Safety Assessment of Polymerized Tetramethylcyclotetrasiloxanes

as Used in Cosmetics

Status: Draft Report for Panel Review Release Date: August 28, 2015 Panel Meeting Date: September 21-22, 2015

The 2015 Cosmetic Ingredient Review Expert Panel members are: Chair, Wilma F. Bergfeld, M.D., F.A.C.P.; Donald V. Belsito, M.D.; Ronald A. Hill, Ph.D.; Curtis D. Klaassen, Ph.D.; Daniel C. Liebler, Ph.D.; James G. Marks, Jr., M.D.; Ronald C. Shank, Ph.D.; Thomas J. Slaga, Ph.D.; and Paul W. Snyder, D.V.M., Ph.D. The CIR Director is Lillian J. Gill, D.P.A. This report was prepared by Lillian C. Becker, Scientific Analyst/Writer.

© Cosmetic Ingredient Review 1620 L Street, NW, Suite 1200 Washington, DC 20036-4702 ph 202.331.0651 fax 202.331.0088 cirinfo@cir-safety.org

__________________________________________________________________________________________ 1620 L Street, NW Suite 1200, Washington, DC 20036

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MEMORANDUM

To: CIR Expert Panel and Liaisons

From: Lillian C. Becker, M.S. Scientific Analyst and Writer

Date:

August 28, 2015

Subject: Polymerized Tetramethylcyclotetrasiloxanes

Attached is the draft report on polymerized tetramethylcyclotetrasiloxanes (polysilicone-2, polysilicone-4, and polysilicone-5) as used in cosmetics. [PLYCTS092015Rep] This report was scheduled for review at the March, 2015 meeting. At the request of Industry, the report was tabled at that meeting to allow for sufficient time to gather data on these ingredients.

Industry requested the 6 months in order to provide the following data on polysilicone-2:

• Physical and chemical properties • Impurities and residual monomers • Method of manufacture • Dermal sensitization and irritation

The Panel requested that industry provide the same data (identified above) for polysilicone-4 and polysilicone-5. Additionally, the following data were requested for all three ingredients:

• Molecular weight ranges • Concentration of use • Absorption/metabolism • If dermally absorbed: reproductive toxicity, 28-day dermal toxicity, and genotoxicity

As of the data cut off for presentation at the September meeting, no new data arrived except, concentration of use. Concentration of use data have been incorporated into the report. [PLYCTS_092015_Data1,2]

The Panel is to examine the minimal data in the report and decide if the data are sufficient to issue a conclusion of safety. If a conclusion can be reached, the Panel is to issue a tentative report and develop the basis for the Discussion section of the report. If an Insufficient Data Announcement is appropriate, the Panel is to develop a list of data needs.

SAFETY ASSESSMENT FLOW CHART

INGREDIENT/FAMILY _____ Polymerized Tetramethylcyclotetrasiloxane __________________________________

MEETING ________Sept 2015______________________________________________________________________________________

Public Comment CIR Expert Panel Report Status

Priority List INGREDIENT

PRIORITY LIST

Notice to Proceed Dec 2014

60 day public comment period

Draft Report

Table IDA TR (Mar 2015)

IDA Notice IDA

60 day public comment period Draft TR

Table

Tentative Report

60 day Public comment period

Draft FR

Table Different Conclusion

PUBLISH Final Report

DRAFT REPORT Mar 2015; Sept 2015

DRAFT TENTATIVE

REPORT

DRAFT FINAL REPORT

Issue TR

Issue

FR

Table (for 2 mtgs)

Table

Table

Report History – Polymerized Tetramethylcyclotetrasiloxanes

2014 – Finalized for the 2015 Priority List.

December, 2014 – After an extensive literature search, a Notice to Proceed was posted.

March, 2015 – No data were submitted by Industry or the public. At the request from Industry, the Panel did not issue an Insufficient Data Announcement. Instead, the Panel tabled the report until September, 2015 to give Industry time to collect data and submit it to be incorporated into the report.

Industry requested the 6 month hold in order to provide the following data on polysilicone-2:

• Physical and chemical properties • Impurities and residual monomers • Method of manufacture • Dermal sensitization and irritation

The Panel requested that industry provide the same data (identified above) for polysilicone-4 and polysilicone-5. Additionally, the following data were requested for all three ingredients:

• Physical and chemical properties, especially molecular weight ranges • Concentration of use • Absorption/metabolism • If dermally absorbed: reproductive toxicity, 28-day dermal toxicity, and

genotoxicity

June, 2015 – The report is not brought to the Panel because it is tabled until September, 2015.

September, 2015 – As of the time of the data cut off, no data new has been received except concentration of use. The Panel is to decide if a conclusion can be reached with the available data or if an Insufficient Data Announcement is warranted.

Distributed for comment only -- do not cite or quote

Polymerized Tetramethylcyclotetrasiloxanes Data Profile for September, 2015. Writer - Lillian Becker

ADME Acute toxicity Repeated dose toxicity Irritation Sensitizatio

n

Derm

al P

enetration

Log Kow

Use

Oral

Derm

al

Inhale

Oral

Derm

al

Inhale

Ocular

Irritation

Derm

al Irr. A

nimal

Derm

al Irr H

uman

Sensitization

Anim

al

Sensitization

Hum

an

Repro/D

evel toxicity

Genotoxicity

Carcinogenicity

Phototoxicity

polysilicone-2 X polysilicone-4 X polysilicone-5 X

Distributed for comment only -- do not cite or quote

Search Strategy

SciFinder - Polysilicone-2, 258521-91-4, 76684-67-8, Polysilicone-4, 9004-73-3, Polysilicone-5, 848302-17-0, Poly(tetramethylcyclotetrasiloxane)

848302-17-0 – 2 hits. Not useful

258521-91-4 – 9 hits. Not useful.

