safety assessment of alkoxyl alkyl silanes as used in ... · subject: safety assessment of alkoxyl...

Safety Assessment of Alkoxyl Alkyl Silanes as Used in Cosmetics

Status: Draft Final 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: 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 [email protected]

mailto:[email protected]

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

(Main) 202-331-0651 (Fax) 202-331-0088 (Email) [email protected] (Website) www.cir-safety.org

Commitment & Credibility since 1976

MEMORANDUM

To: CIR Expert Panel and Liaisons

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

Date:

November 11, 2016

Subject: Safety Assessment of Alkoxyl Alkyl Silanes as Used in Cosmetics

Attached is the draft final report of Alkoxyl Alkyl Silanes as used in cosmetics. [alalsi122016Rep] These four ingredients are grouped because they are structurally related as silanes bearing both simple alkyl and simple alkoxyl groups. These ingredients function as binders, skin-conditioning agents – miscellaneous, and skin-conditioning agents – emollient.

In June 2016, the Panel issued a tentative report with the conclusion that these ingredients are safe in cosmetics in the present practices of use and concentration described in this safety assessment. The Panel discussed the use of these ingredients as surface modifiers, the presence of residual starting materials (e.g., disilazane), and the use of inference (read-across) in assessing safety.

No new data were submitted. The Wave 2 data from June have been incorporated into the report. Council comments have been addressed. [alalsi122016PCPC_1,2]

The Panel should carefully review the Abstract, Discussion, and Conclusion of this report and issue a final report.


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

SAFETY ASSESSMENT FLOW CHART

INGREDIENT/FAMILY ____Alkoxy Alkyl Silanes__________________________________________

MEETING _____Dec 2016______________________________________________________________

Public Comment CIR Expert Panel Report Status

Priority List INGREDIENT

PRIORITY LIST

SLR January 19, 2016

60 day public comment period

Draft Report

Table IDA TR

IDA Notice IDA

Draft TR

Table

Tentative Report June 13, 2016

60 day Public comment period

Draft FR

Table Different Conclusion

PUBLISH Final Report

DRAFT REPORT June 2016

DRAFT TENTATIVE REPORT

DRAFT FINAL REPORT Dec 2016

Issue TR

Issue FR

Table

Table

Table

History – Alkoxy Alkyl Silanes

June, 2015 – Added to the Priority List. January, 2016 – SLR posted. June, 2016 – Panel examined the draft report. The Panel issued a Tentative Report with a

conclusion of safe as used. The Panel discussed the use of these ingredients as surface modifiers, the presence of residual starting materials (e.g., disilazane), and inference (read-across).

December, 2016 – The Panel is to examine the report, especially the Abstract, Discussion, and

Conclusion. The Panel should issue a Final Report.

Distributed for comment only -- do not cite or quote

Alkoxy Alkyl Silanes Data Profile for September, 2016. Writer – Lill Becker ADME

Acute toxicity

Repeated dose toxicity Irritation Sensitization

Derm

al P

enetration

Log Kow

Use

Oral

Derm

al

Inhale

Oral

Derm

al

Inhale

Ocular A

nimal

Ocular In V

itro

Derm

al Anim

al

Derm

al Hum

an

Derm

al In Vitro

Anim

al

Hum

an

In Vitro

Repro/D

evel

Genotoxicity

Carcinogenicity

Phototoxicity

Bis-Stearoxydimethylsilane X X X X X X X X Stearoxytrimethylsilane X Triethoxycaprylylsilane X X X X X X X X X X Trimethoxycaprylylsilane X X X X X X X Triethoxycaprylylsilane-coated titanium oxide particles

X

Triethoxycaprylylsilane-coated zinc oxide particles

X

Triethoxycaprylylsilane-coated zinc oxide

X X


Search Strategy – Alkoxyl Alkyl Silanes SciFinder Group Links: Compounds searched by identifiers (text and structure): 29043-70-7 – 5 hits. 0 useful. 18748-98-6 – 79 hits. Filtered for adversed effects/toxicity, biological studies, properties, and additional related refs - 56 hits. Removed Patents – 8 hits, 0 useful. 3069-40-7 – 1163 hits. Filtered for adversed effects/toxicity, biological studies, properties, and additional related refs - 189 hits. Removed patents – 107 hits, 1 useful. 2943-75-1 – 2115 hits. Filtered for adversed effects/toxicity, biological studies, properties, and additional related refs - 532 hits. Removed patents – 180 hits, 2 useful. References from text and structures searches: 3037 hits. Removed patents – 1023 hits. English – 922 hits. Toxicity – 17 hits, (same 3 useful). Irritation – 3 hits, 1 useful. Sensitization – 61 hits, 0 useful. Genotoxicity – 0 hits. Reproduction – 17 hits, 0 useful. How toxic is Bis-Stearoxydimethylsilane 29043-70-7 – 5 hits for “stearoxydemthylsilane or 29043-70-7, 0 useful. How toxic is Stearoxytrimethylsilane 18748-98-6 – not useful How toxic is Triethoxycaprylylsilane 2943-75-1 – 1 hit, retrieved. How toxic is Stearoxytrimethylsilane 18748-98-6 – not useful How toxic is Trimethoxycaprylylsilane 3069-40-7 – not useful Cosing – No restrictions, no opionions. HPVIS – no hits. ECHA - Bis-Stearoxydimethylsilane 29043-70-7 – no hits; Stearoxytrimethylsilane 18748-98-6 – hits; Triethoxycaprylylsilane 2943-75-1 – Data available; Trimethoxycaprylylsilane 3069-40-7 Data available. The same data sets were in both ECHA profiles. PUBMED – ingredient names and tox* - 2 hits, already had 1, acquired the other. CAS no. and tox* - 0 hits


Panel Transcripts – Alkoxyl Alkyl Silanes June, 2016

Dr. Belsito’s Team

DR. BELSITO: So alkoxy alkyl silanes, that is under alkoxyl silanes. So this is the first time we're looking at these four ingredients. They're binder, skin conditioning agents and emollients. They're used in 413 leave-ons and therefore, I guess, for rinse-offs. And use concentrations are up to 2.6 percent in suntan products. And then, it goes on to say that one ingredient, trimethoxycaprylylsilane is a surface modifier.

I'm not sure why that's important but I guess does that mean that you think it should go back in other report with the polysilicones?

MS. BECKER: No, it's just the -- DR. BELSITO: It's just that it's a new use that the Dictionary has incorporated? MS. BECKER: No, it's a use that the last time was a controversy because of the difference between it actually

being a surface modifier and not being a surface modifier where this one it's not a problem. And I just wanted to make sure you didn't conflate the two.

DR. BELSITO: Right. DR. SNYDER: Only a surface modifier? MS. BECKER: No. DR. BELSITO: No, no. MS. BECKER: It can be used as both with -- DR. BELSITO: But the others we had data only on surface modification of zinc particles and so that we approved

it for that and said if it was used for other uses that were then in the Dictionary, it would -- we would need to reconsider. So what Lillian is saying here one of these is a surface modification use and that's a new cosmetic definition that the INCI dictionary included, is that right?

MS. BECKER: No, no. DR. BELSITO: So surface modification existed as a function in the prior Dictionary? DR. HELDRETH: Yeah but typically surface modifier means something a little bit different -- DR. BELSITO: Right. DR. HELDRETH: -- than this. It wasn't -- DR. BELSITO: Coating bead. DR. HELDRETH: -- a coata [coated?] particle. DR. BELSITO: Right. DR. HELDRETH: Now in this case these are different from those polymers we were looking at before because

these are not polymers. DR. BELSITO: Right. DR. HELDRETH: The polysilicones we looked at before in situ the monomers were preliminarized [polymerized?]

around those particles. This is seriously just a coating of the small molecules onto the metal particles. DR. BELSITO: Okay. DR. HELDRETH: But there is no polymerization involved. DR. BELSITO: So Dan, you're happy with this grouping? DR. LIEBLER: Yeah, I didn't have any issues with it. DR. BELSITO: Okay. We don't -- the highest concentration of use is for the tricaprylyl at two percent. And we

don't have sensitization at that level. I'm not -- we have the triethoxycaprylylsilane and an animal study that I really couldn't follow the dilutions on on page 16. It says under the sensitization protocol so you had a product that had percent the stearoxydimethylsilane. And then, it says 7.5 percent Bis-stearoxymethylsilane. Is that 7.5 percent of a product that originally had 75 percent or is that 7.5 of the actual ingredient?

MS. BECKER: I haven't found where you are yet. Can you tell me again, please? DR. BELSITO: PDF 16 the only study under sensitization. I'm just trying to clear a two percent level for an

unrelated product because the highest level of use, because otherwise I can go safe when formulated to be non-irritating but I don't have sensitization data and I'm just trying to figure out where this level is in the one sensitization study we have because it was very confusing to me. The animals were challenged with the test substance. It says 50 percent 37.5 percent.

So I'm assuming that and I don't follow that if the material is 75 percent Bis-stearoxy. I can't figure out the math here.


MS. BECKER: Okay. The product had 75 percent of the ingredient and they put 10 percent on it so that's 7.5 percent --

DR. BELSITO: Okay. MS. BECKER: -- of the challenge. DR. BELSITO: Okay. MS. BECKER: I mean, of the induction. DR. BELSITO: Induction was 7.5. MS. BECKER: Right. And then, the -- was -- the test substance -- the product was administered again at 75

percent which brought the ingredient down to 52.5. DR. BELSITO: Okay. MS. BECKER: And then, two weeks later it was challenged again at 50 percent which brought the ingredient

down to 37.5. DR. BELSITO: Okay. That's what I thought. So the extent that it's reasonable to use Bis-stearoxydimethylsilane

as a read-across for sensitization for the dicaprylyl and I -- but I'm not seeing the chemical structures there, Dan, so I have to punt to you. Is it reasonable to assume that the trietho -- that the triethoxy can be read-across for the tricapryl?

DR. LIEBLER: It's triethoxy would be, you know, more extensively absorbed probably similar hydrolysis. So using the rule of thumb of the more reactive, more biologically potentially active compound is the read-across this would be okay.

DR. BELSITO: Okay. So then I thought we could go safe as used when formulated to be non-irritant. DR. BERGFELD: Using the animal model for your safety of irritation sensitivity? DR. BELSITO: Yeah. Well, we have triethoxycaprylylsilane. Did I get that backwards? That's at 2.6 percent.

And the sensitization study was on stearoxydimethyl. So does the stearoxydimethyl -- you're saying, Dan, that would penetrate more than the --

DR. LIEBLER: I would think that that would penetrate less than the caprylyl. DR. BELSITO: Right. DR. LIEBLER: Yeah, because caprylyl is a shorter chain. DR. BELSITO: Right. DR. LIEBLER: And ethyl's way shorter so. DR. BELSITO: And would there be, you know, my concern would be would there be more stearic hindrance with

a stearoxytrimethyl so that you might see sensitization with a tricapryl where you didn't with the stearoxymethyl or are these all going to be so poorly absorbed because of their -- well, their molecular weight is not so high is it? They're all absorbable based on molecular weight.

DR. LIEBLER: Yeah, I think they would be. DR. BELSITO: Yeah. DR. LIEBLER: Honestly, I think that the rates of absorption would differ and so the stearoxydimethyl would be the

slowest. The triethoxycaprylyl will be the next fastest, the next slowest, excuse me, and then, the trimethoxycapryl -- or actually, yeah, trimethoxycaprylyl will be about the same. So I wouldn't expect any difference in sensitization based on differences in their physical properties.

DR. BELSITO: Yeah, so the stearoxy has a molecular weight of 343. The ethoxycaprylyl of 376. DR. LIEBLER: Right. DR. BELSITO: The logKow we don't have for the stearoxy, for the caprylyl it's approximately 3.7 calculated. But

you're comfortable that based upon the design of these molecules that we can substitute the sensitization study for the stearoxy. We can read-across for the tricaprylyl?

DR. LIEBLER: I think so. DR. BELSITO: I guess if anything, looking at the diagrams in table one there probably would be more stearic

hindrance with the caprylyl, no? DR. LIEBLER: Are you talking -- you're using the term stearic hindrance in a way that would be pretty unfamiliar

to chemists. So I think you're really just talking about the size -- DR. BELSITO: When it binds. DR. LIEBLER: -- it would be attempted to absorb or -- DR. BELSITO: No, when it binds to the molecule how many side chains or other structures does it have that

would impede T-cell recognition -- DR. LIEBLER: Oh, I see. DR. BELSITO: -- on antigen presenting cell? DR. LIEBLER: I don't --


DR. BELSITO: You know, that's why, you know, in general -- DR. LIEBLER: Yeah. DR. BELSITO: -- parasubstituted groups tend to be more allergenic then ortho or meta because the binding is

usually at the amine terminal for those. DR. LIEBLER: Yeah, that's -- I'm not sure I would agree with that way of putting it but I mean there are

differences in chemical reactivities of reactive parasubstituted versus metasubstituted, for example -- DR. BELSITO: Right. DR. LIEBLER: -- for most aromatic systems. For these, I mean, I suppose if you're arguing that these would

somehow covalently modify biological nucleophiles which I don't think is very likely. DR. BELSITO: Okay. DR. LIEBLER: These silic -- I mean, they'll hydrolyze. They'll react with water but I don't think they're -- these

kinds of molecules efficiently form adducts with, you know, cysteines and histidines and things like that and proteins.

DR. BELSITO: Okay. DR. LIEBLER: So I don't think this is -- these are going to be, like, halved and forming reactive enemy species

like certain aldehyde alpha, beta unsaturated carbonyl compounds like -- DR. BELSITO: Okay. DR. LIEBLER: So I think that kind of thing is off the table here. The main issue with these comparing them would

just be their relative rates of absorption and you would expect the smaller ones to be absorbed more quickly than the Bis-stearoxydimethylsilane for example which is the largest one shown.

DR. BELSITO: Okay. DR. LIEBLER: Table on [one?]. DR. BELSITO: So then safe as used and then, the only other question is formulated to be non-irritating in the

conclusion or they're used at such a low concentration we don't need that? DR. LIEBLER: Try to remember the irritation data was at a pretty high concentration? DR. SNYDER: Very high. DR. BELSITO: Yeah, very high. DR. LIEBLER: I don't think it needs to be in the conclusion, non-irritating. DR. BELSITO: So then just safe as used? DR. LIEBLER: Yeah. I did have one question and maybe Bart can help me with this or Lillian, I'm not sure. On

pdf page 13, the description of the triexthoxycaprylylsilane coated particles. So Bart just mentioned coated particles but that this was coated in another way. I'm not sure if these coated particles were relevant to our safety assessment in the way that the coating is on these particles used in a study. Is that a form of these -- of this ingredient that would be encountered in use and cosmetic products coated on the particles like this?

