BLUE BOOK 1
Methyl Acetate
CIR EXPERT PANEL MEETING AUGUST 30-31, 2010
Memorandum
To: CIR Expert Panel Members and Liaisons
From: Bart Heldreth Ph.D., Chemist
Date: July 30, 2010
Subject: Draft Final Report of Methyl Acetate, Simple Alkyl Acetate Esters, Acetic Acid and its Salts as used in Cosmetics .
This review includes Methyl Acetate and the following acetate esters, relevant metabolites and acetate salts: Propyl Acetate, Isopropyl Acetate, t-Butyl Acetate, Isobutyl Acetate, Butoxyethyl Acetate, Nonyl Acetate, Myristyl Acetate, Cetyl Acetate, Stearyl Acetate, Isostearyl Acetate, Acetic Acid, Sodium Acetate, Potassium Acetate, Magnesium Acetate, Calcium Acetate, Zinc Acetate, Propyl Alcohol, and Isopropyl Alcohol.
At the June 2010 meeting, the Panel reviewed information submitted in response to an insufficient data announcement for HRIPT data for Cetyl Acetate at the highest concentration of use (lipstick). On reviewing the data in the report, evaluating the newly available unpublished studies and assessing the newly added ingredients, the Panel determined that the data are now sufficient, and issued a Tentative Report, with a safe as used conclusion.
Included in this report are Research Institute for Fragrance Materials (RIFM) sponsored toxicity studies on Methyl Acetate and Propyl Acetate, which were provided in “wave 2” at the June Panel Meeting but are now incorporated in full.
The Tentative Report was issued for a 60 day comment period (60 days as of the August panel meeting start date). The Panel should now review the Draft Final Report, confirm the conclusion of safe, and issue a Final Report.
All of the materials are in the Panel book as well as in the URL for this meeting's web page http://www.cir- safety.org/aug10.shtml.
CIR Panel Book Page 1 CIR Panel Book Page 2 CIR Expert Panel History with Methyl Acetate
2009 – Methyl Acetate was selected for review.
December 2009 - CIR issued a Scientific Literature Review.
Draft Report April 2010 - The draft report was brought before the Expert Panel, with the addition of Acetic Acid and the metal salt ingredients. The Panel decided to request a draft tentative report. The Panel stated that additional data are needed, specifically an HRIPT of Cetyl Acetate at the highest concentration of use (reportedly 17% at the time of the panel meeting) to address the issue of sensitization.
Draft Tentative Report June 2010 – The draft tentative report was brought before the Expert Panel, with the addition of an unpublished maximization study of Cetyl Acetate at 12.6% in a lipstick formulation (which, according to industry, is the actual highest use concentration in a lipstick for Cetyl Acetate, not 17%). The Expert Panel determined that all data needs had been met and requested that a Tentative Report be issued, with a safe as used conclusion.
Tentative Report July 1, 2010 – The tentative report was prepared and made available for a 60 day public comment period.
CIR Panel Book Page 3 Ingredient Managers: Angela Howard & Bart Heldreth Dates: 9/1/2009-2/28/2010
Ingredient Name(s): CAS RN Ingredient Name(s): CAS RN Ingredient Name(s): CAS RN Ingredient Name(s): CAS RN Ingredient Name(s): CAS RN Methyl Acetate 79-20-9 Isobutyl Acetate 110-19-0 Stearyl Acetate 822-23-1 Isopropyl Alcohol 67-63-0 Potassium Acetate 127-08-2 Butoxyethyl Acetate 112-07-2 Isopropyl Acetate 108-21-4 Myristyl Acetate 638-59-5 Magenesium Acetate 142-72-3 t -Butyl Acetate 540-88-5 Isostearyl Acetate NL Nonyl Acetate 143-13-5 Acetic Acid 64-19-7 Calcium Acetate 62-54-4 Cetyl Acetate 629-70-9 Propyl Acetate 109-60-4 Propyl Alcohol 71-23-8 Sodium Acetate 127-09-3 Zinc Acetate 557-34-6
Checklist Database Search Terms Date Hits Notes Free PubMed A, B 8/18/2009 D 11/3/2009 E 11/4/2009 F 2/5/2010 Free HPDB A
HSDB; Chem Idplus, Toxline, CCRIS, CPDB, DART, 100- GENETOX, IRIS, ITER, LactMed, CIR 200/ch Multi-Database, TRI, Haz-Map, Free TOXNET A, F em Household Products, TOXMAP Panel Free NTP A Free search/ Pay retrieval NTIS
Book Yr license Merck A FDA A Federal Register Notices SCCP A, B, F Opinions and EU Directives Page IPCS A 11/20/2009 Password Required RIFM F
4 Pay Service STN A, F RTECS, Beilstein OECD A 9/3/2009 SIDS Reports HPVIS A 12/17/2009 High Production Volume Iinformation System
FOIA Submitted FOIA Results
Search Terms Key A CAS No(s) B INCI Names C Methanol D isopropyl alcohol AND toxicity E propyl alcohol AND toxicity F Acetic Acid and the metal acetate salts via name and CAS Nos. (and CAS files where available)
Transcripts/ Minutes
115th COSMETIC INGREDIENT REVIEW EXPERT PANEL MEETING
Washington, D.C. Monday, June 28, 2010
CIR Panel Book Page 5 2
11 DR. BELSITO: Okay. In April we went
12 insufficient asking for an HRIPT for cetyl acetate
13 at the highest use concentration of lipstick. And
14 we got those data from the Council. It was for 24
15 subjects -- 27 subjects and essentially was
16 negative. And so the question now is is the data
17 adequate and do we -- are we comfortable with the
18 discussion? And this morning we got some updated
19 concentration of use on the acetic acid and
20 acetates.
21 Is this yours, also, Lillian? Oh, okay.
22 So is there anything different from what we had
CIR Panel Book Page 6 81
1 before on the concentrations?
2 DR. HELDRETH: Well, for the acid and
3 the salts I had added them to this grouping after
4 the cycle of requesting the data. So this is new.
5 We didn't have on the acid and the salts, we
6 didn't have concentration of use yet.
7 DR. BELSITO: Oh.
8 DR. HELDRETH: These are -- for the acid
9 and the salts.
10 DR. BELSITO: Okay.
11 DR. LIEBLER: Right. I think previously
12 we didn't have anything, right, with these?
13 DR. BELSITO: So this is all new data.
14 Okay. So all quite low.
15 DR. HELDRETH: The high uses were in the
16 -- the higher uses I should say were in the
17 esters. And we had that data.
18 DR. BELSITO: Right.
19 DR. HELDRETH: So this is only related
20 to the acids and the salts that were added in
21 April.
22 DR. BELSITO: Okay. So are we
CIR Panel Book Page 7 82
1 comfortable with the information that we have on
2 manufacturing and impurities?
3 DR. LIEBLER: I think it's brief, but
4 reasonable.
5 DR. BELSITO: Okay. So in the
6 irritation and sensitization studies, at the last
7 meeting we looked at a study with 11.7 percent
8 cetyl acetate and I don't see that here. I see
9 12.6 percent. And unfortunately, I didn't save
10 the whole report. I just saved the conclusion in
11 my old report. But I had noted that it was 11.7
12 percent. These were studies that were handed out
13 at the last meeting. So did I just copy the
14 concentration down wrong?
15 DR. BRESLAWEC: You had what percentage?
16 DR. BELSITO: My note was 11.7 percent
17 cetyl acetate.
18 DR. BRESLAWEC: Could it have been 17
19 percent?
20 DR. BELSITO: I mean, it could have been
21 anything because it's not in this document and I
22 didn't save -- this was CIR supplement page 250.
CIR Panel Book Page 8 83
1 You know, I didn't save all 250 pages in my
2 document. I just stuck this in my old document,
3 so I don't --
4 DR. HELDRETH: No, you're correct. It's
5 not in the back of the book here. We had the 11.7
6 percent and we asked that we would get an HRIPT
7 study at the maximum dose and Industry did come
8 back with a maximization.
9 DR. BELSITO: Right. And that's the
10 only one you included. But why throw out an
11 existing study?
12 DR. HELDRETH: It was an accident on my
13 part.
14 DR. BELSITO: Okay.
15 DR. HELDRETH: It will be in there.
16 DR. BELSITO: And then we also had one
17 on isopropyl alcohol at at 80.74 percent that's
18 not in this current document either that we
19 reviewed last time.
20 DR. BRESLAWEC: It was isopropyl alcohol
21 at what percentage?
22 DR. BELSITO: It was isopropyl alcohol
CIR Panel Book Page 9 84
1 at 80.74 percent.
2 DR. BRESLAWEC: Okay. We will find it
3 and include it.
4 DR. BELSITO: Yeah. The derm signing
5 off on it was Norm Cainoff. Again, I just have
6 the last conclusion pages, but I'll keep them in
7 my book.
8 Okay. In the discussion on page 26, the
9 third line, what is ASDFHQE?
10 DR. BRESLAWEC: That is a special coding
11 system.
12 (Laughter)
13 DR. BELSITO: Just for the heck of it I
14 typed it in to search the web. It didn't come up
15 with anything either.
16 DR. HELDRETH: I think what happened is
17 I inserted a citation there and somehow when the
18 citations were updated it left the gibberish there
19 and I didn't catch it before it got in
20 publication.
21 DR. BELSITO: Okay. So we need to add
22 to this report or the summary the two missing
CIR Panel Book Page 10 85
1 studies that I just found out. And then the 12.6
2 percent cetyl acetate RIPT is not in the study, in
3 the summary rather. It needs to be put in the
4 summary. But overall I thought they look fine.
5 Safe as used? Is that where we're going? I mean,
6 we got the data we asked for.
7 DR. LIEBLER: Yes.
8 DR. SNYDER: Yeah.
9 DR. BELSITO: Okay. And is there
10 anything that anyone feels is not in the
11 discussion that needs to be added to the
12 discussion?
13 DR. BERGFELD: I wonder if I could ask
14 Halyna, when are you going to put these summaries
15 in? Not only this document, but others, the
16 italicized summaries that are under the captured
17 topics. Is there a game plan for that?
18 DR. BRESLAWEC: The game plan is to add
19 them to all newly developed reports. This report
20 was started last fall and it's still kind of part
21 of the old scheme, but --
22 DR. BERGFELD: There are some in this
CIR Panel Book Page 11 86
1 though.
2 DR. BRESLAWEC: There are some in this.
3 Now, they may be in it because they're data from
4 old reports. The whole italic thing is a little
5 bit confusing because in re-reviews the italics
6 are used to signify that it's data from old
7 reports. In other reports the italics are used to
8 signify a summary and we're still trying to figure
9 out how best to deal with that. In this report
10 they signify old report because it has no
11 summaries. But our intent is to include summaries
12 with everything new from a point forward and this
13 is pre that point.
14 DR. BERGFELD: Is it everything new or
15 every major topic? For instance, toxicity.
16 DR. BRESLAWEC: I'm sorry. I was
17 talking about the development of the report. It
18 should be consistent for every topic. If there
19 are a lot of information under a particular
20 category, we may add another summary. But it
21 should be for each topic.
22 DR. KLAASSEN: Okay. So on page 16, I
CIR Panel Book Page 12 87
1 was very confused about this also. Yes. Page 16,
2 for example. And under most of the categories,
3 like carcinogenicity, there's three or four lines
4 in italics. Right? Now, that means what?
5 DR. BRESLAWEC: In this report.
6 DR. HELDRETH: In this case this is
7 summarizing what's below.
8 DR. KLAASSEN: Okay. This is
9 summarizing below. Okay, now, in that regard, for
10 genotoxicity at the top of the page we don't have
11 a summary. Is that purposeful or not? I couldn't
12 quite understand the whole system this time.
13 DR. BRESLAWEC: I can see why. We'll
14 address that.
15 DR. KLAASSEN: Okay. Okay. Fine.
16 DR. LIEBLER: Maybe it just needed to be
17 italicized under genotoxicity, the first two
18 lines. It looks like a mini abstract part,
19 doesn't it?
20 DR. BRESLAWEC: Yes, it does.
21 DR. HELDRETH: Yes.
22 DR. BELSITO: I guess one way of doing
CIR Panel Book Page 13 88
1 that is your summary is italicized and should
2 occur all the time. And then the first paragraph,
3 if there's been a prior report and you just want
4 to summarize it you don't need to put it in
5 italics. It just -- in a prior report from CIR,
6 the reference, it was found that or it was
7 reported that boom, boom, boom, and just a summary
8 of that.
9 DR. KLAASSEN: Yes.
10 DR. BELSITO: And so the first paragraph
11 when we're doing re-reviews we'll always, we'll
12 know is the summary of what we looked at already.
13 And what's in italics is the summary of the whole
14 section. And that's it. And then new data below
15 it.
16 DR. BERGFELD: I like the format that's
17 on 18 under Clinical Assessment where you have
18 sort of the italics part of the captured summary
19 and then you have the single spaced indented
20 review of the other document insert. So it's
21 distinctively different. I recommend that.
22 DR. BRESLAWEC: I think those are two
CIR Panel Book Page 14 89
1 good suggestions and maybe you can discuss that
2 tomorrow.
3 DR. SNYDER: Yeah. I think we need to
4 have a continued discussion about it because in
5 the current format it's very confusing. And I
6 like these summary statements that summarize all
7 of the findings under the major headings because
8 that signals to me whether or not I need to go any
9 deeper and look for more detail. But I think
10 currently we just don't -- we haven't really
11 captured that to the maximum efficiency yet.
12 Some other comments. If you go to the
13 introduction on pages 1 and 2, so then on the
14 third paragraph there's a parenthetic statement
15 there, "the ability and efficiency of esterase in
16 the skin is often species dependent." I think we
17 need to capture that in the ADME -- absorption,
18 distribution, metabolism, excretion -- section. I
19 think that has relevance there. It's a
20 significant relevance so it shouldn't be just
21 parenthetical. I think it should be captured in
22 that section.
CIR Panel Book Page 15 90
1 And then throughout this introduction we
2 talk about metabolism of all of them. T-butyl
3 acetate is metabolized to t-butyl alcohol. I
4 think we can capture that in just a simple
5 sentence that they're metabolized to the simple
6 alcohol -- to their relevant alcohol. And then
7 have that kind of referenced to that in the
8 absorption metabolism and excretion section. So
9 we don't need to have it in two. I think we just
10 have a single sentence. But because they're all
11 expected to be metabolized to their respective
12 alcohols, the following alcohol reports were used
13 to support this document instead of having all
14 that gibberish in the first part.
15 And then do we -- this sort of goes back
16 down. Do we always refer to it as a fragrance
17 ingredient (inaudible) in as a use or do we not go
18 there?
19 DR. BRESLAWEC: We actually got a
20 comment from the Council which we will incorporate
21 and that sentence will read, "CIR does not review
22 the safety of ingredients used as a fragrance
CIR Panel Book Page 16 91
1 unless there are other reported functions as is
2 the case with the ingredients in this report."
3 Does that clarify it?
4 DR. SNYDER: Because some of them we
5 start off that that's their first function in
6 cosmetics, fragrance. And I don't think we want
7 to go there. Or we typically don't go there.
8 DR. BRESLAWEC: Would that correction
9 clarify that?