76684-67-8 – 0 hits.

9004-73-3 – 3354 hits. Culled by “adverse effect, including toxicity; biological study; properties; additional related references”. 1169 hits. Removed patents. 633 hits. Culled by relevant Concept Headings – 49 hits, 1 ordered.

References from text and structures searches:

Polysilicone references: 3318 hits. Removed patents 1301 hits. English – 1111 hits. Culled by relevant Concept Headings – 41 hits. 1 useful (same as above)

ECHA – CAS Nos. No results.

High Production Volume Information System (HPVIS) - CAS Nos. No results.

Google – Names and CAS Nos. – No results.

NTP – CAS Nos. No results.

Distributed for comment only -- do not cite or quote

Transcripts - Poly Tetramethylcyclotetrasioxanes March, 2015

Dr. Marks’ Team

DR. MARKS: The next, and I think we had a notice, the siloxanes. This is the cyclotetrasiloxanes. This is the first review of these polymerized ingredients. There are three of them. Again, Tom and Ron's are the three ingredients okay in whatever our needs, and then wasn't there a memo this morning from industry?

DR. HILL: Here. DR. MARKS: Thank you. Actually, I was going to ask, Becker, do you want to comment,

or Carol, as to what the memo said since, perhaps, not everybody saw it? DR. EISENMANN: The memo was a request to table the report for approximately 6

months because they would like to provide additional data, and the data is listed. DR. MARKS: Table, okay. I was going to say insufficient data notice. That may be

somewhat similar, but any rate, table. Industry wanted to provide -- DR. EISENMANN: The list of data is on the memo. I'd have to -- DR. MARKS: Where's that memo -- DR. EISENMANN: -- it's method of manufacture -- DR. MARKS: Yes. DR. EISENMANN: -- physical, chemical properties of polysilicone 2, impurities and

residual monomers method of manufacture, dermal sensitization, and irritation studies. DR. MARKS: Mm-hmm. DR. EISENMANN: This ingredient is very similar to other ingredients you've already

reviewed. It has the same core as methicone. We don't really think there would be any safety concerns, and it is a polymer. We think that may be sufficient information, especially if you pull information on methicone.

DR. MARKS: Everything that Lillian has in her February 20, 2015, memo, in that second paragraph where it says 'no results,' we can expect in 6 months we'll get results. Yep. Table?

DR. WEINTRAUB: I have a question. What's the practical difference between tabling and issuing an insufficient data --

DR. MARKS: An insufficient data notice. DR. WEINTRAUB: -- because obviously the goal is to obtain more data. Is it more

useful to issue an insufficient data announcement so we're clear -- that Panel is clear beyond the list of things that this one particular company wants to offer if there are other things that the Panel thinks is important.

DR. MARKS: I'll let Lillian answer it because I have my take on it: One's a stick and one's a prod.

(inaudible)(Laughter) DR. GILL: Yes, yes. I too think that there may be data needs that the Panel would like to

see above and beyond what the company has offered to provide in 6 months, so I think issuing this as an insufficient notice and maybe not bringing it back in June but maybe the September meeting might be a better option so that all of the data that the Panel thinks is necessary to come in gets covered by the insufficient notice.

DR. MARKS: Team? (inaudible) insufficient data or table? I think essentially we're accomplishing the 6 month timeline since we aren't going to review it in June; it would be in September. Looking at that, which do you prefer: Table or insufficient data notice? I mean, that's --

DR. HILL: My preference would be table in this particular case. That's just my preference.

Distributed for comment only -- do not cite or quote

DR. MARKS: Ron Shank? DR. SHANK: I would also like skin absorption data on the smallest of the three, and

that's not in the list provided by this letter. I would prefer insufficient announcement so we could add absorption of the polysilicone 2.

DR. MARKS: Actually all the needs are listed in that second paragraph. You concur with that second paragraph in Lillian's memo? Chemical and physical properties, impurities, toxicokinetic, dermal absorption, that's what she just mentioned -- residual monomers, oral, inhalation and/or dermal tox, ocular irritation, sensitization.

DR. HILL: Yeah, I was just wondering whether if you table it and -- I guess does insufficient data announcement get more people's attention than if you tabled with a list of needs that would go in our minutes? What do you think?

DR. GILL: I think a table with a list of needs is an insufficient data announcement. (Laughter)

DR. HILL: It's basically the same thing. A practicality, but I was just wondering if an industry with the insufficient announcement would get more of my attention to a greater extent. I don't --

DR. GILL: I think industry would have to answer that. One thing about tabling, Ron, is that versus insufficient -- and I think by answering this I'm probably answering your question -- is that the next step, when the information doesn't come in, is to categorize these as insufficient due to zero use of whatever category they may fall into. It is a stick to get the data in, and we have had instances in the past where the promise of 6 months just didn't materialize.

DR. HILL: I appreciate that we have I've seen it. But on the flip side, I would rather see robust studies than a shortcut to get there artificially sooner, I guess, is all I'm saying.

DR. GILL: According to the memo, it's some of the same things we've seen. It should not be an issue to get it in 6 months.