DR. HELDRETH: If I'm looking at the right one you're talking about where it looks like they basically spray coated the particles?

DR. LIEBLER: This was the pulmonary toxicity study. DR. HELDRETH: Okay. DR. LIEBLER: Let's see. I don't think they described how they made the particles. They just said

triethoxycaprylylsilane coated titanium dioxide particles were instilled into the lungs blah, blah, blah. MS. BECKER: And it was not clear what these particles were being used for in the original document. DR. LIEBLER: Yeah. So in the uses it says or I'm sorry, in the introduction I guess, they're a surface modifier.

So I didn't know if this kind of particle coating was an example of a surface modifier use of this ingredient as might be encountered in a cosmetic product or a surface modifier in the context of this ingredient means something else.

MS. BECKER: The original studies in that say what these particles are being used for. However, in your wave two, that data is from the etchi [ECHA] data and that is for cosmetic ingredients.

DR. LIEBLER: Okay. I don't remember. I did look at the wave two on this but I don't remember seeing that. So surface modifier could mean that this compound's present in a cosmetic product and let's just say it just sort of coats the skin and that's the function. In other words, it's not used on a bead and delivered in a bead in cosmetic products.

DR. HELDRETH: But the other way is possible is a cosmetic surface modifier. DR. EISENMANN: What I can say in European regulations for their sunscreens for nanozinc and nanotitanium

dioxide, this is specifically listed as a permitted coating or I don't know if it's the right terminology. DR. LIEBLER: Okay.


DR. LANGE: I think it's to prevent aggregation to the titanium and zinc oxide particles in a sunscreen. DR. LIEBLER: Ah. That makes sense and these are titanium dioxide so that okay. Yeah, without any context I

couldn't tell. That makes sense now that you put it that way. Okay. I was just wondering whether the study should be included in the report or not because I didn't know if this stuff on beads was really relevant to its use but it might be relevant to its use if that's the case.

MS. BECKER: And surface modifier is a function so - - DR. LIEBLER: Right. No, I'm not arguing with that. I'm just -- surface modifier, you take the stuff out of a tube.

It's not on beads. You squirt it onto your skin and now you've modified your surface, that's one thing. But you put it on beads in the factory and then, you take that and squirt it on your skin, that's a different presentation and a different use and that's why I was wondering whether or not this study was relevant to our assessment. But I'm satisfied now that it --

DR. BELSITO: So do you need to make any language changes there, Dan? DR. LIEBLER: If we can document that this material is sometimes coated on beads, to prevent aggregation of

beads in sunscreens, if we can come up with something that that could be added to the use section as by way of clarification?

MS. BECKER: So far all I have is that the Annex 6 from the European regulations allows this to be used on those. I don't have a reason for them to be used.

DR. LIEBLER: Okay. So you've got this data on coated particles and my problem was I don't know if that's relevant to the way that these ingredients would be used in a cosmetic product or a cosmetic ingredient, okay? And from what you've told me, I'm still not convinced. But from what Carol and Beth just said, it sounds like they could be.

So if there's information to support that, that should go into the report to justify this section being here. MS. BECKER: Do you have a reference? I don't at the moment. DR. EISENMANN: Other than the SCCS opinion that included some information on this material that was coated. DR. LIEBLER: Right, so -- DR. EISENMANN: That's in wave two. DR. LIEBLER: Okay. So if you could bring a little of that in here? MS. BECKER: Sure. DR. LIEBLER: To clarify? DR. SNYDER: So that data does talk about it as a surface modifier (inaudible) oxide, right, where they came up

with that inhalation tox study? Titanium -- DR. EISENMANN: I'm not sure it's an inhalation tox study but it's an SCCS opinion. It's what -- there's a gene tox

and something else. I can't remember. So it's in wave two. DR. SNYDER: Well, we have a wave two that doesn't have a lowest observed adverse effect level for it at.05

milligrams per meter [m2?]. DR. HELDRETH: Right. And it also says that the triethoxycaprylylsilane is used as a coating for zinc oxide

nanoparticles. So that's what you need. DR. SNYDER: Yeah, yeah, put it in. That's what -- DR. SADRIEH: I just want to make sure that sunscreens we know are not cosmetics, right, they're drugs. DR. LIEBLER: But cosmetics -- so in gre -- cosmetics -- cosmetic ingredients that to into sunscreen products as

opposed to the sunscreens themselves? DR. SADRIEH: It's the titanium dioxide, zinc oxide, they're used as a, you know, and they're made according to

the monograph as a sunscreen. DR. LIEBLER: Right. DR. SADRIEH: That would make the product a drug because -- DR. LIEBLER: So the titanium dioxide is a drug? DR. SADRIEH: Correct. DR. LIEBLER: Because it's a sunscreen. DR. SADRIEH: Correct. DR. LIEBLER: But the stuff that you coat it with to keep it from sticking to other titanium dioxide particles is not a

drug. DR. SADRIEH: Titanium dioxide would have to be made according to the monograph so that's -- I don't know that

you could coat it with something else. It has to be made according to the monograph. You cannot coat it. DR. LIEBLER: Somebody's doing this and didn't talk to either of us obviously. DR. SADRIEH: So I don't -- yeah, I'm just letting you know what the law says.


DR. LIEBLER: All right, well, we will let the experts stir this pot. All I wanted was some reason to feel that this study belonged in our report.

DR. BELSITO: But there are, Dan, cosmetic ingredients that claim an anti-aging effect but not a sunscreen effect based upon their use of things like zinc oxide and titanium dioxide. So it's possible that these could be used as coating particles in cosmetics as well.

DR. LIEBLER: Okay. DR. BELSITO: So I don't think we should discount that. MS. BECKER: And just to clarify for titanium dioxide, reported functions include colorants, light stabilizer,

opacifying agent, and sunscreen agent. DR. BELSITO: Right. DR. SNYDER: It's in there. DR. BELSITO: Yeah. So but we don't have, I mean, we really don't have details on the European regulation.

What we have in wave two it says that Annex 6 zinc oxide is not to be used in applications that may link to exposure by the end user's lung by inhalation, da, da, da, which includes uncoated or coated. So it's the zinc oxide particle that they're regulating not the coating.

So I don't know that that, I mean, all that European legislation implies is that these can be used as coatings for zinc oxide particles.

MS. BECKER: Correct. DR. BELSITO: So does that answer everything you wanted to know about that use, Dan? DR. LIEBLER: At this point it certainly does. DR. BELSITO: Okay. Fine. So it should just be brought in someplace that according to this regulation these are

used to coat zinc oxide, titanium dioxide particles. Anything else? So safe as used. We don't have to restrict the irritation because the irritation occurs at very high concentrations

and these are used at low concentrations. A little more description about their use as particle encapsulaters and that should do it, is that correct?

Dr. Marks’ Team DR. MARKS: Alkyl Silanes. This is the first review of these ingredients. Four ingredients, are those okay, but

then in the data profile, you included the bottom two particles. I wasn't quite sure, were the particles to be included in these ingredients or not?

MS. BECKER: The particles themselves are not the ingredient, the ingredient can coat these particles, and I thought it was important that you see in that particular function, it is a separate set of data.

DR. MARKS: Okay. That is what I figured, but I wanted to confirm that. Ron and Tom, are these four ingredients okay?

DR. HILL: Good group. DR. MARKS: The four, there is not an outlier there. Ron Shank, insufficient. DR. HILL: Let's before we move on, can I just or do -- we can come back at your discretion -- about those two

particles that you added at the bottom of the table. Now, or when we get to inhalation or never -- comments (inaudible).

DR. MARKS: And in your -- and I assume on page 7 in the minutes, a PEG was amiss. Go to page 7. MS. BECKER: Oh. DR. MARKS: I assume they have no relevance to this report. MS. BECKER: No they do not. DR. MARKS: Okay. That's what I figured, but I wanted to be sure I wasn't missing something. Okay. MS. BECKER: We had some accidental moves. DR. MARKS: So let's go to what are the needs? And if we had needs, this would be an insufficient data notice.

Ron Shank, you've already -- DR. SHANK: Skin sensitization data -- DR. MARKS: Mm-hmm. DR. SHANK: -- on three of them. We haven't (inaudible) animal for the base compound. But the other three, we

need sensitization data. And we need absorption data -- dermal absorption -- 428 dermal toxicity and genotoxicity for the stearoxytrimethylsilane.

DR. MARKS: Let me -- let me go back here. So we'll put it in. Yeah, I wanted the sensitization data also. DR. SHANK: On three of them?


DR. MARKS: Yeah. I took the one with the highest concentration, but the other three, let's ask for it. I took the one on the triethoxycaprylylsilane --.

DR. SHANK: Caprylylsilane. DR. MARKS: -- since that has lots of uses for 117 with the highest leave-on of 2.6 percent. But, certainly, we

could ask for the other two. There is just four uses of the trimethyl and that was .77 concentration in 10 uses that have the stearo at .55. So I -- that's fine. Since we're insufficient data notice at this point, I don't know how much you can -- do read across the abyss. We had animal sensitization at -- and this was interesting because it was 38 percent, and in 100 percent concentration, it was okay for sensitization. But it's being used at .38, which, to me, I'm wondering if it's really being used at a maximum concentration of .38, why would there be such high sensitization concentrations used?

But, yeah, that -- so the tri, the stearo -- so the three -- stearo and the trimethyl. SPEAKER: Did she call me? SPEAKER: (Inaudible). SPEAKER: I guess she did. DR. MARKS: So that's the first. And then, Ron, a second thing you mentioned was -- DR. SHANK: For stearoxytrimethylsilane, we need dermal absorption data for 2018 [?] dermal toxicity and

genotoxicity. Because we have no -- no data at all in that compound. DR. MARKS: Okay. SPEAKER: (Inaudible). DR. SHANK: Just use. And then we need phototoxicity data for two of them -- the triethoxycaprylylsilane and the

stearoxytrimethylsilane, because these are used in suntan products at 2.6 percent. DR. MARKS: So the triethoxy and the stearo? DR. SHANK: Yes. DR. MARKS: So -- DR. SHANK: For the particles, Lillian -- MS. BECKER: Mm-hmm. DR. SHANK: -- the last two -- the inhalation data. Is that from wave two -- MS. BECKER: No. That's -- DR. SHANK: -- where we thought the data? MS. BECKER: -- there's more in wave two. DR. SHANK: Yes. MS. BECKER: These two are already in this report and then wave two had another. DR. SHANK: Okay. Because the wave two is nanoparticles, which is -- MS. BECKER: Yeah, it -- that -- DR. SHANK: -- entirely different. MS. BECKER: Well, they call it nano, but there's no definition of whether it's a constructed particle or it's just

small. We usually think of nanoparticles as being constructed in tubes or balls -- like buckyballs. DR. HILL: Nanoparticles is really defined based on size. MS. BECKER: Right. And so all we know is it's small. DR. SHANK: And those are the (inaudible) are -- MS. BECKER: Well, we know that -- DR. SHANK: -- wave two. MS. BECKER: -- what we know, well, I got a look, did they have size, but if they call it that size, we know that the

metal particle is small, but we don't know the size of the coating. MR. ANSELL: The definition of the nano would be based on internal structure. The particles that you actually

use are composed of -- would be much, much larger. It's a definitional issue. It's -- it's not a physical description. It's a regulatory definition.

DR. HILL: Well, this says the inhalation -- DR. SHANK: Maybe by regulatory it's defined that way, but in toxicology -- MR. ANSELL: It settles like a much larger particle. DR. HILL: It's not clear to me in that case that's what's going on. They were trying to make nanoparticles and do

something with them, if I read this correctly. DR. SHANK: That's right. MR. HELDRETH: So oxy-coating -- would there be significant agglomeration? DR. HILL: Who knows? Or released from the particles -- that's the other question we don't have as far as I see.

But --


DR. MARKS: So I have the three needs at this point is sensitization on the stearoxy, the trimethoxy, and the triethoxy. The -- we want dermal absorption on the stearoxy and if absorbed in a 28 day tox studies. And then, three, phototoxicity data on the stearoxy and the triethoxy, since they're being used in sunscreens. Tom, did you have anything more?

DR. SLAGA: Did you mention the genotoxicity (inaudible)? MS. BECKER: No, he didn't. DR. MARKS: No. MS. BECKER: Genotox on the stearoxy. DR. SLAGA: Well, there's genotoxicity on two of the -- on two of the -- MS. BECKER: I saw -- DR. MARKS: So you'd like genotox? DR. SLAGA: Well, if we're asking insufficient, why not see if (inaudible)? DR. MARKS: Geotox -- and that one's on -- MS. BECKER: Stearoxy -- it's missing. DR. SLAGA: The stearoxy. DR. MARKS: Stearoxy. MS. BECKER: Eight. DR. MARKS: Yep. Okay. DR. HILL: I have a couple of additions. One is very basic. In the introduction, which is on page 10 if you want to

go there, but you don't have to. It says according to the cosmetic ingredient dictionary and handbook, the functions of this polymerized tetromethylcyco-tetrasiloxane ingredients include. These aren't polymerized or polymers, are they?

DR. MARKS: No. DR. HILL: Are they? And then, actually -- MS. BECKER: Oh. DR. HILL: -- in the next paragraph, it also has polymers -- siloxane polymers. But I don't think these are

polymerized in this particular case. It need -- at least not intentionally, are they? Or do we know? My question was here clarification as to whether any of these are, in fact, polymerized?

MR. HELDRETH: As defined in monomers. DR. HILL: That's what I thought, but -- MR. HELDRETH: Not monomers, but (inaudible) small molecules. That second paragraph -- that other siloxanes

are polymers, but that's something different. DR. HILL: Yes. And the other -- the other need I had was we don't have any method and manufacture stuff in the

table, but this was coming off of what we did have. If hexamethyldisiloxane or any other disiloxanes are used in the commercial production process, the information about how those levels are minimized or analytical data showing that they have been minimized.

MS. BECKER: Say that again. DR. HILL: Hexamethyldisiloxane or any other disiloxane might be used -- disilaxane -- that might be used in the

production of these. How are the -- how is that speed stock removed in the manufacturing process or minimized? Or otherwise analytical information to show that it has been done? Or that they're not used in the particular production process or any siloxanes?