10 DR. SNYDER: Yes.
11 DR. KLAASSEN: Yes.
12 DR. SNYDER: And then on page 6, so the
13 second, under General Biology in the second
14 paragraph, what do we consider to be a low
15 molecular weight ester? I'm not a chemist, but I
16 don't know what you qualify as a low molecular
17 ester.
18 DR. BELSITO: Less than 500.
19 DR. SNYDER: Seriously?
20 DR. KLAASSEN: Semi-seriously.
21 SPEAKER: Which line are you referring
22 to?
CIR Panel Book Page 17 92
1 DR. SNYDER: Second paragraph.
2 DR. BELSITO: We know that things that
3 readily penetrate the skin are less than or equal
4 to 500 Daltons. So I'm assuming the low molecular
5 weight ester that will readily penetrate is less
6 than 500 Daltons. But I agree with you; I don't
7 know what that means.
8 DR. LIEBLER: It didn't mean anything to
9 me, so.
10 DR. SNYDER: Oh, page 6. I'm on the
11 wrong page.
12 DR. HELDRETH: Originally it would refer
13 back to it being -- I guess it could have more
14 readily said the shorter-chain alkyl acetates that
15 I defined in the introduction instead of lower
16 molecular weight which turned out to be the same.
17 DR. LIEBLER: So this is -- this is
18 actually a sentence that I flagged, but I flagged
19 the "in general" part because I said are there
20 exceptions. And so I think you said the term "in
21 general" happens several times in this report.
22 And I think you're insulating yourself against the
CIR Panel Book Page 18 93
1 possible exception that you're unaware of, but I
2 think it's unnecessary in almost all cases where
3 you use that.
4 DR. HELDRETH: Okay.
5 DR. LIEBLER: Low molecular weight
6 esters here was, I think, more contextual. Right?
7 You were probably thinking about propyl acetate.
8 Isopropyl acetate as opposed to cetyl acetate. So
9 you may want to rethink about what you're trying
10 to say there and do you need to even make that
11 distinction.
12 DR. HELDRETH: Okay.
13 DR. SNYDER: And then as another
14 organizational point, under the Animal Toxicity
15 Studies, which begin on page 9, under the first
16 subheading, Acute Toxicity.
17 DR. HELDRETH: Okay.
18 DR. SNYDER: The next paragraph covers
19 oral, dermal, and inhalation. And we typically
20 pull those out and put all the oral together in a
21 subheading, all the dermal in a subheading, all
22 the inhalation in a subheading, rather than
CIR Panel Book Page 19 94
1 running them all together in one sentence. That
2 goes throughout all of the sections. You've
3 lumped them all together, but the preference is to
4 have them split out so we can quickly evaluate
5 whether or not we have a data gap. Like, if we
6 don't have any inhalation data and there's an a
7 aerosol use and things like that, it's very
8 helpful for the reviewer.
9 DR. HELDRETH: I agree. I think when we
10 first started this report we didn't have much of
11 any of the individual groups and we kind of just
12 put it all in one paragraph because it was a very
13 small amount of information. But I agree. Now
14 that we can actually fill out those groups it
15 should be separated.
16 DR. SNYDER: And then on page 14, the
17 italicized section under Reproductive
18 Developmental Toxicity, "resulted in significant
19 different activity measurements as compared to
20 controls." I wasn't quite certain what you were
21 meaning by that. Is that behavioral? Is that a
22 behavioral assessment you're talking about?
CIR Panel Book Page 20 95
1 Clinical observations? So we just need to clarify
2 what that -- what you mean by different activity
3 measurements.
4 DR. HELDRETH: Okay.
5 DR. BELSITO: Any other comments? Okay.
6 So we're going safe as used. And again, anything
7 that Bart needs to put into the discussion that
8 isn't currently there? No? We're happy with it?
9 Okay. Good.
10 Okay. It's 10:30. Why don't we take a
11 10-minute break and regroup at 10:40.
CIR Panel Book Page 21 243
1 CERTIFICATE OF NOTARY PUBLIC
2
3 I, Carleton J. Anderson, III do hereby certify
4 that the forgoing electronic file when originally
5 transmitted was reduced to text at my direction;
6 that said transcript is a true record of the
7 proceedings therein referenced; that I am neither
8 counsel for, related to, nor employed by any of
9 the parties to the action in which these
10 proceedings were taken; and, furthermore, that I
11 am neither a relative or employee of any attorney
12 or counsel employed by the parties hereto, nor
13 financially or otherwise interested in the outcome
14 of this action.
15 /s/Carleton J. Anderson, III
16 Notary Public # 351998
17 in and for the Commonwealth of Virginia
18 My Commission Expires: November 30, 2012
19
20
21
22
CIR Panel Book Page 22
CIR Panel Book Page 23
115th COSMETIC INGREDIENT REVIEW EXPERT PANEL MEETING BREAKOUT SESSION
Washington, D.C. Monday, June 28, 2010
CIR Panel Book Page 24 2
20 DR. MARKS: Let's see. Okay. It's
21 where we're leading.
22 Okay, we'll see how the discussion goes
CIR Panel Book Page 25 195
1 tomorrow. Since I'm the one that makes the
2 motion, after I move to reopen it, then we will
3 see how it goes.
4 Any other comments? Okay. I kind of
5 like the idea. I want to see the table. Okay,
6 next one is Methyl Acetate, Simple Acetate Esters
7 and Relevant Metabolites, Pink 2. A draft
8 tentative report of this was issued at the April
9 meeting of this year, with an Insufficient Data
10 Announcement for cetyl acetate at the highest
11 concentration use in lipstick.
12 We got more data, and now I think that's
13 safe. And so we could issue a tentative report,
14 these ingredients as "safe as used."
15 DR. SLAGA: Good.
16 DR. MARKS: Any comments?
17 DR. SLAGA: Not here.
18 MS. EISENMANN: Just, my material -- you
19 know, the butoxyethanol has a different
20 conclusion. If you want to write a separate
21 conclusion for the acetate to make it reflect that
22 conclusion.
CIR Panel Book Page 26 196
1 And it's not used. So --
2 DR. SHANK: What's wrong with it?
3 MS. EISENMANN: Well, butoxyethanol has
4 the conclusion of "safe as used in hair and nail
5 products at concentrations up to 10 percent." But
6 then in the re-review, you also said it was okay
7 in nail polish removers up to 50 percent.
8 So I don't know how you would word the
9 conclusion for the acetate. But it seems to me
10 like it should have a similar, a similar
11 conclusion.
12 So you might have two different
13 conclusions, one for all the other ingredients,
14 and then the other one, a separate conclusion.
15 DR. MARKS: That was, again -- let me
16 look (inaudible). So, methyl acetate -- where is
17 it? Go to page 26.
18 Which one are you talking about here?
19 MS. EISENMANN: Page 5.
20 DR. MARKS: Page 5. Page 5 in this
21 draft?
22 MS. EISENMANN: Well, the conclusion is
CIR Panel Book Page 27 197
1 of butoxyethanol. So, page 2, the second complete
2 paragraph --
3 DR. MARKS: Page?
4 MS. EISENMANN: -- describes, in the
5 introduction, describes the current conclusion for
6 butoxyethanol, since butyl acetate is metabolized
7 to butoxyethanol.
8 I just thought, to be consistent, you
9 might want to have the same conclusion.
10 DR. HILL: I've thought about this quite
11 a bit, because I worked on butoxyethanol with
12 somebody who was studying the toxicology. Because
13 it's interesting. On the one hand, the acetate
14 might actually enhance dermal penetration. And on
15 the other hand, thinking from a dermal exposure
16 route, penetration, unless it was applied to a
17 wide area of skin, shouldn't be that high compared
18 to oral dosing. It's really oral dosing is where
19 I know the problems arise.
20 So, I didn't know how to think about
21 that.
22 DR. MARKS: So, Carol, go back. You're
CIR Panel Book Page 28 198
1 saying that in that paragraph, that butyl acetate,
2 even though that a conclusion of "safe" --
3 MS. EISENMANN: Yes, the second
4 paragraph, butoxyethyl acetate is the ingredient
5 that I'm --
6 DR. MARKS: Okay.
7 MR. BAILEY: Butoxyethanol is safe in
8 hair and nail products in concentrations up to 10
9 percent.
10 MS. EISENMANN: Mm-hmm.
11 MR. BAILEY: The proposed conclusion is
12 --
13 MS. EISENMANN: But it's not used.
14 MR. BAILEY: Regardless of what it's
15 used for.
16 MS. BRESLAWEC: Butoxyethanol, or butoxy
17 --
18 MS. EISENMANN: Acetate.
19 MS. BRESLAWEC: -- ethyl acetate.
20 MS. EISENMANN: And the use data that
21 was what's reflected in this report, you might be
22 saying it's okay to use at the same levels, that
CIR Panel Book Page 29 199
1 it's like cetyl acetate. And then the product
2 types that it's used at. Whereas, I mean, the
3 other ingredient has limits.
4 So would a "safe as used" conclusion for
5 that mean it's safe in lipstick and makeup bases
6 and -- for this one?
7 DR. HILL: Which this provides, by the
8 way, a beautiful illustration of an innocent
9 looking molecule, if you didn't know anything
10 about the toxicology of butoxyethanol you would
11 say this is a nice interpolation, and we've got no
12 problems.
13 DR. MARKS: Okay. Well, I guess -- so
14 the question is, can we handle this in the
15 discussion? Should we delete --
16 DR. SHANK: It's not used.
17 DR. MARKS: -- butyl --
18 DR. SHANK: So I would say just delete
19 it.
20 DR. MARKS: Delete it.
21 DR. SHANK: Simplify the document.
22 DR. MARKS: Yes. That's one tack.
CIR Panel Book Page 30 200
1 MS. EISENMANN: That's what I was saying
2 all along. Because it belongs with butoxyethanol.
3 DR. MARKS: Right.
4 DR. SHANK: Yes.
5 DR. HILL: But it's interesting, because
6 if you look at the LD50 data -- well, all the
7 toxicology data -- on page 50, Table 6, it's
8 really high doses before anything shows up with
9 this acetate. So I thought that was -- that was
10 what caused me not to worry about it.
11 MS. EISENMANN: Okay. Well --
12 DR. HILL: But, I mean, that's just me.
13 DR. MARKS: Well, no, I think that's an
14 important point. It kind of gets back to when
15 you're testing the actual ingredient, when we
16 talked about some of the other things, where the
17 different names of the ingredients actually may
18 not be chemically exactly the same. But when
19 you're testing it in a cosmetic, you get results
20 which you interpret as safe.
21 With this, one gets into if it's
22 metabolized to butoxyethanol, is the concentration
CIR Panel Book Page 31 201
1 high enough with that, so on and so forth, that
2 one would be concerned -- if you have tests in
3 here that would indicate at least the cosmetic
4 ingredient, butoxyethyl acetate is safe?
5 I'm sure that's how we -- how did this
6 paragraph jump in here? Or was it there before
7 and we just didn't -- we ignored it? Carol,
8 thanks for pointing it out.
9 MS. EISENMANN: It's been there.
10 DR. MARKS: Yeah.
11 DR. HILL: And it's interesting, because
12 the ultimate toxicant, as I recall, was butoxy
13 acetic acid. And that root is actually more
14 problematic, as I recall, in rats, most species of
15 rats than it is in humans. There's lots of
16 exposure data for humans, because of workers who
17 are in the industry where they produce it. And,
18 actually, relatively generous limits, I think --
19 exposure limits.
20 But, anyway, I just see in the table
21 here that all the data sort of suggests it's not a
22 problem. And so we have an acetate, and it could
CIR Panel Book Page 32 202
1 -- but then, again, companies might avoid this
2 anyway, just based on that information being out
3 there. I don't know.
4 DR. MARKS: So, Ron, how would you feel
5 more comfortable? Dealing with this in a
6 discussant? Or just as --
7 DR. HILL: Where's the paragraph that
8 you --
9 DR. MARKS: -- Ron Hill. It's on book
10 page 24. Page 2 of the actual report. And it's
11 the second paragraph from the top.
12 So, one way, as Ron Shank has suggested,
13 we could just delete it from this group of
14 ingredients. Or we could leave it in and deal it
15 as a -- in the discussion section, and not be
16 hidden here but, I think, pulled out into the
17 discussion, and actually deal with it directly
18 there.
19 But which -- and there may be some other
20 ways to handle it. It would make it quicker to
21 remove it, but --
22 DR. SLAGA: Remove it, if it's not used.
CIR Panel Book Page 33 203
1 DR. MARKS: Although we haven't removed
2 ingredients in the past just because they weren't
3 used.
4 DR. SLAGA: We selectively do.
5 DR. MARKS: We selectively -- okay. I
6 hear you, Tom.
7 MS. BRESLAWEC: Let me make sure I
8 understand what the issue is here.
9 You're concerned because the butoxyethyl
10 acetate metabolizes to an ingredient that has
11 previously been reviewed, for which limits have
12 been set.
13 DR. MARKS: Correct.
14 MS. BRESLAWEC: And that those limits
15 are not being reflected in our safety assessment
16 for the acetate.
17 DR. MARKS: And that's correct. We
18 would have just a "safe," with no limits.
19 MS. BRESLAWEC: And yet the data that we
20 have for that acetate shows a very high LD50.
21 DR. MARKS: Right. And that's getting
22 back to why we didn't get an alert before.
CIR Panel Book Page 34 204
1 So I think the question, as I said, is
2 what do we do with the issue of this metabolite,
3 which we've set limits on? Do we deal with that
4 in the discussion, and say -- point it out, it's
5 not used, and the safety data within this document
6 suggests that it is safe. Or delete it.
7 MR. BAILEY: Well, the conclusion right
8 now, is what I'm hearing, is "safe as used,"
9 (inaudible).
10 DR. MARKS: Mm-hmm. Yep.
11 MR. BAILEY: So, again, the problem is
12 that it could be used at a level that's higher by
13 virtue of metabolism than the existing conclusion
14 for butoxyethanol of 10 percent. That's by
15 metabolism. I mean, we don't know the rates or
16 that that's even going to happen, reach 10 percent
17 of the butoxyethanol -- right?
18 DR. MARKS: Yes. I think there again
19 you could handle it in the discussion, saying as
20 long as it doesn't -- yeah, as long as it doesn't
21 reach the levels of butoxyethanol --
22 MR. BAILEY: I mean, but the problem
CIR Panel Book Page 35 205
1 with taking things out because there's zero uses
2 is they may become non- zero uses. And do you
3 want to deal with this again?
4 And so it sounds to me like there are no
5 concerns. We could deal with it in the
6 discussion. And if there's anything that needs to
7 be done, maybe the butoxyethanol needs to go back
8 and be formally raised.
9 DR. MARKS: Well, we did that in 2002.
10 MR. BAILEY: So -- I would just do it in
11 the discussion.
12 DR. MARKS: Ron, is that okay? Ron
13 Hill? So that, at least to my mind, added some
14 meat to the discussion as we have it now on book
15 page 48. I thought the discussion was usually --
16 to me, there are couple large questions. One was
17 why we came to a "safe" conclusion is usually in
18 the discussion, sort of synthesizing the facts we
19 have. And then also the discussion was where any
20 issues such as this one right here would be put
21 in. So I'd include that.
