50 was not achieved at a dose of 2.0 g/kg (1.89 ml/kg). 4

An LD50 of 18.3 g/kg for PPG-12-Buteth-16 was reported in an acute oral toxicity study involving rats. Acute oral LD50s ranging from 4.49 to 8.57 ml/kg have been reported for PPG-7-Buteth-10 in studies involving rats. Oral LD50s of 7.46 ml/kg (mice) and 1. 77 ml/kg (rabbits) for PPG-7- Buteth-10 also have been reported.

The oral LD50 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 LD50 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 LD50 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, LD50s of 45.2 ml/kg and 49.4 ml/kg, respectively, were reported. In studies using rabbits, an LD50 of 15.8 ml/kg was reported for PPG-33-Buteth-45.

Acute inhalation LC50 values for PPG Buteths that have been reported for rats are as follows: 4670 mg/m3 and > 5230 mg/m3 for males and females, respectively (PPG-12-Buteth-16); 4.77 mg/m3 (males and females) for PPG-7-Buteth-10; 330 mg/m3 (males and females) for PPG-20-Buteth-30; and 14 7 mg/m3 for PPG-33-Buteth-45. LC50 values of 17 4 mg/m3 (mice); 511 mg/m3 (hamsters); and 293 mg/m3 (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 LD50 values of the PPG butyl ethers ranged from 1.6 - 2.9 ml/kg (PPG-2 Butyl Ether) to 48.7 ml/kg (PPG-40 Butyl Ether). For rabbits, the cutaneous LD50 values were 5.9 - 7.1 ml/kg (PPG-2 Butyl Ether) to > 20 ml/kg (PPG-40 Butyl Ether).1

PPG-2 Butyl Ether vapors were produced o apparent toxic effects 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 inhaled vapors of PPG-9, -18, and -24 Butyl Ethers 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.

The dermal LD50 of Buteth-3 in rats was 3.5 g/kg,15 of PPG Butyl Ether, undefined was >2 g/kg in rats,28 and of Propylene Glycol Butyl Ether was >2 g/kg in rats9,29,30 and at least 1.4 g/kg in rabbits.29 The oral LD50 in rats of Buteth-3, PPG Butyl Ether, undefined, and Propylene Glycol Butyl Ether was 6.6 g/kg,15 between 0.3-2 g/kg,28 and >2 g/kg,9,29 respectively. The inhalation LC50 of Propylene Glycol Butyl Ether in rats was >651 ppm.15,28,31

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 no-observed effect levels (NOELs) of PPG BE400, 800, 910, and 1020 were 0.047 g/kg/day, 0.16 to 0.67 g/kg/day, 0.25% of the diet, and 0.0625% 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. With dermal dosing, effects on the skin were reported in a 21-day toxicity study of Buteth-3 (1000 mg/kg, occlusive application)27 and 28-day toxicity studies of Propylene Glycol Butyl Ether (at concentrations of ≥5.69%, open applica-tions)32,33 in rabbits, and in 3 mos studies in rats9,29,34 and rabbits.9,35 Clinical signs of toxicity generally were not observed;


however some increase in liver weights without microscopic changes were reported. In short-term oral toxicity studies in rats, PPG Butyl Ether, undefined had a NOEL of 100 mg/kg bw28 and Propylene Glycol Butyl Ether had a no-observed adverse effect level (NOAEL) of 400 mg/kg.9,29,36 In subchronic (13 wk) studies in rats, both PPG-3 Butyl Ether25 and Propylene Glycol Butyl Ether9,29 had a NOAEL of 350 mg/kg. The NOAEL of Propylene Glycol Butyl Ether in short-term (9 exposure) inhalation studies in rats was ≥600 ppm.9,29,37

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

Developmental and reproductive toxicity (DART) studies summarized here are detailed in Table 11.

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 > 1ml/kg).13 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) 9,13,28 or rabbits (≤100 mg/kg bw/day applied on days 7-18 of gestation).9,13,31

In oral (gavage) DART studies no test-article related adverse developmental or reproductive effects were observed in rats dosed with up to 500 mg/kg bw/day PPG Butyl Ether, undefined (prior to and during mating),28 or rats dosed with up to 1000 mg/kg Buteth-3 (days 7-16 of gestation).27

GENOTOXICITY STUDIES

Genotoxicity studies of PPG Butyl Ether, undefined and Propylene Glycol Butyl Ether are summarized here and described in Table 12.

PPG Butyl Ether, undefined was not genotoxic in an Ames test (≤5000 µg/plate), a mammalian chromosomal assay in rat lymphocytes (≤5000 µg/ml), or a mammalian cell mutation assay in Chinese hamster ovary (CHO) cells (≤2500 µg/ml).28 Propylene Glycol Butyl Ether was not mutagenic in numerous genotoxicity studies, including an Ames test (20 µl/plate),38 mammalian chromosomal aberration assays in CHO cells (≤6000 µg/ml), 9,29,39 mouse lymphoma cell assays in T5178Y TK+/- lymphoma cells (≤6000 µg/ml),9,40 unscheduled DNA synthesis (UDS) assays in primary rat hepatocytes (≤6000 µg/ml).41

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

Read-Across Read-across inhalation carcinogenicity data are provided in Table 3.

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 semi-occlusive 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.

Details of the dermal irritation and sensitization studies summarized below are described in Table 13.


PPG Butyl Ether, undefined was classified as non-corrosive in an EpiDermTM study.28 In rabbits, Propylene Glycol Butyl Ether was slightly irritating at a concentration of 50%9,29,44 and was generally irritating when applied undiluted.9,29,45 In guinea pigs, undiluted Propylene Glycol Butyl Ether was a minimal irritant in one study;9 it was not irritating or sensitizing in a Buehler test (three induction patches with 80% and a challenge with 40%).9,29,46

In human repeated insult patch tests (HRIPT), hair styling wax containing 71% PPG-40 Butyl Ether (applied neat)47 and undiluted PPG-40 Butyl Ether48 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 potential of undiluted Propylene Glycol Butyl Ether in rabbit eyes ranged from not irritating (according to criteria established by the European Union EU) to moderately irritating (according the Draize scores) (Table 14).

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 all share a common structural motif, namely a butyl chain (4 carbon alkyl chain) connect-ed to a polyoxyalkylene (PPG, PEG, or both). This safety assessment is a compilation of the 23 butyl polyoxyalkylene ethers named in those two reports, as well as an additional 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.

Seventeen of the 46 ingredients assessed in this report are used in cosmetic formulations. PPG-26-Buteth-26 has the highest frequency of use, with 1091 reported uses. Buteth-3 has the next highest frequency of use, with 433 reported uses. 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 remarkable increase in the frequency of use of PPG-26-Buteth-26, from 13 reported uses in 1997 to the 1091 uses reported in 2016.

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/cm2/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 exposure. The primary routes of excretion are via the urine and expired air; a small amount is excreted in the feces. Absorption via dermal route is slower, but subsequent distribution is rapid. Additionally, Propylene Glycol Butyl Ether (a monoglycol ether) is absorbed better than diglycol and triglycol ethers. However, diglycol and triglycol ethers may be present on the skin much longer than monoglycol ethers because of lower vapor pressures.

2-Butoxypropionic acid, a metabolite of Propylene Glycol Butyl Ether, appeared in the urine (at a concentration of 0.06 mg/ml) of 6 subjects who were exposed to vapors in an office 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 (0.012 – 0.014 mg/l).

The dermal LD50 of Buteth-3 in rats was 3.5 g/kg of PPG Butyl Ether, undefined was >2 g/kg in rats, and of Propylene Glycol Butyl Ether was >2 g/kg in rats and at least 1.4 g/kg in rabbits. The oral LD50 in rats of Buteth-3, PPG Butyl Ether, undefined, and Propylene Glycol Butyl Ether was 6.6 g/kg, 0.3-2 g/kg, and >2 g/kg, respectively. The inhalation LC50 of Propylene Glycol Butyl Ether in rats was >651 ppm.

With dermal dosing, effects on the skin were reported in a 21-day toxicity study of Buteth-3 (1000 mg/kg, occlusive applica-tion) and 28-day toxicity studies of Propylene Glycol Butyl Ether (at concentrations of ≥5.69%, open applications) in rabbits, and in 3 mos studies in rats and rabbits. Clinical signs of toxicity generally were not observed; however some increase in liver weights without microscopic changes were reported. In short-term oral toxicity studies in rats, PPG Butyl Ether,


undefined had a NOEL of 100 mg/kg bw and Propylene Glycol Butyl Ether had a NOAEL of 400 mg/kg. In subchronic (13 wk) studies in rats, both PPG-3 Butyl Ether and Propylene Glycol Butyl Ether had a NOAEL of 350 mg/kg. The NOAEL of Propylene Glycol Butyl Ether in short-term (9 exposure) inhalation studies in rats was ≥600 ppm.

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 > 1ml/kg).13 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). In oral (gavage) DART studies no test-article related adverse developmental or repro-ductive effects were observed in rats dosed with up to 500 mg/kg bw/day PPG Butyl Ether, undefined (prior to and during mating) or rats dosed with up to 1000 mg/kg Buteth-3 (days 7-16 of gestation).

PPG Butyl Ether, undefined was not genotoxic in an Ames test (≤5000 µg/plate), a mammalian chromosomal assay in rat lymphocytes (≤5000 µg/ml), or a mammalian cell mutation assay in Chinese hamster ovary (CHO) cells (≤2500 µg/ml). Propylene Glycol Butyl Ether was not mutagenic in numerous genotoxicity studies, including an Ames test (20 µl/plate), mammalian chromosomal aberration assays in CHO cells (≤6000 µg/ml), mouse lymphoma cell assays in T5178Y TK+/- lymphoma cells (≤6000 µg/ml), or UDS assays in primary rat hepatocytes (≤6000 µg/ml).

PPG Butyl Ether, undefined was classified as non-corrosive in an EpiDermTM 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%).

In HRIPTs, hair styling wax containing 71% PPG-40 Butyl Ether (applied neat) and undiluted PPG-40 Butyl Ether were not sensitizers.

DRAFT 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 or not the conclusion should be reaffirmed. Because the ingredients included in the reports on the butyl PPG ethers and the butyl PPG/PEG ethers all share a common structural motif, namely a butyl chain (4 carbon alkyl chain) connected 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. Additionally, the Panel determined it was appropriate to include 23 butyl polyoxyalkylene ethers that have not yet been reviewed, because these ingredients also share the same structural motif.

For many of the ingredients included in the report, the frequency of use has increased since the Panel’s original review. However, there has been a remarkable increase in the frequency of use of PPG-26-Buteth-26, from 13 reported uses in 1997 to the 1091 uses reported in 2016. Additionally, at the time of the original review, concentrations of use were not reported; it is now known that the maximum use concentration for PPG-40-Butyl Ether is up to 71% for leave-on formulations (a hair wax) and 73.5% in rinse-off formulations (hair tint).

Remainder to be developed…

CONCLUSION

To be determined.


TABLES 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

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

Note: ingredients that were reviewed previously are indicated in blue Table 2. Definitions, structures, and functions of butyl polyoxyalkylene ethers (5; CIR Staff)

Ingredient CAS No. Definition & Structure Function Butyl PPG/PEG Ethers the butyl PPG/PEG ethers included in this report all conform generally to the

formula:

the value of “x” and “y” varies for each ingredient, and these values are specified with each definition

PPG-2-Buteth-1 9038-95-3 (generic) 9065-63-8 (generic)

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

hair conditioning agent; skin-conditioning agent - misc



fragrance ingredient; hair condition-ing agent; skin-conditioning agent – misc; surfactant – emulsifying agent



fragrance ingredient; hair condition-ing agent; skin-conditioning agent – misc; solvent


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













fragrance ingredient; hair condition-ing agent; skin-conditioning agent – misc; solvent; surfactant – emulsifying agent






fragrance ingredient; hair condition-ing agent; skin-conditioning agent - misc; surfactant - emulsifying agent





Table 2. Definitions, structures, and functions of butyl polyoxyalkylene ethers (5; CIR Staff)

Ingredient CAS No. Definition & Structure Function PPG-12-Buteth-12 9038-95-3 (generic) 9065-63-8 (generic)





fragrance ingredient; hair condition-ing 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 condition-ing agent; skin-conditioning agent – misc; surfactant - emulsifying agent



fragrance ingredient; hair condition-ing agent; skin-conditioning agent - misc; surfactant - emulsifying agent



fragrance ingredient; hair condition-ing agent; skin-conditioning agent – misc; surfactant – cleansing agent; surfactant – solubilizing agent



fragrance ingredient; hair condition-ing agent; skin-conditioning agent – misc







Butyl PPG Ethers the butyl PPG ethers included in this report all conform generally to the formula:

the value of “n” varies for each ingredient, and this value is specified with each definition

PPG-2 Butyl Ether 9003-13-8 (generic)

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

hair conditioning agent; skin-conditioning agent – misc; solvent

PPG-3 Butyl Ether 55934-93-5


hair conditioning agent; skin-condi-tioning agent – misc; solvent



hair conditioning agent; skin-condi-tioning agent – misc








Table 2. Definitions, structures, and functions of butyl polyoxyalkylene ethers (5; CIR Staff)

Ingredient CAS No. Definition & Structure Function PPG-12 Butyl Ether 9003-13-8 (generic)













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-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











Butyl Propylene Glycol Ether Propylene Glycol Butyl Ether 29387-86-8 (mixture); 5131-66-8 (α-isomer); 15821-83-7 (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 PEG Ether Buteth-3 [143-22-6]