MR. HELDRETH: No. I don't think these were submitted -- manufacturing methods. MS. BECKER: No. MR. HELDRETH: We just looked for some general methodologies. DR. HILL: And I don't know why you need method and manufacture here. So if the SLR didn't include, that's an

oversight and not to be done. MR. HELDRETH: Well, we did this search. It's just no submissions came in. DR. HILL: Yeah. Ok. Somewhere in there hexamethyldisiloxane was mentioned. I can -- I'm sure I can find it if I

looked. MS. BECKER: It's in the method and manufacture. DR. HILL: Yeah. It's in there. Okay. MS. BECKER: It's an alternative method of -- DR. HILL: Yeah. I've used hexamethyldisiloxane in the lab on multiple occasions. So that's -- and I know what it

does and I know how you get of it at the end, but -- in the lab. MS. BECKER: Mm-hmm. DR. HILL: And I also you need to get rid of it if you're going to give it a product made that way to people.


MS. BECKER: Okay. So is that an insufficient data request (inaudible)? DR. HILL: Yeah. DR. MARKS: What is this now, Ron? DR. HILL: I want information as to whether any hexamethyldisiloxane actually is in the method and manufacture

or any other disiloxane that might be used by analogy based on the structures of these. How it is eliminated from the finished product -- I should say marginally eliminated. You can never do 100 percent -- point zero, zero, zero, zero, zero. Or, alternatively, analytical information to show that those levels are small.

DR. MARKS: So, specifically, for the hexamethyldisiloxane, what do you want? DR. HILL: I want to know how it's gotten rid of or, again -- DR. MARKS: Or residual? DR. HILL: -- documentation that it is -- the finished product is rid of that or any other disiloxane that gets used in

the manufacture of these. DR. MARKS: So level of disiloxanes. DR. HILL: If used. DR. MARKS: Okay. In the ingredient, obviously, that we're dealing with. Okay. DR. HILL: And one other thing, since Ron Shank already asked for the phototoxicity. I don't remember seeing

the indirect phototoxicity before, although clearly raised as an issue and needs to be answered. And I was curious the take on that. These are coming by light generated radicals, not on the substance itself initially as I understand it.

DR. SHANK: Where is this? DR. HILL: Uh, it's -- I mean, you asked for phototoxicity -- DR. SHANK: Yes. DR. HILL: -- so I'm assuming that wasn't based on UV absorption, which is a nonissue here. And I agree with

your request, but it says, clearly in the information in the report, it's an indirect phototoxicity effect. That it's not the light hitting the compound itself, but it's because the -- I think oxygen in the air is what was specifically mentioned generating oxygen radicals or oxygen is a diradical effectively.

MS. BECKER: Oh, page 10. DR. HILL: Yeah. I didn't mark a page number here. DR. MARKS: Page 10. MS. BECKER: Physical and chemical properties. DR. HILL: Yeah. It's -- MS. BECKER: Second paragraph. DR. HILL: Well, is that -- is that where the indirect phototoxicity is mentioned? You've got -- MS. BECKER: Photolysis. DR. HILL: -- photolysis. That's it. That's the basis for why you would need -- and, yes, you can say photolysis. MS. BECKER: Okay. DR. MARKS: It's page 10? MS. BECKER: Yes. DR. HILL: It must be on page 11. I see what's going on here. It was just something I didn't remember us

encountering before, and I think it doesn't hurt the need for and I'm just finding it interesting in pointing out because there shouldn't be any -- based on the structure, there shouldn't be any direct --

DR. SLAGA: Double bonds. DR. MARKS: But we still at this point want to see the phototox of-- DR. HILL: Yes, sir. DR. MARKS: -- stearoxy -- or not stearoxy. Yeah, stearoxy and the triethoxy, because Ron Shank, as he pointed

out, they're used in sunscreens. DR. HILL: Yes. DR. MARKS: You would expect a phototox would exist. DR. SHANK: Used in suntan products. DR. MARKS: Suntan or sunscreen? DR. SHANK: It says suntan. DR. HILL: I think it's a spray on that color your skin, you know. DR. MARKS: Okay. DR. HILL: So what is that? Sunless tanning? Would be the right way to call it? MS. BECKER: That's the name of the -- indoor tanning preparations and suntan products.


DR. HILL: Oh, indoor and suntan products? MS. BECKER: Yes. DR. MARKS: Yeah, that's -- that could be interpreted as -- as you say. Adding a coloring agent to the skin or

often times suntan is also used in place of sunscreens. But we'll use the terminology they used here -- that's because it's used in suntan products. So insufficient data notice tomorrow. The data needs are sensitization on stearoxy, trimethoxy, and triethoxy. Dermal absorption on stearoxy and if absorbed in 28 day tox. Phototox on stearoxy and triethoxy and in less -- no, fourth genotox on stearoxy and for the level of the disiloxanes and the ingredients. Okay.

DR. HILL: Or method and manufacture to show a removal step. DR. MARKS: And that would be -- DR. HILL: It wouldn't be a removal in the sense. It'd probably be hydrolyzing it so that it's gone. DR. MARKS: Yeah. Okay. Any other comments? Okay. Let me close that. And we're now at 13 of the hour.

Do you want to move on to the propylene glycol esters? DR. SHANK: Sure. DR. HILL: Not really, but I think we should.

Day Two DR. BERGFELD: Okay. That's all right. All right, Dr. Marks, you're up next, again. Silanes -- alkoxyl silanes. DR. MARKS: So this is the first time we are renewing the four ingredients in this draft report on the safety

assessment of oxy alkyl silanes. And our team felt that we should issue an insufficient data notice. The data needs were the sensitization on the stearoxy, trimethyloxy, and triethoxy ingredients of three out of the four. We wanted dermal absorption on the stearoxy, and if absorbed, then a 28-day tox. We wanted phototoxicity on stearoxy and triethoxy since they're used in suntan products. And then genotox on the stearoxy ingredient. Let me see, and then five, the level -- the fifth need is the level of disil -- A-Z --

DR. HILL: Disilazane. DR. MARKS: Thank you, Ron Hill -- in the ingredients. So we have insufficient data notice and five different

needs: Sensitization data, dermal absorption data, phototox data, genotox data, and the disilazanes in the ingredients, what level of those.

DR. BELSITO: We had none of those needs. But in particular, I'm not sure why you're concerned that looking at the molecular structure of these would absorb light.

DR. BERGFELD: Ron? DR. HILL: They don't absorb light. What we have in one case is indication that there is indirect photolysis that

can happen. Basically, as far as I can see, it's radicals generated in the air that then generate radicals on the silanes. So we had information suggesting this could potentially be a problem, and --

DR. LIEBLER: What was the information? DR. HILL: Where was it -- I'm trying to remember if it was in wave II or wave I. If I remember, we found this

yesterday, it's in there. DR. BECKER: Page 10 of the PDF. DR. HILL: Page 10 in the PDF. This wasn't the need raised by me, actually, initially. DR. BELSITO: Dan, comment? DR. LIEBLER: Okay. It's the last sentence under Physical and Chemical Properties. Triethoxy caprylyl silane.

And air is not expected to undergo direct photolysis but may undergo indirect photolysis through hydroxyl radical oxidation. So in principle, if something generated a hydroxyl radical in the proximity of this molecule, it may in turn oxidize to a radical by the hydroxyl radical. That's true for virtually all organic molecules. I mean there's nothing unique about this. And the likelihood that that chemistry would happen in any appreciable yield is so vanishingly small. I mean, hydroxyl radicals are very inefficient oxidants because they're so indiscriminately reactive. So I'm not sure -- I didn't read this reference, but this is --

DR. HILL: What got my attention on that was that these are organosilanes, and we don't see those, every day in ingredients used directly in humans.

DR. LIEBLER: Well, I mean they're basically alkyl silica compounds, I mean they're all (COX?) [alkoxyl?] silica compounds. I mean certainly, Don's point -- they don't have a chromophore. So they don't fit the profile of a photosensitizing compound in the most -- in what is the most common mechanism for photosensitization or phototox. So that's why I didn't even think of that. And this, I think, is not likely to occur in -- if you get enough hydroxyl radical to oxidize these molecules in your skin, that's the least of your problems.


DR. HILL: You're right. DR. MARKS: Ron Shank, did you have any comments because you brought up the issue of the phototox? DR. SHANK: No, it's been explained. DR. MARKS: Okay. So you're fine. So we could delete that then. DR. BELSITO: Okay. So then you also asked for sensitization data. I guess essentially for all -- DR. MARKS: No. DR. BELSITO: -- three of them. DR. MARKS: Right -- DR. BELSITO: But -- DR. MARKS: -- we had the one with very high concentration -- DR. BELSITO: Right. DR. MARKS: -- was not sensitized. DR. BELSITO: So you have that, and that's the one that's used at the highest concentration at 2.6 in the leave

on. All of the others are like 0.77, 0.55, 0.38. Why do you feel you cannot read across from a, you know, a Freund's complete adjuvant intradermal injection of 50 percent concentration of triethoxy caprylyl silane to the others that are used at less than one percent? So I didn't see that need for sensitization.

DR. MARKS: Ron Shank, do you want to comment on that too? DR. SHANK: The triethoxy caprylyl silane is used at 2.6. DR. BELSITO: Right, and we have data on that. We have data of Freund's complete adjuvant where it was

injected at 50 percent. DR. SHANK: Let me found out. DR. BELSITO: I'm sorry, it's the stearoxy dimethylamine. But still, it's at 75 percent intradermally injected with

7.5 percent with and without Freund's adjuvant. A week later, they were dermally administered 52.5 percent. Two weeks later, they were challenged with 37.5 percent.

DR. MARKS: Which page? That's the -- DR. BELSITO: This is PDF page 16, sensitization. Stearoxydimethylsilane. DR. MARKS: I thought it was the bis compound. I had the bis compound. DR. BELSITO: Yeah, it -- I'm sorry, it's not triethoxy, it's stearoxy. DR. MARKS: Yeah. DR. BELSITO: But still, at a very high concentration. DR. MARKS: I agree. That concentration -- there was no issue, both at 38 percent and it looks even higher. DR. BELSITO: So, I mean we're talking about taking that and reading it across to triethoxy at a concentration of

2.6. DR. MARKS: And the others were between 0.55 and -- DR. BELSITO: Right. DR. MARKS: -- and 0.77. And the one that had the highest uses was the triethoxy at 2.6 percent. DR. BELSITO: Right. DR. MARKS: My first blush is I've felt similar but then when Ron Shank brought up the issue of sensitization, I felt

okay, if we're going to first pass at this, let's ask for sensitization, but if you feel comfortable and convince Ron that it's okay, then that's fine with me. Because it is -- we had the bis with very high.

DR. BERGFELD: Ron Shank, are you agreeing or not? DR. SHANK: If the chemists are happy with the read across, then I concede. DR. HILL: Do you feel comfortable reading across to the -- Do you feel comfortable reading across to the

stearoxytrimethyl -- let's see, that's not listed as being -- what's the use on that concentration? DR. LIEBLER: Out of 10 uses 0.55 percent. DR. HILL: 0.55, okay. DR. LIEBLER: So a small number of uses. The big one was the -- in terms of uses was the triethox. DR. SHANK: So chemists? DR. LIEBLER: You're reading across from the bis- stearoxy -- DR. SHANK: Right. DR. LIEBLER: -- so that's one of the larger molecules in this group. And you're reading across to the triethoxy

caprylyl, which is only a C8 chain. So it's smaller -- you'd think the smaller more extensive absorption may be greater potential for trouble. On the other hand, the overwhelmingly high concentration tested with the bis-stearoxy kind of alleviated my concern. I mean you're lathering the stuff on and nothing happened, so.

DR. SHANK: Okay.


DR. BERGFELD: It's okay? Ron Hill, okay? So you're going to restate your motion? DR. HILL: No, we will have two other things to -- DR. BERGFELD: Okay. DR. HILL: -- discuss. So we have -- you believe there are concerns with -- DR. BELSITO: You had absorption. DR. HILL: Yeah, dermal absorption of the stearoxy. DR. BELSITO: And if absorbed -- DR. HILL: Yeah. DR. SNYDER: So why wasn't the systemic toxicity data sufficient? Because it doesn't really have any systemic

toxicity in both oral studies, lung -- pretty substantial oral studies and inhalation studies. And then also on the genotox table -- Table 4 has a number of genotox studies. So did you -- was there something different? I mean or -- because I thought we were reading across using these four.

DR. HILL: Stearoxy, itself, just the stearoxytrimethyl has no -- no tox data. DR. SNYDER: But would it behave differently than the others? DR. HILL: It's mono as opposed to bis or tri. DR. SNYDER: I mean there's no indication of any toxicity in the others, which I felt was a pretty good range of

studies, both inhalation and systemic. So we weren't really concerned about systemic toxicity. And then the genotox, there's a Table 4 that --

DR. SLAGA: I came to the same conclusion initially. (inaudible). DR. MARKS: Ron Shank, is that okay with you? DR. BERGFELD: Curt, do you have a comment? DR. KLAASEN: Yes. I'm okay with it. DR. BERGFELD: Okay. DR. MARKS: Okay, now we're down to -- you're chipping away at us. That's great. The last one in terms of data

needs, and Ron Hill, I'll let you speak to this, was the level of disilazane. DR. HILL: Disilazane. DR. MARKS: Yeah, let's get rid of that one. Anyway, what was your concern with that? DR. HILL: Yeah, so hexamethyldisilazane is a volatile and dangerous substance. And I don't -- we only have

information that one of them that's used in the manufacturer. We don't have that information one way or the other from the others. So my need was not necessarily analytical assessment of those levels but some information as to how that molecule is reacted in the process or, alternatively, analytical data telling us that the levels are very low, with a low level of detection. For that silazane and any other silazane that might potentially be used in the synthesis.

DR. BERGFELD: Are there comments? DR. BELSITO: Out of my (inaudible). Dan? DR. LIEBLER: Yeah, there's -- the description is just a little too cursory. I think it should be possible with a better

description of the method to essentially deal with the concern about residual disilazanes. Because if there is alcohol in excess, they're going to be completely chewed up.

DR. HILL: If there's alcohol in excess and the temperature is a little elevated, you're right, they're gone. And I think a little further information will resolve that.

DR. LIEBLER: And if these go in to anything aqueous, bye, bye, they're gone also. DR. HILL: Agreed. DR. LIEBLER: So in a formulation, even if the possibility that there's a little residual disilazane, if you put it in any

kind of a product formulation such as the uses here, it's going to see water and it's going to be hydrolyzed immediately. So I guess I -- even though it doesn't strictly, speaking, you know, this is kind of like asking for the concentration of the monomer.