22 What I saw in the discussion didn't
CIR Panel Book Page 36 206
1 really -- wasn't much of a -- didn't discuss
2 anything. It was sort of, "This is what was in
3 there."
4 MS. BRESLAWEC: Well, yes, the point of
5 the discussion at that point was that it was
6 insufficient.
7 DR. MARKS: Yes. Okay. So issue a
8 tentative report. Ingredients as safe. And the
9 discussion will include the important issue of
10 butoxyethanol metabolite.
11 MS. WEINTRAUB: Can I ask a question?
12 Page 26, Panel Book 48, is it code or some huge
13 typo? (Laughter)
14 MR. HELDRETH: It was putting it on a
15 reference citation editor, and didn't catch that
16 it didn't convert it properly.
17 MS. WEINTRAUB: Okay.
18 MS. BRESLAWEC: Yes, it's an elaborate
19 new coding system. In addition to reformatting,
20 you're starting a new language.
21 DR. HILL: And also, this is just
22 editorial, but the salts are not metabolites. So
CIR Panel Book Page 37 207
1 the only metabolite there is acetic acid. So you
2 have to say something like, "acetic acid and its
3 salts." "The metabolites of acetic acid and its
4 salts."
5 DR. MARKS: Okay. Any other comments?
6 Carol, thank you for bringing that to our
7 attention.
CIR Panel Book Page 38
115th COSMETIC INGREDIENT REVIEW EXPERT PANEL
MEETING
Washington, D.C.
Tuesday, June 29, 2010
CIR Panel Book Page 39
2
16 DR. BERGFELD: Is there any other
17 informal request for data? Seeing none, moving on
18 them.
19 The third group is methyl acetate. Dr.
20 Marks?
21 DR. MARKS: We yesterday reviewed a
22 draft tentative report of methyl acetate, simple
CIR Panel Book Page 40
46
1 acetate esters and their metabolites. These
2 appeared to be okay. There was concern at our
3 April meeting that there was insufficient data for
4 cetyl acetate in its use in a lipstick and that we
5 needed some sensitization data to confirm its
6 safety. We not only received that HRIPT report
7 confirming its safety in a lipstick at a
8 concentration of 12.6 percent, but we also found
9 that in the use and concentration table it had
10 actually been listed as having a higher
11 concentration than it actually was. So with that
12 in mind we move to issue a tentative report with
13 these ingredients being safe.
14 DR. BERGFELD: Is there a second?
15 DR. BELSITO: Second.
16 DR. BERGFELD: Is there any discussion?
17 DR. BELSITO: There were two bits of
18 data that we received at the last panel that were
19 just not included in this and it had to do with a
20 sensitization study on isopropyl alcohol at 80.74
21 percent and a sensitization study on cetyl acetate
22 at 11.7 percent that were clean and needed to be
CIR Panel Book Page 41
47
1 added back into this document. Then Paul felt
2 that in the discussion we needed to refer back to
3 the t-butyl alcohol document to cover some of the
4 renal issues that were raised in this report.
5 Paul, you may want to discuss that further.
6 DR. SNYDER: I think that we discussed
7 the renal issue in the t-butyl alcohol very
8 thoroughly and so we should reference that rather
9 than going through a full description here because
10 we didn't really come to the conclusion here of
11 how we interpreted those renal lesions and I think
12 we don't need to do that here, I think we just
13 need to refer to our already published safety
14 assessment.
15 DR. MARKS: Paul, did you feel you
16 wanted that in the discussion, because it is
17 mentioned on the panel book at page 24 under the
18 introduction and we had a significant discussion
19 about that also yesterday and felt that that
20 should be moved into the discussion and felt that
21 the metabolism of butoxy ethyl acetate-2, butoxy
22 ethanol, that the concentration of the butoxy
CIR Panel Book Page 42
48
1 ethanol in the metabolism would be so low that it
2 wouldn't pose a safety risk.
3 DR. SNYDER: I think both of those
4 should be covered in the same context, that there
5 is no way to attain that level in the first place
6 through the transformation, and second of all, we
7 dealt with the issue of the renal lesions in the
8 t-butyl alcohol report.
9 DR. BERGFELD: Are there any other
10 comments by the panel members? Seeing none, I
11 call for the vote. All those in favor of a safe
12 conclusion please indicate by raising your hands.
13 Thank you.
14 Moving on to the fourth ingredient, the
15 trimoniums, Dr. Belsito?
CIR Panel Book Page 43 Report
Draft Final Report
Methyl Acetate, Simple Alkyl Acetate Esters, Acetic Acid and its Salts as used in Cosmetics
August 30, 2010
The 2010 Cosmetic Ingredient Review Expert Panel members are: Chairman, Wilma F. Bergfeld, M.D., F.A.C.P.; Donald V. Belsito, M.D.; Curtis D. Klaassen, Ph.D.; Daniel C. Liebler, Ph.D.; Ronald A Hill, 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 F. Alan Andersen, Ph.D. This report was prepared by Bart Heldreth, Ph.D., Chemist.
© Cosmetic Ingredient Review 1101 17th Street, NW, Suite 412 " Washington, DC 20036-4702 " ph 202.331.0651 " fax 202.331.0088 " [email protected]
CIR Panel Book Page 44 TABLE OF CONTENTS
INTRODUCTION ...... 1 CHEMISTRY ...... 2 USE ...... 3 GENERAL BIOLOGY ...... 4 ANIMAL TOXICOLOGY ...... 7 SHORT-TERM TOXICITY ...... 9 SUBCHRONIC TOXICITY ...... 9 CHRONIC TOXICITY ...... 10 DERMAL IRRITATION ...... 11 OCULAR IRRITATION ...... 12 REPRODUCTIVE/DEVELOPMENTAL TOXICITY ...... 13 GENOTOXICITY ...... 15 CARCINOGENICITY ...... 15 CLINICAL ASSSESSMENT OF SAFETY ...... 17 SUMMARY ...... 24 REFERENCES ...... 0
CIR Panel Book Page 45 Abstract
The main function of Methyl Acetate in cosmetic products is as a solvent in nail polish removers. However, the cosmetic functions of the alkyl acetate ingredients in this assessment vary considerably. The potential for these acetate ingredients to be metabolized to the parent alcohol and acetic acid is recognized and evaluated as part of this assessment.
The currently available toxicity data support the conclusion of safe as used in current practices and concentrations for methyl acetate, propyl acetate, isopropyl acetate, t-butyl acetate, isobutyl acetate, butoxyethyl acetate, nonyl acetate, myristyl acetate, cetyl acetate, stearyl acetate, isostearyl acetate, acetic acid, sodium acetate, potassium acetate, magnesium acetate, calcium acetate, zinc acetate, propyl alcohol and isopropyl alcohol, in cosmetics.
INTRODUCTION
This document presents a summary of the available safety information that pertains to methyl acetate, ten alkyl
acetates, acetic acid, five acetate salts and two corresponding esterase metabolites, and their use in personal care
products/cosmetics.
The ingredients included in this safety assessment are: methyl acetate, propyl acetate, isopropyl acetate, t-butyl
acetate, isobutyl acetate, butoxyethyl acetate, nonyl acetate, myristyl acetate, cetyl acetate, stearyl acetate, isostearyl acetate,
acetic acid, sodium acetate, potassium acetate, magnesium acetate, calcium acetate, zinc acetate, propyl alcohol and isopropyl
alcohol. The CIR Expert Panel has reviewed Ethyl Acetate,1 Butyl Acetate,1 Ethyl Alcohol (as “Alcohol Denat.” with methyl alcohol),2 and Butyl Alcohol3 and concluded that these ingredients are safe in the present practices of use and concentration.
The following ingredients are metabolites of the ingredients in this safety assessment and have been previously
reviewed: methanol, t-butyl alcohol, butoxyethyl alcohol, myristyl alcohol, cetyl alcohol, stearyl alcohol and isostearyl
alcohol. Citations for the completed reports are provided, however, toxicity information on these previously reviewed
ingredients has not been duplicated in this safety assessment, with the exception of excerpts from the clinical sections of each
prior report.
The alkyl acetate ingredients are esters of acetic acid and the corresponding alcohols and can be metabolized via
hydrolysis, by esterases present in skin, back to the parent alcohol and acetic acid (or a salt).
CIR does not review the safety of ingredients used as a fragrance, unless there are other reported functions, as is the
case with a number of the ingredients in this report.
1
CIR Panel Book Page 46 CHEMISTRY
Definition and Structure
The registry numbers, definitions, functions and CIR review history of the ingredients under review are presented in
Table 1 and the structures are presented in Figure 1. The technical names for these ingredients are listed in Table 2. A map of how the structures and metabolic pathways of these ingredients are related is presented in Figure 2.
Physical and Chemical Properties
The shorter chain aliphatic esters are colorless and highly volatile liquids. Volatility decreases as the molecular mass (chain length) increases.4 The physical and chemical properties of the acetates are shown in Table 3. Experimental
boiling point, density, vapor pressure, solubility, and logKow values were available for the shorter alkyl esters while only estimated logKow values were available for the longer alkyl esters. The shorter alkyl esters (methyl acetate to butoxyethyl
acetate) have logKow values ranging from 0.18 – 1.78 (values for isopropyl acetate and butoxyethyl acetate were estimated
using EPI Suite v. 4.0) while the longer alkyl esters (nonyl acetate to isostearyl acetate) have estimated logKow values > 4.
Acetic acid and the metal acetate salts dissociate readily in water and therefore have negative log octanol/water partioning coefficients, and high solubilities in water. Propyl alcohol and isopropyl alcohol are volatile liquids. The physical and chemical properties of acetic acid, the acetate salts and alcohols are shown in Table 4.
Manufacture and Production
In general, the alkyl acetates can be produced industrially via esterification of acetic acid.4 The manufacture of methyl acetate, for example, is traditionally accomplished via a reactive distillation process between acetic acid and methanol.5 Methanol and ethanol are normally obtained via fermentation of natural sources. However, some sources of
alcohols with chains longer than ethanol are often produced synthetically. An important process for producing C3-C20
industrial alcohols involves a process known as oxo-synthesis (a process for the production of aldehydes which occurs by the
reaction of olefins (which can be natural or petroleum sourced) with carbon monoxide, hydrogen and a catalyst (typically
cobalt based)), followed by hydrogenation of the aldehyde products, to form the alcohols.6 More recently, a green, biocatalytic process developed specifically for the manufacture of esters for use in the formulation of cosmetic and personal care ingredients (i.e. for producing cosmetic grade esters) has been used.7
Acetic acid is most commonly manufactured by metal (e.g., rhodium or iridium) catalyzed carbonylation of methanol (via addition of carbon monoxide), or oxidation of ethylene (through an acetaldehyde intermediate and in the presence of manganese acetate, cobalt acetate, or copper acetate), also known as the Wacker process.8
2
CIR Panel Book Page 47 Impurities
The manufacturing processes of the alkyl esters are typically high yielding (>90%) and easily purified (e.g., by distillation). Therefore, the starting materials and water, at least, may be expected to be present in preparations of these esters as the major impurities.4 For example, methyl acetate is available with a minimum of 96% purity, wherein the major contaminants are methanol (<2.5%) and water (<1.5%).9 In the case of isopropyl acetate, which is available at 99.6% purity,
the major impurities are isopropanol (<0.2%), water (<0.05%), and acetic acid (<0.005%). 9
Propyl alcohol and isopropyl alcohol can be obtained as 99.8% pure. 9
Acetic acid can be obtained as glacial acetic acid (99.85% acetic acid, 0.15% water).9
Analytical Methods
The esters, acids and alcohols can be analyzed using gas chromatography/mass spectroscopy (GCMS), nuclear magnetic resonance (NMR) spectroscopy, ultraviolet (UV) spectroscopy and infrared (IR) spectroscopy.4,6,10 No UV spectroscopy data was found.
USE
Cosmetic
The Voluntary Cosmetic Registration Program (VCRP) administered by the FDA indicates total number of uses in cosmetic formulations in 2010 for methyl acetate (7), propyl acetate (46), isopropyl acetate (6), isobutyl acetate (4), cetyl acetate (264), stearyl acetate (1), acetic acid (11), sodium acetate (88), calcium acetate (7), zinc acetate (1), propyl alcohol (1) and isopropyl alcohol (1748) (Table 5).11 Use information was not available for t-butyl acetate, nonyl acetate, butoxyethyl
acetate, or isostearyl acetate.
The main use of methyl acetate is in nail polisher removers. Concentration of use surveys conducted in 2007, 2009
and 2010 by the Personal Care Products Council reported use percent ranges for methyl acetate (10-60), propyl acetate
(0.005-39), isopropyl acetate (0.5-), t-butyl acetate (10), isobutyl acetate (6-45), nonyl acetate (0.0004), cetyl acetate (0.01-
17), stearyl acetate (0.02-0.5), isostearyl acetate (0.002-5), propyl alcohol (0.0001-0.5), isopropyl alcohol (0.002-100), acetic
acid (0.0003-0.3), sodium acetate (0.0002-0.5), potassium acetate (3), and magnesium acetate (0.02-0.03).12,13 Concentration of use survey results for calcium acetate and zinc acetate have not yet been received. Neither use nor concentration information was available for butoxyethyl acetate or myristyl acetate.
In the EU, methanol is allowed only as a denaturant for ethanol and isopropyl alcohol at a concentration of 5%, calculated as a % ethanol or % isopropyl alcohol.14 Additionally, the EU limits the amount of zinc acetate in cosmetics to 1%
calculated as zinc.
3
CIR Panel Book Page 48
Non-Cosmetic
The following ingredients in this report are permitted for direct addition to food for human consumption for
flavoring purposes and are generally recognized as safe (GRAS) according to the USFDA: methyl acetate, propyl acetate,
isopropyl acetate, isobutyl acetate, nonyl acetate, propyl alcohol, isopropyl alcohol, acetic acid, sodium acetate, potassium
acetate, magnesium acetate, and calcium acetate.15 Zinc acetate is an approved ingredient for OTC skin protectant drug
products.16
Additionally, esters are used as solvents in paints, lacquers and coatings, and as intermediates in various chemistry
processes.4
Alcohols are commonly used as solvents and antiseptics.17
Isopropyl Alcohol (rubbing alcohol) is an approved ingredient for topical antimicrobial OTC drug products.18
GENERAL BIOLOGY
Absorption, Distribution, Metabolism, Excretion
Exposure to these ingredients is expected to occur mostly by inhalation and dermal routes, although some oral or ocular exposure could occur depending upon the product types in which these ingredients are used in. Shorter acetic esters, readily penetrate the skin and mucous membranes and are metabolized via esterases to the parent alcohol and acetic acid.
The alcohols are further metabolized to the corresponding aldehyde or ketone and then to the corresponding acid.
ADME studies are reported by ingredient in the animal and in the human sections.
The alkyl acetate ingredients are esters of acetic acid and the corresponding alcohol, with the shorter chain alkyl acetates (methyl, propyl, isopropyl, t-butyl, isobutyl and butoxyethyl; MW range 74-160 g/mol) functioning in cosmetics as fragrance ingredients and solvents, and the longer chain alkyl acetates (nonyl, myristyl, cetyl, stearyl and isostearyl; MW range 186-312) functioning in cosmetics as skin conditioning agents.