Buteth-3 is the polyethylene glycol ether of butyl alcohol that conforms generally to the formula:

solvent


Table 3. Read Across Data End Point Animals/Group or Test System Vehicle Dose/Concentration Procedure Results Reference

read-across to PPG-3 Butyl Ether

[(Butoxymethylethoxy)methylethoxy]propan-1-ol also identified as tripropylene glycol n-butyl ether 31 CAS # (55934-93-5) corresponds to PPG-3 Butyl Ether, but there is a difference in the structure31

acute toxicity - dermal 5 Wistar rats/sex none 2 g/kg test article purity –99 %

in accord with OECD Guideline 402 25 h semi-occlusive patch

LD50 >2 g/kg 31

acute toxicity - dermal 2 male NZW rabbits none 2 g/kg test article purity – 85%

in accord with OECD Guideline 402 24h patch; type of coverage not stated

LD50 >2 g/kg no dermal effects

31

acute toxicity - oral 3 female Fischer rats none 2 g/kg bw test article purity – 85%

in accord with OECD Guideline 401 single dose by gavage

>2 g/kg bw 1 animal died

31

acute toxicity – oral 6 Wistar rats/sex CMC 2 g/kg bw in accord with OECD Guideline 423 single dose by gavage

>2 g/kg bw 1 female died

31

acute toxicity – oral 1 Wistar rat/sex none 2.5, 4, and 5 mg/kg bw test article purity – 99%

in accord with OECD Guideline 401 (preliminary study) single dose by gavage

both animals of the 4 and 5 g/kg group died within 24 h of dosing

31

acute toxicity - oral 5 Wistar rats/sex none 2.4, 3.2, and 4.2 g/kg bw test article purity – 99%

in accord with OECD Guideline 401 single dose by gavage

~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

31

short-term oral toxicity 5 F344 rats/sex corn oil 0, 100, 350, or 1000 mg/kg bw test article purity - 80.67%

in accord with OECD Guideline 407 28-day study dosed 1x/day, 5 days/wk by gavage

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

31


Table 3. Read Across Data End Point Animals/Group or Test System Vehicle Dose/Concentration Procedure Results Reference subchronic oral toxicity 10 Fischer 344 rats/sex none 0, 100, 350, or 1000 mg/kg

bw; 0 and 1000 mg/kg (recovery group) test article purity – 97.7%

in accord with OECD Guideline 408 90-day study administered in drinking water

NOAEL – 1000 mg/kg bw no clinical signs of toxicity; statistically significant changes included: decrease in body wts and feed con-sumption of high dose animals; treatment-related in-creases 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 in-creased in high-dose males mid- and high-dose females Changes in hematology, clinical chemistry, and urinaly-sis parameters were not considered toxicologically significant

31

genotoxicity – in vitro S. typhimurium TA1535, TA1537, TA98, TA100

DMSO 50-5000 µg/plate, +/- metabolic activation test article purity – 96.12%

in accord with OECD Guideline 471 Ames test; negative and positive controls were included

negative controls gave expected results

31

genotoxicity – in vivo 5 CD-1 mice/sex/group corn oil 0, 187.5, 625, and 1875 mg/kg bw test article purity – 96.12%

in accord with OECD Guideline 474 mammalian erythrocyte micro-nucleus test animals were given a single dose by gavage solvent and positive controls


31

dermal irritation 3 NZW rabbits none not provided in accord with OECD Guideline 404 4-h semi-occlusive patch

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 was reported

31

dermal irritation 3 female NZW rabbits none 0.5 ml test article purity – 99%

in accord with OECD Guideline 404 4-h semi-occlusive patch applied to shaved skin

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

31

dermal irritation 1 male NZW rabbit none 0.5 ml (semi-occlusive application) 0.1 ml (open applications) test article purity – 85%

in accord with OECD Guideline 404 24-h semi-occlusive patches were applied to intact and abraded skin of the abdomen; 3 applications were made to abraded skin and 5 to intact skin 5 daily open applications were made to intact skin on the medial surface of the left ear pinna, received

not irritating repeated contact resulted in very slight to slight erythema and exfoliation

31

dermal sensitization female Hartley guinea pigs; 20 test, 10 control

undiluted in petrolatum

0.5% (w/w); dose volume not provided test article purity – 98.47%

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

not sensitizing 31

ocular irritation 3 female NZW rabbits none 0.1 ml test article purity - 99%

in accord with OECD guideline 405 eyes were not rinsed contralateral eye served as a control

not irritating; Draize score = 12 (60 min) slight conjunctival redness and obvious to moderate chemosis; 1 animal showed slight injection of the iris after 24 h; no adverse effects on the cornea, except for epithelial damage in 2 animals visualized with fluorescein

31


Table 3. Read Across Data End Point Animals/Group or Test System Vehicle Dose/Concentration Procedure Results Reference ocular irritation 3 NZW rabbits none 0.1 ml in accord with OECD guideline 405

eyes were not rinsed contralateral eye served as a control

not irritating no corneal or iridial irritation; conjunctival redness (score = 2) was reversible within 48 h

31

ocular irritation 1 NZW rabbits none 0.1 ml test article purity – 85%

in accord with OECD guideline 405 test instilled into both eyes; one eye was rinsed after 30 sec, the other after 1 h

not irritating moderate conjunctival redness and swelling, and slight to moderate reddening of the iris; corneal effects in-cluded very slight, transient haziness and moderate corneal injury

31

1-(2-butoxy-1-methylethoxy)-propan-2-ol (aka dipropylene glycol n-butyl ether) MW 190.28; produced as a 4 isomer mixture9

ADME 4 male Fischer 344 rats 1% methylcellulose

0.4 and 4.4 mmol/kg bw test article was 14C-labelled

in accord with OECD Guideline 417 - single oral dose by gavage - urine, feces, expired air, blood and tissues were collected and analyzed for total 14C-activity

low dose (after 48 h): 42% of the dose was excreted in urine, 4% in the feces, and 42% as 14CO2; tissues, car-cass and skin retained 11% of the dose; peak blood levels of 14C-activity occurred at 0.5 h after dosing high dose (after 48 h): 51% of the dose was excreted in urine, 11% in the feces, and 35% as 14CO2; tissues, carcass and skin retained 7% of the dose; peak blood levels of 14C-activity occurred at 4 h after dosing - distribution of 14C-activity in tissues was similar between dose groups with liver, bone marrow and kidneys retaining the highest percentage - urinary metabolites: the sulfate conjugate of 1-(2-butoxy-1-methylethoxy)-propan-2-ol, propylene glycol n-butyl ether, dipropylene glycol, and propylene; the parent material was found in the urine

9,9,29

acute toxicity - dermal 5 Wistar rats/sex none 2 mg/kg bw in accord with OECD guideline 402; 24-h occlusive patch to intact skin

>2000 mg/kg bw 9

acute toxicity - oral 4 male CD-1 mice none 0.1, 0.316, 1.0, and 10 ml in accord with OECD guideline 401 2160 mg/kg bw (calculated) 9

acute toxicity - oral 5 Wistar rats/sex none 3200, 4200, or 5600 mg/kg single dose by gavage in accord with OECD guideline 401

LD50 combined – 4000 mg/kg LD50 males – 4400 mg/kg LD50 females – 3700 mg/kg

9

acute toxicity - oral rats; number not stated none not stated in feed 1850 mg/kg bw 9 acute toxicity - inhalation 5 F344 rats/sex 328 mg/m3 in accord with OECD guideline

403; 4 h whole body exposure LC50>328 mg/m3 9

short-term - oral 6 Sprague-Dawley rats/sex propylene glycol 0, 100, 200, or 400 mg/kg bw in accord with OECD guideline 407; 2-wk gavage study

NOAEL – 400 mg/kg 9


Table 3. Read Across Data End Point Animals/Group or Test System Vehicle Dose/Concentration Procedure Results Reference short-term - oral 5 Sprague-Dawley rats/sex 0, 250, 500, or 750 mg/kg bw in accord with OECD guideline

407; 2-wk feed study NOAEL – >750 mg/kg 9

short term toxicity - inhalation

5 F344 rats/sex 0, 160, 320 mg/m3 in accord with OECD guideline 412; 9 – 6/h nose-only exposures in 2 wks

NOAEL – 320 mg/m3 9

short term toxicity - inhalation

5 F344 rats/sex 0, 160, 320 mg/m3 in accord with OECD guideline 412; 9 – 6/h nose-only exposures in 2 wks

NOAEL – 320 mg/m3 9

5 F344 rats/sex 0, 200, 810,or 2010 mg/m3 in accord with OECD guideline 412; 9 – 6/h nose-only exposures in 2 wks

NOAEL – 200 mg/m3 LOAEL – 810 mg/m3

9

subchronic - dermal 10 Wistar rats/sex propylene glycol 0, 91, 273, or 910 mg/kg bw/day

in accord with OECD guideline 411; 5 open applications/wk for 13 wk; animals wore collars to prevent ingestion

NOAEL – 91 mg/kg/day LOAEL – 273 mg/kg/day (based on body weight changes and increased neutrophil count) skin irritation was observed at all test sites (including controls)

9

subchronic - oral 20 Sprague-Dawley rats/sex; additional 5 for interim sacrifice

propylene glycol 0, 200, 450, or 1000 mg/kg bw in accord with OECD guideline 408;13-wk feed study

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 corrobated liver changes high-dose females: absolute and relative kidney weights were increased in high dose females with no accompanying histopathology.

9

combined repeated dose toxicity study with the reproduction /develop-mental toxicity screening test

12 Crl:CD(SD) rats/sex

0.5% methylcellulose

0, 100, 300, or 1000 mg/kg bw/day test article purity – 99.34%

in accord with OECD guideline 422 Males were 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)

NOAEL for systemic toxicity - 100 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 hepato-cellular hypertrophy that occurred in males of all dose groups and in mid- and high-dose females correlated with increased liver weights in mid- and high-dose males and high dose females; these changes were con-sidered to be an adaptive response associated with increased hepatic metabolism - treatment-related increases in absolute and relative kidney weights also were reported in high-dose animals; hyaline droplet formation in the proximal renal tubules was observed in mid- and high-dose males; a histopathologic correlation to the higher kidney weights was not evident for females

31

DART results: NOEL for reproductive effects was 1000 mg/kg/day There were no treatment-related effects on any reproductive parameters


Table 3. Read Across Data End Point Animals/Group or Test System Vehicle Dose/Concentration Procedure Results Reference DART – dermal 22 (control), 21 (low-dose), and

25 (high-dose) 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

in accord with OECD guideline 414 open applications (20 cm2) were made on days 6-15 of gestation; collars were used to prevent ingestion; animals were killed on day 21 of gestation

- minor skin reactions were not considered toxicologically relevant; no clinical signs of toxicity; no mortality; organ weights were comparable for test and control groups - pre- and post-implantation loss, number of viable fetuses, and fetal weights and lengths were comparable between treatment and control groups, and there were no signs of developmental toxicity - not embryotoxic, fetotoxic, or teratogenic

9,28,31

genotoxicity – in vitro Salmonella typhimurium TA98, TA100, TA1535, TA1527, TA1538

DMSO 279-5000 µg/ml +/- activation test article purity – 98.97%

in accord with OECD guideline 471, Ames test, with and without metabolic activation

negative 9

genotoxicity – in vitro CHO-K1, S1B cells culture medium 0, 333, 1000, or 3333 µg/ml with and 0, 1000, 2000, 3000, and 4000 µg/ml without activation

in accord with OECD guideline 473, chromosomal aberration assay

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.

9

genotoxicity – in vitro CHO-K1, S1B cells culture medium 0 and 3500 µg/ml with and 0 and 4500 µg/ml without activation


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

9

genotoxicity – in vitro CHO-K1, S1B cells culture medium 0, 500, 1000, 2000, and 3000 µg/ml with and 0, 500, 1000, 2000, 3500, and 5000 µg/ml without activation


positive chromatid and chromosome gaps and breaks and fragments detected in all groups, including negative controls, in cells with activation; however, a dose-response increase was not evident without activation, a more pronounced increase was observed in cells, significant to a higher p value at the highest dose; but a dose-response still was not apparent.

9

genotoxicity – in vitro CHO-K1, CCL61cells culture medium 0, 500, 1667, and 5000 µg with and without metabolic activation


negative 9

genotoxicity – in vitro CHO-K1, S1B cells culture medium 0, 500, 1667, and 5000 µg with and without metabolic activation


negative 9

genotoxicity – in vitro CHO cells DMSO 279-5000 µg/ml +/- activation test article purity – 98.97%

in accord with OECD guideline 476 mammalian CHO/HGPRT forward mutation assay

negative 9,31

genotoxicity – in vivo 5 CD-1 mice/sex 0, 250, 833, and 2500 mg/kg bw

in accord with OECD guideline 475, micronucleus assay; mice were given a single dose by gavage

negative 9

dermal irritation 3 female NZW rabbits none 0.5 ml 4-h semi-occlusive patch PDII – 2; slightly irritating EU classification - not irritating

9

skin sensitization 10 guinea pigs/sex propylene glycol 80% for induction; 40% for at challenge

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

not a sensitizer 9

skin sensitization 82 human subjects 0.4 ml RIPT; 24 h patches 9


Table 3. Read Across Data End Point Animals/Group or Test System Vehicle Dose/Concentration Procedure Results Reference ocular irritation 3 female NZW rabbits none 0.1 ml in accord with OECD guideline

405; eyes were not rinsed Draize score (1 h) – 12.7/110, slightly irritating (EC classification – not irritating)

9

PPG-3 Methyl Ether (aka Tripropylene Glycol Methyl Ether isomeric mixture with CAS No. 25498-49-1) MW – 206.32; produced as an 8 isomer mixture9

CIR conclusion: safe as cosmetic ingredients in the practices of use and concentration11

ADME 3 male rats 1% methylcellulose

1 and 4 mmol/kg test article was 14C-labelled

single oral dose by gavage urine, feces, expired air, and tissues were collected and analyzed for total 14C-activity

low dose (after 48 h): 75% of the dose was excreted in urine, 5% in the feces, and 16% as 14CO2; carcass retained 1-2% high dose (after 48 h): 69% of the dose was excreted in urine, 5% in the feces, and 16% as 14CO2; carcass retained 1-2% of the dose - distribution of 14C-activity in tissues was similar between dose groups with liver, kidneys,and skin retaining the highest percentage - urinary metabolites: 11-18% of the sulfate conjugate of 1-(2-butoxy-1-methylethoxy)-propan-2-ol, 12-25% di-propylene glycol methyl ether, 1.3-3.8% propylene gly-col, 54-56% 3 isomers (50%) of dipropylene glycol and 2 isomers (50%) of 2-(1-hydroxy-2-propoxy) propanoic acid, described as “isomers of a cyclic dehydration product, and 6-12% isomers of tripropylene glycol