DR. HILL: Okay. DR. BERGFIELD: I have a comment. I think that we don't often have a request from

industry to table because they're going to supply us with information, and we go insufficient when we don't have it. I think a gesture here, because they have asked us, might be to go to table.

DR. MARKS: Wilma here got my sentiments too. I would agree. It's a collaboration between the CIR and industry, yes. Do you want to identify yourself and come up?

DR. MAIT: Russell Mait. I'm with SESHC, the Silicone Environmental Health and Safety Council, and I don't know anything about the memo, but from the industry's perspective we are looking at the three chemistries. We evaluated the chemistry that was written in the document. We're out surveying our industry members to see whether they concur with the description.

I'll offer that from my knowledge I'm not familiar with the reaction sequence that is identified there. Providing the data that you're looking for is problematic at this point until we identify the chemistry and the process that's going forward, as you recognized.

This the first time that we've had a chance to see that, so we'll be prepared to provide the information you're looking for in terms of maybe a better definition of what the chemistry is and how the reaction sequences go with the supporting data that you're looking for.

DR. EISENMANN: But the memo is from a different company that's going to be providing the information, and this company is not a U.S.-based company, and I think that's part of the reason why they requested table because they see an insufficient data announcement in their country as something a little different than I think what some companies see it in the United States.

DR. MARKS: With that caveat, I think tabling, as Wilma has suggested, is the right way to go.

DR. WEINTRAUB: But is this a missed opportunity for the Panel's ability to articulate other data needs?

DR. MARKS: No. I think the minutes of this discussion and tomorrow, they will be

Distributed for comment only -- do not cite or quote

elucidated. I think the data needs will be very clear. DR. HILL: I also became coincidentally aware this past week that the Environ

Corporation has looked at D4 and D5 cyclomethicones in a QRA-type analysis of safety assessment, and they were actually looking at multiple root exposure. I got the sense that that publication might actually come out within the next 6 months or at least be ready in preprint form, and I probably could get my hands on it. It might be another piece of information, but I know it's not going to come out next month or the month after that.

DR. MARKS: Okay. I don't think we have to list the needs that are actually in Lillian's memo. You've had in your memo -- was it from you, Carol, or you, Beth? Maybe Beth. You had everything except, I think, the absorption, which Dr. Shank mentioned for the two. I think that's the starting point, and then in 6 months if we don't get the information, then it'll be the appropriate time to go forward with an insufficient data notice. Lillian?

MS. BECKER: Mm-hmm. Yes. I'll be listing the data needs in the post-meeting announcements so they will at least be reiterated again for (inaudible). Also, just remember if we table it and we don't get what we need, it'll then go out as an insufficient data announcement and it'll be another meeting after that that will be --

DR. MARKS: Right. That's okay. MS. BECKER: Just to point that out. DR. MARKS: Yeah, I don't think we're worried about this, that a few months' delay is

going to severely impact the safety of the general public. We always use that in consideration. I'll move tomorrow to table to get the data needs which are outlined below by you, Lillian. The expectation is that we are going to see this report again in September.

MS. BECKER: September. DR. MARKS: Okay. Any other comments? Thank you, Wilma.

Dr. Belsito’s Team

DR. BELSITO: Okay. Let me get my eyes back in focus. So now we are looking at Cyclotetrasiloxanes. Is that correct?

DR. SNYDER: Correct. DR. BELSITO: And did we get something handed to us on that today? MS. BECKER: Yes. Industry is asking to table it. DR. BELSITO: Oh. Where is what they handed us? MS. BECKER: I don't have a copy then, that you can get. DR. BELSITO: Yeah, but where did I put mine? Okay. I'm missing mine. So

polysilicone 2, 4 and 5, it says, a Council Member company has indicated they've plan on providing the following additional information within the next six months. Physical chemical properties of polysilicone-2 impurities in residual monomers, method of manufacture, dermal sensitization and irritation; and after reading the current document, I thought it was insufficient for impurities, cosmetic grade and metabolism depending upon these other designates maybe necessary, alternatively the 28th day dermal sensitization irritation repro and genotox.

So, they are asking us to table for physical chemical properties, impurities and residual monomers, which is one of my insufficient; method of manufacture, dermal sensitization. So they got everything, and then depending upon impurities we may also need repro and genotoxicity 28- day dermal.

DR. SNYDER: At least there's no (inaudible). DR. BELSITO: They are going to get it to us in six months. So do we want to table it or

not? DR. KLAASSEN: Sure. DR. LIEBLER: Yeah. I mean, that's the core of what I had missing. I mean, we can't do

anything until --

Distributed for comment only -- do not cite or quote

DR. BELSITO: Right. DR. LIEBLER: We don't even know what data to ask for toward that information. DR. SNYDER: Well we have data use for only the two. None for 4 or 5, and it's 514

uses and no concentration, so this is like nothing. There's no data here. DR. BELSITO: Right. MS. BECKER: The debate in the other room is whether or not to table until we bring it

back in September, or to put out an insufficient data announcement with the extended time limit, so that it's announced to the world that we are also looking for those things, or not just this company.

DR. BELSITO: I have no objection one way or the other. You know I'm a profound believer in moving the process. And to move the process, I suppose, if we go out with insufficient that moves it along, and then we just -- it's March, so we neglect it in November.