These ingredients can be metabolized via hydrolysis, by esterases present in skin, to the parent alcohol and acetic acid (or a salt). The ability and efficiency of esterases in the skin is often species dependent and may even vary considerably
between individuals of the same species.19 Esterases found in the skin, such as human acetyl cholinesterase (hAchE), are capable of metabolizing branched substrates, including tertiary esters.20
Shorter chain esters readily penetrate the skin and mucous membranes. Acetic acid esters can be metabolized by esterases (present in the respiratory tract, skin, blood and gastrointestinal tract21,22) to the parent alcohols and acetic acid.4 As
4
CIR Panel Book Page 49 such, methyl acetate is metabolized to methyl alcohol, t-Butyl acetate is metabolized to t-butyl alcohol, and so forth as illustrated in Figure 2.
The rate of ester hydrolysis can be increased by raising the temperature and decreased by lowering pH. Secondary and tertiary acetates are hydrolyzed more slowly than primary acetates. Acetic acid is oxidized via the citric acid cycle to carbon dioxide and water. The parent alcohols can be oxidized via alcohol dehydrogenases to produce the corresponding aldehydes or ketones. The aldehydes can then further be oxidized via aldehyde dehydrogenases to the corresponding acids.
Acetic acid is a principal metabolite of all of the above alkyl acetates, and in addition to its sodium, potassium, magnesium, calcium and zinc acetate salts, is a cosmetic ingredient and has been included in this safety assessment.
Isobutyl alcohol and nonyl alcohol are principal metabolites of isobutyl acetate and nonyl acetate, respectively.
They are not currently listed as cosmetic ingredients in the INCI, but available data has been provided for the evaluation of the parent alkyl acetates.
t-Butyl alcohol is slowly metabolized by alcohol dehydrogenases and is eliminated in urine as a glucuronide conjugate and acetone. t-Butyl alcohol is also eliminated in exhaled air as acetone and carbon dioxide.10,23
Propyl alcohol and isopropyl alcohol are principal metabolites of propyl acetate and isopropyl acetate, respectively.
Propyl alcohol is metabolized to propanal and propanoic acid, which can be further metabolized to acetaldehyde and acetic
acid.24 Isopropyl alcohol is metabolized to acetone and then to acetate, formate and ultimately carbon dioxide.25 The half-
life of acetone in humans is 22.5 hours.
Bioavailability following inhalation, dermal or gavage exposure has been examined for acetic acid, propyl acetate,
isopropyl acetate, t-butyl acetate and isopropyl alcohol in animals and methyl alcohol bioavailability has been examined in
humans.
Animal
Acetic Acid
Acetic acid is absorbed from the gastrointestinal tract and through the lungs and is readily, although not completely,
oxidized.26 As noted above, acetic acid can be metabolized and eliminated as carbon dioxide and water.
Propyl Acetate
Rats (strain/sex/number not specified) were exposed via inhalation to 2,000 ppm (8360 mg/m3) for 90 min.27 Propyl acetate was rapidly hydrolyzed to propyl alcohol. During the 90 min exposure period, blood levels of propyl alcohol were between 2.6 and 7.7 fold greater than propyl acetate.
Isopropyl Acetate
5
CIR Panel Book Page 50
Male Sprague-Dawley rats (n=6) were placed in a chamber charged with 2000 ppm isopropyl acetate and allowed to
inhale for 90 min.28 During this time, the concentration in the chamber decreased and correction for the amount of test
compound lost to the chamber and on the surface of the animal was completed. Blood samples were taken at 0, 5, 10, 20, 25,
30, 40, 50, 60 and 90 min. Blood levels of isopropyl alcohol exceeded those of isopropyl acetate at 5 min into the exposure
and at each time-point thereafter. At 90 min, 245 µM isopropyl alcohol and 24 µM isopropyl acetate were detected in the
blood.
t-Butyl Acetate
Female Sprague-Dawley rats (n=5) were exposed via a tracheal cannula to 440 ppm (1900 mg/m3) t-butyl acetate in
air for 5 h.29 The concentrations of both the acetate and the alcohol increased continuously in the blood over the course of the
exposure. By the end of the exposure, the concentration of t-butyl alcohol in the blood (~340 µmol/L) was greater than that of t-butyl acetate (285 µmol/L). In a second experiment, female Sprague-Dawley rats (n=5) were exposed via a tracheal cannula to 900 ppm (4275 mg/m3) t-butyl acetate in air for 255 min. A similar pattern was observed with concentrations in the blood at the end of the exposure of approximately 400 and 450 µmol/L blood for t-butyl acetate and t-butyl alcohol respectively.
Isopropyl Alcohol
Male rabbits (3/group; strain not specified) were treated by different routes of exposure to compare the absorption and metabolism of isopropyl alcohol.30 Groups 1 and 2 were treated via gavage with the equivalent of 2 and 4 ml/kg absolute isopropyl alcohol, respectively, as a 35% isopropanol/water solution. Groups 3 and 4 were treated via whole-body inhalation for 4 h (towels soaked with isopropyl alcohol were place in the inhalation chamber and replenished at ½ hour intervals to maintained a saturated environment; no exact concentration given), with Group 3 animals receiving an additional dermal exposure in the form of a towel soaked with 70% isopropyl alcohol applied to the animals’ chests and Group 4 animals having plastic barriers on their chests and towels prepared the same way as in Group 3 applied on top of the plastic barriers.
The alcohol on the towels was replenished at half hour intervals throughout the duration of the experiment. Blood samples were taken at 0, 1, 2, 3 and 4 h. Samples were analyzed for isopropyl alcohol and the metabolite acetone.
Following gavage exposure to 2 or 4 ml/kg, maximum blood levels of 147 and 282 mg/dl, respectively, of isopropyl alcohol were measured. Concentrations of acetone rose steadily over the 4 h period and were 74 and 73 mg/dl following exposure to 2 or 4 ml/kg, respectively. The authors stated that the maximum levels of isopropyl alcohol observed in this experiment, correlated with inebriation and near coma in the animals. Following inhalation and dermal exposure, the concentration of isopropyl alcohol in the blood continued to rise and was 112 mg/dl at 4 h while the concentration of acetone
6
CIR Panel Book Page 51 was 19 at 4 h. Inhalation exposure with a plastic barrier between the soaked towel and the chest resulted in isopropyl alcohol
and acetone blood levels of <10 mg/dl.
The researchers concluded that isopropyl alcohol is absorbed by the dermal route but that prolonged dermal
exposure (i.e. repeated sponging or soaking for several hours) would be required to produce significant toxicity.
Butoxyethanol
The results of eight studies on the metabolism, distribution, and excretion of Butoxyethanol were presented in the
CIR expert panel review of butoxyethanol.31 These data show that butoxyacetic acid is the major metabolite (and toxicant)
of butoxyethanol, that the first step of metabolism is mainly by alcohol dehydrogenase in the liver, and that excretion is
mainly via urine.
ANIMAL TOXICOLOGY
With the exception of acetic acid which has an oral LD50 of 3.31 g/kg, the oral LD50 values, for those ingredients
with acute toxicity data, are greater than 5 g/kg. With the exception of butoxyethyl acetate which has a dermal LD50 of 1.5 g/kg and acetic acid which has a dermal LD50 of 3.36 g/kg, all of the other ingredients with acute dermal toxicity data had
LD50 values greater than 5 g/kg. Central Nervous system depression has been documented in animals exposed to acetic acid
and the smaller solvent acetates at high concentrations.
Acute Toxicity
Table 6 provides a summary of the available literature on the acute toxicity and LD50 data for ingredients in this assessment.32-38 Narcotic-like effects have been associated with the inhalation of high concentrations of volatile esters (i.e. methyl, propyl, isopropyl, isobutyl, and t-butyl acetates).39 Skin, eye and upper respiratory irritation are also associated with exposure to the volatile esters.39
Acute Oral Toxicity
35 An oral LD50 of 6.97 ml/kg (6500 mg/kg) was reported in rats for methyl acetate.
33 Oral LD50 values of 9370 and 8300 mg/kg were reported in rats and mice respectively for propyl acetate.
Isopropyl acetate has a reported oral LD50 of 6750 mg/kg while isobutyl acetate has a reported oral LD50 of 15.4 ml/kg (13400 mg/kg).34
38 Nonyl acetate has a reported oral LD50 value greater than 5000 mg/kg in rats.
32 Cetyl acetate has a reported oral LD50 value greater than 5000 mg/kg in rats and rabbits.
35 For butoxyethyl acetate, an oral LD50 of 7.46 ml/kg (7000 mg/kg) was reported in rats. Hemolysis was observed in
acutely treated animals. 7
CIR Panel Book Page 52 Oral LD50 values of 3.15 ml/kg (3310 mg/kg) and 0.4-3.2 ml/kg (420-3400 mg/kg) were reported in rats for acetic
40,41 42 acid. An oral LD50 of 4280 mg/kg was reported in rats for calcium acetate. An oral LD50 of 8610 mg/kg was reported
42 42 in rats for magnesium acetate. An oral LD50 of 3250 mg/kg was reported in rats for potassium acetate. An oral LD50 of
3530 mg/kg in rats was observed with sodium acetate. 42
Inhalation Toxicity
3 No inhalation LC50 was reported for methyl acetate, but exposure to 32000 ppm (96960 mg/m ) for 4 h caused 6/6 rats to die within 14 days.35
10 mice were exposed to inhalation of isopropyl acetate, ranging from 1374 to 2000 ppm for 4 hours.43
Neurobehavioral changes (i.e. duration of immobility during a three minute behavioral despair swimming test) were dose
dependent and ranged from 19 to 81%, compared to controls.
32,44 An inhalation LC50 of 5620 ppm was reported in mice for acetic acid. In rats, a 4 hour exposure to 16000 ppm killed 1 of six rats.
3 42 An inhalation LC50 greater than 30 g/m in rats was observed with sodium acetate.
Dermal Toxicity
38 Nonyl acetate has a reported dermal LD50 value greater than 5000 mg/kg in rats.
32 Cetyl acetate has a reported dermal LD50 value greater than 5000 mg/kg in rats and rabbits.
38 Methyl acetate has a reported dermal LD50 value greater than 5000mg/kg in rabbits.
45 Propyl acetate has a reported dermal LD50 value greater than 5000mg/kg in rabbits.
In another report, the dermal LD50 values for propyl, isopropyl and isobutyl acetates are greater than 20 ml/kg
(~17400 mg/kg).
,37 For butoxyethyl acetate, a dermal LD50 of 1.58 ml/kg (1500 mg/kg) was reported in rabbits.
40 A cutaneous LD50 of greater than 3.2 ml/kg (3360 mg/kg) was reported for 28% acetic acid on guinea pigs. A 5%
solution of acetic acid (equivalent to vinegar) resulted in a cutaneous LD50 of greater than 20 ml/kg (21000mg/kg). An
inhalation LC50 of 5620 ppm was reported in mice for acetic acid. In rats, a 4 hour exposure to 16000 ppm killed 1 of six
rats.
42 A subcutaneous LD50 of 3200 mg in mice was observed with sodium acetate.
Additional reports were identified in reference texts that did not provide complete information.26 These data have
not been evaluated by CIR and are not included in the table.
8
CIR Panel Book Page 53 SHORT-TERM TOXICITY
Butoxyethyl Acetate
Wistar rats (40 male and female rats divided into groups of 10 males or 10 females) and New Zealand rabbits
(4/group) were exposed via inhalation to air-vapor mixtures of butoxyethyl acetate (approximately 400 ppm) 4 hr/day, 5 days/week for 1 month.37 No effects were observed on body weight gain, as compared to controls. Red blood cell (RBC)
counts and hemoglobin decreased slightly in 2 of 4 rabbits after 3 weeks of treatment. Hemoglobinuria and hematuria were
observed in the rabbits, but were less pronounced in treated rats. Two rabbits died during the fourth week of treatment and
blood filled kidneys and bladders were observed at necropsy in these two animals. No other gross pathological lesions were
observed in the other animals killed at either the end of the study or after a 1-week recovery period.
Acetic Acid
Three out of five rats (sex and strain not specified) exposed via inhalation to 1300 µg/l of acetic acid showed slight
red staining around the nose, with one animal showing staining around the mouth.46 Very focal lesions in the respiratory epithelium of the dorsal meatus of level 1 of the nasal cavity in three out of five rats were observed. Acetic acid also increased spleen and kidney weights/damage at 23-31 mg/kg in rats, and induced hyperplasia in both organs at 60 mg/kg.42
SUBCHRONIC TOXICITY Acetic Acid
Rats (number, sex and strain not specified) were exposed to 0.01% to 0.25% solutions, via drinking water, of acetic acid (corresponding to 0.2 ml/kg) with no toxic effects over a period of two to four months. However, 0.5% solutions
(corresponding to 0.33 ml/kg) immediately affected feed consumption and growth. A maximum toleration level of 30 mM
(1.8 g/L) daily for two weeks was established for rats.26
Sodium Acetate
In contrast to the maximum toleration level recited above for acetic acid, sodium acetate in drinking water was reported to have a maximum toleration level of 80 mM (4.2-4.8 g/L).26
Isobutyl Alcohol
Isobutyl alcohol, the primary metabolite of isobutyl acetate, was evaluated for potential neurotoxicity in Sprague-
Dawley rats. Rats (10/sex/group) were exposed via inhalation to isobutyl alcohol vapor concentrations of approximately 0,
770, 3100, or 7700 mg/m3, for 6 h/day, 5 days/week, for 14 weeks.10 The functional observational battery was conducted
along with endpoints of motor activity, neuropathology and scheduled-controlled operant behavior. A slight reduction in
responsiveness to external stimuli was observed in all treated groups during exposure. This effect resolved upon cessation of
exposure to isobutyl alcohol. 9
CIR Panel Book Page 54 Isopropyl Alcohol
Fischer 344 rats and CD-1 mice (10/sex/group) were exposed via inhalation to 0, 100, 500, 1500, or 5000 ppm (0,
246, 1230, 3690, or 12,300 mg/m3) isopropyl alcohol for 6 h/day, 5 days/wk for 13 weeks.47 To evaluate the neurobehavioral
effects of isopropanol exposure, an additional 15 rats/sex were exposed (via inhalation) to 0, 500, 1500, or 5000 ppm (0,
1230, 3690, or 12,300 mg/m3) for 6 h/day, 5 days/wk for 13 weeks. Clinical signs, feed and water consumption, and body
weights were recorded throughout the study. At 6 weeks, hematological and clinical chemistry evaluations were performed,
and at the end of the study, necropsy, and hematological and clinical chemistry evaluations were performed on
10/rats/sex/group and 10/mice/sex/group.
Ataxia, narcosis, hypoactivity and the lack of a startle reflex were observed during exposure at 5000 ppm.
Hypoactivity was observed in animals exposed to 1500 ppm isopropyl alcohol. At 6 weeks, male rats had decreased platelet
counts and female rats had decreased red blood cell counts at 1500 ppm. These effects were not observed at the 13-week
hematological evaluation. At 13 weeks, no gross lesions were observed. Microscopic examination of control and 5000 ppm
exposed animal tissues showed hyaline droplets within the kidneys of male rats only. The size and frequency of the droplets
was increased in the treated group. The authors concluded that the NOAEL for this study was 500 ppm and the LOAEL was
1500 ppm based upon clinical signs and changes in hematology at 6 weeks. Isopropyl alcohol did not produce any changes
to the parameters of the functional observations battery which was conducted at 1, 2, 4, 9 and 13 weeks.