9

acute toxicity - dermal 4 male rabbits none 7720 or 15,400 mg/kg 24h occlusive patch LD50 – 15,400 mg/kg; 2/4 high dose animals died on days 2 and 3

9

acute toxicity - oral 5 Sprague-Dawley CFY rats/sex

none 00, 2300, 3000, 3900, and 5000 mg/kg; 90% polypropyl-ene glycol methyl ether (tri- and higher)

single dose by gavage in accord with OECD guideline 401

LD50 -5.66 ml/kg (5462 mg/kg bw) 9

acute toxicity - oral 5 males none 20, 4.0, or 8.0 ml/kg single oral dose LD50 combined – 4000 mg/kg LD50 males – 4400 mg/kg LD50 females – 3700 mg/kg

9

acute toxicity - inhalation rats; number not stated 253 mg/m3 in accord with OECD guideline 401; 8 h exposure

LC0 >253 mg/m3 9

short-term toxicity - inhalation

5 B6C3F1 mice/sex 0, 150, 360, and 1010 mg/m3 in accord with OECD guideline 412, 9 6-h exposures in 2 wks

NOAEL – <150 mg/m3 LOAEL – 150 mg/m3 increased liver weights in all test males and high-dose females; these changes were not accompanied by histological damage in the low and mid dose group males or in the high dose females. Males but not females in the high exposure group exhibited staining changes but no frank evidence of histologic damage to hepatocytes

9


Table 3. Read Across Data End Point Animals/Group or Test System Vehicle Dose/Concentration Procedure Results Reference short-term toxicity - inhalation

5 Fischer 344 rats/sex 0, 150, 360, and 1010 mg/m3 in accord with OECD guideline 412, 9 6-h exposures in 2 wks

NOAEL – 150 mg/m3 LOAEL – 360 mg/m3 a statistically significant increase in absolute and relative liver weights in both high-dose males and females; increased relative( but not absolute) liver weights in mid-dose males but not females; changes were not accompanied by histological damage

9

subchronic toxicity - dermal

5-8 male rabbits undiluted 0, 965, 2895, 4825, and 9650 mg/kg

90-day study; 65 occlusive (5 days/ wk) 7.5 cm2 patches

NOAEL – 965 mg/kg LOAEL – 2895 mg/kg 7/8 high-dose animals dose; decreased body wts and increased kidney wts were observed in this group; microscopic observations were largely normal in all organs in the high dose group with the exception that kidneys occasionally showed granular degeneration and hydropic changes tubular necrosis was reported in the 965 and 2895, but not the 4825, mg/kg groups

9

DART – inhalation exposure

25 gravid female Sprague-Dawley rats

0, 100, 300, or 1000 mg/m3; avg. average mass median particle diameter ranged from 2.47 - 3.75 µm

in accord with OECD guideline 414; animals were dosed via whole body exposure (length of daily exposure not specified) on days 6-15 of gestation

Not embryotoxic, fetotoxic, or teratogenic - NOAEL >1000 mg/m3 for teratogenicity - NOAEL and LOAEL were 300 mg/m3 for maternal toxicity; a “high incidence” of muzzle staining was observed in the 1.0 mg/l group

9,28

genotoxicity – in vitro S. typhimurium TA98, TA100, TA1535, TA1537, and TA1538

0-100,000 µg/plate in accord with OECD guideline 471, Ames test with and without metabolic activation

negative 9

genotoxicity – in vitro male rat hepatocytes 0, 20.6, 65.2, 206, 652, 2063, 6520, or 20,630 mg/l

in accord with OECD guideline 482, UDS assay

negative 9

dermal irritation 5 male rabbits none 0.010 ml unoccluded 24-h exposure PDII – 1/10; non-irritating 9 ocular irritation 5 male rabbits none 0.005, 0.02 and 0.1 ml eyes were not rinsed moderately irritating; moderate injury with 0.1 ml, trace

corneal injury and iritis with 0.02 ml, no irritation with 0.005 ml

9


Table 3. Read Across Data End Point Animals/Group or Test System Vehicle Dose/Concentration Procedure Results Reference Methoxyisopropanol MW – 90.1

CIR conclusion: safe for use in nail care products in the practices of use and concentration (it was only reported to be used in nail products)10 combined chronic toxicity/carcinogenicity – inhalation

50 B6C3F1 mice/sex none 0, 300, 1000, or 3000 ppm test article: >97% 1-methoxy-2-propanol: <3% 2- methoxy-1-propanol

in accord with OECD Guideline 453 2 yr study animals were exposed by whole body exposure for 6 h/day, 5days/wk

NOAEL – 1000 ppm based on slight body wt decreases in males and females - high dose males had increased mortality after 18 mos; high-dose animals exhibited decreased activity, incoordination, and transient sedation during wk 1of exposure; “large” but not statistically significant decreases in body wts in the mid- and high-dose groups - liver wts were increased in high dose animals - no treatment-related effects on clinical chemistry, hematology, or urinalysis parameters - there was an increase in S-phase DNA synthesis and in MFO activity in the livers of high-dose males - an increase in renal epithelial tumors was not observed at any dose level, and no treatment-related neoplastic or non-neoplastic microscopic findings were reported

31

combined chronic toxicity/carcinogenicity - inhalation

50 Fischer 344 rats/sex none 0, 300, 1000, or 3000 ppm test article: >97% 1-methoxy-2-propanol: <3% 2- methoxy-1-propanol

in accord with OECD Guideline 453 2 yr study animals were exposed by whole body exposure for 6 h/day, 5days/wk

NOAEL – 300 ppm based on altered hepatocellular foci in males - high dose males had increased mortality after 18 mos; high-dose animals exhibited decreased activity, uncoordi-nation, and transient sedation during wk 1of exposure, these signs reappeared at 12-18 mos; statistically signifi-cant decreases in body wts in the high-dose groups - liver and kidney wts were increased in high dose animals; no treatment-related effects on hematology or urinalysis parameters; some clinical chemistry parameters were affected in high dose males - statistically significant increased labeling indices for hepatic cell proliferation were observed in high dose males; no changes in renal cell proliferation - slight increase in the incidence of dark foci in the liver of mid-and high-dose males that correlated with the presence of altered hepatocellular foci - other gross pathological observations and palpable masses that were observed in all groups were not treatment-related - eosinophilic hepatocellular foci and cystic degeneration in mid- and high-dose males - an increase in S-phase DNA synthesis (not significant) and in MFO activity in the liver in high-dose males - an increase in 2µ-globulin nephropathy in mid- and high dose males; no increase in renal epithelial tumors was observed

31


Table 3. Read Across Data End Point Animals/Group or Test System Vehicle Dose/Concentration Procedure Results Reference DART

30 Sprague-Dawley rats/sex none 0, 300, 1000 or 3000 ppm test article consisted of 97.99% - 98.07% α-isomer; 1.86% -1.90% β-isomer

in accord with OECD guideline 416 2-generation study - animals were exposed by inhalation via whole body exposure for 6 h/day, 5 days/wk prior to mating and 6 h/day, 7 days/wk during mating, gestation and lactation - breeding of the P1 adults P2 adults (i.e., 30 F1b weanlings/sex/group; first exposed on PND 28) commenced after ~10 wks of treatment; each female was placed with a male from the same exposure group (1:1 mating); P1 rats were mated twice to produce F1a and F1b litters; P2 adults produced F2 litters - maternal rats were not exposed from day 20 of gestation through day 4 post-partum

parental NOAEL–300 ppm; F1 and F2 NOAEL–1000 ppm - toxicity in high dose P1 and P2 animals was evidenced primarily as an increased incidence of sedation for several weeks early in the exposure regimen and significant decreases in body wts; decreased body wts persisted throughout the pre-breeding, gestation and lactation phases of the study - lengthened estrous cycles, decreased fertility, decreased ovary wts and an increased incidence of ovarian atrophy was observed in high-dose P1 and P2 females - no treatment-related differences in sperm counts or motility were observed among P1 or P2 adult males - neonatal effects observed in the high-dose group consisted of decreased pup body wts, reduced pup survival and litter size, increased time to vaginal opening or preputial separation, and histopathologic observations in the liver and thymus of weanling rats; these neonatal effects were considered secondary to maternal toxicity - mild parental toxicity was evidenced in the mid-dose group by slightly decreased pre-mating body weights among P1 and P2 females, but was not accompanied by any statistically significant effects on parental reproduction or neonatal survival, growth or development - there were no treatment-related parental or neonatal effects in the low dose group

28,31

read across to Propylene Glycol Butyl Ether 1-(2-butoxy-1-methylethoxy)-propan-2-ol

see read across for PPG-3 Butyl Ether9,29,31

Methoxyisopropanol see read across for PPG-3 Butyl Ether29,31 Abbreviations: CHO – Chinese hamster ovary; CMC – carboxymethylcellulose; DMSO – dimethyl sulfoxide; LOAEL – lowest-observable adverse effect level; MFO - mixed function oxidase; NOAEL – no-observed adverse effect level; NOEL – no-observed-effect level; NZW – New Zealand White; OECD – Organisation for Economic Co-operation and Development; PII – primary irritation index; RIPT – repeated insult patch test


Table 4. Physical and Chemical Properties Property Value Reference

PPG-3 Butyl Ether Physical Form liquid 14,31 Color colorless 14,31 Odor practically none

mild 14 31

Molecular Wt 248.4 g/mol 14 Density (20ºC) (25ºC)

0.930 g/cm3 0.927 g/cm3

14

Specific Gravity (25/25ºC) 0.930 Viscosity (mm2/s @ 25ºC) 7 14 Vapor Pressure (20ºC – extrapolated) <0.01 mm Hg 14 Vapor Density (air = 1) >6 14 Boiling Point (760 mm Hg) 275ºC 14,31 Water Solubility (25ºC) 40.2 g/l 14 log Pow 1.9 14,31

Propylene Glycol Butyl Ether Physical Form clear liquid 29,42 Color colorless 29,42 Molecular Wt. 132.23 42 Density (20ºC) (25ºC)

0.88 g/cm3 0.87 g/cm3

29

Relative Density (water =1; 25ºC) 0.879 42 Viscosity (25ºC) 2.9 mm2/s 42 Vapor Pressure 0.6 mm Hg (20°C)

1.40 mm Hg (25ºC) 43 42

Relative Vapor Density (air = 1) 4.55 42 Melting Point below -75°C 42 Boiling Point 171°C 42 Solubility 6 g/100 ml water (moderate) 42 log Pow 1.2 ()experimental)

1.15 (calculated) 29 42

Buteth-3 Physical Form clear crystalline substance 15 Vapor Pressure (25ºC) 0.0025 mm Hg 15 Solubility water soluble 15

Polypropylene Glycol Butyl Ether, undefined Physical Form liquid 28 Color brown 28 Density (20ºC) 0.949 g/cm3 28 Viscosity (20ºC) (40ºC)

19 mPa·s 16 mPa·s

28

Vapor Pressure (20ºC) 0.0006 mm Hg 28 Melting Point < -20ºC 28 Boiling Point ( ~760 mm Hg) 306ºC 28 Solubility (solvent in water @ 25ºC) 42.3 g/l; very soluble 28 log Pow (28°C) 1.18 – 4.37 28


Table 5. Frequency and concentration of use of previously reviewed butyl polyoxyalkylene ethers according to duration and exposure16-18 # of Uses Max Conc of Use (%) # of Uses Max Conc of Use (%) PPG-9-Buteth-12 PPG-12-Buteth-16 2016 1997 2015 1995; 1999# 2016 1997 2015 1995; 1999# Totals* 2 2 NR NR 340 53 0.001-2 0.5-31 Duration of Use Leave-On 0 0 NR NR 7 15 0.15-1 0.5-31 Rinse-Off 0 0 NR NR 328 16 0.0001-2 0.6-4 Diluted for (Bath) Use 2 2 NR NR 5 22 0.8-1.3 0.6-0.7 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; 4a 10a; 1b 0.53; 0.5a 0.5-31a Incidental Inhalation-Powder NR NR NR NR NR 1b NR 1

Dermal Contact 2 2 NR NR 295 34 0.15-1.3 0.5-1 Deodorant (underarm) NR NR NR NR NR NR NR NR Hair - Non-Coloring NR NR NR NR 43 18 0.0001-2 1-31 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 288 27 0.8-1.3 0.6-0.7 Baby Products NR NR NR NR 1 1 NR NR PPG-26-Buteth-26 PPG-28-Buteth-35 2016 1997 2015 1995; 1999# 2016 1997 2015 1995; 1999# Totals* 1091 13 0.000025-8 NR 9 10 NR 1 Duration of Use Leave-On 660 7 0.000025-8 NR 6 1 NR NR Rinse-Off 422 6 0.01-8 NR 3 9 NR 1 Diluted for (Bath) Use 9 0 0.025 NR NR NR NR NR Exposure Type Eye Area 25 NR 0.002-3.6 NR NR NR NR NR Incidental Ingestion 1 NR NR NR NR NR NR NR Incidental Inhalation-Spray 396; 92a; 100b 5a; 1b 0.000025-6.2;

0.06-1.8a NR 5a NR NR NR

Incidental Inhalation-Powder 1; 100b NR 8c NR NR NR NR NR Dermal Contact 986 13 0.000025-8 NR 4 3 NR NR Deodorant (underarm) 8a 1a spray: 0.099 NR 1a NR NR NR Hair - Non-Coloring 96 NR 0.0001-8 NR 5 7 NR 1 Hair-Coloring 2 NR 0.055-0.9 NR NR NR NR NR Nail NR NR NR NR NR NR NR NR Mucous Membrane 351 2 0.01-2 NR NR 1 NR NR Baby Products 3 NR 0.9 NR NR NR NR NR PPG-2 Butyl Ether PPG-14 Butyl Ether 2016 1998 2015 1998 2016 1998 2015 1998 Totals* 6 1 2-8 ** 50 45 0.05-17.5 ** Duration of Use Leave-On 1 1 2 ** 35 16 1-17.5 ** Rinse-Off 5 NR 3-8 ** 15 29 0.05-8 ** 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; 1a; 2b 9; 4a; 1b 1-10 ** Incidental Inhalation-Powder NR NR NR ** 2b 1b 4-4.5c ** Dermal Contact 4 NR 2-8 ** 50 45 1-17.5 ** Deodorant (underarm) NR NR NR ** 24a 2a 6-17.5 ** Hair - Non-Coloring NR NR NR ** NR NR 0.05-8 ** Hair-Coloring 2 NR 5 ** NR NR NR ** Nail NR 1 NR ** NR NR NR ** Mucous Membrane 3 NR NR ** 15 29 NR ** Baby Products NR NR NR ** NR NR 0.05 **