DR. SNYDER: In June. MS. BECKER: No, we neglect it in June. DR. BELSITO: I mean, neglect it in June, and then come back to it September. Our

September meeting is late September this year, right? It's September 20-something? MS. BECKER: I don't have that. DR. BELSITO: So it will be -- DR. SNYDER: Twenty-one. DR. BELSITO: -- it's certainly, you know, that's six months away, and if they say the can

do it in six months, that's a way of getting them to come in on time, so sure. I'll go insufficient for impurities, cosmetic grade, and metabolism, depending upon these.

DR. SNYDER: Absorption. DR. BELSITO: Other data may be necessary, or alternatively they can provide 28-day

dermal tox, sensitization, irritation, repro and genotox. DR. SNYDER: In use concentration. DR. BELSITO: In use concentration. Are we -- table or go insufficient in -- DR. LIEBLER: I think it's fine. DR. BELSITO: -- well, forget to look at in June, and look at it again in September. DR. LIEBLER: It sounds like a good deal. Comment over there? MS. BECKER: Do you have a comment with that? MR. MAIT: Yes. DR. LIEBLER: Could you step up by one place. DR. BELSITO: And introduce yourself, name and affiliation. MR. MAIT: Sure. Russell Mait -- Thank you. I'm Russell Mait, with Silicones

Environmental Health and Safety Council. We represent the silicone industry in the U.S. This is the first time -- we are not familiar with the letter that you got, the memo that you got, but as far as the industry goes, we are surveying our members as far as the chemistry and the application and use. So we would be willing to support the effort to fill any data gaps.

I will say that, looking at the chemistry for myself, I'm not familiar with the structure and the process of manufacture, so that's one of the questions we have, and that's certainly something we want to go back to our members to be sure, that what we are seeing is accurate and correct. So we'll be willing to get back here and get back to you.

DR. LIEBLER: Good. Thank you. DR. SNYDER: Do you want to explain the insufficiency for us? If it goes into insufficient,

if there's a time -- SPEAKER: I doubt we need that. DR. BELSITO: Well, I mean -- Yeah, I mean, if this remains insufficient for two years,

then it -- but we haven't gotten there yet, this is going out as a tentative insufficient, so right -- final insufficient?

Distributed for comment only -- do not cite or quote

MS. FIUME: This is the first time you've seen it, so these are insufficient. DR. BELSITO: So just insufficient. MS. BECKER: Just insufficient. DR. BELSITO: So we are not even close to the two- year clock beginning to run? MS. BECKER: Right. Should we move along, if we give it six months, and I assume it

will be in that -- final in December. DR. BELSITO: Right. MS. BECKER: And then the clock will start clicking. DR. BELSITO: Right. DR. ANSELL: So I'll make my boilerplate that I don't think it should go insufficient on the

first review. I think there should be an opportunity for the industry to look at the report, and be able to come back with data that may have been missed in the first report.

DR. BELSITO: But they will have the opportunity, Jay. We are just putting you on a timeline. You told us six months we'll give you six months.

DR. ANSELL: All right. DR. LIEBLER: I think you see this as the scarlet eye. DR. ANSELL: Something like that. DR. LIEBLER: The Scarlet Letter, right? DR. ANSELL: It suggests that the data is not available, when -- it was never asked for.

So I say this -- and I say this every time, and the industry really doesn't like it, but I have failed to succeed in any of my arguments, but I felt the need to at least put it in the record.

DR. BELSITO: Okay. So, what you can respond back to industry, at least from Don Belsito is, we've tabled things many times and then not gotten the data when we told you you would get it. So, from the Panel's perspective, one way of holding industry to what they tell us they can do, is to proceed.

MS. BECKER: It's what the main difference would come down to, is if an insufficient data announcement, it would be worded that we know that industry has promised this data, these were the concerns of the Panel, and these were the data they would like to see, and if we -- if it's just tabled, and come September the data needs aren't met, then it's another delay, because then insufficient data announcement would have to go out.

Whereas if the insufficient data announcement went out while you are waiting for the data, if everything that was wanted is not received, then in September a tentative report could be issued. That's the main difference.

DR. BELSITO: And you know -- I mean, our only obligation is to wait 90 days for comment, we are not obliged to take it up immediately in 90 days --

MS. BECKER: It's actually 60. DR. BELSITO: Or 60 days, or whatever. What we are telling industry is we are willing to

wait 6 months to take it up again. So we won't bring this back until September, we are not going to bring it back in June, so we are giving you what you want, but we are holding you to your promise that you'll have it in six months.

DR. LIEBLER: I think everyone has said their piece. DR. BELSITO: Yeah. Okay. So let me gather the needs. Impurities cosmetic grade,

metabolism, concentration of use depending upon these, other data may be necessary. DR. SNYDER: We need absorption. DR. BELSITO: Absorption. DR. LIEBLER: And what we've really -- in terms of the chemistry, meaning the chemical

and physical properties particularly molecular weight range. DR. BELSITO: Okay. So insufficient chemical and physical properties, chemical weight

range, impurities in the cosmetic grade, right? Absorption.