Clinical signs observed in mice, during the exposure, included ataxia, narcosis, hypoactivity and lack of a startle
reflex at 5000 ppm. Narcosis, ataxia and hypoactivity were observed in animals exposed to 1500 ppm isopropyl alcohol. At
5000 ppm, increased body weight and increased rate of weight gain were observed in female mice. Water consumption was
increased in male and female mice. Hemoglobin, hematocrit, and mean corpuscular volume were increased in female mice.
Clinical chemistry changes were also noted in the 5000 ppm female mice group including increased total protein, albumin, globulin, total bilirubin, direct bilirubin and inorganic phosphorus. No clinical chemistry changes were observed in male mice or in the other treated female mice groups. At 13 weeks, no gross lesions were observed and no treatment-related microscopic changes were observed. A 10% and 21% increase in relative liver weight was observed in female mice at 1500 and 5000 ppm, respectively. The authors concluded that the NOAEL for this study was 500 ppm and the LOAEL was 1500 ppm based on clinical signs and increased liver weights.
CHRONIC TOXICITY Butoxyethyl Acetate
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CIR Panel Book Page 55 Wistar rats (40 male and female rats divided into groups of 10 males or 10 females) and New Zealand rabbits
(2/sex/group) were exposed via inhalation to 100 ppm butoxyethyl acetate (butylglycol acetate (BGA)) 4 h/day, 5 days/week for 10 months.37 No effects on body weight gain, as compared to controls, and no hematological changes were observed.
Upon necropsy, rabbits exhibited very discrete renal lesions including a few areas of tubular nephritis. Additionally, dilation of Henle’s loop and the distal convoluted tubules was observed to a greater degree than in control animals. Treated and control rats also exhibited discrete renal lesions such as tubular enlargement in males and tubular nephrosis in females.
Additional chronic toxicity results are described in the CARCINOGENICITY section.
DERMAL IRRITATION
Acetic acid and the alkyl acetate ingredients are minor skin irritants in animal studies. At high concentrations, acetic acid is an irritant.26
Propyl Acetate
Male and female rabbits (n=4; strain not specified) were tested for primary irritation on intact, abraded skin using the Draize method. Undiluted propyl acetate (0.5 ml) was applied to the skin without occlusion and produced only minor irritation with slight erythema in 1 of 4 animals. No edema was observed 72 h after application.26
No irritation was observed in 5 rabbits (sex/strain not specified), following a 24-h non-occluded treatment with 0.01 ml of undiluted propyl acetate (no further experimental details provided).26
Erythema and necrosis were observed in rabbits (sex/strain/number not specified) exposed to 20 ml/kg bw (17,756
mg/kg bw) undiluted propyl acetate.26 Erythema and desquamation were observed in guinea pigs (sex/strain/number not specified) exposed to 10 ml/kg bw (8,880mg/kg bw), undiluted propyl acetate, for 24 h with occlusion. In the guinea pigs, the skin appeared normal after 14 days.
Butoxyethyl Acetate
New Zealand rabbits (6/group/1500 mg/kg) were tested for primary irritation on intact, abraded skin using the
Draize method.37 Butoxyethyl acetate (1500 mg/kg) produced slight erythema (Grade 1) in 4 of 6 rabbits at 24 h. At the 72-
h reading, there was no perceptible irritation; the primary irritation index was reportedly 0.17.
Acetic Acid
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CIR Panel Book Page 56 Glacial acetic acid (equivalent to 95% acetic acid) caused complete destruction of the skin of guinea pigs on 24-hour
contact. 28% acetic acid, however, resulted in only moderate irritation after 24-hours.40 At high concentrations, acetic acid is a irritant which can cause tissue destruction.26
Zinc Acetate
The dermal irritancy of six zinc compounds was examined in three animal models. In open patch tests involving five daily applications, aqueous zinc acetate (20%) was severely irritant in rabbit, guinea-pig and mouse tests, inducing epidermal hyperplasia and ulceration. Epidermal irritancy in these studies is related to the interaction of zinc ion with epidermal keratin. t-Butyl Alcohol
Reniconen and Tier (1957) conducted an experiment to investigate the intradermal irritation of t-BuOH to rabbits. There were no vehicle controls. Eight rabbits were injected intradermally with t-BuOH (vehicle unspecified). The size of the local skin reaction after injection of 35 mg t-BuOH was 14 mm2, and after 10 mg t-BuOH was 43 mm2. No explanation of the significance of these results was provided. Jacobs et al. (1987) tested skin irritation by hydrocarbons including 32 monoalcohols. A Teflon® exposure chamber containing a patch soaked with 0.5 ml of test substance was applied to shaved sites on New Zealand white rabbits (one per compound). The exposure time was 4 h, after which the patch was removed and the skin cleaned. The animals were examined for erythema and edema at 1, 24, 48, and 72 h. All the alcohols tested had calculated limit concentrations of 50% (w/w) including 1-Butanol, 1-Methylpropanol, and 2-Methylpropanol, which are structurally similar to t-BuOH. Results indicated that branching in alcohols had no effect on the limit concentrations for the aliphatic isomers. Although t-BuOH was not studied, the results demonstrated that the 50% limit concentration applied to all the alcohols with a molecular weight between that of Ethanol and 1-Undecanol. In a study by Rhone-Poulenc Inc. (1992), six New Zealand white rabbits each received a single dermal application of 0.5 ml of a mixture of ethanol and t-BuOH (concentrations unspecified). Two 2.5 cm2 test sites were used, one abraded and one intact. One rabbit exhibited moderate irritation at both the abraded and intact site. Three rabbits exhibited mild irritation at the abraded site, including one which also exhibited mild irritation at the intact site. None of the other four rabbits exhibited any irritation at the intact site. It was concluded that the test article was not a primary dermal irritant to rabbits tinder the conditions of the study. Dow Chemical Company (1994) reported that t-BuOH (concentration unspecified) was found to have no irritating effect on the skin of shaved rabbits (strain unspecified) when observed for a period of one week.
(Excerpted from CIR final report on t-butyl alcohol)48
OCULAR IRRITATION
The metal acetate ingredients have been labeled minor eye irritants in animal studies.26 Acetic acid (5%) and isopropyl alcohol have been labeled severe ocular irritants in rabbit ocular irritation tests.
Propyl Acetate Undiluted propyl acetate (0.5 ml) caused minor corneal injury described as Grade 2 on the Draize scale (0-10) in the
rabbit eye (n/sex/strain not specified).27
Butoxyethyl Acetate
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CIR Panel Book Page 57 New Zealand rabbits (6/group) were tested for eye irritation using the Draize method.37 (Standard Draize method -
0.1 ml or 0.1 g solid or semisolid was instilled in the conjunctival sac of one eye for 24 h. Both eyes were examined at 1, 24,
48 and 72 h after treatment.) Butoxyethyl acetate produced slight conjunctival redness and discharge in 2 of 6 rabbits at 24 h.
At 48 and 72 h observations, no irritation was observed.
Isopropyl Alcohol
Isopropyl alcohol has been labeled a severe ocular irritant based on rabbit ocular irritation tests involving application of 0.1 ml of a 70% solution in water.25
Acetic Acid
Acetic acid at concentrations greater than 10% caused severe permanent eye injury in rabbits. In contrast, a 5%
solution (equivalent to vinegar) caused severe, but reversible (two week recovery), eye injury.40
REPRODUCTIVE/DEVELOPMENTAL TOXICITY
For t-butyl acetate, NOAELs for maternal and embryo-fetal developmental toxicity in rats were 800 and 400 mg/kg, respectively. Exposure to 3500 ppm propyl alcohol resulted in significantly different fertility as compared to controls. For isopropyl alcohol, NOAELs for maternal and developmental toxicity of 400 mg/kg each were reported in rats. In rabbits, the corresponding NOAEL values were 240 and 480 mg/kg, respectively.
Oral t-Butyl Acetate
Pregnant female Sprague-Dawley rats (22/group) were exposed to 0, 400, 800, or 1600 mg/kg/day t-butyl acetate via gavage on gestational days (GD) 6 through 19.49 Dams were monitored for clinical effects, feed consumption and changes in
body weight, and the fetuses examined for body weight, sex and visceral and skeletal alterations at GD 20. Two dams died
after treatment with 1600 mg/kg. Necropsy findings on these animals included liver hypertrophy, stomach expansion and
congestion/hemorrhage of the small intestines. Clinical signs in the 1600 mg/kg group included piloerection, abnormal gait,
decreased activity, loss of fur, reddish vaginal discharge, nasal hemorrhage, and coma. There were no deaths and no clinical
signs in the 400 and 800 mg/kg groups. A dose-dependent decrease in gestational weight gain was observed during the
treatment period, but this was not statistically significant as compared to controls. Feed consumption was significantly
decreased on GD 6 and 9 in the 1600 mg/kg treatment group as compared to controls. No effects were observed on maternal
reproductive health, including the number of corpora lutea, implantations, fetal deaths, litter size, and gender ratios. Male
fetal body weight was significantly decreased in the 1600 mg/kg group as compared to controls. Female fetal body weight
was also decreased at this exposure level, but the difference was not statistically significant. An increase in the incidence of
skeletal variation and a delay in fetal ossification were observed in the 1600 and 800 mg/kg treatment groups, with the
changes in the 800 mg/kg treatment group described as minimal by the authors. No evidence of teratogenicity was observed
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CIR Panel Book Page 58 at any tested exposure level. The authors concluded that the observed developmental effects were due to maternal toxicity and determined NOAEL’s for both maternal and embryo-fetal developmental toxicity in rats of 800 and 400 mg/kg, respectively.
Isopropyl Alcohol
Female Sprague-Dawley rats (25/group) were exposed to 0, 400, 800, or 1200 mg/kg/day isopropyl alcohol via gavage on gestational days (GD) 6 through 15.50 Female New Zealand white rabbits (15/group) were exposed to 0, 120, 240,
or 480 mg/kg/day isopropyl alcohol via gavage on GD 6 through 18. Animals were observed for body weight, clinical effects
and feed consumption and the fetuses examined for body weight, sex and visceral and skeletal alterations at GD 20 for rats and GD 30 for rabbits. In rats, 2 dams died at the 1200 mg/kg dose and 1 dam died at the 800 mg/kg dose. Maternal gestational weight gain was reduced at the highest dose tested. No other effects were observed on maternal reproductive health. Fetal body weights at the two highest doses were decreased statistically. No evidence of teratogenicity was observed at any dose. In rabbits, four does died at the 480 mg/kg dose. Treatment related clinical signs of toxicity were observed at the 480 mg/kg dose and included, cyanosis, lethargy, labored respiration and diarrhea. No treatment related findings were observed at GD 30. Decreased feed consumption and maternal body weights, at 480 mg/kg, were statistically significant. No other effects were observed on maternal reproductive health. No evidence of teratogenicity was observed in the rabbits at any dose. The authors determined NOAEL’s for both maternal and developmental toxicity of 400 mg/kg, each, in rats and
240 and 480 mg/kg, respectively, in rabbits.
Acetic Acid
No effects were observed on nidation or on maternal or fetal survival in mice, rats, and rabbits at oral doses
(intubation/dosed day 6 of gestation) up to 1600 mg/kg bw/day of acetic acid. 42 Protocol not stated.
Sodium Acetate
No maternal of neonatal effects were observed in mice exposed (gavage/dosed daily on days 8-12 of gestation) to
1000 mg/kg of sodium acetate.42 Sodium acetate was also determined to be nonteratogenic to chick embryos (10mg/egg).
Inhalation
Propyl Alcohol
The effects of propyl alcohol on fertility were investigated by exposing male Sprague-Dawley rats (18/group) to 0,
3500 or 7000 ppm (0, 8.61 or 17.2 mg/L) propyl alcohol vapor via inhalation 7 h/day, 7days/week for 62 days, prior to
mating with unexposed virgin females.51 Female Sprague-Dawley rats (15/group) were similarly exposed and mated with unexposed males. Following parturition, litters were culled to 4/sex and the pups fostered by unexposed dams. The pups
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CIR Panel Book Page 59 were weaned on post natal day (PND) 25 and weighed on PND’s 7, 14, 21, 28 and 35. Male rats exposed to 7000 ppm
exhibited a decrease in mating success with 2/16 producing a litter (1 male died as a result of a cage fight and 1 male did not mate). Mating success was not affected in 3500 ppm exposed males or in females. Six males from the 7000 ppm group were retained to determine if this effect was reversible. All 6 males successfully mated 15 weeks after exposure. The authors reported that weight gain was not affected in 7000 ppm exposed females (data not shown), but feed intake was decreased in
this treatment group. Crooked tails were observed in 2-3 offspring in 2 of 15 litters from the 7000 ppm maternally exposed
group. No other effects on female fertility were reported. No significant differences resulted between offspring of the 7000
ppm group and controls on several behavioral toxicology measures including the Ascent test, Rotorod test, Open Field test,
activity test, running wheel activity, avoidance conditioning, and operant conditioning. Activity measures were significantly
different between offspring of the 3500 ppm exposure group and controls.
GENOTOXICITY
Methyl Acetate, Propyl Acetate, Isopropyl acetate, t-Butyl Acetate, Propyl Alcohol and Isopropyl Alcohol have been tested in vitro and were not mutagenic. Acetic acid was also not mutagenic, when buffered to a physiological pH.
Methyl Acetate, Propyl Acetate, Isopropyl acetate, t-Butyl Acetate, Propyl Alcohol and Isopropyl Alcohol
Methyl acetate, propyl acetate, isopropyl acetate, t-butyl acetate, propyl alcohol and isopropyl alcohol were not mutagenic in in vitro bacterial and mammalian cell assays.27,52-58 Isopropyl alcohol was not genotoxic in an in vivo micronuclei assay.59 Details of these studies are provided in Table 7.
Acetic Acid
Acetic acid was reported to be slightly mutagenic to E. coli and mammalian cells, but, a more recent mammalian assay suggests that acetic acid is not mutagenic and that previous results were an aberration due strictly to low pH, and not the identity of the pH reducer.60,61
CARCINOGENICITY
For isopropyl alcohol, no neoplastic lesions were observed in male or female mice exposed to 2800 or 5000 ppm for 78 weeks. For t-butyl alcohol, all orally treated females showed nephropathy and a dose-related (up to 650 mg/kg/day) increase in kidney weight, while males also demonstrated increased kidney weights (only at 420 mg/kg/day), they demonstrated combined adenoma and carcinoma after 24 months of exposure.
Inhalation Isopropyl Alcohol
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CIR Panel Book Page 60 Fischer 344 rats and CD-1 mice (65/rats/sex/group; 55/mice/sex/group) were treated via inhalation with 0, 500,
2500, or 5000 ppm (0, 1230, 6150, or 12,300 mg/m3) isopropyl alcohol for 6 h/day, 5 days/wk for 104 weeks in rats and 78
weeks in mice.62 An additional 10/animals/sex/species were treated with these same concentrations of isopropyl alcohol for
6 h/day, 5 days/wk for 72 weeks in rats and 54 weeks in mice and underwent an interim evaluation. Another 10 mice/sex/group were treated according to the paradigm described above for 54 weeks and then allowed to recover before being killed at 78 weeks. Animals were observed and evaluated for body and organ weights, ophthalmology, and clinical and anatomic pathology.