Table 5. Frequency and concentration of use of previously reviewed butyl polyoxyalkylene ethers according to duration and exposure16-18 # of Uses Max Conc of Use (%) # of Uses Max Conc of Use (%) PPG-16-Butyl Ether PPG-18 Butyl Ether 2016 1998 2015 1998 2016 1998 2015 1998 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 2016 1998 2015 1998 2016 1998 2015 1998 Totals* 1 6 1-10 ** 13 46 0.75-73.5 ** Duration of Use Leave-On NR 6 1-10 ** 6 7 0.75-71 ** Rinse-Off 1 NR NR ** 7 39 2-73.5 ** 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 5; 1a 2-2.1; 10a ** 6a 6a 0.75-10; 7-23a ** Incidental Inhalation-Powder NR NR NR ** NR NR NR ** Dermal Contact 1 6 1-2.1 ** NR 1 NR ** Deodorant (underarm) NR NR NR ** NR NR NR ** Hair - Non-Coloring NR NR 10 ** 6 6 0.75-71 ** Hair-Coloring NR NR NR ** 7 39 73.5 ** 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 2016 1998 2015 1998 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 23a ** 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


Table 6. Frequency (2016) and concentration of use (2015) of previously unreviewed butyl polyoxyalkylene ethers # of Uses16 Max Conc of Use (%)19 # of Uses16 Max Conc of Use (%)19 # of Uses16 Max Conc of Use (%)19 PPG-5-Buteth-5 PPG-7-Buteth-4 PPG-7-Buteth-10 Totals* NR 0.05-0.5 NR 0.1-4 1 0.023 Duration of Use Leave-On NR 0.05-0.5 NR NR 1 0.023 Rinse-Off NR 0.05-0.2 NR 0.1-4 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; 0.5a NR NR NR NR Incidental Inhalation-Powder NR 0.05b 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 0.05-0.5 NR 0.1 1 0.023 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-33-Buteth-45 Totals* 1 2-6.2 NR 1.3-2 5 0.03 Duration of Use Leave-On 1 2-6.2 NR 2 NR NR Rinse Off NR 2 NR 1.3 5 0.03 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 1a NR NR 2 NR NR Incidental Inhalation-Powder NR 6.2b NR NR NR NR Dermal Contact 1 2-6.2 NR 1.3 NR NR Deodorant (underarm) NR NR NR NR NR NR Hair - Non-Coloring NR NR NR 2 5 0.03 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-38-Buteth-37 Buteth-3 Totals* 2 0.4-0.8 433 0.00043-0.33 Duration of Use Leave-On NR 0.8 48 0.0005-0.33 Rinse-Off 2 0.4-0.8 356 0.00043-0.33 Diluted for (Bath) Use NR NR 29 0.065-0.33 Exposure Type Eye Area NR NR NR NR Incidental Ingestion NR NR NR NR Incidental Inhalation-Spray NR NR 6; 32a; 6c 0.065-0.13; 0.065a Incidental Inhalation-Powder NR NR 1; 6c 0.065b Dermal Contact NR NR 354 0.00043-0.33 Deodorant (underarm) NR NR NR NR Hair - Non-Coloring NR 0.8 17 0.0005-0.33 Hair-Coloring 2 0.4 61 0.02-0.1 Nail NR NR 1 0.33 Mucous Membrane NR NR 307 0.00043-0.33 Baby Products 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


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-20-Buteth-30

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 con-sumption when used as boiler water additives

21CFR173.310

n-butoxypoly(oxyethylene)-poly(oxypropylene)glycol; viscosity range of 4850-5350

secondary direct food additive permitted in food for human con-sumption when used as a defoaming agent in processing beet sugar

21CFR173.340

butoxy polyethylene polypropylene glycol; mol. wt. 900-4200 Da indirect food additive permitted in adhesives 21CFR175.105 polyoxybutylene-polyoxypropylene-polyoxyethylene glycol; minimum mol. wt. 3700

indirect food additive permitted as a defoaming agent used in coatings

21CFR176.200

butoxy polyethylene polypropylene glycol; mol. wt. 900-4200 Da indirect food additive permitted as a defoaming agent used in the manufacture of paper and paperboard

21CFR176.210

[alpha]-butyl-omega-hydroxypoly(oxyethylene) poly(oxypropyl-ene) produced by random condensation of a 1:1 mixture by wt of ethylene oxide and propylene oxide with butanol; minimum mol. wt. 1500 Da (CAS No. 9038-95-3)

indirect food additive permitted for use in surface lubricants with incidental food contact; addition to food not to exceed 10 ppm

21CFR178.3570

[alpha]-butyl-omega-hydroxypoly(oxypropylene); minimum mol. wt. 1500 Da (CAS No. 9003-13-8)

[alpha]-Butyl-[omega]-hydroxypoly (oxyethylene)-poly (oxy-propylene) (CAS No. 9038-95-3), produced by random conden-sation of a 1:1 mixture by weight of ethylene oxide and propyl-ene oxide with butanol; minimum mol. wt. of 1000 Da

indirect food additive permitted for use in surface lubricants used in the manufacture of metallic articles.

21CFR178.3910

oxirane, methyl-, polymer with oxirane, monobutyl ether residues resulting from the use of the polymer as an inert ingredi-ent in a pesticide chemical formulation, including antimicrobial pesticide chemical formulations, are exempted from the require-ment of a tolerance under FFDCA section 408, if such use is in accordance with good agricultural or manufacturing practices

40CFR180.960

Abbreviations: FFDCA - Federal Food, Drug, and Cosmetic Act ; mol. wt. – molecular weight


Table 9. Acute Toxicity Studies Ingredient Animals No./Group Vehicle Concentration/Dose/Procedure Results Reference

DERMAL Buteth-3 rats not specified not specified details not provided LD50 3.5 g/kg 15

PPG Butyl Ether, undefined*

Fischer344 rats 5/sex none in accord with OECD guideline 402 2 g/kg 24-h application using an occlusive 2” x 3” patch (10% of body area)

LD50 >2 g/kg bw; no animals died; no signs of gross toxicity, dermal irri-tation, adverse toxicologic effects, or abnormal behavior

28

Propylene Glycol Butyl Ether

Wistar rats 5/sex none in accord with OECD Guideline 402 2 g/kg bw 24-h semi-occlusive patch

LD50 >2 g/kg 9,29,30


NZW rabbits 4 males none in accord with OECD Guideline 402 24-h occlusive patch

LD50 1.4 g/kg (estimated) 29


NZW rabbits 4 males none in accord with OECD Guideline 402 24-h occlusive patch


ORAL Buteth-3 rats not specified not specified details not provided LD50 6.6 g/kg 15 PPG Butyl Ether, undefined

Fisher rats 3 female none in accord with OECD Guideline 423 gavage study; 0.3 (2 groups) or 2.0 g/kg bw

LD50 between 0.3 and 2 g/kg bw 2/3 high dose animals died; 0/6 low dose animals died

28


Wistar rats 5/sex none in accord with OECD Guideline 401 1.8, 2.4, 3.2 g/kg bw single dose by gavage

LD50 3.3 g/kg (calculated) 1 female of the mid dose group and 4 females and 1 male of the high dose group died

9,29


Wistar rats 5/sex none in accord with OECD Guideline 401 single dose by gavage



Wistar rats 6/sex CMC in accord with OECD Guideline 401 2 g/kg ; single dose by gavage

LD50 >2 g/kg 29

INHALATION Propylene Glycol Butyl Ether

Fischer 344 rats 5/sex none in accord with OECD Guideline 403 651 pp; 4-h whole-body exposure

LC50 >651 ppm 9,29


rats 6 none in accord with OECD Guideline 403 saturated vapor; 8-h whole-body exposure

no mortality 29

Abbreviations: CMC – carboxymethylcellulose; NZW – New Zealand White; OECD – Organisation for Economic Co-operation and Development *For reference in all tables: Poly[oxy(methyl-1,2-ethanediyl)],α-butyl-ω-hydroxy- (also identified as Dowanol™ TPnB-H Glycol Ether)


Table 10. Short-Term and Subchronic Toxicity Studies

Ingredient Animals/Group Study Duration Vehicle Dose Procedure Results Reference SHORT-TERM TOXICITY STUDIES

Dermal Buteth-3 (99.9% pure)

5 NZW rabbits/sex

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 were used to prevent ingestion during dosing; the test sites were rinsed following dosing the animals were killed within 1 day of termination of dosing

there were no clinical signs of toxicity, and no effect on body wt gains; no mortality slight erythema and edema were observed starting at day 6 and day 7 respectively; both were reported in all test animals as of day 11; desquamation was observed in 1-8 animals on days 10-17; fissuring was reported in 3-5 animals on days 8-16; no signs of irritation were observed in controls there were no treatment-related effects on hematol-ogy or clinical chemistry parameters no gross lesions were observed 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

27


5 NZW rabbits/sex

4 wks 50/50 ethanol/ water

0, 0.569, 5.69, and 56.9%; 2 ml/kg

open 7-h applications were made 5 days/wk for 4 wks to clipped abraded skin; collars were used to prevent ingestion

the mid-dose produced slight erythema (6 animals),the high-dose resulted in moderate ery-thema and desquamation (n=10), slight edema (n=9) and atonia (n=5), and slight (n=6) to moder-ate (n=4) fissuring there were no clinical signs of toxicity , and there were no changes in body, liver, or kidney wts

32


5 NZW rabbits/sex

28 days distilled water

0, 50,and 100%; 2 ml/kg open 7-h applications were made 5 days/wk for 4 wks to clipped abraded skin; collars were used to prevent ingestion

no clinical, gross, or microscopic signs of toxicity - slight to moderate (low dose group) and slight to severe (high doses group) erythema, slight atonia, and slight desquamation ; there were no observa-tions of edema, fissuring, eschar, or exfoliation

33

Oral PPG Butyl Ether, undefined

12 Crj: CD(SD rats/sex

46 day, males 53 days, females

CMC 0, 20, 100, or 500 mg/kg bw/day

in accord with OECD Guideline 422 (combined repeated dose toxicity study with the reproduction /develop-mental toxicity screening test) - males were dosed daily by gavage for 14 days prior to mating and continuing throughout mating for 32 days - females were dosed once daily for 14 days prior to mating, and continuing through breeding (2 wks), gestation (3 wks), and lactation (4 days)

NOEL – 100 mg/kg bw/day, for clinical observa-tions, higher absolute and relative liver wts, and an increased incidence of liver and thyroid gland hypertrophy 500 mg/kg/day: treatment-related transient clinical observations were observed in males and females during all phases of the study and included 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 there were not significant effects on body wt or body wt gains, feed consumption, hematology, clinical chemistry, urinalysis

28


2 Sprague-Dawley rats/sex

8 days propylene glycol

0, 200, 500, and 1000 mg/kg bw

in accord with OECD Guideline 407 dosed by gavage 1x daily

1 mid-dose male and 1 high-dose female died 29


6 Sprague-Dawley rats/sex

14 days propylene glycol

0, 100, 200, and 400 mg/kg bw

in accord with OECD Guideline 407 dosed by gavage 1x daily

NOAEL and LOAEL – 400 mg/kg bw no signs of toxicity; no effect of body weights, organ weights, hematology or clinical chemistry

9,29,36



Ingredient Animals/Group Study Duration Vehicle Dose Procedure Results Reference Inhalation

Propylene Glycol Butyl Ether (98.8% pure)

main study: 10 Fischer 344 and 5 Sprague-Daw-ley rats/sex recovery: addi-tional 10 sex/ strain control and high dose

11 days none 0, 10, 100, 300, and 600 ppm (equivalent to 0, 270, 1081, and 3785 mg/m3, respectively; mean nominal concentrations of 13.6, 102, 312, and 735 ppm, respectively)

in accord with OECD Guideline 412 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

NOAEL 600 ppm F344 rats: statistically significant increase in absolute and relative liver (to body and to brain) weights (600 ppm males) and relative liver to body weights (600 ppm females) without microscopic changes; low incidence of mild eye lesions (300 and 600 ppm groups) Sprague Dawley rats: no exposure-related effects

29,43


5 Fischer 344 rats/sex

2 wks none 0, 50, 200, and 700 ppm (equivalent to 0, 270, 1081, and 3785 mg/m3, respectively)

in accord with OECD Guideline 412 9 whole body exposure; 6 h/day, 5 days/wk

NOAEL and LOAEL >700 ppm slightly increased relative liver weight in high dose males and females without microscopic effects

9,29,37


13 exposures 600 ppm exposed 6 h/day, 5 days/wk increased liver weights without microscopic changes (females)

9

SUBCHRONIC TOXICITY STUDIES Dermal


10 Wistar rats/sex 13 wks propylene glycol

0, 88, 264, 880 mg/kg in accord with OECD Guideline 411 1 open 24-h application/day, 5 days/wk; collars were used to prevent grooming

NOAEL – 880 mg/kg bw irritation was observed at all application sites, in-cluding controls; focal necrosis of the epidermis, crust formation, mild inflammatory changes and acanthosis were observed; difference in severity between treated and control animals was not significant no clinical, gross, or microscopic signs of toxicity were observed

9,29,34


5 NZW rabbits/sex

91 days water 2 ml/kg bw in accord with OECD Guideline 411 1 open 7-h application/day, 5 days/wk; collars were used to prevent grooming

NOEL – 1.76 mg/kg bw/day mild to moderate irritation at the application site no clinical signs of toxicity