DR. HILL: Well, yeah, but I mean, you know, if you put it in an oil-based cream, it's probably not seeing any water. And so, you know, I think it's not an unreasonable thing to request. What's the deal here? If they heat it a little bit in water and if there's excess alcohol and it's heated, whatever. I think we could get more information without asking somebody to give up something proprietary to tell us and give us a high level of confidence that this really dangerous chemical, that I've used in the lab, so I know what precautions are necessary, is minimized or eliminated.

DR. BELSITO: What is the danger?


DR. HILL: It's reactive with all kinds of proteins, genetic information. If it has genetic molecules, if it has access, there's an array of hazards that are associated with that chemical. And I know because I had to explain it to graduate students who were using it on numerous occasions, to make sure that they understood.

DR. LIEBLER: Well, I mean the thing that I remember about using it in the lab is that you use it to derivative to (siolate?) [isolate?] compounds. And it's so reactive, mainly with water, that once you open a vial of it and use

part of it, it's no good the next day because it's all been hydrolyzed. So -- DR. HILL: Yes. DR. LIEBLER: -- again, that sort of guides my thinking about it. I don't really -- I just don't share your concern

about the residual material because it's just. Even in Tucson in June it will be hydrolyzed. DR. BERGFELD: Okay. DR. MARKS: I'm going to withdrawal my motion, and I move that we issue a tentative report with a safe

conclusion for these four ingredients. So I think you've done an excellent job at addressing our concerns. DR. BERGFELD: Thank you. Nice discussion. Any other comments before we move the question? Not seeing

any. All those in favor? Opposed. One opposed. Thank you. [] – brackets are used by the analyst/writer to correct or offer a guess at what the speaker was saying that the

person typing out the transcripts may not have understood.


Safety Assessment of Alkoxyl Alkyl Silanes as Used in Cosmetics

Status: Draft Final 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: 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 [email protected]



ABSTRACT This is a safety assessment of alkoxyl alkyl silanes as used in cosmetics. The functions of these ingredients include: binder, skin-conditioning agent – miscellaneous, skin-conditioning agent – emollient, and surface modifier. The Cosmetic Ingredient Review (CIR) Expert Panel (Panel) reviewed relevant data related to these ingredients. The Panel concluded that Bis-Stearoxydimethylsilane, Stearoxytrimethylsilane, Triethoxycaprylylsilane, and Trimethoxycaprylylsilane are safe as cosmetic ingredients in the practices of use and concentration described in this safety assessment.

INTRODUCTION This is a review of the scientific literature and unpublished data relevant for assessing the safety of the alkoxyl alkyl

silanes as used in cosmetics. The ingredients in this report are structurally-related silanes bearing both alkyl and alkoxyl groups. The 4 ingredients in this report are:

• Bis-Stearoxydimethylsilane • Stearoxytrimethylsilane • Triethoxycaprylylsilane • Trimethoxycaprylylsilane

According to the International Cosmetic Ingredient Dictionary and Handbook (Dictionary), the functions of these

ingredients include: binder, skin-conditioning agent – miscellaneous, skin-conditioning agent – emollient, and surface modifier (Table 1).1

The Panel reviewed other siloxane ingredients, 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 cyclic siloxanes, the cyclomethicones (e.g., Cyclotetrasiloxane, Cyclopentasiloxane and Cyclohexasiloxane), and concluded that they were safe as used in cosmetic products.3

Trimethoxycaprylylsilane is reported to function as a surface modifier; therefore toxicity studies of metal particles coated with alkoxyl alkyl silanes are included in this safety assessment.

Some of the data included in this safety assessment were found on the European Chemicals Agency (ECHA) website.4 In this safety assessment report, ECHA is cited as the reference for summaries of information from industry obtained from the ECHA website.

CHEMISTRY

Definition and Structure The ingredients in this report are structurally-related silanes bearing both alkyl and alkoxy groups (Figure 1).

Figure 1. Alkoxyl Alkyl Silanes, where m+n=4 and R & R’ are methyl or alkyl groups

Physical and Chemical Properties Triethoxycaprylylsilane and Trimethoxycaprylylsilane are liquids that work well as dispersants for substances such as titanium dioxide. Triethoxycaprylylsilane and Trimethoxycaprylylsilane are clear and colorless (Table 2).4,5

Method of Manufacture

The alkoxyl alkyl silanes can be synthesized via hydrosilation of the appropriate alkoxy silane with an olefin (e.g., Triethoxycaprylylsilane may be synthesized via hydrosilation of 1-octene with triethoxysilane and a platinum catalyst).6 Alternatively, these ingredients may be synthesized via silation of appropriate alcohols with a disilazane (e.g., Stearoxytrimethylsilane may be synthesized via silation of octadecanol with hexamethyldisilazane and an organocatalyst).7 At the completion of the reaction, water is added and the organic materials are extracted with ethyl acetate.

Impurities A product mixture containing Bis-Stearoxydimethylsilane (approximately 75%), stearyl alcohol (approximately 16%), and dimethicone (approximately 9%), may contain <0.1% cyclotetrasiloxane as a manufacturing impurity.8 Analysis of three batches of this mixture showed that Al, As, Ba, Be, Bi, Ca, Cd, Co, Cr, Cu, Fe, Hg, Mn, Mo, Ni, Pb, Sb, Sn, Sr, Tl, V, W, Zn, and Zr were not present (detection level < 2 ppm); trace levels (<0.1%) of cyclotetrasiloxanes, cyclopentasiloxane, and cyclohexasiloxane were present.


Triethoxycaprylylsilane is reported to be 95%-100% pure.5 Impurities are reported to include ethanol (0.2%), octane (<1.5%), siloxanes (<2%), and branched octyltriethoxysilanes (<2%).

USE

Cosmetic The safety of the cosmetic ingredients included in this safety assessment is evaluated based on data received from

the Food and Drug Administration (FDA) and the cosmetics industry on the expected use of these ingredients in cosmetics. The data received from the FDA are collected from manufacturers through the FDA’s Voluntary Cosmetic Registration Program (VCRP), and include the use of individual ingredients in cosmetics by cosmetic product category. The data received from the cosmetic industry are collected by the Council in response to a survey of the maximum reported use concentrations by category.

According to 2016 VCRP survey data, Triethoxycaprylylsilane is reported to be used in 417 formulations, 413 leave-on formulations and 4 rinse-off formulations (Table 3).9 Stearoxytrimethylsilane and Trimethoxycaprylylsilane are reported to be used in 10 and 4 formulations, respectively.

The results of the concentration of use survey conducted by the Council in 2015 indicate that Triethoxycaprylylsilane has the highest reported maximum concentration of use; it is used at up to 2.6% in suntan products.10 The other three ingredients are reported to be used at 0.77% or lower.

No uses were reported in the VCRP for Bis-Stearoxydimethylsilane, but concentration of use data were received from industry; it was reported to be used in a foundation in the Council survey. Therefore, it can be assumed that there is at least one use for this ingredient.

Three of the alkoxyl alkyl silanes are in products that are used around the eyes (e.g., Triethoxycaprylylsilane in eye shadow up to 2.5%), and Triethoxycaprylylsilane is used in products that could possibly be ingested and/or have exposure to the mucous membranes (e.g., in lipstick up to 1%).

Additionally, Triethoxycaprylylsilane is used in cosmetic sprays and could possibly be inhaled; it is reported to be used at up to 0.021% in body and hand sprays and up to 0.011% in perfumes. In practice, 95%-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.11,12 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.13,14 Triethoxycaprylylsilane is used in face powders at up to 2%. Conservative estimates of inhalation exposures to respirable particles during the use of loose-powder cosmetic products are 400-fold to 1000-fold less than protective regulatory and guidance limits for inert airborne respirable particles in the workplace.15-17

None of the alkoxyl alkyl silanes named in the report are restricted from use in any way under the rules governing cosmetic products in the European Union.18 According to Annex VI to European Regulations (EC) No 1223/2009 Triethoxycaprylylsilane is listed as a permitted zinc oxide (nano) coating for UV filters.19 Zinc oxide (nano) is not to be used in applications that may lead to exposure of the end-user's lungs by inhalation. Zinc oxide is only to be used under certain conditions, which include “…uncoated, or coated with [T]riethoxycaprylylsilane, dimethicone, dimethoxydiphenylsilanetri-ethoxycaprylylsilane cross- polymer, or octyl triethoxy silane.”

TOXICOKINETIC STUDIES

Dermal Penetration Bis-Stearoxydimethylsilane A product mixture (3 mg/mL in ethanol/water) containing Bis-Stearoxydimethylsilane (approximately 75%) was placed in a donor chamber. The test was conducted using porcine ear skin.8,20 Samples of receptor fluid were taken at 0, 0.5, 1, 2, 4, 6, 8, and 24 h and analyzed by atomic absorption spectroscopy. None of the product was detected in the receptor chamber. It was concluded that the test item did not penetrate through porcine skin.

Absorption, Distribution, Metabolism, and Excretion (ADME) Human Triethoxycaprylylsilane

No toxicokinetics data were discovered; however, in humans, hydrolysis of Triethoxycaprylylsilane is expected to produce three moles of ethanol for each mole of octylsilanetriol.5 Triethoxycaprylylsilane undergoes rapid hydrolysis with a half-life of 0.3-0.6 h at a pH of 7.0 and 25˚C and 1.2-1.9 h at pH 4.0.5 Survival of Triethoxycaprylylsilane is expected to be transient depending on the test system, and observed intrinsic toxicity is likely due to a mixture of the parent molecule and the hydrolysis products ethanol and octylsilanetriol, and to a lesser degree any polymerization products. Based on the chemical structure of Triethoxycaprylylsilane, the hydrolysis products are expected at a ratio of 3 moles ethanol to 1 mole octylsilanetriol.


TOXICOLOGICAL STUDIES Acute Toxicity Studies

Dermal Triethoxycaprylylsilane

New Zealand White rabbits (n=5/sex/dose) were dermally exposed to Triethoxycaprylylsilane (2000, 4000 or 8000 mg/kg) under occlusion for 24 h.5 The study protocol was in accordance with the Environmental Protection Agency’s (EPA) Toxic Substances Control Act (TSCA) Health Effects Test Guideline.[40 CFR 798.1100] The rabbits were observed for 14 days following exposure. One female and three male rabbits died in the 8000 mg/kg group; one male rabbit died in the 4000 mg/kg group. Signs of toxicity were transient, involved the central nervous system, and included limb paresis or paralysis. Other clinical signs included labored breathing, iritis, slight wetness of the perinasal fur, and weight loss (some with emaciation). Necropsy of the rabbits that died revealed hemorrhaged intestines and a small amount of blood in the urine. Gross pathologic examination of all survivors revealed dark or bright red lungs. One rabbit exhibited intestines partially filled with gas, an enlarged spleen, and a raised tan nodule on one kidney. There were no treatment-related microscopic lesions in selected tissues (including spinal cord, sciatic nerve, kidneys, and urinary bladder). The acute dermal LD50 in male rabbits was 6730 mg/kg and in female rabbits > 8000 mg/kg. Trimethoxycaprylylsilane When Trimethoxycaprylylsilane (100%; 0.5 mL) was applied to the shaved dorsal skin of white Russian rabbits (n=3) under occlusion for 4 h, no systemic effects were detected.4 No further information was provided. Oral Bis-Stearoxydimethylsilane When a product mixture (2000 mg/kg) containing Bis-Stearoxydimethylsilane (concentration approximately 75%, dosage approximately 1500 mg/kg), stearyl alcohol, and dimethicone was orally administered to rats (n=5/sex), none of the rats died, there were no clinical signs of toxicity, and the necropsies were unremarkable.8,21 There were no effects on body weight changes during the 14-day observation period. Triethoxycaprylylsilane

A single dose of Triethoxycaprylylsilane (7280, 10,300 and 14,600 mg/kg in a 0.25% aqueous methyl cellulose solution) was administered by gavage to Sprague-Dawley rats (n=5/sex), and the rats were observed for 14 days.5 The study protocol in accordance with EPA TSCA Health Effects Test Guideline.[40 CFR 798.1175] The predominant signs of toxicity included effects on the central nervous system (sluggishness, aggressive behavior, and unsteady gait with limb paresis or paralysis, loss of righting reflex, and prostration). Other clinical signs included an unkempt and/or moribund appearance, emaciation, a red crust on the perinasal and periocular fur, and a moderate amount of blood in the urine. All deaths occurred within 4-9 days after dosing (total deaths not specified); three moribund female rats in the 14,600 mg/kg group were killed early for humane reasons. Necropsy of the rats that died during treatment or observation period revealed discolored lungs, livers, stomachs and intestines, small stomachs, hemorrhaged or gas-filled intestines, bladders distended with red liquid or urine (males); a large amount of blood was present in the urine of three males. The rats that survived the observation period had no gross lesions at necropsy. Selected tissues (brain, spinal cord, sciatic nerve, lungs, kidneys, and urinary bladder) from eight male and seven female rats were examined microscopically; the only lesions that were considered to be treatment-related were tubular dilation of the kidneys, renal mineralization and hemorrhages of the urinary bladder. The LD50 was 12,200 mg/kg for male rats, 11,500 mg/kg for female rats, and 11,800 mg/kg for the combined sexes.

Triethoxycaprylylsilane (5110 mg/kg in peanut oil) was administered by gavage to Bor: WISW (SPFCpb) rats (n=5/sex) and the rats were observed for 14 days.5 The study protocol was in accordance with the Organisation for Economic Co-operation and Development Test Guideline (OECD TG) 401. The predominant clinical signs of toxicity were effects on the central nervous system (incoordination, stilted gait, labored breathing, sunken sides and vocalization on handling). Other signs of toxicity included hypokinesia, diarrhea, piloerection, red encrusted snout, and body weight reduction. One female died on day 7 after dosing; at necropsy, the gastrointestinal tract was severely autolytic. At necropsy no abnormalities were detected in the animals that survived until the end of the study. The LD50 was >5110 mg/kg for male and female rats. Trimethoxycaprylylsilane

The reported oral LD50 for Trimethoxycaprylylsilane in Wistar rats (n=10/sex) was >3500 mg/kg for both males and females.4 After a dosage of 3236 mg/kg, there were coordination disturbances, piloerection, chromodacryorrhea, increased salivation, and red nasal discharge. At 4752 mg/kg, there was additional decreased muscle tone, loss of righting reflexes, and increased diuresis. Other clinical signs included tremors, vocalization on handling, lacrimation, opacity of the cornea, and green discolored urine. The development of toxic effects was not always immediate; coordination disturbances were observed 2 h after administration of the test material, and the other clinical signs occurred between days 2 and 5. All clinical signs resolved by day 21 of the observation period.