In rats, increased mortality due to chronic renal disease was observed at 5000 ppm (both sexes) and at 2500 ppm
(males only). Hypoactivity and lack of startle reflex were observed in 2500 ppm treated rats and hypoactivity, lack of startle reflex and narcosis were observed in 5000 ppm treated rats. With the exception of the ataxia, the clinical signs were transient and ceased when the exposure ended. Increases in body weight, body weight gain, and liver weights were observed in 2500 and 5000 ppm treated rats. Chronic renal disease was exacerbated in rats treated with isopropyl alcohol. Male rats had a concentration related increase in absolute and relative testes weights. At the interim euthanasia (after 72 weeks) male rats treated with 5000 ppm had an increased frequency of testicular seminiferous tubule atrophy upon microscopic evaluation. At the terminal euthanasia (104 weeks), male rats had a concentration dependent increase in the incidence of interstitial (Leydig) cell adenomas of the testes at all administered doses. No other tumor types were increased in rats under these treatment conditions as compared to controls.
In mice, no differences in mortality were observed between control and treated animals. Hypoactivity, lack of a
startle reflex, narcosis, ataxia, and prostration were observed in 5000 ppm treated mice. Hypoactivity, lack of startle reflex
and narcosis were observed in 2500 ppm treated mice. Increases in body weight, body weight gain, and liver weights were
observed in 2500 and 5000 ppm treated mice. Male mice in all treatment groups had a decrease in relative testes weights,
and female mice exposed to 5000 ppm isopropyl alcohol exhibited decreases in absolute and relative brain weights. At the
terminal euthanasia (78 weeks) an increased incidence of minimal to mild renal tubular proteinosis was observed in males
and females in all treatment groups. Male mice exposed to 2500 and 5000 ppm exhibited an increased incidence of dilation
of the seminal vesicles. No neoplastic lesions were observed in male or female mice. The authors reported a NOAEL for
toxic effects of 500 ppm for both rats and mice based on kidney and testicular effects.
IARC (International Agency for Research on Cancer) has determined that isopropyl alcohol is not classifiable as to
its carcinogenicity to humans (Group 3).63
Oral
t-Butyl Alcohol
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CIR Panel Book Page 61 F-344 rats (n=60/group, males and females) were exposed orally, via drinking water, to t-butyl alcohol at various doses for 15 months to 103 weeks. At 420 mg/kg/day in males and 650 mg/kg/day in females there was decreased survival.64
Additionally, a dose related decrease in body weight gain was observed. All treated females had nephropathy and a dose-
related increase in kidney weight. Males also demonstrated kidney weight gain, but not at all doses.64
After 24 months of exposure, combined adenoma and carcinoma of the renal tubules was found in 8/50, 13/50,
19/50 and 13/50 of the control, low-, mid-, and high-dose males (not females), respectively.64
CLINICAL ASSSESSMENT OF SAFETY
An LDlo of 2-4 ml/kg of isopropyl alcohol has been reported in adults and 6 ml/kg was reported to induce coma in
children. Individual susceptibilities to Methyl Alcohol varied, but typically, the ingestion of 80 to 150 ml of 80% Methyl
Alcohol was fatal. 12.6% Cetyl Acetate caused no dermal sensitization. 2% Propyl Acetate in petrolatum caused no dermal
irritation or sensitization. 10% Methyl Acetate in petrolatum caused no sensitization reactions. In multiple dermal occlusion
studies, Propyl Alcohol caused no irritation. 10% Acetic Acid is reported to cause irritation.
Clinical data from previous CIR reports are interspersed below, and delineated by block quotations, to supplement
metabolite profiles. Complete assessments of these metabolites may be found in the cited reports.
Absorption, Distribution, Metabolism, Excretion
Butoxyethyl Alcohol
The percutaneous absorption of Butoxyethanol was evaluated using five healthy male volunteers (weights not stated) who had not been exposed to Butoxyethanol in the workplace. Each subject placed four fingers of the left hand into a polyethylene jar (21°C) filled with undiluted Butoxyethanol. Unexposed fingers served as controls. At the conclusion of the 2-h exposure, each subject washed the exposed hand with a mild soap and tap water. There was no evidence of skin irritation; however, exposed fingers appeared wrinkled and somewhat more rigid after exposure. These effects reached a maximum at 2-4 h post exposure and then gradually disappeared. The percutaneous uptake rate of Butoxyethanol into the blood varied from 127 to 1891 µmol. These values corresponded to 7-96 nmol Butoxyethanol/min/cm2 of exposed area. During the decay phase, the half-time of Butoxyethanol ranged from 0.6 to 4.8 h (geometric mean 1.3 h). A linear regression analysis for all of the experiments suggested that, on the average, 17% of the absorbed dose of Butoxyethanol was excreted in the urine. Two adult male subjects (between 30 and 45 years old) and one female subject (24 years old) breathed 200 ppm Butoxyethanol during two 4-h periods, separated by a 30-min lunch. Blood pressure and pulse rate were determined three times, and erythrocyte fragility tests were conducted twice during the day of exposure. Urinalyses for glucose and albumin were conducted during the morning after exposure, and butoxyacetic acid concentrations were determined in 24-h urine samples that were collected at the end of the day of exposure. One male subject and the female subject excreted considerable amounts of butoxyacetic acid, while the other male subject excreted only trace amounts. All three subjects experienced immediate irritation of the nose and throat, followed by ocular irritation and disturbed taste. The female
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CIR Panel Book Page 62 subject, who excreted the largest amount of butoxyacetic acid, reacted most adversely to the exposure. She acquired a headache that lasted for 24 h.
(Excerpted from CIR final report on butoxyethyl alcohol)65
Methanol
Methyl acetate is metabolized to methanol and therefore, data on the effects in humans following inhalation
exposure are applicable to this assessment. Metabolism of methyl acetate to methanol proceeds at a rate directly proportional
to the exposure level. Methanol is further metabolized to formaldehyde and then to formic acid. The CIR Expert Panel
concluded that Formic Acid is safe where used in cosmetic formulations as a pH adjustor with a 64 ppm limit for the free
acid.66 The main toxicological risks in humans are severe metabolic acidosis with increased anion gap, typically following oral exposure resulting in > 100 mg/L of formate in the urine.67 The acidosis and the formic acid metabolite are believed to
play a central role in both the central nervous system toxicity and the ocular toxicity.
A study to determine the formate levels that resulted from exposure of human volunteers to 200 ppm of methanol for
4 h was conducted. Human volunteers (n=27; age 20-55 y) were exposed to 200 ppm methanol (the Occupational Safety and
Health Administration (OSHA) Permissible Exposure Limit) for 4 h and to water vapor for 4 h in a double-blind, random
study.68 Urine samples were collected at 0, 4 and 8 h and blood samples were collected from the subjects before they entered the chamber, every 15 min for the first hour, every 30 min from the first to the third hour and at 4 h. Urine and serum samples were analyzed for formate (LOD 0.5 mg/L). Twenty-six of 27 enrolled subjects completed the study (11 females and 15 males). One volunteer withdrew from the study due to blood drawing intolerance. Urine formate data were excluded for one subject due to their consumption of high levels of vitamin C which interfered with the formate assay. The researchers did not find any statistically significant differences in serum or urine formate levels between the two exposure conditions at any time point. At the end of the 4 h methanol exposure, formate concentrations of 14.28 ± 8.90 and 7.14 ± 5.17 mg/L were measured in serum and urine, respectively. Under control conditions, formate concentrations of 12.68 ± 6.43 (p=0.38; n=26) and 6.64 ± 4.26 (p=0.59; n=25) mg/L were measured in serum and urine respectively. After 8 h (4 h of no exposure) the serum concentrations were not statistically different with 12.38 ± 6.53 mg/L under methanol exposure conditions and 12.95 ±
8.01 (P=0.6; n=26) under control conditions. Urine formate concentrations after 8 h were 6.08 ± 3.49 and 5.64 ±3.70 (p=0.6; n=25) in exposed and control conditions, respectively, and were not statistically significantly different.
Methyl Acetate
15 ml of methyl acetate was applied to the skin of the forearm with cotton dipped into the solvent and filled in a
plastic vessel of 12.5 cm2, which was fixed to the arm with a rubber band and covered with polyethylene film.69 The amount
of skin absorption was estimated by determining concentrations of the relevant solvents and their metabolites in blood,
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CIR Panel Book Page 63 expired air, and urine. Blood samples were taken before and immediately after application. All the subjects were men and 1-
4 subjects served in each experiment. The concentrations of solvents in blood were determined by gas chromatographic
method after separating them by gas-liquid equilibrium method. Blood concentration levels of methyl acetate ranged from
0.9 µg/ml at 1 hour post-application, to as great as 3.8 µg/ml at 2 hours
Toxicity
Isopropyl Alcohol
An LDlo of 2-4 ml/kg of isopropyl alcohol has been reported in adults and 6 ml/kg (9 ml/kg 70% isopropyl alcohol)
was reported to induce coma in children.25
Methyl Alcohol
Clinical data show that Methyl Alcohol can cause severe metabolic acidosis, blindness, and death: toxicity was manifested earlier and at a lower dose compared to ethyl alcohol, but the comparative fatal dose was the same for both alcohols. All routes of exposure were toxicologically equivalent, as the alcohol distributed readily and uniformly throughout all tissues and organs. Individual susceptibilities to Methyl Alcohol varied, but typically, the ingestion of 80 to 150 ml of 80% Methyl Alcohol was fatal. Symptoms of Methyl Alcohol intoxication after ingestion were delayed for 12 to 18 hours; afterwards, the symptoms included headache, anorexia, weakness, fatigue, leg cramps, and/or pain and vertigo. Severe gastrointestinal pain, nausea, vomiting, diarrhea, mania, failed vision, and convulsions could occur. Chronic exposure to Methyl Alcohol could cause edema, granular degeneration, and necrosis of heart muscle fibers, as well as fatty degeneration of the heart muscle; sudden cardiac failure was associated with Methyl Alcohol intoxication. The liver and kidneys often had parenchymatous degeneration, and the liver had focal necrosis and fatty infiltration. Severe acidosis was necessary for the development of blindness. Similar symptoms were observed after percutaneous or inhalation exposure to Methyl Alcohol.
(Excerpted from CIR final report on methyl alcohol)70
Irritation and Sensitization
Cetyl Acetate
According to unpublished data, a lipstick containing 12.6% Cetyl Acetate caused no dermal sensitization in 99
human test subjects.71
Propyl Acetate
In a human maximization test pre-screen, 2% propyl acetate in petrolatum was applied to the backs of 25 healthy subjects for 48 hours under occlusion. No subject experienced any irritation or sensitization.45
Methyl Acetate
Human maximization tests were carried out with 10% methyl acetate in petrolatum on various panels of volunteers.
Application was under occlusion to the same site on the forearms or backs of all subjects for five alternate-day 48-hour periods.72 Patch sites were pre-treated for 24 hours with 2.5% aqueous sodium lauryl sulfate (SLS) under occlusion.
Following a 10 – 14 day rest period, challenge patches were applied under occlusion to fresh sites for 48 hours. Challenge
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CIR Panel Book Page 64 applications were preceded by a 60 minute SLS treatment. Reactions were read at patch removal and again at 24 hours
thereafter. The following results were obtained: No sensitization reactions were observed in any of the 25 subjects tested.
Methyl Alcohol
Methyl Alcohol caused primary irritation to the skin; prolonged and repeated contact with Methyl Alcohol resulted in defatting and dermatitis. In one occupational study, 3.2% of 274 metalworkers with dermatitis had positive results to a patch test of 30% Methyl Alcohol. Typical allergic responses observed after contact with alcohols were eczematous eruption and wheal and flare at the exposure sites. Eczema and erythema were reported after the consumption of alcoholic beverages by persons sensitized to ethyl alcohol. Five percent Methyl Alcohol caused a slight positive (+) reaction in a closed patch test for allergic contact dermatitis, and concentrations of 7% and 70% caused (+++) reactions.
(Excerpted from CIR final report on methyl alcohol)70
Propyl Alcohol
A cumulative irritation study was conducted involving 20 male subjects, where the relative irritancy of free fatty acids of different chain lengths was evaluated.73 Equimolar concentrations (0.5 M and 1.0 M) of even- and odd-numbered -
straight chain saturated fatty acids were dissolved in propanol. Each Al-test® patch containing a fatty acid (0.5 M) was
applied to the interscapular area of 10 subjects, and, similarly, each fatty acid was applied at a higher concentration (1.0 M)
to the remaining 10 subjects. A control patch containing propanol was also applied to each subject. Patches remained in
place for 24 h and reactions were scored 30 minutes after patch removal. This procedure was repeated daily for a total of 10
applications. In both groups of 10 subjects, there were no reactions to propanol.
In an irritation study, wherein 116 healthy male subjects (21 to 55 years old) were patch tested with pelargonic acid
at concentrations of 5%, 10%, 20%, and 39.9% in propanol, a propanol-treated control patch was used.74 Dose response curves were developed. Patches (Al-test® discs) were saturated with 0.04 ml of a test solution and applied to the upper back for 48 h. Reactions were scored at 48 h and 96 h post-application. There were no reactions to propanol.
In an another irritation study, wherein 16 volunteers (10 females, 6 males; median age of 29.5 years) were patch tested (closed patches, Finn chambers) with 20% pelargonic acid in propanol (pH of 4.3), propanol was one of the controls used.75 Patches were applied to the anterolateral surface of both upper arms for 24 h. Reactions were scored at 24, 48, and
96 h post-application according to the following scale: 0 (no reaction) to 3 (strong positive reaction: marked erythema, infiltration, possibly vesicles, bullae, pustules and/or pronounced crusting). There were no reactions to propanol.
A skin irritation study was conducted using 42 healthy, non-atopic male volunteers (mean age = 34 years; skin types: II [20 subjects], III [17 subjects], and IV [5 subjects]).76 Pelargonic acid was patch-tested (Finn chambers, volar
forearm) at the following concentrations (in propanol): 40% (12 subjects), 60% (32 subjects), 70% (32 subjects), and 80%
(28 subjects), and propanol was used as a control. Each subject received between 3 and 10 patch tests. The patches remained
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CIR Panel Book Page 65 in place for 48 h, and reactions were scored 1 h later according to the following scale: - (no visible reaction) to 4+ (intense
erythema with bullous formation). There were no reactions to propanol.
In an irritation study, wherein 16 healthy subjects (ages not stated) were patch tested with pelargonic acid (20% in
propanol), propanol was used as a control.77 Closed patches (Finn chambers) containing the test substance were applied to
the anterolateral surface of both upper arms. The patches were removed at 24 h post-application and reactions were scored at
24 h and 96 h post-application. There were no reactions to propanol.