Distributed for comment only -- do not cite or quote

DR. SNYDER: Yeah. And it's absorbed to the referral of the standard. DR. BELSITO: What about metabolism? Absorption and metabolism? DR. SNYDER: Yes. DR. BELSITO: Absorption and metabolism, and if absorbed, do we need a 28-day

dermal? DR. SNYDER: Yes, and in repro; it will absorb. DR. BELSITO: But do we need a 28-day dermal if it's not absorbed? DR. KLAASSEN: No. DR. BELSITO: Will it still have effects on the skin? No? DR. SNYDER: Yeah. DR. BELSITO: Okay. Concentration of use? DR. SNYDER: Yes. DR. BELSITO: Okay. And if absorbed -- if absorbed 28-day dermal, repro and

genotoxicity and sensitization and irritation. Okay? So that we don't need -- MS. BECKER: Sensitization and irritation if absorbed, or anyway? DR. SNYDER: Anyway. MS. BECKER: That's what I thought. DR. LIEBLER: Right, concentration use. Phototox is not an issue? DR. BELSITO: No. I don't think. Do you? DR. LIEBLER: No. I'll be right back. DR. BELSITO: If you are getting coffee, get me some too. DR. LIEBLER: Okay. DR. BELSITO: And not decaf. Okay. So let me just repeat this. So insufficient chemical

and physical properties particularly the chemical weight range, impurities of the cosmetic grade, sensitization and irrigation, absorption and metabolism, and if absorbed other data, such as 28-day dermal sensitization and irritation, repro and genotox -- Or, I'm sorry, other data 28-day dermal, repro and genotox. Right?

DR. SNYDER: Okay. DR. BELSITO: Okay. Anything else? Oh, my, god, I didn't save my changes. Who is

reporting on this? DR. SNYDER: Jim. DR. BELSITO: Okay. I just lost all of our requests. Could you just repeat them to me,

Lillian, I'm sorry. MS. BECKER: Sure. Impurities, metabolism, absorption, if absorbed repro, 28-day

dermal and genotox. DR. BELSITO: Metabolism, sensitization and irritation. MS. BECKER: Concentration of use. DR. BELSITO: Method of manufacture and particular molecular weight range. DR. SNYDER: Chemical physical property. DR. BELSITO: And chemical and physical property. MS. BECKER: Chemical and physical property, especially molecular weight range. Did

you want (inaudible) too? DR. SNYDER: It's basically everything. MS. BECKER: Pretty much like memo. DR. BELSITO: Okay. So I've got use concentration, chemical and physical properties,

molecular weight range, metabolism, impurities, sensitization and irritation, absorption and metabolism, depending upon absorption. Okay. I'm not sure why this isn't saving. Now it seems to be.

DR. LIEBLER: I've got it. DR. BELSITO: Okay. Thanks, Dan.

Distributed for comment only -- do not cite or quote

DR. LIEBLER: Sure.

Day 2 DR. BERGFELD: ... Moving on to the next group Dr. Marks, cyclotetrasiloxane. I don't

know how you pronounce that. Thank you. DR. MARKS: So this is the first time we've seen these three ingredients, and we had a

request from industry to table this report. There are a lot of data needs and the expectation is that we will receive these by September. So my motion is to table these ingredients till the September meeting.

DR. BERGFELD: Is there a second? DR. SHANK: Second. DR. BERGFELD: Thank you. (laughter) There's [no?] a discussion on the table, so we

have to call the vote. All those in favor of tabling this ingredient till September in hopes to receive the data. So it's 50/50. All right, so I'm going to break the tie and it's tabled. Thank you. Any discussion though regarding this ingredient?

DR. BELSITO: Yeah, it was just the point of my team that we've been promised by industry many times that something would come in six months. And six months from now it didn't come. That the data that has been promised would allow us to go with the safe as used conclusion. That we would be willing to delay the re-review of this report that went out as insufficient to September, which is the timeline industry tells us that they would get us the data. And it would be a way of moving this along and holding industry to their promise that they will have it in six months.

So it was just our feeling that they said they could do it. We're willing to play ball with them. We're giving them six months, but we're putting them on notice that they have six months. Because in the past, quite honestly, they have not fulfilled their promises to come in on time with data.

DR. MARKS: We had the same discussion, and I think it just depends -- I think I referred to it as do we use the stick or carrot, and we decided not to use the stick this time but the carrot. And we expect we will receive the needs as outlined in the memo from Lillian by September. So I think it's just a little different approach. These are not -- there's not an urgency that I'm aware of among the consumers on ruling on this. So we felt that even though we didn't have the stick with an insufficient, that moving forward with a motion with an insufficient conclusion, that we would do an insufficient data notice. So it's just a different approach.

DR. BERGFELD: Were there other needs that need to be listed? DR. MARKS: I think they're outlined right by Lillian in her memo, that second paragraph. DR. BERGFELD: Okay. DR. MARKS: Very clearly. Actually lots of needs and they're clearly documented there.

So actually the vote has occurred and -- but I think -- DR. BERGFELD: More discussion here for a moment. Lillian, when this is reported and

made an announcement, it's going to be stated it was tabled with the expectation of the company coming forward in September with the premise needs.

DR. GILL: Um hum. DR. BERGFELD: Will it also tack on the other needs that are -- have been recorded in

the teams? All right, thank you. So for clarification there, we'll be put on alert by the minutes as well as the announcement.

Distributed for comment only -- do not cite or quote

Safety Assessment of Polymerized Tetramethylcyclotetrasiloxanes

as Used in Cosmetics

Status: Draft Report for Panel Review Release Date: August 28, 2015 Panel Meeting Date: September 21-22, 2015

The 2015 Cosmetic Ingredient Review Expert Panel members are: Chair, Wilma F. Bergfeld, M.D., F.A.C.P.; Donald V. Belsito, M.D.; Ronald A. Hill, Ph.D.; Curtis D. Klaassen, Ph.D.; Daniel C. Liebler, Ph.D.; James G. Marks, Jr., M.D.; Ronald C. Shank, Ph.D.; Thomas J. Slaga, Ph.D.; and Paul W. Snyder, D.V.M., Ph.D. The CIR Director is Lillian J. Gill, D.P.A. This report was prepared by Lillian C. Becker, Scientific Analyst/Writer.