Inhalation Triethoxycaprylylsilane

In a study conducted in a manner similar to OECD TG 403, Crl:CD (R) BR, VAF (R) PLUS, Sprague-Dawley rats (n=5/sex) were exposed to a saturated vapor concentration of Triethoxycaprylylsilane in air (approximately 248 mg/m3) in a whole-body inhalation chamber for 4 h and then observed for 14 days.5 There were no deaths during the exposure or the observation period. Hyperactivity during the exposure period was observed in one rat. No exposure-related effects were noted on body weights and no abnormal gross lesions were noted at necropsy. The LC50 was greater than the saturated vapor concentration. Trimethoxycaprylylsilane Wistar rats (n=5/sex) were exposed to aerosolized Trimethoxycaprylylsilane in a whole-body chamber (duration not specified); because the concentration of the test material did not reach the desired levels (actual concentrations achieved not specified and no further information was provided), a nose-only apparatus was used to expose the rats.4 It is not clear if the same or new rats were used when the authors switched methods of exposure. The rats were exposed for 4 h in the nose-only apparatus and observed for 14 days thereafter. The mean actual concentrations of exposure in the nose-only apparatus were 0.9, 2.36, 2.53, and 6.2 g/m3 (corresponding nominal concentrations: 3.5, 9.8, 15.4, and 27.6 g/m3, respectively).

None of the rats died in the 0.9 g/m3 group, one male and three female rats died in the 2.36 g/m3 group, no males and four females died in the 2.53 g/m3 group, and one male and all five females died in the 6.2 g/m3 group.

During exposure to 0.9 g/m3 in the nose-only apparatus, the rats had a hunched appearance, piloerection, and mostly closed eyes. Breathing patterns were superficial and irregular during the first hour of exposure; breathing patterns became more regular concomitant with a decreased breathing frequency (1-2 breaths/sec vs 3-4 breaths/sec normally). Directly after exposure, breathing frequency was irregular in rats exposed to 0.9 g/m3. No abnormalities were observed 4 days after exposure to 0.9 g/m3. However, exposure to 0.9 g/m3 resulted in reduced body weight gain in male rats measured 14 days after exposure, and reduced body weight or body weight gain in female rats 7 and 14 days after exposure. Piloerection was observed during the first 4 days of observation in one female rat exposed to 2.36 g/m3. Superficial breathing patterns and wet heads were observed in rats exposed to 2.36 or 2.53 g/m3, and labored breathing was observed in four female rats exposed to 2.53 g/m3. Rats in the 2.36 g/m3 group showed drowsiness shortly after the end of exposure. Body weight gain of the surviving rats exposed to 2.36 or 2.54 g/m3 was generally not affected. No abnormalities were observed after 4 days in rats exposed to 2.53 g/m3. Exposure to 6.2 g/m3 in the nose-only apparatus resulted in a very low, deep or superficial, irregular breathing frequency (<1 breath/sec) 30 min after the start of exposure. In general, breathing patterns became more stable thereafter (1-2 breaths/sec). The rats exhibited wet heads 2 h after the start of the exposure. Directly after exposure, breathing frequency was labored in rats exposed to 6.2 g/m3. The rats with labored breathing were lethargic. The first 4 days of the observation period revealed piloerection, wet noses, drowsiness, and tightly closed eyes in surviving rats exposed to 6.2 g/m3. Piloerection remained until day 7 post exposure. Dyspnea was observed in one male 14 days after exposure; its limbs were blue, the rat was skinny and showed piloerection and signs of ataxia. All four surviving rats exposed to 6.2 g/m3 showed severe body weight reduction 7 days after exposure; body weight gain was observed 14 days after exposure in 3 of these rats.

At necropsy, red discolored lungs were observed in rats exposed to 2.36 g/m3. Rats exposed to 2.53 g/m3 had rusty-brown discolored lungs. Dark-red discolored, and sometimes swollen or darkly spotted, and/or edematous lungs were found in the rats that died, or were killed in extremis after exposure to 6.2 g/m3. Furthermore, grey-white spots were observed on the lung lobes of three female rats. In the other rats in the 6.2 g/m3 group that were killed in extremis, no other abnormalities were observed. In all surviving rats necropsied at the end of the 14-day observation period, no abnormalities were found, except for spotted lungs in one male exposed to 6.2 g/m3. The LC50 for Trimethoxycaprylylsilane was 7.5 and 1.9 g/m3 for male and female rats, respectively. The combined LC50 was 3.9 g/m3.4

Triethoxycaprylylsilane - Coated Particles In a pulmonary toxicity study, Triethoxycaprylylsilane-coated titanium dioxide particles (2 and 10 mg/kg) were instilled into the lungs of male Crl:CD (SD)IGS BR rats (n=6/group/recovery time) with and without Tween 80 (1%).22 The Triethoxycaprylylsilane-coated titanium dioxide particles were 230 nm (assumed diameter; mean or median not reported), with a particle size range of 0.1–0.9 µm, and a surface area of 8.2 m2/g; these particles were hydrophobic. Saline was the control substance. After saline instillation (2 from each group) and at 24 h, 1 week, 1 month, and 3 months (4 from each group), the rats were then killed, their lungs were lavaged with warm phosphate-buffered saline, and the lungs were examined. The numbers of cells recovered by broncho-alveolar lavage from the lungs of any of the Triethoxycaprylylsilane-coated titanium dioxide particles-exposed groups were not different from saline-instilled controls at any post-exposure time point. Histopathological analyses of a lung tissue section of rats in the high dose groups at 1 month post-exposure showed normal pulmonary architecture and, other than a few particle-laden macrophages, were not very different from a saline-instilled lung section at 1 month post-exposure. The authors concluded that the Triethoxycaprylylsilane-coated titanium dioxide particles did not cause pulmonary toxicity. Zinc oxide particles coated with Triethoxycaprylylsilane (1, 4, 8, 16, 32, 64, or 128 µg) suspended in water with 2% mouse serum were intratracheally instilled into the lungs of C57BL/6N mice (n=3).23 The particles were 130 nm in diameter; when analyzed in suspension, the median diameter was 208±74 nm and mean diameter was 225±32 nm, indicating


agglomeration and an asymmetrical particle-size distribution. The mice were killed and necropsied 24 h after instillation. Acute pulmonary inflammation was observed (marked by polymorphonuclear neutrophil influx) with cell damage (marked by increased lactate dehydrogenase and total protein) in broncho-alveolar lavage fluid (BALF) in the 64 and 128 µg groups. Systemic inflammation was indicated by increased blood neutrophils and decreased blood lymphocytes in the lung tissue. These signs were not observed in the 1-32 µg groups.

Short-Term Toxicity Studies Oral Bis-Stearoxydimethylsilane

In a 28-day oral study (administered by gavage) conducted in accordance with OECD TG 407, a product mixture (50, 200, 1000 mg/kg) containing Bis-Stearoxydimethylsilane (approximately 75%) was reported to have a no-observed-adverse-effect level (NOAEL) of 1000 mg/kg/d (approximately 750 mg/kg/d Bis-Stearoxydimethylsilane) in SPF-bred Wistar rats.8,24,25 None of the rats died and there were no clinical signs during the test period. There were no adverse effects observed in the grip strength test and locomotor activity test during week 4 of the test period. Feed consumption and body weight changes were similar to the control group (vehicle only). Hematology and clinical biochemistry parameters of blood collected at the end of treatment were similar in the test and control groups. Macroscopic and microscopic findings at necropsy were unremarkable; organ weights were similar in the control and treatment groups. Triethoxycaprylylsilane

In a combined repeated-dose/reproductive/developmental toxicity screening test conducted in accordance with OECD TG 422, Triethoxycaprylylsilane (0, 100, 300 or 1000 mg/kg/d in dried, de-acidified peanut oil) was administered 7 days a week by gavage to Sprague-Dawley rats (n=10/sex).5 There was a group of females evaluated for repeated-dose toxicity and another group evaluated for reproductive toxicity. The same males were used in both the toxicity and reproductive phases of the study. Males and females of the repeated-dose toxicity study were treated for 28 and 29 days, respectively. Females of the reproductive-toxicity group were treated with the same dose rates for up to 45 days (prior to mating through post-partum day 4). Animals were observed twice daily for mortality, morbidity, and moribundity. Clinical examinations were performed daily following dosing. Functional observational battery (FOB) and motor activity evaluations were performed on males and females of the repeated-dose toxicity group. Detailed physical examinations and body weight measurements were performed weekly. Individual feed consumption was recorded weekly, except during the cohabitation period. Blood samples for hematology and serum chemistry evaluations were collected at the scheduled necropsy. Complete necropsies were performed, and selected organs were weighed. Microscopic examination was performed on protocol-specified tissues from the control and high-dose males, and females of the repeated-dose toxicity and reproductive-toxicity groups. Based on clinical and histopathology findings in the high dose group, various target tissues of the males and females of the repeated-dose toxicity and reproductive-toxicity groups were examined at the mid- and low-dose groups. [See results specific to reproduction in the Developmental and Reproductive Toxicity section.]

Clinical signs included an increase in soiling of the head (around the nose, chin, and muzzle) in the mid- and high-dose males and females of the repeated-dose toxicity groups, and in the females of the high-dose reproductive-toxicity group. Clinical observations consistent with neuromuscular toxicity (decreased activity, dragging of the hind limbs, and/or uncoordinated gait) occurred only in the high-dose reproductive toxicity group, and were not observed in the males or females of the repeated-dose toxicity group. Due to the severity of these clinical signs, three females of the high-dose reproductive-toxicity group were killed prior to scheduled necropsy. There were no changes observed during FOB and motor activity tests conducted with males and females of the repeated-dose toxicity group (no clinical signs before termination), most likely due to the shorter duration of exposure compared to the females of the reproductive-toxicity group (29 days for females of the repeated-dose toxicity group vs up to 45 days for females of the reproductive-toxicity group). Treatment-related decreases in group mean body weights and/or body weights gains were observed in all rats in the high-dose groups with associated decreases in feed consumption in the females of the repeated-dose and reproductive-toxicity groups. There were no treatment related clinical pathology findings.

There was an increase in mean absolute and relative liver weights of males and females in the toxicity group in the high-dose group. Histopathological findings were identified in the liver as dose-related increases in the incidence of centrilobular hypertrophy in the mid- and high-dose groups in the repeated-dose toxicity and reproductive-toxicity studies, which was associated with an increase in mean absolute and relative liver weights; these liver effects were not considered adverse because these changes are consistent with common adaptive changes that occur in the liver upon xenobiotic administration. Histopathological findings were identified in the bladder as diffuse epithelial hyperplasia in all rats in the high-dose groups in the repeated-dose toxicity study. Other unspecified histopathological findings were also identified in the kidneys, adrenal glands, thymus, spleen, brain, spinal cord, peripheral nerves, and skeletal muscles in the high-dose groups. In the brain, 40% and 80% of the high-dose groups in the repeated-toxicity study and females in the reproductive-toxicity study, respectively, exhibited white matter degeneration. Degeneration of the spinal cord occurred in 50% and 90% of the females of the high-dose group in the repeated-dose toxicity study and reproductive-toxicity groups, respectively. The peripheral nerves (sciatic and tibial) also showed minimal to severe degeneration and demyelination in the high-dose group in the repeated-toxicity study and reproductive-toxicity groups, with less incidence and severity occurring in the repeated-dose


toxicity females. Based on the bladder epithelial hyperplasia in males and the neuromuscular findings in the females of the repeated-dose toxicity and reproductive groups at 1000 mg/kg/d, the NOAEL for systemic toxicity was 300 mg/kg/d.5

Fischer 344 rats (n=5/sex, 10/sex in high-dose and control group) were administered Triethoxycaprylylsilane (200, 2000, and 10,000 ppm) in the diet for 28 days.5 The study protocol was similar to that of OECD TG 407. Mean test substance consumption values for males were 12.2, 114.4, and 592.2 mg/kg/d for the 200, 2000, and 10,000 ppm target concentrations, respectively. Mean test substance consumption for females was 13.4, 122.6, and 639.6 mg/kg/d for the 200, 2000, and 10,000 ppm target concentrations, respectively. Following termination of dosing, 5 rats/sex from the high-dose and control groups were allowed a 2-week recovery period. Clinical signs, feed consumption, body and organ weights, hematology, clinical chemistry evaluations, gross pathology and histopathology evaluations were monitored; no changes indicating an adverse effect were observed. The NOAEL was determined to be >10,000 ppm (the highest dose tested), corresponding to dose rates of approximately 592.2 and 639.6 mg/kg/d for male and female rats, respectively.

Inhalation Triethoxycaprylylsilane - Coated Particles

In an inhalation toxicity study, male Wistar rats (n=17/group/time point) were exposed to Triethoxycaprylylsilane-coated zinc oxide nanoparticles (0, 0.5, 2.5, and 12.5 mg/m3; 22,126, 87,044, 233,360 particles/cm3, respectively) in a head/nose only apparatus for 6 h/day for 5 days in accordance with OECD TG 412.26 During exposure, the 12.5 mg/m3 exposure was measured at 219,031 particles/cm3; particle size and surface area were not specified. Twelve rats in each group were killed and necropsied on either day 4 or 25; nine of these rats were examined histopathologically and organ burdens were determined in three rats (results not reported). On study days 7 and 28, the lungs of the remaining five rats in each group were lavaged, and the BALF was analyzed for markers indicative of injury of the broncho-alveolar region. On exposure days, clinical examination was performed before, during and after exposure. The inhalation of zinc oxide nanoparticles coated with Triethoxycaprylylsilane for five days resulted in local inflammation in the lungs of the rats. Examination showed activation of the draining lymph nodes. Minimal to moderate necrosis of the olfactory epithelium was observed. The effects occurred in a concentration-dependent manner and were reversed by the end of the recovery period, except for a multifocal increase in alveolar macrophages that was still present. At the lowest concentration of 0.5 mg/m3, increased levels of a few mediators in the BALF and in serum were determined. Also, of the six rats examined, minimal (grade 1) multifocal necrosis of the olfactory epithelium was noted in the nasal cavity in one rat treated at the lowest dose. Therefore, a no-observed-adverse-effect-concentration (NOAEC) could not be established. The lowest concentration of 0.5 mg/m3 was considered to be the low-observed-adverse-effect-concentration (LOAEC).26

DEVELOPMENTAL AND REPRODUCTIVE TOXICITY (DART) Triethoxycaprylylsilane

As stated previously, Triethoxycaprylylsilane (0, 100, 300 or 1000 mg/kg/d in dried, de-acidified peanut oil) was administered 7 days a week by gavage to 10 rats/sex/group for up to 45 consecutive days in a combined repeated-dose/reproductive/developmental toxicity screening test.5 The study was in accordance with OECD TG 422. Females were divided into a repeated-toxicity group and a reproductive-toxicity group. The same males were used for both the repeated-dose toxicity and reproductive-toxicity phases of the study. Males were treated for 28 days. Reproductive-toxicity group females were treated for up to 45 days (14 days prior to mating, during mating, gestation, and up to and including postpartum day 4). Mating was initiated after 2 weeks of dosing. Females in the reproductive-toxicity group cohabitated with males of the same treatment group until positive evidence of mating occurred. A maximum of 14 days were allowed for mating. Reproductive parameters evaluated included evidence of mating, pregnancy, duration of gestation, mean number of corpora lutea and mean number of uterine implantation sites, mean mating and fertility indices and evaluation of loss of offspring (pre-implantation and post-natal loss). [See results specific to toxicity in the Short-Term Toxicity Studies section.]