In study conducted to investigate a possible seasonal variation in the skin response to pelargonic acid during the
winter and summer, propanol was used as a control.78 The study was conducted using 17 healthy volunteers (10 males, 7 females; mean age = 27 years). The test substance was applied (closed patch, Finn chamber) to each arm for 24 h. Reactions were scored at 30 min post-removal. Reactions were not observed at sites treated with propanol, water, or to which an empty chamber was applied.
Isopropyl Alcohol
According to unpublished data, a 80.74% spray concentrate did not exhibit any potential for dermal sensitization in
9 human subjects.79
According to unpublished HRIPT study on 109 test subjects, a 2.85% hair dye base formulation of isopropyl alcohol
and 1.95% isopropyl acetate caused no dermal sensitization in humans.80
The applicability of fluorescence confocal laser scanning microscopy for in situ imaging of irritant contact dermatitis caused by pelargonic acid using 12 healthy individuals (8 males, 4 males; 18 to 64 years old) was studied.81 Using
Finn chambers (occlusive patches), the flexor side of the right and left forearm was exposed to 60 µl of 10% (w/v) pelargonic
acid in isopropanol solution and isopropanol vehicle. Isopropanol was used as a control. The Finn chambers were removed
at 24 h post-application and reactions were scored according to the following scale: 0 (no visible reaction) to 4+ (intense
erythema with bullous formation). Reactions were not observed at sites treated with isopropanol.
Butoxyethyl Alcohol
The skin sensitization potential of 10.0% (vol/vol) aqueous Butoxyethanol was evaluated using 214 male and female subjects between 18 and 76 years of age. A total of 201 subjects completed the study; withdrawal from the study was not related to administration of the test substance. Challenge reactions were observed in 14 subjects. Definite erythema, with no edema, was observed in one subject at 72 h and doubtful (barely perceptible erythema, only slightly different from surrounding skin) responses were observed in 13 subjects: 6 subjects at 48 and 72 h, 6 subjects at 72 h, and 1 subject at 48 h. Eleven of the 14 subjects with challenge reactions also had reactions ranging from doubtful to definite erythema, but with no edema, during the induction phase. Additionally, a total of 52 subjects had reactions only during the induction phase; 35 subjects had doubtful reactions and 17 subjects had reactions ranging from doubtful to definite erythema, but with no edema. The authors concluded that there was no evidence of sensitization to 10.0% aqueous Butoxyethanol.
21
CIR Panel Book Page 66 (Excerpted from CIR final report on butoxyethyl alcohol)65
Cetyl Alcohol
A topical tolerance study involving an 11.5% Cetyl Alcohol cream base was conducted with 80 male subjects, ranging in age from 21 to 52 years and in weight from 120 to 220 pounds. The preparations were applied five times daily (every 3 hours) for 10 days. One subject had erythema, folliculitis, and pustule formation (forearm site). A formulation containing 6.0% Cetyl Alcohol was tested for its skin irritation potential in 20 subjects according to the protocol stated above. The product did not induce skin irritation. In another study, the skin irritation potential of a cream containing 6.0% Cetyl Alcohol was evaluated in 12 female subjects (18-60 years old). The total irritation score (all panelists) for the 21 applications was 418, indicating mild cumulative irritation. The skin irritation and sensitization potential of a product containing 8.4% Cetyl Alcohol was evaluated in 110 female subjects. Fourteen days after scoring of the tenth application site, a challenge patch was applied to each subject and removed after 48 h; sites were scored after patch removal. The product did not induce primary irritation or sensitization. The sensitization potential of a cream containing 3.0% Cetearyl Alcohol was evaluated in 25 subjects (18-25 years old). Following a 10-day non-treatment period, occlusive challenge patches were applied to new sites and removed after 48 h. Sensitization reactions were not observed in any of the subjects.
(Excerpted from CIR final report on cetyl alcohol)82
Myristyl Alcohol
A moisturizing lotion containing 0.80% Myristyl Alcohol was applied to the face of each of 53 subjects over a period of 4 weeks. None of the subjects had signs of skin irritation. In another study, the irritation potential of a moisturizing lotion containing 0.25% Myristyl Alcohol was evaluated in 51 subjects, used daily during a 1-month period. A burning sensation was experienced by 1 of the subjects 1 day after initial use of the product. None of the subjects had signs of skin irritation. A moisturizing lotion containing 0.25% Myristyl Alcohol was applied to the backs of 229 male and female subjects via occlusive patches for 24 h. The product was reapplied to the same sites following a 24-h non-treatment period and repeated for a total of 10 induction applications. None of the subjects had reactions to the product. The product was considered neither an irritant nor an allergen. (Excerpted from CIR final report on myristyl alcohol)82
Stearyl Alcohol
In 24-hour single insult occlusive patch tests, mild irritation was produced by 100 percent Stearyl Alcohol.83
(Excerpted from CIR final report on stearyl alcohol)83
Isostearyl Alcohol
The skin irritation potential of lsostearyl Alcohol was evaluated in 19 male and female subjects (18-65 years old) at a concentration of 25.0% in petrolatum. The test substance did not induce skin irritation in any of the subjects (Primary Irritation Index = 0.05). In three similar studies, three different lipstick products containing 25.0, 27.0, and 28.0% Isostearyl Alcohol, respectively, were tested according to the same protocol. The three products did not induce skin irritation. The irritation and sensitization potential of Isostearyl Alcohol (25% v/v in 95.0% isopropyl alcohol) was evaluated in 12 male subjects (21-60 years old). Challenge applications were made to original 22
CIR Panel Book Page 67 and adjacent sites 2 weeks after removal of the last induction patch. Three of 12 subjects had slight erythema during induction, and there was no evidence of sensitization. The sensitization potential of a pump spray antiperspirant containing 5.0% Isostearyl Alcohol was evaluated using 148 male and female subjects. The product was applied via an occlusive patch to the upper arm for a total of nine induction applications (3 times/week for 3 weeks). Each patch remained for 24 h, and sites were scored immediately before subsequent applications. During the challenge phase, a patch was applied to the induction site and to a new site on the opposite arm of each subject. Reactions were scored 48 and 96 h after application. Ten of the twelve subjects with reactions suggestive of sensitization were re- challenged with the product 2 months later. Patches remained for 24 h, and sites were scored at 48 and 96 h post-application. Six subjects had reactions during the re-challenge. Four of the six subjects were then tested with 5.0% Isostearyl Alcohol in solution with ethanol 6 weeks after scoring of the first rechallenge; all had positive responses. Negative responses were reported when the product (without lsostearyl Alcohol) and 100.0% ethanol each were tested. In a second study, the same product was applied to 60 male and female subjects (same protocol). Five of the subjects had positive responses after the first challenge. One of the five was re-challenged with 5.0% Isostearyl Alcohol in ethanol solution, and a positive reaction was observed.
(Excerpted from CIR final report on isostearyl alcohol)82
Acetic Acid
Human volunteers (96/sex not provided) were tested for acetic acid dermal irritation via an interlaboratory 4-hour patch test.84,85 At a concentration of 10% acetic acid, 70-94% of volunteers, depending on the laboratory, reported irritation.
Photosensitization
Cetyl Alcohol
The photosensitization potential of a lipstick product containing 4.0% Cetyl Alcohol was evaluated in 52 subjects. The experimental procedure was not stated. Photosensitization reactions were not noted in any of the subjects. In another study, a skin care preparation containing 1.0% Cetyl Alcohol did not induce photosensitization in the 407 subjects tested. The experimental procedure was not stated.
(Excerpted from CIR final report on cetyl alcohol)82
Myristyl Alcohol
A moisturizing lotion containing 0.10% Myristyl Alcohol was evaluated for its photosensitization potential in a study involving 52 subjects. The experimental procedure was not stated. The product did not induce photosensitization in any of the subjects.
(Excerpted from CIR final report on myristyl alcohol)82\
Case Reports t-Butyl Alcohol
A woman who had a positive patch test reaction to ethanol was tested with 100% t-BuOH. The alcohol was applied for 48 h and the site was scored at 3, 24, and 48 h after removal of the test material. The woman did not react to t-BuOH. Four female patients were tested on the upper back with 1% and 10% t-BuOH in water. The patches were applied for 24 h and reactions were read 24 and 48 h after removal. None of the women had any reaction to t-BuOH.
23
CIR Panel Book Page 68 Edwards and Edwards described a case of allergic contact dermatitis to the t-BuOH component of SD-40 alcohol in a commercial sunscreen preparation. A man who had a widespread, pruritic, red, vesicular eruption of his face, neck, arms, and chest and who had used a variety of sunscreens was patch- tested with sunscreens and with the individual components of the product to which he reacted. A 70% concentration of t-BuOH was applied to the forearms. At 72 h. erythema was observed and at 96 h, vesiculation was observed. No reactions were observed in two controls who also had applied t-BuOH to their forearms.
(Excerpted from CIR final report on t-butyl alcohol)48
Stearyl Alcohol
Contact sensitization to Stearyl Alcohol has been reported in 3 individuals: 2 had an urticarial-type reaction, and 1 of these reactions was thought to be due to impurities in the Stearyl Alcohol sample.
(Excerpted from CIR final report on myristyl alcohol)83
SUMMARY
The ingredients methyl acetate, propyl acetate, isopropyl acetate, t-butyl acetate, isobutyl acetate, butoxyethyl
acetate, nonyl acetate, myristyl acetate, cetyl acetate, stearyl acetate, and isostearyl acetate are alkyl esters that function in
cosmetics as fragrance ingredients, solvents and skin conditioning agents. The ingredients acetic acid, sodium acetate,
potassium acetate, magnesium acetate, calcium acetate and zinc acetate are also included because they represent the acetic
metabolite of the above alkyl acetates and they function as one or more of the following agents: pH adjusters, buffering
agents viscosity controllers, cosmetic astringents, cosmetic biocides, skin protectants and fragrance ingredients. The
ingredients propyl alcohol and isopropyl alcohol are also included because they are metabolites of propyl acetate and
isopropyl acetate, respectively and they function in cosmetics as antifoaming agents, fragrance ingredients, solvents and
viscosity decreasing agents.
Exposure to these ingredients is expected to occur mostly by the inhalation and dermal routes, although some oral or
ocular exposure could occur depending on the types of products that they are used in. Shorter acetic esters, readily penetrate
the skin and mucous membranes and are metabolized via esterases to the parent alcohol and acetic acid. The alcohols are
further metabolized to the corresponding aldehyde or ketone and then to the corresponding acid. The LD50 values, for those
ingredients in this assessment with acute toxicity data, are greater than 1 g/kg.
Alkyl acetates:
Central nervous system depression and narcotic like effects have been documented in animals for the shorter alkyl
chain acetates.86 The alkyl acetate ingredients have been labeled minor skin and eye irritants in animal studies. Those alkyl
acetate ingredients that have been tested have been found negative for mutagenicity, in vitro.
24
CIR Panel Book Page 69 A formulation of 1.95% isopropyl acetate did not cause sensitization in humans in one report. A formulation of
11.7% cetyl acetate did not cause sensitization in humans in one report, or in a formulation of 12.6% cetyl acetate in humans
in another report. A formulation of 10% methyl acetate did not cause sensitization in humans in one report. A formulation of
2% propyl acetate did not cause sensitization in humans in one report.
NOAELs for reproductive toxicity were greater than or equal to 400 mg/kg in rats for t-butyl acetate.
Ethyl acetate and butyl acetate have been found safe as used by the CIR Expert Panel.
Acetic acid/salts:
Central nervous system depression has been documented in animals for acetic acid. Acetic acid has been labeled a minor skin irritant, at low concentrations, in animal and human studies, and a severe ocular irritant in a rabbit ocular irritation test. The sodium salt of acetic acid has a more than two-fold higher toleration level than the pure free acid, and acetic acid is not mutagenic when buffered to physiological pH.
The metabolite of acetic acid, formic acid, has been found to be safe as used up to a 64 ppm concentration by the
CIR Expert Panel.
Alcohols:
The alcohol metabolites ethyl alcohol, butyl alcohol, t-butyl alcohol, butoxyethyl alcohol (with qualifications), myristyl alcohol, cetyl alcohol, stearyl alcohol and isostearyl alcohol have been found safe as used by the CIR Expert Panel.
Isopropyl alcohol has been labeled a severe ocular irritant in a rabbit ocular irritation test. Isopropyl alcohol was negative in an in vivo micronuclei assay. A formulation of 2.85% isopropyl alcohol did not cause sensitization in humans, in one report. Central nervous system depression behavioral effects have been documented in humans for isopropyl alcohol.
Reproductive toxicity NOAEL’s for isopropyl alcohol were reported for maternal and developmental toxicity of 400 mg/kg
each in rats and 240 and 480 mg/kg in rabbits, respectively. In an inhalation carcinogenicity study of isopropyl alcohol, rats
exhibited an exacerbation of chronic renal disease and a concentration dependent increase in interstitial cell adenomas of the testes. Male mice exhibited dilation of the seminal vesicles at 2500 ppm, but no neoplastic lesions were observed.
Exposure to 3500 ppm of n-propyl alcohol resulted in significantly different offspring behavioral toxicology measures as compared to controls.
Inhalation exposure to isobutyl alcohol induced a slight reduction in responsiveness to external stimuli in rats.
Long term oral exposure of t-butyl alcohol to rats resulted in more combined adenoma and carcinoma of the renal tubules than in controls (13-19/50 versus 8/50).
Discussion
25
CIR Panel Book Page 70 A Scientific Literature Review (SLR) for Methyl Acetate, Propyl Acetate, Isopropyl Acetate, t-Butyl Acetate,
Isobutyl Acetate, Butoxyethyl Acetate, Nonyl Acetate, Myristyl Acetate, Cetyl Acetate, Stearyl Acetate, Isostearyl Acetate,
Propyl Alcohol, and Isopropyl Alcohol was announced in December 2009.
Interested parties had 60 days to respond to this formal request for data. Industry identified an unpublished repeat insult patch study of formulations containing Isopropyl Alcohol and Isopropyl Acetate, which has been incorporated into this report.
The CIR Expert Panel was informed that a similar relevant metabolite and its salts (Acetic Acid, Sodium Acetate,
Potassium Acetate, Magnesium Acetate, Calcium Acetate, and Zinc Acetate) are also cosmetic ingredients. At the April
2010 meeting, the Panel agreed that the relevant metabolite and its salts should be incorporated into the assessment. The
Panel requested that further information on impurities and the method of manufacture be identified and incorporated.
An unpublished maximization study of a lipstick formulation containing Cetyl Acetate showed no sensitization at the highest reported concentration of use (12.6%). Additionally, sensitization data was received that supported the lack of potential for human dermal sensitization to Methyl Acetate, Propyl Acetate and Isopropyl Acetate. The Panel determined that the ingredients assessed herein are safe in present practices of use and concentration.
The Panel recognized that Butoxyethanol, a metabolite of Butoxyethyl Acetate, was previously determined to be safe as used with the qualification that it may be safely used up to 10% in hair and nail products and 50% in nail polish removers. However, the Panel determined that the concentration of Butoxyethyl Acetate that would be required to generate appreciable quantities of butoxyethanol through metabolic pathways is well above the present use concentrations of related alkyl acetates in cosmetics. (Butoxyethyl Acetate is not currently being used in cosmetics.) Furthermore, the LD50 values
reported for Butoxyethyl Acetate are relatively high. Accordingly, the Panel has determined that Butoxyethyl Acetate should
be included in the safe as used assesment.