29


5 NZW rabbits/sex

13 wks 50/50 ethanol/ water

0, 10, 100, or 100 mg/kg bw/day; 2 ml/kg bw

in accord with OECD Guideline 411 1 7-h application/day, 5 days/wk; collars were used to prevent grooming

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 was observed in the mid and high dose groups; in the high dose group, dosing pro-duced severe erythema, slight to moderate edema, slight to moderate atonia, moderate desquamation, and slight to moderate fissuring. – the study authors considered skin lesions to be a direct, local effect from the solvents and the clipping procedure. no clinical signs of toxicity

9


5 NZW rabbits/sex

91 days 50/50 ethanol/ water

0, 0.569, 5.69, and 56.9 2 ml/kg

open 7-h applications were made to intact skin of the back 5 days for 13 wks; collars were used to prevent grooming

- slight erythema and severe erythema were observed in the mid- and high-dose groups, respectively -there were no significant differences in body wt parameters or absolute organ or relative organ wts of the test animals when compared to the vehicle control group

35



Ingredient Animals/Group Study Duration Vehicle Dose Procedure Results Reference Oral

PPG-3 Butyl Ether 10 F344 rats/sex 13 wks none 0, 100, 350, or 1000 mg/kg bw administered in drinking water Histopathological and organ weight alterations of liver and kidney (males) and liver (females) NOAEL – 350 mg/kg bw; LOAEL – 1000 mg/kg bw

25

Propylene Glycol Butyl Ether (99.4% pure)

10 Fischer 344 rats/sex

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 were given untreated water for 4 wks following dosing

NOAEL – 350 mg/kg bw; LOAEL – 1000 mg/kg - absolute and relative liver weights were increased in high dose males ad absolute and relative kidney weights were increased in high dose females with no accompanying histopathology - no changes were observed in organs selected for examination, including the testes

9,29

Abbreviations: CMC – carboxymethylcellulose; LOAEL – lowest-observed adverse effect level; NOAEL – no-observed adverse effect level; NOEL – no-observed effect level; NZW – New Zealand White Table 11. Developmental and Reproductive Toxicity Studies

Test Article Animals/Group Vehicle Dose/Concentration Procedure Results Reference DERMAL 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

maternal and developmental NOEL - > 1 ml/kg local skin reactions were observed in all treated animals; there were no signs of maternal toxicity No reproductive or teratogenic effects

13

Propylene Glycol Butyl Ether (>98% pure)

25 gravid Wistar rats propylene glycol (test article was provided as 2 mixtures vehicle at ratios 12:60 and 40:60)

0, 0.3 and 1.0 ml/kg bw/day (equivalent to 0, 264, and 880 mg/kg bw/day)

in accord with OECD Guideline 414 open applications (20 cm2) were made on days 6-16 of gestation; collars were used to prevent ingestion; animals were killed on day 21 of gestation

NOAEL for maternal toxicity, embryotoxicity, and teratogenicity – 880 mg/kg/day Not embryotoxic, fetotoxic, or teratogenic Minor skin reactions were 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 were comparable for test and control groups. No test-article related visceral and skeletal malformations, anomalies or variants

9,13,28

Propylene Glycol Butyl Ether (100% pure)

gravid NZW rabbits; 19/test group, 17 control

water 0, 10, 40, and 100 mg/kg bw/day

in accord with OECD Guideline 414 6-h applications were made 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

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 the other groups

9,13,31

ORAL PPG-Butyl Ethers, undefined

12 Crj: CD(SD)/sex

CMC 0, 20, 100, or 500 mg/kg bw/day

combined repeated dose toxicity study with the reproduction /developmental toxicity screening test (described previously in Table 10)

no indication of reproductive toxicity at any dose; no adverse effects on prenatal/early neo-natal growth and survival of the offspring. NOEL for reproductive effects - 500 mg/kg/ day

28


Table 11. Developmental and Reproductive Toxicity Studies

Test Article Animals/Group Vehicle Dose/Concentration Procedure Results Reference Buteth-3 10 gravid rats/group water 0, 250, or 1000 mg/kg animals were dosed by gavage on days 7-16

of gestation 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

27

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 Table 12. Genotoxicity studies Test Article Concentration/Vehicle Procedure Test System Results Reference

IN VITRO PPG-Butyl Ether, undefined 1.5-5000 µg/plate, +/-

metabolic activation in accord with OECD guideline 471 Ames test; negative and positive controls were included

S. typhimurium TA1535, TA1537, TA98, TA100 Escherichia coli WP2 uvr A


28

PPG-Butyl Ether, undefined 78.1-5000 µg/ml with, 39.1- 5000 µg/ml with-out, metabolic activation

in accord with OECD guideline 473 mammalian chromosomal aberration assay (4 h exposure) ; negative and positive controls

rat lymphocytes negative controls gave expected results

28

PPG-Butyl Ether, undefined 500-2500 µg/ml +/- activation (initial assay) 1400-2400 µg/ml with and 1000-2000 µg/ml without activation

in accord with OECD guideline 476 mammalian cell mutation assay; negative and positive controls

CHO cells negative controls gave expected results

28

Propylene Glycol Butyl Ether 1.0-20 µl/plate in DMSO Ames test Salmonella typhimurium strains TA98, TA100, TA1535, TA1537, TA1538; solvent and appropriate positive controls were used

negative 38


0-4500 µg/ml with and of 0-6000 µg/ml without metabolic activation in culture medium

mammalian chromosome aberration assay, in accord with OECD Guideline 473

CHO cells negative 9,29

Propylene Glycol Butyl Ether 500, 1667, and 5000 µg/ml with and without metabolic activation in culture medium

mammalian chromosome aberration assay, in accord with OECD Guideline 473

CHO cells negative 39

Propylene Glycol Butyl Ether dose-range finding study: 0.005 – 100 µl/ml in 50% solution of 95% ethanol

mouse lymphoma cell assay, with and without metabolic activation

dose-range finding study: no growth with ≥5.0 µl/ml

40

main study: 0.5 – 5.0 µl/ ml in 50% solution of 95% ethanol

T5178Y TK+/- lymphoma cells main study: negative results

Propylene Glycol Butyl Ether 0-6000 µg/ml mouse lymphoma cell assay, with and without metabolic activation, in accord with OECD Guideline 476

T5178Y TK+/- lymphoma cells negative 9

Propylene Glycol Butyl Ether 0.01-0.80 µl/ml in ethanol/water (50:50)

UDS assay; appropriate negative and positive controls were used

primary rat hepatocytes negative doses >0.65 µl/ml wee too toxic to score

41


Table 12. Genotoxicity studies Test Article Concentration/Vehicle Procedure Test System Results Reference Propylene Glycol Butyl Ether 0-6000 µg/ml in culture

medium UDS assay, with and without metabolic activation, in accord with OECD Guideline 482

primary rat hepatocytes negative 9

Abbreviations: CHO – Chinese hamster ovary; DMSO – dimethyl sulfoxide; OECD – Organisation for Economic Co-operation and Development; UDS – unscheduled DNA synthesis Table 13. Dermal irritation and sensitization studies Test Article Concentration/Dose Test Population Procedure Results Reference

In Vitro PPG-Butyl Ether, undefined EpiDermTM study to evaluate skin corrosivity classified as non-corrosive; mean tissue viability following

the 3 min and 1 h exposure periods was 89.2% and 92.6%, respectively

28

ANIMAL Irritation

Propylene Glycol Butyl Ether 25, 50, and 75% in water; 0.5 ml

3 female NZW rabbits in accord with OECD Guideline 404 semi-occlusive 4 h patch applied to 6 cm2 area of clipped unabraded skin

25%: non-irritating; PDII - 0 no significant irritation was observed 50%: slightly irritating; PDII – 0.8 observations included very slight erythema in 3 animals, edema in 1 animal; all resolved by day 7 75%: moderately irritating; PDII –2.5 observations included well-defined erythema in 2 animals; eschar in 1 animal; very slight edema in 3 animals; all resolved by day 7

9,29,44

Propylene Glycol Butyl Ether undiluted; 0.5 ml 3 female NZW rabbits in accord with OECD Guideline 404 semi-occlusive 4 h patch applied to 6 cm2 area of clipped unabraded skin

moderately irritating; PDII – 4; erythema/eschar 2.66, edema – 1.33 on day 1, eschar formation was observed in 1 animal; this mostly resolved by day 14, except for chronic dermal inflammation on a small area well defined erythema and slight edema were observed, with some scaliness , were observed in the other 2 rabbits on days 2 and 3

9,29,45

Propylene Glycol Butyl Ether undiluted; 0.5 ml 3 NZW rabbits in accord with OECD Guideline 404, EU Method B.4, and EPA OPPTS 870.2500 semi-occlusive 4 h patch applied to 2.5 cm2 area of clipped unabraded skin

not irritating mean 24-72 h erythema score – 1.6/4; erythema scores of 2 in all animals at 1and 24h, 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

29

Propylene Glycol Butyl Ether undiluted; 0.01 ml 5 albino rabbits in accord with OECD Guideline 404 open 24 h application applied to clipped skin

irritating PDII – 2/10

29

Propylene Glycol Butyl Ether undiluted; 0.01 ml 5 albino rabbits in accord with OECD Guideline 404 open 24 h application applied to clipped skin

irritating PDII –3/10

29

Propylene Glycol Butyl Ether (purity >98%)

100%, 5, 10, and 50% in propylene glycol

Hartley guinea pigs, # not stated

preliminary dose-range finding study for a sensitization test minimal irritation with undiluted material; no irritation at lower concentrations

9


Table 13. Dermal irritation and sensitization studies Test Article Concentration/Dose Test Population Procedure Results Reference

Sensitization Propylene Glycol Butyl Ether (purity >98%)

induction: 80% challenge: 40% 0.3 ml vehicle – propylene glycol

Hartley guinea pigs 10/sex - test and 5/sex - control

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

non-sensitizing and non-irritating 9,29,46

HUMAN Sensitization

hair styling wax containing 71% PPG-40 Butyl Ether

applied neat; 0.1 – 0.15 g ~25-38 µg/cm2

48 subjects RIPT; induction consisted of nine 24-h semi-occlusive patches (2 cm2) applied over a 3 wk period - challenge was performed after a 2-wk non-treatment period at a previously unpatched site

not an irritant or a sensitizer no reactions were observed during induction or at challenge

47

PPG-40 Butyl Ether undiluted; 0.2 ml 199 subjects RIPT; induction consisted of one 24-h occlusive patches (2 cm2) applied over a 3 wk period - challenge was performed after a 2-wk non-treatment period at a previously unpatched site

not a sensitizer 48

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 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 870.2400 eyes were scored after 24 h contralateral eye served as a control

irritating at 24 h, the mean scores were: 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

29

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

not irritating according to EU criteria mean 24-72 h scores were: 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

29

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

moderately irritating; 1-h Draize score – 34/110; classifiable as an “eye irritant” according to European criteria mean 24-72 h scores were: 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

9,49

Propylene Glycol Butyl Ether undiluted; 0.1 ml rabbits; # not specified in accord with OECD Guideline 405 eyes were not rinsed

not irritating according to EU criteria corneal opacity was 7/10

29

Abbreviations: NZW – New Zealand White; OECD – Organisation for Economic Co-operation and Development


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):39-52. http://www.cir-safety.org/ingredients.

2. Andersen FA. Final Report on the Safety Assessment of PPG-40 Butyl Ether. J Am Coll Toxicol. 1993;12(3):257-259. http://www.cir-safety.org/ingredients.

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):47-67. http://www.cir-safety.org/ingredients.

4. 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-35. 2000. This report is avialbleon the CIR website http://www.cir-safety.org/ingredients.

5. Nikitakis J and Lange B. International Cosmetic Ingredient Dictionary and Handbook. 16 ed. Washington, D.C.: Personal Care Products Council, 2016.

6. 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):169-244.

7. 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. 2013. Final report available from CIR http://www.cir-safety.org/ingredients.

8. European Chemicals Agency (ECHA). Information on Chemicals [pamphlet]. 2016.

9. Organisation for Economic Co-operation and Development (OECD). Propylene Glycol Ethers; Screening Information Data Set (SIDS) Initial Assessment Report for SAIM 17. http://www.inchem.org/documents/sids/sids/pges.pdf. Last Updated 2003. Date Accessed 6-20-2016.

10. Andersen FA. Final Report on the Safety Assessment of Methoxyisopropanol and Methyoxyisopropanol Acetate as Used in Cosmetics. Int J Toxicol. 2008;27(Suppl 2):25-39.

11. Robinson V, Bergfeld WF, Belsito DV, Klaassen CD, Marks JG Jr, Shank RC, Slaga TJ, Snyder PW, and Andersen FA. Final Report on the Safety Assessment of PPG-2 Methyl Ether, PPG-3 Metyl Ether, and PPG-2 Methyl Ether Acetate. Int J Toxicol. 2009;28(6S):162S-174S.

12. 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):2714-2721.

13. Spencer PJ. New toxicity data for the propylene glycol ethers - a commitment to public health and safety. Toxicology Letters. 2005;156(1):181-188.

14. Dow. Technical Data Sheet: Dowanol TPnB (PPG-3 Butyl Ether). http://msdssearch.dow.com/PublishedLiteratureDOWCOM/dh_08ad/0901b803808ad696.pdf?filepath=oxysolvents/pdfs/noreg/110-00621.pdf&fromPage=GetDoc. Last Updated 2012. Date Accessed 5-10-2016.

15. Environmental Protection Agency (EPA). Triethylene glycol monobutyl ether (CASRN 143-22-6). https://cfpub.epa.gov/ncea/iris/iris_documents/documents/subst/0639_summary.pdf. Last Updated 1992. Date Accessed 5-12-2016.

16. Food and Drug Administration (FDA). Frequency of use of cosmetic ingredients. FDA Database. 2016.

17. Personal Care Products Council. 8-22-2016. Concentration of Use: Propylene Glycol Butyl Ether. Unpublished data submitted by Personal Care Products Council.