Changes in reproductive parameters were observed in the high-dose group and were associated with marked maternal toxicity. Mating and fertility were unaffected by treatment. The mean duration of gestation was increased (5.6%) compared to the control group. Of the seven dams that successfully initiated parturition, four exhibited dystocia (difficult/prolonged labor). The authors concluded that it was not possible to determine with confidence if 1000 mg/kg/d represents the NOAEL. Therefore, the reproductive toxicity NOAEL was considered to be >300 mg/kg/d.

To evaluate the developmental toxicity of Triethoxycaprylylsilane, dams and pups were killed on postpartum day 4 and examined for external gross lesions. Developmental parameters evaluated included total litter size, mean litter size, mean live litter size, mean litter weight, mean ratio of live births/litter size, sex ratio, pup viability, pup body weight, and body weight gain. Changes in developmental parameters were observed in the high-dose group and were associated with marked maternal toxicity; the total litter sizes in this group were unaffected by treatment but the mean number of live male and female pups/dam at first litter check on post-natal day (PND) 0 was decreased (39.3%) compared to controls. PND 0 mean litter weights, average pup body weights and body weight gains were similar to controls. By PND 4, several dams in the high-dose group had been killed due to the severity of various clinical signs and/or difficulty during labor. Only 4 dams survived to PND 4. Of these litters, the total viable pups on PND 4 were decreased compared to controls, resulting in a 25.2% decrease in percent viability of pups/dam on PND 4 compared to controls. This decrease was due to a single dam with a 14.3% post-natal loss of offspring. The remaining dams had no post-natal loss of pups between Days 0-4. PND 4 mean litter weights, average pup body weights and body weight gains in the high-dose group were also decreased compared to


controls. External gross lesions were not observed for treated dams or pups. The authors concluded that it was not possible to determine with confidence if 1000 mg/kg/d represents the NOAEL. Therefore, they considered the developmental toxicity NOAEL to be >300 mg/kg/d.5

GENOTOXICITY STUDIES In Vitro

Genotoxicity studies are summarized in Table 4. In multiple genotoxicity assays, Bis-Stearoxydimethylsilane (up to 5000 µg/plate), Trimethoxycaprylylsilane (up to

5000 µg/plate), and Triethoxycaprylylsilane (up to 10,000 µg/plate) were negative for genotoxicity. Trimethoxycaprylylsilane was not cytotoxic.4,5,8,24,27

In Vivo

Triethoxycaprylylsilane - Coated Particles A mouse micronucleus assay was conducted in accordance with OECD TG 474 with intraperitoneally injected Triethoxycaprylylsilane-coated zinc oxide nanoparticles (0, 15, 30, 60 mg/kg; 10 mL/kg) using male NMRI mice (n=5/dose/time).26 Bone marrow cells were harvested for evaluation of micronuclei at 24 h post-dose (vehicle, positive controls, and low-, mid-, and high-dose) and 48 h post-dose (vehicle and high-dose only). There were no statistically significant or biologically relevant differences in the number of erythrocytes containing micronuclei either between the vehicle control groups and the three dose groups, or between the two intervals (24 and 48 h). The number of normochromatic or polychromatic erythrocytes containing small micronuclei or large micronuclei did not deviate from the vehicle control values at either of the intervals and was within the historical vehicle control data range. The controls had the expected results.

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

DERMAL IRRITATION AND SENSITIZATION STUDIES

Irritation Animal Bis-Stearoxydimethylsilane A product mixture containing Bis-Stearoxydimethylsilane (approximately 75%) was reported to be non-irritating in rabbits.8 No further information was provided. Triethoxycaprylylsilane

Triethoxycaprylylsilane (100%; 0.5 mL) was applied under occlusion for 4 h to the intact skin of New Zealand White rabbits (n=3/sex).5 The study protocol followed EPA TSCA Health Effects Test Guideline. [40 CFR 798.4470] The rabbits were restrained for the 4-h contact period; when the coverings were removed, excess test substance was removed. Moderate erythema (grade 2) and moderate edema (grades 2-3) were observed in all rabbits at the 1-h observation time; this was resolved on day 7. At day 7, desquamation was observed on two animals. The Primary Irritation Index (PII) was 3.041 (3=primary skin irritant; 4=corrosive to the skin). The substance was considered to be moderately irritating to the skin.

Triethoxycaprylylsilane (100%; 0.5 mL) was applied to the skin of Russian white rabbits (n=2 male, 1 female) for 4 h under occlusion in accordance with OECD TG 404.5 The coverings were removed and the test substance was not washed off. Moderate erythema (grades 2-3) and moderate-to-severe edema (grades 3-4) were observed in all three rabbits at 1 h. Desquamation was observed in all animals beginning on day 7. All skin effects had completely resolved on day 10. The Primary Dermal Irritation Index (PDII) was 5.1 on a scale of 0 to 8. The substance was considered to be highly irritating to the skin.

In a toxicological study described previously, New Zealand White rabbits (n=5/sex) were dermally exposed to Triethoxycaprylylsilane (2000, 4000 or 8000 mg/kg) under occlusion for 24 h.5 The study protocol followed EPA TSCA Health Effects Test Guideline. [40 CFR 798.1100] Dermal reactions included erythema, edema, necrosis, fissuring, desquamation and alopecia; it was not specified which dose level(s) caused these reactions. Trimethoxycaprylylsilane

Trimethoxycaprylylsilane (assumed 100%; 0.5 mL) was administered to the shaved dorsal skin of white Russian rabbits (n=3) under occlusion for 4 h.4 The test site was observed at 1, 24, and 72 h, then daily for 14 days. Moderate to severe erythema was observed in all three rabbits immediately after removal of the patches, which resolved by day 10 of observation. Slight edema in one rabbit and moderate edema in the other two rabbits was observed immediately after the end of exposure, which was resolved by day 9. All rabbits showed eschar formation from the middle of the first observation week, which had not completely peeled off in two rabbits until the end of the observation period. The mean PDII was 4.9 on a scale of 0 to 8; the mean value for erythema/eschar was 2.42, and the mean value for edema was 2.5. Trimethoxycaprylylsilane was considered irritating to rabbit skin.


Sensitization

Animal Bis-Stearoxydimethylsilane

In a Magnusson/Kligman assay conducted according to OECD TG 406 using guinea pigs (n=20, control=10) of a product mixture containing Bis-Stearoxydimethylsilane (75%), the test group was intradermally injected with the test substance (10%, 7.5% Bis-Stearoxydimethylsilane; with and without Freund’s complete adjuvant).8,24,28 One week later, the test substance was dermally administered (75% in Alembicol D, 52.50% Bis-Stearoxydimethylsilane). Two weeks later, the guinea pigs were challenged with the test substance (50%, 37.5% Bis-Stearoxydimethylsilane). There was no sensitization response observed.

OCULAR IRRITATION STUDIES

Animal Bis-Stearoxydimethylsilane

A product mixture containing Bis-Stearoxydimethylsilane (approximately 75%) was reported to be non-irritating in the eyes of rabbits.8 No further information was provided. Triethoxycaprylylsilane

A single instillation of Triethoxycaprylylsilane (assumed 100%; 0.1 mL) was made into one eye of each New Zealand White rabbit (n=3/sex) and the eyes were not rinsed.5 The study protocol was in accordance with the EPA TSCA Health Effects Test Guideline.[40 CFR 798.4500] The untreated eyes served as controls. Irritation was scored according to the Draize method at 1, 24, 48 and 72 h after administration. Transient iritis (grade 1) was apparent in 4 treated eyes at 1 h, but had resolved at 24 h. Minor to moderate conjunctival irritation characterized by redness and swelling (grades 1-2) with a moderate amount of ocular discharge (grades 1-2) was observed in all treated eyes. All of the rabbits had a normal ocular appearance by day 7. The maximum average score (MAS) was 12.33 (in a scale of 0 to 110) at 1 h; the scores at 72 h and day 7 were <0. Triethoxycaprylylsilane was considered slightly irritating.

In an acute eye irritation/corrosion study conducted in accordance with OECD TG 405, a single instillation of Triethoxycaprylylsilane (0.1 mL) was applied to conjunctiva of one eye of albino Russian white rabbits (n=1 male, 2 female).5 The untreated eyes served as controls. The eyes were not rinsed. Diffuse redness of the conjunctiva (grade 2) seen in all three rabbits resolved within 48 h. Slight swelling (grade 1) was observed in all three rabbits at 1 h; discharge was also noted in one rabbit at this time point. No effects on the cornea or iris were observed. The irritation index was 2.0 (on a scale of 0 to 110). Triethoxycaprylylsilane was considered slightly irritating. Trimethoxycaprylylsilane In a Draize test using white Russian albino rabbits (n=1 male, 2 females), Trimethoxycaprylylsilane (0.1 mL) was instilled into one eye of each rabbit.4 The test substance was not rinsed and the eyes were observed for 3 days. There were no effects observed on the corneas and irises. The conjunctiva reacted with hyperemia (grade 1) in one rabbit and a diffuse crimson or beefy discoloration (grade 2 or 3) was observed in two rabbits. In addition, slight swelling (grade 1) or swelling with partial eversion of lids (grade 2) was observed. Swelling had completely disappeared at 24 h and redness was not observed 48 or 96 h after instillation. Discharge with moistening around the eye was recorded for two rabbits only at the 1-h observation time. The mean irritation score was 4 out of a possible 80. It was concluded that Trimethoxycaprylylsilane was not irritating to the eyes of rabbits.

SUMMARY

This is a review of the available scientific literature and unpublished data relevant to assessing the safety of the alkoxyl alkyl silanes as used in cosmetics. The ingredients in this report are structurally-related silanes and bear both alkyl and alkoxyl groups. The functions of these ingredients include skin-conditioning agent – miscellaneous, skin-conditioning agent – emollient, binder, and surface modifier.

According to 2016 VCRP survey data, Triethoxycaprylylsilane is reported to be used in 417 formulations, 413 which are leave-on formulations and 4 that are rinse-off formulations. Stearoxytrimethylsilane and Trimethoxycaprylylsilane are reported to be used in 10 and 4 formulations, respectively. Bis-Stearoxydimethylsilane had no reported uses in the VCRP.

The 2015 Council survey reports that Triethoxycaprylylsilane has the highest reported maximum concentration of use; it is used at up to 2.6% in suntan products. The other three ingredients are reported to be used at 0.77% or lower.

A product mixture containing Bis-Stearoxydimethylsilane (approximately 75%) did not penetrate porcine skin in an in vitro assay.

The acute dermal LD50 of Triethoxycaprylylsilane was 6730 mg/kg in male rabbits and > 8000 mg/kg in female rabbits. When Trimethoxycaprylylsilane was administered to the skin of rabbits under occlusion for 4 h, there were no systemic effects observed.


When a product mixture containing Bis-Stearoxydimethylsilane (approximately 1500 mg/kg) was orally administered to rats, none of the rats died, there were no clinical signs of toxicity, and the necropsies were unremarkable. The LD50 was 12,200 mg/kg for Triethoxycaprylylsilane for male rats, 11,500 mg/kg for female rats, and 11,800 mg/kg for the combined sexes. In another assay, the LD50 value was >5110 mg/kg for male and female rats. The reported oral LD50 for Trimethoxycaprylylsilane in rats was >3500 mg/kg for both males and females; after a dose of 3236 mg/kg, there were coordination disturbances, piloerection, chromodacryorrhea, increased salivation, and red nasal discharge.

There were no deaths during exposure or the observation period when rats were exposed to a saturated vapor of approximately 248 mg/m3 of Triethoxycaprylylsilane in a whole body inhalation chamber for 4 h.

The inhalation LC50 for Trimethoxycaprylylsilane following a 4 h exposure was 7.5 and 1.9 g/m3 for male and female rats, respectively; the combined LC50 was 3.9 g/m3. Clinical signs included superficial and irregular breathing during the first hour of exposure, wet heads, lethargy, piloerection, tightly closed eyes. Body weight gains were reduced during the observation period. The lungs of the rats that died or were killed in extremis were discolored and spotted.

Triethoxycaprylylsilane-coated titanium oxide particles at 10 mg/kg did not cause pulmonary toxicity when instilled into the lungs of rats. Zinc oxide particles coated with Triethoxycaprylylsilane caused acute pulmonary inflammation with cell damage in BALF at 64 and 128 µg in mice but not at 1-32 µg.

In a 28-day oral study, a product mixture containing Bis-Stearoxydimethylsilane at approximately 75% was reported to have a NOAEL of 1000 mg/kg/d (approximately 750 mg/kg/d Bis-Stearoxydimethylsilane) in rats.

In a repeated-dose/reproductive/developmental toxicity screening test, the NOAEL for systemic toxicity was 300 mg/kg/d Triethoxycaprylylsilane when administered for 28-29 days. Clinical signs at 300 and 1000 mg/kg/d included an increase in soiling around the nose, chin, and muzzle. Neuromuscular toxicity was observed at 1000 mg/kg/d. Treatment-related decreases in group mean body weights and/or body weights gains were observed in all rats in the high-dose groups with associated decreases in feed consumption in the toxicity group females and reproductive group females. There were no treatment related clinical pathology findings. The NOAEL was >10,000 ppm (the highest dose tested), corresponding to dosages of approximately 592.2 and 639.6 mg/kg/d for male and female rats, respectively, when Triethoxycaprylylsilane was administered in the diet for 28 days.