© Cosmetic Ingredient Review 1620 L Street, NW, Suite 1200 Washington, DC 20036-4702 ph 202.331.0651 fax 202.331.0088 cirinfo@cir-safety.org

Distributed for comment only -- do not cite or quote

INTRODUCTION This is a safety assessment of polysilicone-2, polysilicone-4, and polysilicone-5 (i.e., polymerized tetramethyl-

cyclotetrasiloxanes) as used in cosmetics. These ingredients are synthesized from tetramethylcyclotetrasiloxane and have a core chain of repeating O-Si(R)(CH3)- moieties.

These polymerized tetramethylcyclotetrasiloxanes are reported to function as antifoaming agents, hair conditioning agents, and viscosity increasing agents – nonaqueous in cosmetics (Table 1).1

The CIR Expert Panel reviewed other siloxane polymers, such as methicone and other related methicone-containing ingredients, and concluded that those ingredients were safe as used in cosmetic products.2 The Panel also reviewed other cyclic-siloxanes, the cyclomethicones, and concluded that they were safe as used in cosmetic products.3

CHEMISTRY

Definition, Structure, and Manufacture The ingredients in this report are each synthesized from tetramethylcyclotetrasiloxane (Figure 1). Typically,

synthesis of these polymethylsiloxanes occurs via cationic ring-opening polymerization of the cyclic monomer tetramethylcyclotetrasiloxane, utilizing a Brønsted-Lowry type acid (e.g., triflic acid) as an initiator. The result is a polymer that can easily be functionalized by the addition of vinyl-type monomers (e.g., glyceryl monoallyl ether or tetradecene; Figure 1).

Figure 1. Synthesis of polysilicones 2, 4, and 5.

Although these ingredients are depicted above as straight-chain polymers for the sake of simplicity, these polymers are most likely cross-linked to some degree because of the very highly labile silicone-hydrogen bonds, and the oxophilic nature of silicone. These polymers can range from viscous liquids to hard rubber textures because of variations in temperature and duration of polymerization, and resultant variations of molecular weight and degree of cross-linking.

Physical and Chemical Properties Data on the chemical and physical properties of polymerized tetramethylcyclotetrasiloxanes were not found in the

published literature and no unpublished data were provided.

Impurities Data on the impurities present in polymerized tetramethylcyclotetrasiloxanes conforming to ingredient definitions

were not found in the published literature and no unpublished data were provided.

USE Cosmetic

The safety of the cosmetic ingredients included in this safety assessment is evaluated based on the expected use of these ingredients in cosmetics. The Panel utilizes data received from the U.S. Food and Drug Administration (FDA) and the cosmetics industry in determining the expected cosmetic use. The data received from the FDA are those it collects from manufacturers on the use of individual ingredients in cosmetics by cosmetic product category in its Voluntary Cosmetic Registration Program (VCRP), and those from the cosmetic industry are submitted in response to a survey of the maximum reported use concentrations by category conducted by the Personal Care Products Council (Council).

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According to the 2015 VCRP data, polysilicone-2 is reported to be used in 209 leave-on formulations and polysilicone-5 is used in 1 makeup fixative.4 The VCRP has no reported uses for polysilicone-4 (Table 2).

The results of the concentration of use survey conducted by the Council in 2015 indicate polysilicone-2 had the highest reported maximum concentration of use; it is used at up to 1% in eye shadows and makeup products.5 Polysilicone-4 was used up to 0.6% in foundations and polysilicone-5 was used up to 0.84% in face powders.

For polysilicone-4, concentration of use data were received, but uses were not reported in the VCRP. Additionally, concentrations of use were reported for 4 makeup products and 1 skin care product but information of use was not reported to the VCRP. Therefore, it should be presumed that there is at least 1 use in every category for which a concentration is reported.

Polysilicone-2 and polysilicone-5 are reported to be used in products that are applied around the eyes and all ingredients in this report are used in products that come in contact with mucus membranes.

Additionally, polysilicone-2 is used in cosmetic sprays and could possibly be inhaled; it is reported to be used at up to 0.000095% in perfumes. 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.6,7 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.8,9

These polymerized tetramethylcyclotetrasiloxanes are not restricted from use in any way under the rules governing cosmetic products in the European Union.10

TOXICOKINETICS

Absorption, Distribution, Metabolism, and Excretion Data on the absorption, distribution, metabolism, and excretion of polymerized tetramethylcyclotetrasiloxanes were

not found in the published literature and no unpublished data were provided.

TOXICOLOGICAL STUDIES Acute Toxicity

Data on the acute toxicity of polymerized tetramethylcyclotetrasiloxanes were not found in the published literature and no unpublished data were provided.

Repeated Dose Toxicity

Data on the repeated dose toxicity of polymerized tetramethylcyclotetrasiloxanes were not found in the published literature and no unpublished data were provided.

REPRODUCTIVE AND DEVELOPMENTAL TOXICITY

Data on reproductive and developmental toxicity of polymerized tetramethylcyclotetrasiloxanes were not found in the published literature and no unpublished data were provided.