18. Personal Care Products Council. 7-11-2016. Updated Concentration of Use by FDA Product Category: Butyl Polyoxyalkylene Ethers. Unpublished data submitted by Personal Care Products Council.







http://www.inchem.org/documents/sids/sids/pges.pdf

http://msdssearch.dow.com/PublishedLiteratureDOWCOM/dh_08ad/0901b803808ad696.pdf?filepath=oxysolvents/pdfs/noreg/110-00621.pdf&fromPage=GetDoc

http://msdssearch.dow.com/PublishedLiteratureDOWCOM/dh_08ad/0901b803808ad696.pdf?filepath=oxysolvents/pdfs/noreg/110-00621.pdf&fromPage=GetDoc

19. Personal Care Products Council. 2016. Updated Concentration of Use by FDA Product Category: Butyl Polyoxyalkylene Ethers. butyl polyoxyalkylene ethers.

20. Johnsen MA. The influence of particle size. Spray Technol Marketing. 2004;14(11):24-27.

21. Rothe H. Special Aspects of Cosmetic Spray Evalulation. 9-26-2011. Unpublished data presented at the 26 September CIR Expert Panel meeting. Washington, D.C.

22. 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):97-104.

23. Bremmer HJ, Prud'homme de Lodder LCH, and Engelen JGM. Cosmetics Fact Sheet: To assess the risks for the consumer; Updated version for ConsExpo 4. 2006. Report No. RIVM 320104001/2006. pp. 1-77.

24. European Commission. CosIng database; following Cosmetic Regulation No. 1223/2009. http://ec.europa.eu/growth/tools-databases/cosing/. Last Updated 2016. Date Accessed 4-7-2016.

25. Anonymous. Draft Interim REL: Tripropylene Glycol n-Butyl Ether (TPnB; CAS #55934-93-5). http://www.arb.ca.gov/consprod/regact/2010ra/tpnb55934935.pdf. Last Updated 2010. Date Accessed 5-11-2016.

26. HERA. Human & Environmental Risk Assessment (HERA) on ingredients of household cleaning products. Propylene Glycol n-Butyl Ether (CAS No. 5131-66-8; 29387-86-8). http://www.heraproject.com/files/41-F-HERA_PnB_RA_Oct2005.pdf. Last Updated 2005. Date Accessed 11-7-2016.

27. 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):507-515.

28. European Chemicals Agency (ECHA). Poly[oxy(methyl-1,2-ethanediyl)],α-butyl-ω-hydroxy- (CAS No. 9003-13-8; EC no. 500-003-1). http://echa.europa.eu/en/registration-dossier/-/registered-dossier/2120. Last Updated 2015. Date Accessed 5-2-2016.

29. European Chemicals Agency (ECHA). 1-Butoxypropan-2-ol (CAS No. 5131-66-8; Propylene Glycol Butyl Ether). http://echa.europa.eu/en/registration-dossier/-/registered-dossier/14287. Last Updated 2015. Date Accessed 6-24-2016.

30. NOTOX. Evaluation of the acute dermal toxicity of Dowanol-PnB (Propylene Glycol n-BUtyl Ether) in the rat. 1987. https://ntrl.ntis.gov/NTRL/. Date Accessed 6-22-2016. NTIS OTS0520760.

31. European Chemicals Agency (ECHA). [(Butoxymethylethoxy)methylethoxy]propan-1-ol (CAS No. 55934-93-5; EC No. 259-910-3 ). http://echa.europa.eu/registration-dossier/-/registered-dossier/13383. Last Updated 2016. Date Accessed 5-11-2016.

32. Hazleton Laboratories America, Inc. 28-Day subchronic percutaneous toxicity test of substance B0964-01 (CAS No. 5131-66-8). 1987. https://ntrl.ntis.gov/NTRL/. Date Accessed 6-22-0016. NTIS OTS0520508.

33. Hazleton Laboratories America, Inc. Final Report: 28-day Subchronic Percutanous Toxicity Study in Rabbits with 81034-02 (CAS No. 5131-66-8). 1987. https://ntrl.ntis.gov/NTRL/. Date Accessed 6-22-2016. Report No. HLA Study No, 297-505. NTIS document OTS0520506.

34. Civo Institutes TNO. Subchronic (13 wk) dermal toxicity study with Propylene Glycol n-Butyl Ether in rats. 1988. https://ntrl.ntis.gov/NTRL/. Date Accessed 6-22-2016. Report No. Study No. 1002. NTIS OTS0520767.

35. Hazleton Laboratories America, Inc. 91-Day subchronic percutaneous toxicity study (CAS No. 5131-66-8). 1987. https://ntrl.ntis.gov/NTRL/. Date Accessed 6-22-2016. NTIS OTS0520507.

36. NOTOX. Assessment of the oral toxicity, including the haemolytic activity, of Dowanol-PnB (Propylene Glycol n-Butyl Ether) in the rat 14-day study. 1987. https://ntrl.ntis.gov/NTRL/. NTIS OTS0520763.

37. Dow Chemical Company. Propylene Glycol n-Butyl Ether: Two-week vapor inhalation study with Fischer 344 rats. 1989. https://ntrl.ntis.gov/NTRL/. Date Accessed 6-22-2016. NTIS OTS0520768.

38. Microbiological Associates. Salmonella/mammalian microsome mutagenesis assay of test substance B0964-01 (1-butoxy-2-propanol; 5131-66-8). 1998. https://ntrl.ntis.gov/NTRL/. Date Accessed 6-22-2016. Report No. Study No. T5294.501. NTIS OTS0520511.


http://ec.europa.eu/growth/tools-databases/cosing/

http://ec.europa.eu/growth/tools-databases/cosing/

http://www.arb.ca.gov/consprod/regact/2010ra/tpnb55934935.pdf

http://www.heraproject.com/files/41-F-HERA_PnB_RA_Oct2005.pdf

http://echa.europa.eu/en/registration-dossier/-/registered-dossier/2120

http://echa.europa.eu/en/registration-dossier/-/registered-dossier/14287

http://echa.europa.eu/registration-dossier/-/registered-dossier/13383

39. Dow Chemical Company. Evaluation of Propylene Glycol-n-Butyl Ether in an in vitro chromosomal assay utilizing Chinese hamster ovary (CHO) cells. 1988. https://ntrl.ntis.gov/NTRL/. Date Accessed 6-22-2016. NTIS OTS0520751.

40. Sitek Research Laboratories. Test for chemical induction of mutation in mammalian cells in culture; the L5178Y +/- mouse lymphoma cells for test substance B0964-01 (butoxypropanol, CAS No. 5131-66-8). 1987. https://ntrl.ntis.gov/NTRL/. Date Accessed 6-22-2016. Report No. Study no. 0048-2400. NTIS OTS00520512.

41. Sitek Research Laboratories. Test for chemical induction of unscheduled DNA synthesis in primary cultures of rat hepatocytes (by autoradiography) of test substance 80964-01 (1-butoyx-2-propanol; CAS No. 5131-66-8). 1986. https://ntrl.ntis.gov/NTRL/. Date Accessed 6-22-2016. Report No. Study No. 0048-5100. NTIS OTS0520510.

42. National Institute for Occupational Health and Safety (NIOSH). International Chemical Safety Card (ICSC) 1614: Propylene Glycol n-Butyl Ether. http://www.cdc.gov/niosh/ipcsneng/neng1614.html. Last Updated 2014. Date Accessed 6-22-2016.

43. Bushy Run Research Center. Propasol® Solvent B: Nine-day vapor inhalation study on rats. 1989. https://ntrl.ntis.gov/NTRL/. Date Accessed 6-22-2016. Report No. BRRC Project No. 87-15-99101; Project Report 51-5. NTIS Document; OTS0557477; pdf pages 1304-1789.

44. 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. 1987. https://ntrl.ntis.gov/NTRL/. Date Accessed 6-22-2016. Report No. 0482/748. NTIS OTS0520761.

45. NOTOX. Assessment of primary skin irritation/corrosion by Dowanol-PnB (Propylene Glycol n-Butyl Ether) in the rabbit. 1987. https://ntrl.ntis.gov/NTRL/. Date Accessed 6-22-2016. NTIS OTS0520762.

46. S.C.K. - C.E.N. Guinea pig sensitization study, modified Buehler method, of Propylene Glcyol n-Butyl Ether. 1987. https://ntrl.ntis.gov/NTRL/. Date Accessed 6-22-2016. Report No. SS87BO1. NTIS OTS0520765.

47. Essex Testing Clinic Inc. 2011. 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. Dow Chemical Company. 1993. Summary of a repeated insult patch test study of PPG-14 Butyl Ether. Unpublished data submitted by Personal Care Products Council.

49. NOTOX. Assessment of acute eye irritation/corrosion of Dowanol-PnB (Propylene Glycol n-Butyl Ether) in the rabbit. 1987. https://ntrl.ntis.gov/NTRL/. Date Accessed 6-22-2016. NTIS OTS0520758.


http://www.cdc.gov/niosh/ipcsneng/neng1614.html

BUTETH-3 01B - Baby Lotions, Oils, Powders, and Creams 1BUTETH-3 02A - Bath Oils, Tablets, and Salts 4BUTETH-3 02B - Bubble Baths 13BUTETH-3 02D - Other Bath Preparations 12BUTETH-3 04A - Cologne and Toilet waters 4BUTETH-3 04E - Other Fragrance Preparation 2BUTETH-3 05A - Hair Conditioner 3BUTETH-3 05F - Shampoos (non-coloring) 10BUTETH-3 05G - Tonics, Dressings, and Other Hair Grooming Aid 4BUTETH-3 06A - Hair Dyes and Colors (all types requiring caution 61BUTETH-3 08G - Other Manicuring Preparations 1BUTETH-3 10A - Bath Soaps and Detergents 32BUTETH-3 10E - Other Personal Cleanliness Products 246BUTETH-3 12A - Cleansing 4BUTETH-3 12C - Face and Neck (exc shave) 2BUTETH-3 12D - Body and Hand (exc shave) 4BUTETH-3 12F - Moisturizing 28BUTETH-3 12J - Other Skin Care Preps 2

PPG-12-BUTETH-16 01A - Baby Shampoos 1PPG-12-BUTETH-16 02B - Bubble Baths 5PPG-12-BUTETH-16 05B - Hair Spray (aerosol fixatives) 1PPG-12-BUTETH-16 05F - Shampoos (non-coloring) 40PPG-12-BUTETH-16 05G - Tonics, Dressings, and Other Hair Grooming Aid 1PPG-12-BUTETH-16 06H - Other Hair Coloring Preparation 2PPG-12-BUTETH-16 10A - Bath Soaps and Detergents 260PPG-12-BUTETH-16 10E - Other Personal Cleanliness Products 23PPG-12-BUTETH-16 12A - Cleansing 2PPG-12-BUTETH-16 12I - Skin Fresheners 1PPG-12-BUTETH-16 12J - Other Skin Care Preps 2PPG-12-BUTETH-16 13B - Indoor Tanning Preparations 2

PPG-15-BUTETH-20 12F - Moisturizing 1

PPG-26-BUTETH-26 01B - Baby Lotions, Oils, Powders, and Creams 1PPG-26-BUTETH-26 01C - Other Baby Products 2PPG-26-BUTETH-26 02B - Bubble Baths 9PPG-26-BUTETH-26 03B - Eyeliner 1PPG-26-BUTETH-26 03C - Eye Shadow 3PPG-26-BUTETH-26 03D - Eye Lotion 3PPG-26-BUTETH-26 03E - Eye Makeup Remover 4PPG-26-BUTETH-26 03F - Mascara 6PPG-26-BUTETH-26 03G - Other Eye Makeup Preparations 8PPG-26-BUTETH-26 04A - Cologne and Toilet waters 196PPG-26-BUTETH-26 04B - Perfumes 26PPG-26-BUTETH-26 04E - Other Fragrance Preparation 161PPG-26-BUTETH-26 05A - Hair Conditioner 6PPG-26-BUTETH-26 05B - Hair Spray (aerosol fixatives) 13PPG-26-BUTETH-26 05F - Shampoos (non-coloring) 17PPG-26-BUTETH-26 05G - Tonics, Dressings, and Other Hair Grooming Aid 43PPG-26-BUTETH-26 05H - Wave Sets 2PPG-26-BUTETH-26 05I - Other Hair Preparations 15PPG-26-BUTETH-26 06D - Hair Shampoos (coloring) 2PPG-26-BUTETH-26 07C - Foundations 1PPG-26-BUTETH-26 07E - Lipstick 1PPG-26-BUTETH-26 07H - Makeup Fixatives 1


PPG-26-BUTETH-26 10A - Bath Soaps and Detergents 222PPG-26-BUTETH-26 10B - Deodorants (underarm) 8PPG-26-BUTETH-26 10E - Other Personal Cleanliness Products 119PPG-26-BUTETH-26 11A - Aftershave Lotion 4PPG-26-BUTETH-26 11G - Other Shaving Preparation Products 1PPG-26-BUTETH-26 12A - Cleansing 40PPG-26-BUTETH-26 12C - Face and Neck (exc shave) 83PPG-26-BUTETH-26 12D - Body and Hand (exc shave) 16PPG-26-BUTETH-26 12E - Foot Powders and Sprays 1PPG-26-BUTETH-26 12F - Moisturizing 24PPG-26-BUTETH-26 12G - Night 2PPG-26-BUTETH-26 12H - Paste Masks (mud packs) 9PPG-26-BUTETH-26 12I - Skin Fresheners 16PPG-26-BUTETH-26 12J - Other Skin Care Preps 18PPG-26-BUTETH-26 13B - Indoor Tanning Preparations 7

PPG-28-BUTETH-35 05G - Tonics, Dressings, and Other Hair Grooming Aid 5PPG-28-BUTETH-35 10B - Deodorants (underarm) 1PPG-28-BUTETH-35 12A - Cleansing 3

PPG-33-BUTETH-45 05F - Shampoos (non-coloring) 5

PPG-38-BUTETH-37 06A - Hair Dyes and Colors (all types requiring caution 1PPG-38-BUTETH-37 06H - Other Hair Coloring Preparation 1