The inhalation of zinc oxide nanoparticles coated with Triethoxycaprylylsilane for five days resulted in local inflammation in the lungs of the rats. A NOAEC could not be established; the lowest concentration of 0.5 mg/m3 was considered to be the LOAEC.

The reproductive and developmental toxicity NOAELs were >300 mg/kg/d for orally administered Triethoxycaprylylsilane in female rats; Triethoxycaprylylsilane was administered from 14 days prior to mating through 4 days postpartum. Reproductive effects only occurred in the 1000 mg/kg/d group in association with marked maternal toxicity.

A product mixture containing Bis-Stearoxydimethylsilane (approximately 75%) was reported to not be mutagenic at doses up to 5000 µg/plate in an Ames assay. In two separate assays, Triethoxycaprylylsilane was negative for mutagenicity in bacterial reverse mutation assays with Salmonella typhimurium and Escherichia coli, with and without metabolic activation at up to 10,000 µg/plate. In an in vitro chromosome aberration assay, Triethoxycaprylylsilane was cytotoxic to CHO cells with metabolic activation at 50 µg/mL and without metabolic activation at 20 µg/mL. In an in vitro chromosome aberration assay, Triethoxycaprylylsilane was negative for the induction of chromosome aberrations and was not clastogenic up to 1570 µg/mL. In Ames tests, Trimethoxycaprylylsilane was not mutagenic to S. typhimurium up to 5000 µg/plate.

A mouse micronucleus assay of Triethoxycaprylylsilane-coated zinc oxide nanoparticles was negative at up to 60 mg/kg.

A product mixture containing Bis-Stearoxydimethylsilane (approximately 75%) was reported to be non-irritating in rabbits. The PII was 3.041 when Triethoxycaprylylsilane (assumed 100%) was administered to rabbits; the substance was considered as moderately irritating to the skin. In another assay (assumed 100%), the PDII was 5.1 and Triethoxycaprylylsilane was considered to be highly irritating to rabbit skin. When rabbits were dermally exposed to Triethoxycaprylylsilane at 2000-8000 mg/kg under occlusion for 24 h, dermal reactions included erythema, edema, necrosis, fissuring, desquamation and alopecia; it was not specified which dose level(s) caused these reactions. Trimethoxycaprylylsilane was considered irritating to rabbit skin at 100%.

A product mixture containing 75% Bis-Stearoxydimethylsilane was reported to be non-sensitizing in a Magnusson Kligman assay using guinea pigs.

A product mixture containing Bis-Stearoxydimethylsilane at approximately 75% was reported to be non-irritating in the eyes of rabbits. After a single instillation of Triethoxycaprylylsilane, the MAS was 12.33 at 1 h; the scores at 72 h and day 7 were <0; Triethoxycaprylylsilane was considered slightly irritating. In an acute eye irritation/corrosion study, the irritation index was 2.0 for Triethoxycaprylylsilane and the test substance was considered slightly irritating. In a Draize test, using rabbits, there were no effects observed on the corneas and irises and Trimethoxycaprylylsilane was considered to be non-irritating.

DISCUSSION

The Panel considered dermal, oral, and inhalation toxicity studies, and DART animal studies, with acute to short-term exposures at concentrations much greater than levels reported to be used in cosmetics (i.e., up to 2.6%). Genotoxicity studies were negative in both in vitro and in vivo studies. A product containing 75% Bis-Stearoxydimethylsilane was not


sensitizing in a Magnusson Kligman assay. While these studies were conducted on animals, the Panel agreed with applying the results of these studies to humans. The Panel also noted that any irritation noted was also at concentrations well above the reported concentrations of use. The Panel was satisfied that the inhalation and genotoxicity studies on metal particles coated with Triethoxycaprylylsilane were sufficient to show that this application (as a surface modifier) of these ingredients would not be toxic when used in cosmetics.

The Panel noted gaps in the available safety data for the alkoxyl alkyl silanes in this safety assessment. The available sensitization data on Bis-Stearoxydimethylsilane are sufficient to cover the other three ingredients in this group. The available overall data for Bis-Stearoxydimethylsilane, Triethoxycaprylylsilane, and Trimethoxycaprylylsilane are sufficient to cover the lack of data for Stearoxytrimethylsilane. Similarity between structural activity relationships can be extrapolated and concentrations of use in cosmetics can be used to support the safety of each member of this group.

There was no evidence presented that the starting material hexamethyldisilazane persists in the finished product. The addition of water at the end of the manufacturing process will consume any residual hexamethyldisilazane. Industry should use good manufacturing practices (GMPs) when producing and using these ingredients to ensure that impurities are not present to any appreciable amount.

The Panel discussed the issue of incidental inhalation exposure from body and hand sprays and perfumes. Triethoxycaprylylsilane is used in face powders at up to 2%. The limited data available from inhalation studies, including acute and short-term exposure data, suggest little potential for respiratory effects at relevant doses. In one study of Triethoxycaprylylsilane-coated titanium dioxide particles, the particles were reported to be 230 nm with a particle size range of 0.1-0.9 µm. The Panel noted the results of high-dosage intratracheal installation studies in animals showing that respirable Triethoxycaprylylsilane-coated titanium dioxide particles caused no effects at the lower dosages tested. In another study, Triethoxycaprylylsilane-coated zinc oxide particles had a reported diameter of 0.13 µm; the median diameter was reported to be 0.208±0.074 µm and the mean diameter was 0.225±0.032 µm, which indicated agglomeration. The Panel believes that the sizes of a substantial majority of the coated particles are larger than those in the respirable range and/or aggregation and agglomeration form larger particles in formulation. The Panel believes that the sizes of a substantial majority of the particles in a cosmetic formulation aggregate and agglomerate to release airborne particles or droplets that would be larger than those in the respirable range. The Panel noted that 95%-99% of droplets/particles would not be respirable to any appreciable amount. Coupled with the small actual exposure in the breathing zone and the concentrations at which the ingredients are used, the available information indicates that incidental inhalation would not be a significant route of exposure that might lead to local respiratory or systemic effects. A detailed discussion and summary of the Panel’s approach to evaluating incidental inhalation exposures to ingredients in cosmetic products is available at http://www.cir-safety.org/cir-findings.

CONCLUSION

The CIR Expert Panel concluded that Bis-Stearoxydimethylsilane, Stearoxytrimethylsilane, Triethoxycaprylylsilane, and Trimethoxycaprylylsilane are safe in cosmetics in the present practices of use and concentration described in this safety assessment.


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

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

TABLES

Table 1. Definitions, CAS Nos., idealized structures, and functions of the alkoxyl alkyl silane ingredients in this safety assessment.1, CIR Staff

Ingredient CAS No. Definition & Structures Function(s) Bis-Stearoxydimethylsilane 29043-70-7

Bis-Stearoxydimethylsilane is the silicon compound that conforms to the formula. [Bis-Stearoxydimethylsilane is an organo-silicon compound, Si-substituted with 2 octadecoxyl groups and 2 methyl groups.]

Skin-conditioning agent - miscellaneous

Stearoxytrimethylsilane 18748-98-6

Stearoxytrimethylsilane is the organo-silicon compound that conforms to the formula. [Stearoxytrimethylsilane is an organo-silicon compound, Si-substituted with 1 octadecoxyl group and 3 methyl groups.]

Skin-conditioning agent - emollient

Triethoxycaprylylsilane 2943-75-1

Triethoxycaprylylsilane is the siloxane ether that conforms to the formula. [Triethoxycaprylylsilane is an organo-silicon compound, Si-substituted with 3 ethoxyl groups and 1 octyl group.]

Binder

Trimethoxycaprylylsilane 3069-40-7

Trimethoxycaprylylsilane is the siloxane ether that conforms to the formula. [Trimethoxycaprylylsilane is an organo-silicon compound, Si-substituted with 3 methoxyl groups and 1 octyl group.]

Binder; surface modifier


Table 2. Chemical and physical properties of alkoxyl alkyl silane ingredients. Property Value Reference

Bis-Stearoxydimethylsilane Physical Form Solid 24 Color White 24 Odor Odorless 24 Molecular Weight g/mol 597.13 29 Density/Specific Gravity @ 50oC 0.84 24 Melting Point oC 35 24

Stearoxytrimethylsilane Molecular Weight g/mol 342.68a Density/Specific Gravity 0.8±0.1 est.b 30 Vapor pressure mmHg@ 25 oC 0.0±0.9 estb 30 Boiling Point oC 387.1±10.0 estb 30 logP 10.65 estb 30

Triethoxycaprylylsilane Physical Form Liquid 5 Color Clear/colorless 5 Molecular Weight g/mol 276.49a Density/Specific Gravity g/cm3 @ 23oC 0.876 5 Vapor pressure mmHg@ 25oC 0.1±0.4 estc 31 Melting Point oC -46

-40 5 31

Boiling Point oC 257 265

5 31

Water Solubility g/L @ 22.8oC <0.13 5 log Kow @ 23oC logP

~3.7b

5.45 estc

5 31

Trimethoxycaprylylsilane Physical Form Liquid 4 Color Clear/colorless 4 Molecular Weight g/mol 231.1 32 Density @ 20oC 0.91 4 Viscosity kg/(s m)@ oC 0.10 4 Vapor pressure mmHg@ 20oC 157.5 4 Boiling Point oC 227

246 4 4

Water Solubility g/L @ 20oC 0.0133 4 log Pow 3.9±0.2 4 a Estimated from molecular formula b The water solubility and log Kow values may not be accurate because the chemical is hydrolytically unstable. c Estimated by ACD/Labs Percepta Platform - PhysChem Module est.=estimated


Table 3. Frequency of use according to duration and exposure of alkoxyl alkyl silanes.9,10

Use type Uses

Maximum Concentration

(%) Uses


(%) Uses


(%) Uses


(%)

Triethoxycaprylylsilane Bis-

Stearoxydimethylsilane Stearoxytrimethylsilane Trimethoxycaprylylsilane Total/range 417 0.000001-2.6 NR 0.38 10 0.1-0.55 4 0.1-0.77

Duration of use Leave-on 413 0.000001-2.6 NR 0.38 10 0.1-0.55 4 0.1-0.77 Rinse-off 4 0.0005-0.087 NR NR NR 0.55 NR NR

Diluted for (bath) use NR 0.001-0.048 NR NR NR NR NR NR

Exposure typea Eye area 120 0.005-2.5 NR NR 1 0.36 1 0.1-0.14

Incidental ingestion 15 0.0024-1 NR NR NR NR NR NR

Incidental Inhalation-sprays

9; 36b; 14c

0.011-0.021; 0.004-0.8b NR NR 7b; 1c NR 1b NR

Incidental inhalation-powders 40; 14c 0.006-2;

0.000001-2.4d NR NR 1c 0.55d NR 0.6d

Dermal contact 386 0.000001-2.6 NR 0.38 10 0.1-0.55 4 0.1-0.77 Deodorant (underarm) NR NR NR NR NR NR NR NR

Hair-noncoloring 4 0.8 NR NR NR 0.55 NR NR Hair-coloring 5 NR NR NR NR NR NR NR

Nail 2 0.18-0.15 NR NR NR NR NR NR Mucous

Membrane 19 0.001-1 NR NR NR NR NR NR

Baby NR NR NR NR NR NR NR NR NR=Not Reported; Totals=Rinse-off + Leave-on + Diluted for Bath Product 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.

Table 4. In vitro genotoxicity studies of alkoxyl alkyl silanes. Ingredient; Concentration Assay Results Reference Bis-Stearoxydimethylsilane (approximately 75%) with stearyl alcohol and dimethicone; 33.3-5000.0 µg/plate

Ames assay, OECD TG 471; S. typhimurium (TA98, TA100, TA1535, and TA1537) with and without metabolic activation. No controls were specified. The experiment was conducted twice.

Negative. No toxic effects were observed.

8,24,27

Triethoxycaprylylsilane; up to 10,000 µg/plate

Ames assay, OECD TG 471; S. typhimurium (strains TA98, TA100, TA1535, TA1537, and TA1538) and Escherichia coli (WP2 uvrA) with and without metabolic activation. No controls were specified. The experiment was conducted twice.

Negative. Cytotoxic concentration in both studies was >5000 µg/plate.

5

Triethoxycaprylylsilane (16-50 µg/mL with metabolic activation, 6.4-35.4 µg/mL without metabolic activation)

Chromosome aberration assay (similar to OECD TG 473). The cells were exposed for 6, 24 and 48 h in the absence of metabolic activation and for 6 h in the presence of metabolic activation.

There were no increases in structural or numerical chromosome aberrations. Cytotoxic to CHO cells with metabolic activation at 50 µg/mL and without metabolic activation 20 µg/mL and higher. The controls had the expected results.

5

Triethoxycaprylylsilane ; 0.016-157 µg/mL in ethanol

Chromosome aberration assay, OECD TG 473, using CHO cells.

Negative with and without metabolic activation. The controls had the expected results.

4

Trimethoxycaprylylsilane; up to 10 mg/plate

Bacterial reverse mutation assay, OECD TG 471; with S. typhimurium (strains TA98, TA100, TA1535, TA1537, and TA1538) and Escherichia coli (WP2 uvrA)

Negative with and without metabolic activation. Not cytotoxic. The controls had the expected results.

4

Trimethoxycaprylylsilane; up to10 mg/plate

Bacterial reverse mutation assay, OECD TG 471; with S. typhimurium (strains TA98, TA100, TA1535, TA1537, and TA1538) and Escherichia coli (WP2 uvrA)


4

Trimethoxycaprylylsilane; 33.3-5000 µg/plate

Ames test; S. typhimurium (strains TA98, TA100, TA1535, and TA1537)


4

CHO=Chinese hamster ovary OECD TG=Organisation for Economic Co-operation and Development Test Guideline


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, W, Belsito, D, Hill, R, Klaassen, C, Liebler, D, Marks Jr, J, Shank, R, Slaga, T, Snyder, P, and Andersen, F. Safety assessment of cyclomethicone, cyclotetrasiloxane, cyclopentasiloxane, cyclohexasiloxane, and cycloheptasiloxane. International Journal of Toxicology. 2011;30(Suppl. 3):149S-227S.

4. European Chemicals Agency. Trimethoxycaprylylsilane 3069-40-7. 2013. http://echa.europa.eu/registration-dossier/-/registered-dossier/5888. Date Accessed 10-6-2015.

5. Organization for Economic Cooperation and Development (OECD) Screening Information Data Set (SIDS). SIDS initial assessment report for SIAM 30. Washington, DC, U.S. Environmental Protection Agency (EPA). 2010. http://webnet.oecd.org/HPV/UI/handler.axd?id=25fcf7df-e401-40da-8737-629b166b934b. pp. 1-28.