GENOTOXICITY

Data on the genotoxicity of polymerized tetramethylcyclotetrasiloxanes were not found in the published literature and no unpublished data were provided.

CARCINOGENICITY

Data on the carcinogenicity of polymerized tetramethylcyclotetrasiloxanes were not found in the published literature and no unpublished data were provided.

IRRITATION AND SENSITIZATION

Data on dermal irritation and sensitization or on the ocular irritation of polymerized tetramethylcyclotetrasiloxanes were not found in the published literature and no unpublished data were provided.

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SUMMARY

This is a safety assessment of polysilicone-2, polysilicone-4, and polysilicone-5 (polymerized tetramethyl-cyclotetrasiloxanes) as used in cosmetics. These ingredients are synthesized from tetramethylcyclotetrasiloxane and have a core repeating chain of O-Si(R)(CH3)- moieties.

The ingredients reviewed in this report are reported to function as antifoaming agents, hair conditioning agents, and viscosity increasing agents – nonaqueous in cosmetics.

According to the 2015 VCRP data, polysilicone-2 is reported to be used in 209 leave-on formulations and polysilicone-5 is used in 1 makeup fixative. The VCRP has no reported uses for polysilicone-4. In 2015, polysilicone-2 had the highest reported maximum concentration of use, up to 1% in eye shadows and makeup products. Polysilicone-4 was used up to 0.6% in foundations and polysilicone-5 was used up to 0.84% in face powders.

There were no toxicity, irritation, or sensitization data for these ingredients discovered in the literature. Unpublished data were not provided for these categories either.

DISCUSSION

The Discussion is scheduled to be developed at the September, 2015 Panel meeting.

CONCLUSION To be determined.

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TABLES Table 1. Definitions, idealized structures, and functions of the ingredients in this safety assessment.1, CIR Staff

Ingredient CAS No. Definition & Structures Function(s) Polysilicone-2 258521-91-4; 76684-67-8

Polysilicone-2 is the polymer formed by the reaction of tetradecene (1-tetradecene) with polymerized tetramethylcyclotetrasiloxane (a.k.a. Polysilicone-4).

O Si OH

CH3

H

n

CH3

Antifoaming agent; hair conditioning agent

Polysilicone-4 9004-73-3

Polysilicone-4 is the reaction product of the polymerization of tetramethylcyclotetrasiloxane.

O Si OH

CH3

H

H

n

Hair conditioning agent; viscosity increasing agent – nonaqueous

Polysilicone-5 848302-17-0

Polysilicone-5 is the reaction product of Polysilicone-4 and glyceryl monoallyl ether (3-(2-propenyloxy)-1,2-propanediol).

O Si OH

CH3

H

n

O OH

OH

Hair conditioning agent; viscosity increasing agent – nonaqueous

Table 2. Frequency of use according to duration and exposure of polymerized tetramethylcyclotetrasiloxanes.4,5

Use type Uses

Maximum Concentration

(%) Uses

Maximum Concentration

(%) Uses

Maximum Concentration

(%) Uses

Maximum Concentration

(%) Polysilicone-2 Polysilicone-4 Polysilicone-5

Total/range 209 0.00005-1 NR 0.0015-0.6 1 0.0015-0.84 Duration of use

Leave-on 209 0.00005-1 NR 0.0015-0.6 1 0.0015-0.84 Rinse-off NR 0.0003-0.06 NR NR NR NR

Diluted for (bath) use NR NR NR NR NR NR

Exposure typea Eye area 27 0.0003-1 NR NR NR 0.02-0.33

Incidental ingestion 96 0.78 NR 0.33 NR 0.68

Incidental Inhalation-sprays 1b; 10c 0.00095;

0.0005b NR NR NR NR

Incidental inhalation-powders 2; 10c 1; 0.091-0.94d NR 0.36; 0.0015d NR 0.84; 0.0015d

Dermal contact 107 0.0003-1 NR 0.0015-0.6 1 0.0015-0.84 Deodorant (underarm) NR NR NR NR NR NR

Hair-noncoloring NR 0.00005 NR NR NR NR Hair-coloring NR 0.06 NR NR NR NR

Nail 2 0.062-0.51 NR NR NR NR Mucous

Membrane 96 0.78 NR 0.33 NR 0.68

Baby NR NR NR NR NR NR NR = Not Reported; Totals = Rinse-off + Leave-on Product Uses. Note: Because each ingredient may be used in cosmetics with multiple exposure types, the sum of all exposure type uses may not equal the sum total uses. a 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. b It is possible these products may be sprays, but it is not specified whether the reported uses are sprays. c Not specified whether a powder or a spray, so this information is captured for both categories of incidental inhalation. d It is possible these products may be powders, but it is not specified whether the reported uses are powders.

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REFERENCES 1. Nikitakis, J and Breslawec HP. International Cosmetic Ingredient Dictionary and Handbook. 15 ed. Washington, DC: Personal Care Products

Council, 2014.

2. Andersen, FA. Final report on the safety assessment of stearoxy dimenticone, dimethicone, methicone, amino bispropyl dimethicone, aminopropyl dimethicone, amodimethicone, amodimethicone hydroxystearate, behenoxy dimethicone, C24-28 alkyl methicone, C30-45 alkyl methicone, C30-45 alkyl dimethicone, cetearyl methicone, cetyl dimethicone, dimethoxysilyl ethylenediaminopropyl dimethicone, heyxyl methicone, hydroxypropyldimethicone, stearamidopropyl dimethicone, stearyl dimethicone, stearyl methicone, vinyldimethicone. International Journal of Toxicology. 2003;22(Suppl. 2):11-35.