PPG-7-BUTETH-10 05I - Other Hair Preparations 1

PPG-9-BUTETH-12 02D - Other Bath Preparations 2

PPG-14 BUTYL ETHER 03G - Other Eye Makeup Preparations 1PPG-14 BUTYL ETHER 04A - Cologne and Toilet waters 5PPG-14 BUTYL ETHER 04E - Other Fragrance Preparation 1PPG-14 BUTYL ETHER 10B - Deodorants (underarm) 24PPG-14 BUTYL ETHER 10E - Other Personal Cleanliness Products 15PPG-14 BUTYL ETHER 12C - Face and Neck (exc shave) 2PPG-14 BUTYL ETHER 12F - Moisturizing 1PPG-14 BUTYL ETHER 12J - Other Skin Care Preps 1

PPG-2 BUTYL ETHER 03B - Eyeliner 1PPG-2 BUTYL ETHER 06A - Hair Dyes and Colors (all types requiring caution 2PPG-2 BUTYL ETHER 10A - Bath Soaps and Detergents 2PPG-2 BUTYL ETHER 10E - Other Personal Cleanliness Products 1

PPG-33 BUTYL ETHER 12A - Cleansing 1

PPG-40 BUTYL ETHER 05G - Tonics, Dressings, and Other Hair Grooming Aid 6PPG-40 BUTYL ETHER 06A - Hair Dyes and Colors (all types requiring caution 7


Concentration of Use by FDA Product Category – Butyl Polyoxyalkylene Ethers*

PPG-26-Buteth-26 PPG-28-Buteth-35 PPG-12-Buteth-16 PPG-9-Buteth-12 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 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 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-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

Ingredient Product Category Maximum Concentration of Use

PPG-26-Buteth-26 Other baby products Leave-on

0.9%

PPG-26-Buteth-26 Bubble baths 0.025% PPG-26-Buteth-26 Eyeliner 0.06-3.6% PPG-26-Buteth-26 Eye shadow 0.18-3.6% PPG-26-Buteth-26 Eye lotion 0.18-1.5% PPG-26-Buteth-26 Mascara 0.002-0.27% PPG-26-Buteth-26 Other eye makeup preparations 0.06% PPG-26-Buteth-26 Colognes and toilet waters 0.05-2.5% PPG-26-Buteth-26 Perfumes 0.000025-6.2% PPG-26-Buteth-26 Other fragrance preparations 2.3% PPG-26-Buteth-26 Hair conditioners 0.05-8% PPG-26-Buteth-26 Hair spray

Aerosol Pump spray

0.0001% 0.34%

PPG-26-Buteth-26 Shampoos (noncoloring) 0.002-1% PPG-26-Buteth-26 Tonics, dressings and other hair grooming aids 0.06-1.8% PPG-26-Buteth-26 Other hair preparations (noncoloring) 0.16% PPG-26-Buteth-26 Hair dyes and colors 0.055-0.9% PPG-26-Buteth-26 Foundations 1.3% PPG-26-Buteth-26 Bath soaps and detergents 1.2-2% PPG-26-Buteth-26 Deodorants

Pump spray 0.099%

PPG-26-Buteth-26 Other personal cleanliness products 0.01-0.038%


PPG-26-Buteth-26 Aftershave lotions 0.77% PPG-26-Buteth-26 Skin cleansing (cold creams, cleansing lotions,

liquids and pads) 0.025-4.5%

PPG-26-Buteth-26 Face and neck products Not spray Spray

0.001-8% 0.23-0.36%

PPG-26-Buteth-26 Body and hand products Not spray Spray

0.025-1.2% 5.4%

PPG-26-Buteth-26 Foot products Spray

8% 2%

PPG-26-Buteth-26 Moisturizing products Not spray

1.5-8%

PPG-26-Buteth-26 Paste masks and mud packs 0.09-0.56% PPG-26-Buteth-26 Skin fresheners 0.45-2% PPG-26-Buteth-26 Other skin care preparations 0.36-1.7% PPG-12-Buteth-16 Bubble baths 1.3% PPG-12-Buteth-16 Other bath preparations 0.8% PPG-12-Buteth-16 Hair conditioners 0.0001% PPG-12-Buteth-16 Shampoos (noncoloring) 0.05-2% PPG-12-Buteth-16 Tonics, dressings and other hair grooming aids 1% PPG-12-Buteth-16 Hair shampoos (coloring) 0.05% PPG-12-Buteth-16 Bath soaps and detergents 0.8% PPG-12-Buteth-16 Aftershave lotion 0.62% PPG-12-Buteth-16 Shaving cream 1% PPG-12-Buteth-16 Skin cleansing (cold creams, cleansing lotions,

liquids and pads) 1%

PPG-12-Buteth-16 Body and hand products Spray

0.62%

PPG-12-Buteth-16 Foot products Spray

0.53%

PPG-12-Buteth-16 Other skin care preparations Not spray

0.15%

PPG-12-Buteth-16 Indoor tanning preparations 0.5% PPG-2 Butyl Ether Eyeliner 2% PPG-2 Butyl Ether Hair dyes and colors 5% PPG-2 Butyl Ether Skin cleansing (cold creams, cleansing lotions,

liquids and pads) 3-8%

PPG-14 Butyl Ether Baby shampoo 0.05% PPG-14 Butyl Ether Eyeliner 1.9% PPG-14 Butyl Ether Colognes and toilet waters 10% PPG-14 Butyl Ether Other fragrance preparations 1% PPG-14 Butyl Ether Shampoos (noncoloring) 8% PPG-14 Butyl Ether Deodorants

Not spray 6-17.5%

PPG-14 Butyl Ether Aftershave lotion 2%


PPG-14 Butyl Ether Face and neck products Not spray

4-4.5%

PPG-14 Butyl Ether Night products Not spray

5%

PPG-14 Butyl Ether Other skin care preparations 6% PPG-33 Butyl Ether Colognes and toilet water 2% PPG-33 Butyl Ether Other fragrance preparations 2.1% PPG-33 Butyl Ether Tonics, dressings and other hair grooming aids 10% PPG-33 Butyl Ether Other skin care preparations

Leave-on 1%

PPG-40 Butyl Ether Hair sprays Aerosol Pump spray

0.75% 2-10%

PPG-40 Butyl Ether Rinses (noncoloring) 2% PPG-40 Butyl Ether Tonics, dressings and other hair grooming aids

Not spray 7-23% 71%

PPG-40 Butyl Ether Hair tints 73.5% PPG-52 Butyl Ether Hair conditioners 3% PPG-52 Butyl Ether Tonics, dressings and other hair grooming aids 23% Buteth-3 Bubble baths 0.33% Buteth-3 Other bath preparations 0.065% Buteth-3 Colognes and toilet waters 0.13% Buteth-3 Perfumes 0.13% Buteth-3 Hair conditioners 0.001% Buteth-3 Shampoos (noncoloring) 0.33% Buteth-3 Other hair preparations (noncoloring) 0.0005% Buteth-3 Hair dyes and colors 0.1% Buteth-3 Hair shampoos (coloring) 0.02% Buteth-3 Other manicuring preparations 0.33% Buteth-3 Bath soaps and detergents 0.00043-0.33% Buteth-3 Skin cleansing (cold creams, cleansing lotions,

liquids and pads) 0.065%

Buteth-3 Depilatories 0.065% Buteth-3 Body and hand products

Not spray Spray

0.065% 0.065%

Buteth-3 Paste masks and mud packs 0.065% Buteth-3 Other skin care preparations

Rinse-off 0.065%

Buteth-3 Indoor tanning preparations 0.065% PPG-5-Buteth-5 Hair sprays

Pump spray 0.05%

PPG-5-Buteth-5 Permanent waves 0.2% PPG-5-Buteth-5 Shampoos (noncoloring) 0.05% PPG-5-Buteth-5 Tonics, dressings and other hair grooming aids 0.5% PPG-5-Buteth-5 Face and neck products


Not spray 0.05% PPG-7-Buteth-4 Shampoos (noncoloring) 0.1% PPG-7-Buteth-4 Skin cleansing (cold creams, cleansing lotions,

liquids and pads) 4%

PPG-7-Buteth-10 Tonics, dressings and other hair grooming aids Not spray

0.023%

PPG-15-Buteth-20 Skin cleansing (cold creams, cleansing lotions, liquids and pads)

2%

PPG-15-Buteth-20 Face and neck products Not spray

6.2%

PPG-15-Buteth-20 Other skin care preparations 2% PPG-17-Buteth-17 Hair sprays

Pump spray 2%

PPG-17-Buteth-17 Skin cleansing (cold creams, cleansing lotions, liquids and pads)

1.3%

PPG-33-Buteth-45 Shampoos (noncoloring) 0.03% PPG-38-Buteth-37 Other hair preparations (noncoloring) 0.8% PPG-38-Buteth-37 Hair dyes and colors 0.4% *Ingredients included in the title of the table but not found in the table were included in the concentration of use survey, but no uses were reported.

Information collected in 2015 Table prepared October 13, 2015

Updated July 7, 2016: PPG-40 Butyl Ether high concentration hair wax increased from 60.5% to 71%


Personal Care Products Council

Memorandum

TO: Lillian Gill, D.P.A.

Committed to Safety, Quality & Innovation

Director- COSMETIC INGREDIENT REVIEW (CIR)

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

DATE: July 6, 2016

SUBJECT: PPG-14 Butyl Ether

The Dow Chemical Company. 1993. Summary of a repeated insult patch test study ofPPG-14 Butyl Ether.

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


PPG-40 Butyl Ether- UCON Fluid LB-1715 Skin Sensitization Information

The Dow Chemical Company Midland, Michigan 48674

The Cosmetic Ingredient Review panel inquired for skin sensitization data availability for PPG·40

Butyl Ether sold under the Dow trade name UCON™ Fluid lB-1715. This is not the case,

however, we recommend that Human Repeated Insult Patch Test (HRIPT) data from PPG· 14

Butyl Ether family member {CAS: 9003-13-8) be used as read-across. The source substance

{PPG-14 Butyl Ether, UCON' .. Fluid AP) is of lower molecular weight (lower number of repeat

oxypropylene units) than PPG-40 Butyl Ether. The lower MW source substance should present a

worst case for the skin sensitization endpoint and bioavailability. The HRIPT on PPG-14 Butyl

Ether was performed with undiluted material. 199 volunteer subjects completed the study.

Under the conditions employed in this study, there was no evidence of sensitization by the

material. For more detail please see the summary below.

Toxicology information for PPG-14 Butyl Ether

Repeated Insult Patch Study (1993)

Performing Laboratory: TKL Research, Inc. Paramus NJ.

Summary: The test material, applied neat, was evaluated to determine its ability to sensitize the skin of normal volunteer subjects using an occlusive repeated insult patch study.

The entire study extended over a six (G)-week period. It involved three phases: (1) Induction, (2) Rest, and (3) Challenge. Prior to study entry, the subjects were screened to assure that they met the specified inclusion/exclusion criteria. Informed consent from subjects was obtained before study start. Each subject was provided with a schedule of the study activities. They were told to avoid wetting the patches and were asked not to engage in activities that caused excessive perspiration. They were instructed to notify the staff if they experienced any discomfort beyond mild itching and/or observed any adverse changes at the evaluation sites, while on the study or within two (2) weeks of completing the study. Total of 220 volunteer subjects were enrolled in the study and 199 subjects completed the study. To be considered a completed case, a subject must have had six (6) or more applications and subsequent readings during Induction Phase and at least one (1) reading during challenge. Only completed cases were used to assess sensitization.

Procedure: 0.2 ml of test material were applied under occlusive patches (Non-porous, plastic film adhesive bandages with a 2 em x 2 em Webril pad) on the infrascapular area of the subjects' back, either to the right or left of the rn~dline.


The Dow Chemical Company Midland, Michigan 48674

The Induction Phase consisted of nine (9) consecutive applications of the study material and subsequent evaluations of the study sites 24 or 48 hours after patch removal. Prior to application of the patches, the sites were outlined with a skin marker, e.g., gentian violet. The subjects were required to remove the patches approximately 24 hours after application. They returned to the facility at 48-hour intervals to have the sites evaluated and identical patches reapplied. Patches applied on Friday were removed by subjects after 24 hours and sites were evaluated on the following Monday, i.e., 72 hours after patch application. Following the ninth evaluation, the subjects were dismissed for a 14-day rest period.

The Challenge Phase was initiated during the sixth week of the study, with identical patches applied to sites previously unexposed to the study material. These patches were removed by subjects after 24 hours and the sites were graded after additional24-hour and 48-hour periods, i.e., 48 and 72 hours after application. Rechallenge, if required, was to be performed whenever there was evidence of possible sensitization. The Rechallenge would have been conducted on naive sites on the back under both

· occlusive and semi-occlusive conditions approximately one (1) or two (2) weeks after challenge had been completed. Patches would have been applied for 24 hours, the patches removed and the sites evaluated 48, 72 and 96 hours after patch application. ·

Findings: One hundred ninety-nine subjects completed the study. Under the conditions employed in this study, there was no evidence of sensitization by the material.

Procedure: HRIPT Shelanski & Shelanski

GLP: In accordance with Federal regulations and proposed guidelines for good clinical practices.


Personal Care Products Council Committed to Safety, Quality & Innovation

Memorandum

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

FROM: Beth A. Lange, Ph.D. -::pr:::fJ 6 ~

Industry Liaison to the CIR Expert Panel ~ MVl..l&/(t;,yL f DATE: July 11,2016

SUBJECT: PPG-40 Butyl Ether

Essex Testing Clinic, Inc. 2011. Clinical safety evaluation repeated insult patch test (hair styling wax containing 71% PPG-40 Butyl Ether).

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


Essex Testing Clinic, Inc.

FINAL REPORT

CLINICAL SAFETY EVALUATION

REPEATED INSULT PATCH TEST

. . . \ . ' ~ ... :· ·. . ~ . . -

Sponsor

~ ~ . - . ~ .~. ·- . ' . ~ . ~ . . r~ ·~ . . ~I • '.\.

' ·.: L~ ._ L· .. ~~·.: ~-, ....

Sponsor Representative

I • ~ •

1.