6. Bai, Y, Peng, J, Li, J, Jiang, J, and Lai, G; inventor. Hangzhou Normal University, People's Republic of China, assignee. Recoverable polymer supported complex platinum catalyst for hydrosilylation of olefins, and its preparation and application. China CN 101850271. 2010.

7. Dekamin, MG, Yazdaninia, N, Mokhtari, J, and Naimi-Jamal, M. Tetrabutylammonium phthalimide-N-oxyl. An efficient organocatalyst for trimethylsilylation of alcohols and phenols with hexamethyldisilazane. Journal of the Iranian Chemical Society. 2011;8(2):537-544.

8. Wacker Chemie AG. 2015. Product dossier Belsil® SDM 6022. Unpublished data submitted by Personal Care Products Council.

9. Food and Drug Administration (FDA). Frequency of use of cosmetic ingredients; FDA Database. Washington, DC, FDA. 2016.

10. Personal Care Products Council. 10-9-2015. Concentration of Use Information: Alkoxy Alkyl Silanes. Unpublished data submitted by Personal Care Products Council.

11. Johnsen MA. The Influence of Particle Size. Spray Technology and Marketing. 2004;14(11):24-27. http://www.spraytm.com/back-issues-2.

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

13. 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.

14. 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.

15. CIR Science and Support Committee of the Personal Care Products Council (CIR SSC). 11-3-2015. Cosmetic Powder Exposure. Unpublished data submitted by the Personal Care Products Council.

16. Aylott RI, Byrne GA, Middleton, J, and Roberts ME. Normal use levels of respirable cosmetic talc: preliminary study. Int J Cosmet Sci. 1979;1(3):177-186. PM:19467066.

17. Russell RS, Merz RD, Sherman WT, and Sivertson JN. The determination of respirable particles in talcum powder. Food Cosmet Toxicol. 1979;17(2):117-122. PM:478394.

18. European Commission. CosIng database: following Cosmetic Regulation No. 1223/2009. http://ec.europa.eu/growth/tools-databases/cosing/. Last Updated 2015.

19. European Commission. Commission Regulation (EU) 2016/621 of 21 April 2016 amending Annex VI to Regulation (EC) No 1223/2009 of the European Parliament and of the Council on cosmetic products . 2016. pp.1-3. http://eur-lex.europa.eu/legal-content/EN/TXT/PDF/?uri=CELEX:32016R0621&from=EN

20. RCC. 2000. Skin permeability in vitro absorption through porcine ear skin with Wacker Belsil SDM 6022 (contains approximately 75% Bis-Stearoxydimethylsilane). Unpublished data submitted by Personal Care Products Council.

21. Research Toxicology Centre S.p.A. 1996. Summary: Acute oral toxicity study in the rat Belsil SDM 6022 (contains approximately 75% Bis-Stearoxydimethylsilane). Unpublished data submitted by Personal Care Products Council.


http://echa.europa.eu/registration-dossier/-/registered-dossier/5888

http://webnet.oecd.org/HPV/UI/handler.axd?id=25fcf7df-e401-40da-8737-629b166b934b

http://www.spraytm.com/back-issues-2

http://www.rivm.nl/bibliotheek/rapporten/320104001.pdf

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

http://eur-lex.europa.eu/legal-content/EN/TXT/PDF/?uri=CELEX:32016R0621&from=EN

http://eur-lex.europa.eu/legal-content/EN/TXT/PDF/?uri=CELEX:32016R0621&from=EN

22. Warheit, DB, Reed, K, and Webb, T. Pulmonary toxicity studies in rats with triethoxyoctylsilane (OTES)-coated, pigment-grade titanium dioxide particles: Bridging studies to prediect inhalation hazard. Experimental Lung Research. 2003;29(8):593-606.

23. Gosens, I, Kermanizadeh, A, Jacobsen, N, Lenz, A-G, Bokkers, B, de Jong, W, Krystek, P, Tran, L, Stone, V, Wallin, H, Stoeger, T, and Cassee, F. Comparative hazard identification by a single dose lung exposure of zinc oxide and silver nanomaterials in mice. PLoS ONE. 2015;10(5):e0126934 http://journals.plos.org/plosone/article?id=10.1371/journal.pone.0126934.

24. Wacker Chemie AG. 2015. Safety data sheet Belsil® SDM 6022. Unpublished data submitted by Personal Care Products Council.

25. RCC. 1999. Summary: 28-Day oral toxicity (gavage) study in the Wistar rat Wacker-Belsil SDM 6022 (contains approximately 75% Bis-Stearoxydimethylsilane). Unpublished data submitted by Personal Care Products Council.

26. Scientific Committee on Consumer Safety (SCCS). Opinion on zinc oxide (nano form). Brussels, European Commission. 2012. http://ec.europa.eu/health/scientific_committees/consumer_safety/docs/sccs_o_103.pdf. Date Accessed 5-24-2016. Report No. SCCS/1489/12. pp. 1-112.

27. RCC. 1996. Summary: Salmonella typhimurium reverse mutation assay with Wacker Be1sil SDM 6022 (contains approximately 75% Bis-Stearoxydimethylsilane). Unpublished data submitted by Personal Care Products Council.

28. Research Toxicology Centre S.p.A. 1996. Delayed dermal sensitization study in the guinea pig. Unpublished data submitted by Personal Care Products Council.

29. National Center for Biotechnology Information. PubChem Compound Database. Compound Summary for CID 120117 - Dimethylbis(octadecyloxy)silane. https://pubchem.ncbi.nlm.nih.gov/compound/120117. Last Updated 2015.

30. ChemSpider Search and Share Chemistry. 1-Trimethylsilyloxyoctadecane. http://www.chemspider.com/Chemical-Structure.79192.html?rid=022021ea-388b-4508-a370-4294bfffc617. Last Updated 2015.

31. ChemSpider Search and Share Chemistry. Octyltriethyoxysilane; ID 68741. http://www.chemspider.com/Chemical-Structure.68741.html?rid=2e1f17af-bf65-46ec-abdc-3cb2b47ce7e3&page_num=0. Last Updated 2015.

32. National Center for Biotechnology Information. PubChem Compound Database. CID=76485, Trimethoxy(octyl)silane. https://pubchem.ncbi.nlm.nih.gov/compound/76485. Last Updated 2015. Date Accessed 12-4-2015.

33. ChemSpider Search and Share Chemistry. Octyltrimethyoxysilane; ID 68955. http://www.chemspider.com/Chemical-Structure.68955.html?rid=470ccf7e-e282-46d3-bd9c-8f8a4020120e&page_num=0. Last Updated 2015. Date Accessed 12-4-2015.


http://journals.plos.org/plosone/article?id=10.1371/journal.pone.0126934

http://ec.europa.eu/health/scientific_committees/consumer_safety/docs/sccs_o_103.pdf

http://www.chemspider.com/Chemical-Structure.79192.html?rid=022021ea-388b-4508-a370-4294bfffc617

http://www.chemspider.com/Chemical-Structure.79192.html?rid=022021ea-388b-4508-a370-4294bfffc617

http://www.chemspider.com/Chemical-Structure.68741.html?rid=2e1f17af-bf65-46ec-abdc-3cb2b47ce7e3&page_num=0

http://www.chemspider.com/Chemical-Structure.68741.html?rid=2e1f17af-bf65-46ec-abdc-3cb2b47ce7e3&page_num=0

http://www.chemspider.com/Chemical-Structure.68955.html?rid=470ccf7e-e282-46d3-bd9c-8f8a4020120e&page_num=0

http://www.chemspider.com/Chemical-Structure.68955.html?rid=470ccf7e-e282-46d3-bd9c-8f8a4020120e&page_num=0

2016 VCRP Data – Alkoxy Alkyl Silanes

03D - Eye Lotion STEAROXYTRIMETHYLSILANE 1 07C - Foundations STEAROXYTRIMETHYLSILANE 1 12D - Body and Hand (exc shave) STEAROXYTRIMETHYLSILANE 1 12F - Moisturizing STEAROXYTRIMETHYLSILANE 4 12G - Night STEAROXYTRIMETHYLSILANE 1 13A - Suntan Gels, Creams, and Liquids STEAROXYTRIMETHYLSILANE 2 10

03A - Eyebrow Pencil TRIETHOXYCAPRYLYLSILANE 2 03B - Eyeliner TRIETHOXYCAPRYLYLSILANE 11 03C - Eye Shadow TRIETHOXYCAPRYLYLSILANE 74 03D - Eye Lotion TRIETHOXYCAPRYLYLSILANE 8 03F - Mascara TRIETHOXYCAPRYLYLSILANE 5 03G - Other Eye Makeup Preparations TRIETHOXYCAPRYLYLSILANE 20 04C - Powders (dusting and talcum, excluding aftershave talc)

TRIETHOXYCAPRYLYLSILANE 4

05B - Hair Spray (aerosol fixatives) TRIETHOXYCAPRYLYLSILANE 4 06E - Hair Color Sprays (aerosol) TRIETHOXYCAPRYLYLSILANE 5 07A - Blushers (all types) TRIETHOXYCAPRYLYLSILANE 21 07B - Face Powders TRIETHOXYCAPRYLYLSILANE 36 07C - Foundations TRIETHOXYCAPRYLYLSILANE 102 07D - Leg and Body Paints TRIETHOXYCAPRYLYLSILANE 4 07E - Lipstick TRIETHOXYCAPRYLYLSILANE 15 07F - Makeup Bases TRIETHOXYCAPRYLYLSILANE 15 07I - Other Makeup Preparations TRIETHOXYCAPRYLYLSILANE 26 08E - Nail Polish and Enamel TRIETHOXYCAPRYLYLSILANE 2 10A - Bath Soaps and Detergents TRIETHOXYCAPRYLYLSILANE 4 12C - Face and Neck (exc shave) TRIETHOXYCAPRYLYLSILANE 13 12D - Body and Hand (exc shave) TRIETHOXYCAPRYLYLSILANE 2 12F - Moisturizing TRIETHOXYCAPRYLYLSILANE 18 12G - Night TRIETHOXYCAPRYLYLSILANE 7 12J - Other Skin Care Preps TRIETHOXYCAPRYLYLSILANE 8 13A - Suntan Gels, Creams, and Liquids TRIETHOXYCAPRYLYLSILANE 3 13B - Indoor Tanning Preparations TRIETHOXYCAPRYLYLSILANE 7 13C - Other Suntan Preparations TRIETHOXYCAPRYLYLSILANE 1 417

03C - Eye Shadow TRIMETHOXYCAPRYLYLSILANE 1 07C - Foundations TRIMETHOXYCAPRYLYLSILANE 1 12F - Moisturizing TRIMETHOXYCAPRYLYLSILANE 1 12J - Other Skin Care Preps TRIMETHOXYCAPRYLYLSILANE 1 4

There were no reported uses in the 2016 VCRP for Bis-Stearoxydimethylsilane


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: June 1, 2016

SUBJECT: Comments on the Draft Safety Assessment of Alkoxy Alkyl Silanes as Used in Cosmetics (prepared for the June 6-7, 2016 meeting)

Key Issue Additional chemical and physical properties of Bis-Stearoxydimethylsilane can be found in the

information provided by industry on the trade name material Besil SDM 6022. This information provides a higher molecular weight (700 and 950) than the molecular weight stated in the CIR report (597.13). Density and melting point are also provided.

Additional Considerations Introduction - Please provide the current INCI names of the components of cyclomethicone, e.g.,

Cyclotetrasiloxane, Cyclopentasiloxane and Cyclohexasiloxane. Impurities - Octamethylcyclotetrasiloxane is a different name for Cyclotetrasiloxane (INCI

name). Please use the INCI name throughout the Impurities subsection. Cosmetic Use - It should be noted that Triethoxycaprylylsilane is specifically listed as a

permitted Zinc Oxide (nano) coating in the EU regulations for UV filters. Acute, Inhalation - As lung distribution is different following pulmonary installation, it would be

helpful to present the lung instillation studies in a separate subsection. Genotoxicity- As Trimethoxycaprylylsilane was not genotoxic, it is not clear why this section

only says it was "not cytotoxic". Table 4- The two bacterial reverse mutation assays on Triethoxcaprylylsilane appear to be the

same study. Both studies are both cited to reference 4 which appears to be incorrect as reference 4 is the ECHA dossier on Trimethoxycaprylylsilane.

1620 LStreet, N.W., Suite 1200 I Washington, D.C. 20036,202.331.1770 I 202.331.1969 (fax) I www.personiJJcarecouncil.org


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: June 23, 2016

SUBJECT: Comments on the Tentative Report: Safety Assessment of Alkoxy Alkyl Silanes as Used in Cosmetics (posted June 13, 2016)

Key Issue Discussion - Please review the CIR Precedents: Aerosols document. This document states that

droplets/particles less than I 0 ~m are respirable. The Discussion of this report implies that particles of208 nm agglomerated to 225 (units not stated) would not be respirable. This is not correct; the zinc oxide Triethoxycaprylsilane particles that were tested would be respirable. Fortunately, particle size of an ingredient does not equate to particle size of a product. The Discussion should state that if respirable particles are used in a product, they should be formulated so that the particles generated by the finished product are of a size that is not respirable.

Additional chemical and physical properties of Bis-Stearoxydimethylsilane can be found in the information provided by industry on the trade name material Besil SDM 6022 (information provide November 11, 20 15). This information provides a higher molecular weight (700 and 950) than the molecular weight stated in the CIR report (597 .13 ). Density and melting point are also provided.

Additional Considerations Acute, Inhalation, Triethoxycaprylylsilane - Coated Particles - Please add the units for the mean

diameter size (225 ± 32). As direct installation results in a different exposure pattern than inhalation, it would be helpful to include an instillation subsection.

Short-term, Inhalation- The description of reference 26 indicates that "organ burdens were determined in three rats". What was measured? What were the results ofthese measurements?

Summary- As there were three Ames assays ofTrimethoxycaprylylsilane, "In an Ames tests" needs to be corrected. Please name the substance with PDII of 5.1 that was considered to be highly irritating to rabbit skin.

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


Discussion - Because "doses" rather than "concentrations" were tested in oral studies, and because the dermal exposure studies were conducted at high dose or high concentrations, the following sentence does not make sense: "However, at concentrations that were closer to those used in cosmetics, these ingredients were not toxic or dennally damaging."

2


safety assessment of alkoxyl alkyl silanes as used in ... · subject: safety assessment of alkoxyl...

Documents