3. Johnson Jr, W, Bergfeld, WF, Belsito, DV, Hill, RA, Klaassen, CD, Liebler, DC, Marks Jr, JG, Shank, RC, Slaga, TJ, Snyder, PW, and Andersen, FA. Safety assessment of cyclomethicone, cyclotetrasiloxane, cyclopentasiloxane, cyclohexasiloxane, and cycloheptasiloxane. International Journal of Toxicology. 2011;30(Suppl. 3):149S-227S.

4. Food and Drug Administration (FDA). Frequency of use of cosmetic ingredients; FDA Database. Washington, DC, FDA. 2015.

5. Personal Care Products Council. 3-6-2015. Concentration of Use by FDA Product Category: Polysilicone-2, Polysilicone-4 and Polysilicone-5. Unpublished data submitted by Personal Care Products Council.

6. Johnsen MA. The Influence of Particle Size. Spray Technology and Marketing. 2004;14(11):24-27. http://www.spraytechnology.com/index.mv?screen=backissues.

7. Rothe H. Special aspects of cosmetic spray safety evaluation. 2011. Unpublished information presented to the 26 September CIR Expert Panel. Washington D.C.

8. Bremmer HJ, Prud'homme de Lodder LCH, and van Engelen JGM. Cosmetics Fact Sheet: To assess the risks for the consumer; Updated version for ConsExpo 4. 2006. http://www.rivm.nl/bibliotheek/rapporten/320104001.pdf. Date Accessed 8-24-2011. Report No. RIVM 320104001/2006. pp. 1-77.

9. 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. 8-28-2011;205(2):97-104. PM:21669261.

10. European Commission. CosIng database; following Cosmetic Regulation No. 1223/2009. http://ec.europa.eu/consumers/cosmetics/cosing/. Last Updated 2014. Date Accessed 1-14-0015.

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2015 VCRP Data for Polymerized Tetramethylcyclotetrasiloxanes

03A - Eyebrow Pencil POLYSILICONE-2 2 03B - Eyeliner POLYSILICONE-2 8 03C - Eye Shadow POLYSILICONE-2 8 03D - Eye Lotion POLYSILICONE-2 2 03F - Mascara POLYSILICONE-2 4 03G - Other Eye Makeup Preparations POLYSILICONE-2 3 07A - Blushers (all types) POLYSILICONE-2 4 07B - Face Powders POLYSILICONE-2 2 07C - Foundations POLYSILICONE-2 14 07E - Lipstick POLYSILICONE-2 96 07G - Rouges POLYSILICONE-2 38 07I - Other Makeup Preparations POLYSILICONE-2 15 08A - Basecoats and Undercoats POLYSILICONE-2 1 08E - Nail Polish and Enamel POLYSILICONE-2 1 12C - Face and Neck (exc shave) POLYSILICONE-2 6 12D - Body and Hand (exc shave) POLYSILICONE-2 4 12G - Night POLYSILICONE-2 1 209

07H - Makeup Fixatives POLYSILICONE-5 1

There were no uses for:

Polysilicone-5

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Memorandum

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

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

DATE: March 6, 2015

SUBJECT: Concentration of Use by FDA Product Category: Polysilicone-2, Polysilicone-4 andPolysilicone-5

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Concentration of Use by FDA Product Category – Polysilicone-2, Polysilicone-4 and Polysilicone-5

Ingredient Product Category Maximum Concentration of Use

Polysilicone-2 Eyebrow pencil 0.81% Polysilicone-2 Eyeliner 0.75% Polysilicone-2 Eye shadow 1% Polysilicone-2 Eye lotion 0.12% Polysilicone-2 Eye makeup remover 0.0003% Polysilicone-2 Mascara 0.4% Polysilicone-2 Perfume 0.00095% Polysilicone-2 Tonics, dressings and other hair grooming aids 0.00005% Polysilicone-2 Hair tints 0.06% Polysilicone-2 Blushers 1% Polysilicone-2 Face powders 1% Polysilicone-2 Foundations 1% Polysilicone-2 Lipstick 0.78% Polysilicone-2 Makeup bases 0.36% Polysilicone-2 Nail polish and enamel 0.062% Polysilicone-2 Other manicuring preparations 0.51% Polysilicone-2 Face and neck products

Not spray 0.091%

Polysilicone-2 Body and hand products Not spray

0.94%

Polysilicone-2 Moisturizing products Not spray

0.03%

Polysilicone-2 Suntan products Not spray

0.038%

Polysilicone-4 Blushers (all types) 0.006% Polysilicone-4 Face powders 0.36% Polysilicone-4 Foundations 0.6% Polysilicone-4 Lipstick 0.33% Polysilicone-4 Face and neck products

Not spray 0.0015%

Polysilicone-5 Eyebrow pencil 0.02% Polysilicone-5 Eyeliner 0.33% Polysilicone-5 Eye shadow 0.3% Polysilicone-5 Blushers 0.02% Polysilicone-5 Face powders 0.84% Polysilicone-5 Foundation 0.62% Polysilicone-5 Lipstick 0.68% Polysilicone-5 Makeup bases 0.0021% Polysilicone-5 Body and hand products

Not spray 0.0015%

Information collected in 2014; Table prepared March 6, 2015

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