- - - ~ - -

Clinical Testing Facility

Essex Testing Clinic, Inc. 799 Bloomfield Avenue

Verona, NJ 07044

Sponsor Code: ETC Panel No.: ETC Entry No.: 20425

Date of Final Report

/IJ ---!o -II

799 Bloomfield Avenue • Verona, NJ 07044 • (973) 857-9541 • Fax# (973) 857-9662


SIGNATURE PAGE

ETC Panel No.: 11261 ETC Entry No.: 20425



Anne mare E. Hollenback, SA Laboratory Manager Study Director

To[ll F. iller, PhD, DABT, BCFE Sptent'itlc Director Principal Investigator

(o Uc} ];QI/ Date

( tt/r/rr Date

Essex Testrng Clinic. Inc. ___________ ~-------


QUALITY ASSURANCE STATEMENT

This study (ETC Panel No.: 11261; ETC Entry No.: 20425) was conducted in accordance with the intent and purpose of Good Clinical Practice regulations described in 21 CFR Part 50 (Protection of Human Subjects- Informed Consent) and the Standard Operating Procedures of Essex Testing Clinic, Inc.

For purposes of this clinical study:

_X_

_x_

Informed Consent was obtained.

Informed Consent was not obtained.

An lAB review was not required.

An lAB review was conducted and approval to conduct the proposed clinical research was granted.

To assure compliance with the study protocol, the Quality Assurance Unit completed an audit of the applicable study records and report. This report is considered a true and accurate reflection of the testing methods and source data.

'/ 0-e::t c-{) I I Date

Essex Testmg Clinic, Inc. ________________ ~---


TABLE OF CONTENTS


1.0 OBJECTIVE ................... .... .. .. .... .. .. .... ........ .... .......... ... .............................. ... 1

2.0 SPONSOR ..... ......................................................... ..................................... 1

2.1 Sponsor Represen1ative .................... ...... .. ............... ... ... .... ... .... ........ 1

3 0 CLINICAL TESTtNG FACILITY ................................. .. ........................... .... 1

4.0 CLINICAL INVESTIGATORS .. .. .. ... .................... .................................... .. .. .. 1

6.0 ETHICS ........................................ ............... ..................... .... .... .................. .. 2 6.1 Ethical Conduct of 1he S1udy .................... .......................... ..... .......... 2

6.2 Subject Information and C·onsent ............................ ........ .. ................ 2

7.0 TEST MATERIAL ........... .. ............................................................................ 2

6.0 TEST SUBJECTS ...................... ........................ .......................................... 2

9.0 TEST PROCEDURE ... .............. ................................................ .... .. ........... .. 3

9. 1 Induction Phase . .. . .. . .. . .. .. .. .. . .. .. .. . . .. ............................................... 3

9.2 Challenge Phase ............................................................ .................. 3

9 3 Data Interpretation ... .. ...... ................................................... .............. 4

10.0 RESULTS AND DISCUSSION ............................ .... ................................... 4

11.0 CONCLUSIONS ..... .. .. .. ....... ... .... .... ............................................................ 4

TABLE 1 -INDIVIDUAL SCORES

Essex Testing Clinic.lnc .. _________________ _




1.0 OBJECTIVE

Page 1 of 4 ETC Panel No.: 11261 ETC Entry No.: 20425

The objective of this study was to determine the irritation and/or sensitization potential of the test article after repeated application under semi-occlusive patch test conditions to the skin of human subjects (non-exclusive panel).

2.0 SPONSOR

2.1 Sponsor Representative - ' ........ ' ' ' -

.:_.:. ! I

. .

·~ . - ... ·: . .. . .... ; . , . : - - ~ - - -

3.0 CLINICAL TESTING FACILITY

The study was conducted by;

Essex Testing Clinic, Inc. 799 Bloomfield Avenue Verona, NJ 07044

4.0 CLINICAL INVESTIGATORS

Study Director: Principal Investigator: Medical Investigator:

5.0 STUDY DATES

Annemarie E. Hollenback, BA Toni F. Miller, PhD, DABT, BCFE John A. Erianne ~ MD, Board-Certified Dermatologist

Study initiation: August 3, 2011

Final evaluation: September 9, 2011

Essex Testing Clinic. Inc .. __________________ _


6.0 ETHICS

6.1 Ethical Conduct of the Study

Page 2 of 4 ETC Panel No.: 11261 ETC Entry No. : 20425

This study was conducted in accordance with the intent and purpose of Good Clinical Practice regulations described in Title 21 of the U.S. Code of Federal Regulations (CFR). the Declaration of Helsinki and/or Essex Testing Clinic (ETC) Standard Operating Procedures.

6.2 Subject Information and Consent

This study was conducted in compliance with CFA Title 21 , Part 50 (Informed Consent of Human Subjects). Informed Consent was obtained from each subject in the study and documented in writing before participation in the study. A copy of the Informed Consent was provided to each subject.

7.0 TEST MATERIAL

The test article used in this study was provided by:

It was received on July 6, 2011 and identified as tallows:

ETC Entry No. Test Art icle LD. Description

20425 White Semi-Solid

8.0 TEST SUBJECTS

At least 50 male and female subjects ranging in age from 18 to 79 years were to be empanelled for this test.

The subjects chosen were to be dependable and able to read and understand instructions. The subjects were not to exhibit any physical or dermatologic condition that would have precluded application of the test articte or determination of potential effects of the test article.

Essc.x Testing Clinic. Inc. ___________________ _


9.0 TEST PROCEDURE

Page 3 of 4 ETC Panel No.: 11261 ETC Entry No.: 20425

The 9 Repeated Insult (semi-occlusive) Patch Test (9-RIPT)1 was conducted as fo llows:

9.1 Induction Phase

A sufficient amount of the test article (an amount to adequately cover the surface ot the patch unit - approximately 0.1 g - 0.15 g) was placed onto an approximate 2 em x 2 em square of Webril® cotton fabric (approximately 25 - 38 mg/cm2 of test material) affixed to Scanpor (AIIerderm) semi-occlusive surgical tape. The patch was then applied to the back of each subject between the scapulae and waist, adjacent to the spinal mid-line. This procedure was performed by a trained technician/examiner and repeated every Monday, Wednesday and Friday until 9 applications of the test article had been made.

The subjects were instructed to remove the patch 24 hours after application. Twenty-four hour rest periods followed the Tuesday and Thursday removals and 48-hour rest periods followed each Saturday removal. Subjects returned to the Testing Facility and the site was scored by a trained examiner just prior to the next patch application.

It a subject developed a positive reaction of a level 2 erythema or greater during the Induction phase or if, at the discretion of the Study Director, the skin response warranted a change in site, the patch was applied to a previously unpatched, adjacent site for the next application. It a level 2 reaction or greater occurred at the new site, no further applications were made. However, any reactive subjects were subsequently Challenge patch tested.

9.2 Challenge Phase

After a rest period of approximately 2 weeks (no applications of the test article) , the Challenge patch was applied to a previously unpatched (virgin) test site. The site was scored 24 and 72 hours after application. All subjects were instructed to report any delayed skin reactivity that occurred after the final Challenge patch reading. When warranted, selected test subjects were called back to the Clinic tor additional examinations and scoring to determine possible increases or decreases in Challenge patch reactivity.

Dermal responses tor both the Induction and Challenge phases of the study were scored according to the following 6-point scale:

0 = No evidence of any eHect + = Barely perceptible (Minimal, taint, uniform or spotty erythema) 1 = Mild (Pink, uniform erythema covering most of the contact site) 2 = Moderate (Pink-red erythema uniform in the entire contact site) 3 = Marked (Bright red erythema with/without petechiae or papules) 4 = Severe (Deep red erythema with/without vesiculation or weeping)

All other observed dermal sequelae (eg, edema, dryness, hypo- or hyperpigmentation) were appropriately recorded on the data sheet and described as mild, moderate or severe.

1 Marzulli FN. Ma1bach HI (1976) Contact allergy: predtct1ve lestmg 1n man Contact Dormat1t1S. 2. 1-17 E~sn T~sting Clinic. Inc .. ___________________ _


9.0 TEST PROCEDURE (CONT'D)

9.3 Data lnterpretatJon

Page 4 of 4 ETC Panel No.: 11261 ETC Entry No. : 20425

Edema, vesicles, papules and/or erythema that persist or increase in intensity either during the Induction and/or Challenge phase may be Indicative of allerg1c contact dermatitis. Allergic responses normally do not resolve or improve markedly at 72·96 hours.

Exceptions to typical skin reactions may occur. These may include, but not be limited to, symptoms of allergic contact sensitivity early in the Induction period to one or more test products. When this occurs in one subject, such a reaction usually suggests either an idiosyncratic response or that the subject had a pre· exposure/sensitization to the test material or component(s) of the test material or a cross-reactivity with a similar producUcomponent. Data for such reactions will be included in the study report but will not be included in the final study analysis/conclusion of sensitization.

10.0 RESULTS AND DISCUSSION

(See Table 1 for Individual Scores)

A total of 55 subjects (12 males and 43 females ranging 1n age from 18 to 79 years) were empanelled for the test procedure. Forty-eight (48/55) subjects satisfactorily completed the test ure on Test Article: . ·. -.. ' - .. . - .. ~ .

1

Seven (7/55) subjects discontinued for personal reasons unrelated to the study. Discontinued subject data are shown up to the point of

discontinuation, but are not used in the Conclusions section of this final report.

Induction Phase Summary

Challenge Phase Summary

There was no skin reactivity observed at any time during the course of the study.

11.0 CONCLUSIONS

Under the conditions of a repeated insult (semi-occlusive) patch test procedure conducted In 48 subjects, Test Article: . ~ ·-· . -. . ' ~ ~ ... \

was "Dermatologist-Tested" and was not associated with skin irritation or allergic contact dermatitis in human subjects.

E!.sex Test1ng Clinic. Inc. ___________________ _



TABLE 1

INDIVIDUAL SCORES

REPEATED INSULT PATCH TEST· SEMI-OCCLUSIVE

Test Article:

Induction Subj. Evaluation Number No. 1 2 3 4 5 6 7 8 9 1 0 0 0 0 0 0 0 0 0 2 0 0 0 0 0 0 0 0 0 3 0 0 0 0 0 0 0 0 0 4 Discontinued 5 0 0 0 0 0 0 0 0 0 6 0 0 0 0 0 0 Discontinued 7 0 0 0 0 0 0 0 0 0 8 0 0 0 0 0 0 0 0 0 9 0 0 0 0 0 0 0 0 0 10 0 0 0 0 0 0 0 0 0 11 0 0 0 0 0 0 0 0 0 12 0 0 0 0 0 0 0 0 0 13 0 0 0 0 0 0 0 0 0 14 0 0 0 0 0 0 0 0 0 15 0 0 0 0 0 0 0 0 0 16 0 0 0 0 0 0 0 0 0 17 0 0 0 0 0 0 0 0 0 18 0 0 0 0 0 0 0 0 0 19 0 0 0 0 0 0 0 0 0 20 0 0 0 0 0 0 0 0 0 21 0 0 0 0 0 0 0 0 0 22 0 0 0 0 0 0 0 0 0 23 0 0 0 0 0 0 0 0 0 24 0 0 0 0 0 0 0 0 0 25 0 0 0 0 0 0 Discontinued 26 0 0 0 0 0 0 0 0 0 27 0 0 0 0 0 0 0 0 0 28 0 0 0 0 0 0 0 0 0 29 0 0 0 0 0 0 0 0 0 30 0 0 0 0 0 0 0 0 0

Scale:O = No evidence of any effect + = Barely perceptible (Minimal, faint, uniform or spot1y erythema) 1 = Mild (Pink, uniform erythema covering most of the contact site) 2 = Moderate (Pink-red erythema uniform in the entire contact site) 3 = Marked (Bright red erythema with/without petechiae or papules) 4 = Severe (Deep red erythema with/without vesiculation or weeping)

Challenge Virgin Site

24hr 72hr 0 0 0 0 0 0

0 0

0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0

0 0 0 0 0 0 0 0 0 0

Essex Testing Clinic, Inc. __________________ _



TABLE 1 (CONT'D)

INDIVIDUAL SCORES

REPEATED INSULT PATCH TEST- SEMI-OCCLUSIVE ---. -

Test Article: ---------- - -- ---

I Subj. 1

No. 1 31 0 32 0 33 0 34 0 35 0 36 0 37 0 38 ! 0 39 0 40 0 41 0 42 0 43 0 44 0 45 0 46 0 47 0 48 0 49 0 50 0 51 0 52 0 53 0 54 0 55 0

2 0 0 0 0 0 0 0 0 0 0 0

3 0 0 0 0 0 0 0 0 0 0 0

Discontinued

Induction Evaluation Number

4 0 0 0 0 0 0 0 0 0 0 0

5 0 0 0 0 0 0 0 0 0 0 0

6 0 0 0 0 0 0 0 0 0 0 0

0 Discontinued 0 0 0 0 0 0 0 0 0 0 Discontinued 0 0 Discontinued 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0

Scale:O = No evidence of any effect

7 0 0 0 0 0 0 0 0 0 0 0

0 0

0 0 0 0 0 0 0 0

8 0 0 0 0 0 0 0 0 0 0 0

0 0

0 0 0 0 0 0 0 0

9 0 0 0 0 0 0 0 0 0 0 0

0 0

0 0 0 0 0 0 0 0

+ = Barely perceptible (Minimal, faint, uniform or spotty erythema) 1 = Mild (Pink, uniform erythema covering most of the contact site) 2 = Moderate (Pink-red erythema uniform in the entire contact site)

'

3 = Marked (Bright red erythema with/without petechiae or papules) 4 = Severe (Deep red erythema with/without vesiculation or weeping)

Challenge Virgin Site

24hr 0 0 0 0 0 0 0 0 0 0 0

0 0

0 0 0 0 0 0 0 0

72hr 0 0 0 0 0 0 0 0 0 0 0

0 0

0 0 0 0 0 0 0 0

Esse.~ Tcs11ng Clime. Inc., __________________ _


Memorandum

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

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

DATE: August 22, 2016

SUBJECT: Concentration of Use: Propylene Glycol Butyl Ether

Propylene Glycol Butyl Ether was included in a concentration of use survey. No uses of this ingredientwere reported.


amended safety assessment of butyl polyoxyalkylene ...2016/11/11 · 3 butyl ether in the june...

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