CONCLUSION The CIR Expert Panel concluded that Methyl Acetate, Propyl Acetate, Isopropyl Acetate, t-Butyl Acetate, Isobutyl
Acetate, Butoxyethyl Acetate, Nonyl Acetate, Myristyl Acetate, Cetyl Acetate, Stearyl Acetate, Isostearyl Acetate, Acetic
Acid, Sodium Acetate, Potassium Acetate, Magnesium Acetate, Calcium Acetate, Zinc Acetate, Propyl Alcohol, and
Isopropyl Alcohol are safe in the present practices of use and concentration.A
A Were ingredients in this group not in current use to be used in the future, the expectation is that they would be used in product categories and at concentrations comparable to others in this group (e.g., this assessment would apply to butoxyethyl acetate if used in product categories and at concentrations comparable to the alkyl acetates in this assessment; and to calcium acetate comparable to other acetate salts found in this assessment. 26
CIR Panel Book Page 71
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66. Andersen, F. A. Final Report on the Safety Assessment of Formic Acid. International Journal of Toxicology. 1997;16(3).
67. International Programme on Chemical Safety.Methanol: Poisons Information Monograph 335. http://www.inchem.org/documents/pims/chemical/pim335.htm. Accessed 10-20-2009.
68. D'Alessandro, A., Osterloh, J. D., Chuwers, P., Quinlan, P. J., Kelly, T. J., and Becker, C. E. Formate in serum and urine after controlled methanol exposure at the threshold limit value. Environ.Health Perspect. 1994;102(2):178-181.
69. Nakaaki, Kenji, Fukabori, Sumie, and Tada, Osamu. An Experimental Study on Percutaneous Absorption of Some Organic Solvents. J.of Science of Labour. 1980;56(12 (Part II)):1-9.
70. Andersen, F. A. Final Report on the Safety Assessment of Methyl Alcohol. International Journal of Toxicology. 2001;20((Suppl. 1)):57-85.
71. Ivy Laboratories (KGL, Inc. Final Report on the Determination of Contact-Sensitization Potential of Four Materials by Means of the Maximization Assay (Including a Lipstick Containing 12.6% Cetyl Acetate). 1993.
72. Research Institute for Fragrance Materials, Inc. Acute toxicity studies in rats, mice, rabbits and guinea pigs. Report to RIFM.Unpublished report 1787 from Kligman A.M.October 20. 1978.
73. Stillman, M. A. Maibach H. I. and Shalita A. R. Relative irritancy of free fatty acids of different chain length. Contact Dermatitis. 1975. 1: pp.65-69.
3
CIR Panel Book Page 75 74. Wahlberg, J. E. and Maibach H. I. Nonanoic acid irrigation: A positive control at routine patch testing? Contact Dermatitis. 1980. 6:(2): pp.128-130.
75. Agner, T. and Serup J. Skin reactions to irritants assessed by polysulfide rubber replica. Contact Dermatitis. 1987. 17:(4): pp.205-211.
76. Willis, C. M. Stephens J. M. and Wilkinson J. D. Experimentally-induced irritant contact dermatitis. Determination of optimum irritant concentrations. Contact Dermatitis. 1988. 1: pp.20-24.
77. Agner, T. and Serup J. Contact thermography for assessment of skin damage due to experimental irritants. Acta Derm Venereol. 1988. 68:(2): pp.192-195.
78. Agner, T. and Serup J. Seasonal variation of skin resistance to irritants. Br J Dermatol. 2010. 121:(3): pp.323-328.
79. Damato JM, Martin DM Fehn PA. Allergic contact sensitization test of a spray concentrate containing 80.74% Isopropyl Alcohol. 1979.
80. Anonymous. Unpublished Data: Final Report Repeated Insult Patch Test of a Hair Dye Base (3373) Containing 2.85% Isopropyl Alcohol and 1.95% Isopropyl Acetate. 2010.
81. Suihko C. and Serup J. Fluorescence Confocal Laser Scanning Microscopy for in vivo Imaging of Epidermal Reactions to Two Experimental Irritants. Skin Res Technol. 2008. 14:(4): pp.498-503.
82. Andersen, F. A. Final Report on the Safety Assessment of Cetearyl Alcohol, Cetyl Alcohol, lsostearyl Alcohol, Myristyl Alcohol, and Behenyl Alcohol. Journal of the American College of Toxicology. 1988;7(3):359- 413.
83. Andersen, F. A. Final Report on the Safety Assessment of Stearyl Alcohol, Oleyl Alcohol, and Octyl Dodecanol. Journal of the American College of Toxicology. 1985;4(5):1-29.
84. Griffiths, H. A., Wilhelm, K.-P., Robinson, M. K., Wang, X. M., McFadden, J., York, M., and Basketter, D. A. Interlaboratory Evaluation of a Human Patch Test for the Identification of Skin Irritation Potential/Hazard. Food and Chemical Toxicology. 1997;35255-260.
85. York, M., Basketter, D. A., Cuthbert, J. A., and Neilson, L. Skin Irritation Testing in Man for Hazard Assessment - Evaluation of Four Patch Systems. Hum.Exp.Toxicol. 1995;14729-734.
86. Jenner, P. M., Hagan, E. C., Taylor, J. M., Cook, E. L., and Fitzhugh, O. G. Food flavourings and compounds of related structure I. Acute oral toxicity. Food and Cosmetic Toxicology. 1964;2327-343.
87. Gottschalck, T. E. and Bailey, J. E. International Cosmetic Ingredient Dictionary and Handbook. 13th ed. Washington DC: Personal Care Products Council, 2008.
88. Howard, P. H. and Meylan, W. Handbook of physical properties of oraganic chemicals. Boca Raton: CRC-Press, 1997.
89. NIOSH.NIOSH Pocket Guide to Chemical Hazards. http://www.cdc.gov/niosh/npg/search.html. Accessed 10-20- 2009.
90. US EPA. EPI Suite (for Windows). 2009. (4.0):Washington DC: Environmental Protection Agency.
91. FDA. VCRP Total Number of Products in Each Product Category; September 28, 2009. Washington, D.C., FDA. 2009.
92. Hygenic Guide Series Acetic Acid. Am Ind Hyg Assoc.J. 1972;624-627.
93. Oro, L. and Wretlind, A. Pharmacological Effects of Fatty Acids, Triolein and Cottonseed Oil. Acta Pharmacol.et Toxicol. 1961;18141-152.
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CIR Panel Book Page 76 94. Gerald L.Kennedy, Jr. and G.Jay Graepel. Acute Toxicity in the Rat Following Either Oral of Inhalation Exposure. Toxicol.Lett. 1991;56317-326.
5
CIR Panel Book Page 77 Figure 1. Structures of the ingredients in this assessment.
Methyl Acetate Propyl Acetate
Isopropyl Acetate t-Butyl Acetate
Isobutyl Acetate Butoxyethyl Acetate
Nonyl Acetate
Myristyl Acetate
Cetyl Acetate
Stearyl Acetate
Isostearyl Acetate
6
CIR Panel Book Page 78
Acetic Acid Zinc Acetate
Sodium Acetate Potassium Acetate
Magnesium Acetate Calcium Acetate
Propyl Alcohol Isopropyl Alcohol
7
CIR Panel Book Page 79 Figure 2. Map of the ingredients in this assessment, and associated esterase metabolites.
8
CIR Panel Book Page 80 Table 1a. The name, CAS registry number, definition, function and CIR review history of metabolites of alkyl acetate ingredients in this assessment, which are also cosmetic ingredients. 87
Ingredient Definition Function CIR Review History of Alcohol Metabolite Methyl Acetate (CAS The ester of Fragrance Methyl Alcohol No. 79-20-9) methyl alcohol Ingredients; IJT 20 (S1):57-85, 2001 and acetic acid Solvents Safe for use as a denaturant in ethyl alcohol Propyl Acetate (CAS No. The ester of Fragrance Propyl Alcohol 109-60-4) propyl alcohol Ingredients; Included in this Review and acetic acid Solvents Isopropyl Acetate (CAS The ester of Fragrance Isopropyl Alcohol No. 108-21-4) isopropyl Ingredients; Included in this Review alcohol and Solvents acetic acid t-Butyl Acetate (CAS Organic Solvents t-Butyl Alcohol No.540-88-5) compound IJT 24 (S2):1-20, 2005 Safe as used
Isobutyl Acetate The ester of Fragrance Isobutyl Alcohol (CAS No. 110-19-0 ) isobutyl alcohol Ingredients; Not listed as a cosmetic and acetic acid Solvents ingredient Butoxyethyl Acetate Organic Fragrance Butoxyethanol (CAS No.112-07-2) compound Ingredients; JACT 15(6):62-526, 1996 Solvents Safe for use in hair and nail products at concentrations up to 10% Nonyl Acetate (CAS No. The ester of Fragrance Nonyl Alcohol 143-13-5) nonyl alcohol Ingredients; Skin- Not listed as a cosmetic and acetic acid Conditioning ingredient Agents-Emollient Myristyl Acetate (CAS Organic Skin-Conditioning Myristyl Alcohol No. 638-59-5) compound Agents-Emollient JACT 7(3):359-413, 1988 Safe as used
Cetyl Acetate (CAS No. The ester of Fragrance Cetyl Alcohol 629-70-9) cetyl alcohol Ingredients; Skin- JACT 7(3):359-413, 1988 and acetic acid Conditioning Agents-Emollient Safe as used Stearyl Acetate (CAS The ester of Skin-Conditioning Stearyl Alcohol No. 822-23-1) stearyl alcohol Agents-Emollient JACT 4(5):1-29, 1985 and acetic acid Safe as used
9
CIR Panel Book Page 81 Ingredient Definition Function CIR Review History of Alcohol Metabolite Isostearyl Acetate (CAS The ester of Skin-Conditioning Isostearyl Alcohol No. NL) isostearyl Agents-Emollient JACT 7(3):359-413, 1988 alcohol and acetic acid Safe as used
Table 1b. The name, CAS registry number, definition, function and CIR review history of acid, metal salts, and alcohol ingredients in this assessment. Ingredient Definition Function CIR Review History of Metabolite Acetic Acid (CAS No. A carboxylic Fragrance Formic Acid 64-19-7) acid Ingredients; pH IJT 16(3) 1997 Adjusters Safe where used in cosmetic formulations as a pH adjustor with a 64 ppm limit for the free acid Sodium Acetate (CAS The sodium salt Buffering Agents; No. 127-09-3) of acetic acid Fragrance Ingredients Potassium Acetate (CAS The potassium Buffering Agents; No. 127-08-2 salt of acetic Fragrance acid Ingredients Magnesium Acetate The magnesium Buffering Agents (CAS No. 142-72-3) salt of acetic acid Calcium Acetate (CAS The calcium salt Fragrance No. 62-54-4) of acetic acid Ingredients (Viscosity Controller – via EWG database) Zinc Acetate (CAS No. The zinc salt of Cosmetic 557-34-6) acetic acid Astringents; Cosmetic Biocides; Skin Protectants Propyl Alcohol (CAS An alkyl Antifoaming No. 71-23-8) alcohol Agents; Fragrance Ingredients; Solvents; Viscosity Decreasing Agents Isopropyl Alcohol (CAS An alkyl Antifoaming No. 67-63-0) alcohol Agents; Fragrance Ingredients; Solvents; Viscosity Decreasing Agents
10
CIR Panel Book Page 82 Table 2. Nomenclature for the ingredients in this safety assessment.17,87
Ingredient Name Other Technical Names IUPAC Name Methyl Acetate Acetic Acid, Methyl Ester Methyl ethanoate Methyl Ethanoate
Propyl Acetate Acetic Acid, Propyl Ester Propyl ethanoate n-Propyl Acetate Propyl Ethanoate 1-acetoxypropane
Isopropyl Acetate Acetic Acid, Isopropyl Ester Methylethyl ethanoate Acetic Acid, 1-Methylethyl Ester Isopropyl Ethanoate 1-Methylethyl Acetate
t-Butyl Acetate Acetic Acid, t-Butyl Ester Dimethylethyl ethanoate Acetic acid 1,1-dimethylethyl ester
Isobutyl Acetate Acetic Acid, Isobutyl Ester 2-Methylpropyl ethanoate Acetic Acid, 2-Methylpropyl Ester 2-Methylpropyl Acetate
Butoxyethyl Acetate 2-Butoxyethyl Acetate 2-Butoxyethyl ethanoate Butyl Glycol Acetate Ethanol, 2-butoxy-, Acetate Ethylene Glycol Monobutyl Ether Acetate Glycol Monobutyl Ether Acetate
Nonyl Acetate Acetic Acid, Nonyl Ester Nonyl ethanoate 1-Acetoxynonane n-Nonyl Ethanoate Perlargonyl Acetate
Myristyl Acetate Acetic Acid, Tetradecyl Ester Tetradecyl ethanoate Tetradecanol Acetate Tetradecyl Acetate
Cetyl Acetate 1-Acetoxyhexadecane Hexadecyl ethanoate 1-Hexadecanol, Acetate Hexadecyl Acetate Palmityl Acetate
Stearyl Acetate Acetic Acid, Octadecyl Ester Octadecyl ethanoate
Isostearyl Acetate Acetic Acid, Isostearyl Ester 16-Methylheptadecyl ethanoate
Acetic Acid Acidum aceticum Ethanoic acid Ethanoic Acid Ethylic Acid Glacial Acetic Acid Methanecarboxylic Acid
Sodium Acetate Acetic Acid, Sodium Salt Sodium ethanoate Natrii acetas
11
CIR Panel Book Page 83 Ingredient Name Other Technical Names IUPAC Name Potassium Acetate Acetic Acid, Potassium Salt Potassium ethanoate Kalii acetas Potassium Ethanoate
Magnesium Acetate Acetic Acid, Magnesium Salt Magnesium ethanoate Magnesium Diacetate
Calcium Acetate Acetic Acid, Calcium Salt Calcium ethanoate Calcium Diacetate
Zinc Acetate Acetic Acid, Zinc Salt Zinc (II) ethanoate
Propyl Alcohol 1-Propanol Propanol n-Propanol n-Propyl Alcohol 1-Hydroxypropane
Isopropyl Alcohol 2-Propanol Methylethanol Isopropanol 1-Methylethanol 2-Hydroxypropane
12
CIR Panel Book Page 84 Table 3. Physical and Chemical properties of the acetate ingredients.4,23,88-90
Methyl Propyl Isopropyl t-Butyl Isobutyl Butoxyethyl Acetate Acetate Acetate Acetate Acetate Acetate
Cas No. 79-20-9 109-60-4 108-21-4 540-88-5 110-19-0 112-07-2
Molecular 74.08 102.13 102.13 116.16 116.16 160.21 Weight (g/mol) Boiling 56.9 101.6 89 97.8 118 187.8 Point (°C) Density 0.933 0.887 0.872 - 0.871 0.943 (g/cm3) Vapor 170 - - 47(@25°C) 13.0 - pressure (mm Hg @ 20°C) Solubility 25 1.5 - - 0.8 - (g/100g @16°C water @ 20°C) Log Kow 0.18 1.24 1.28 (EST) 1.76 1.78 1.57(EST) aConversion 1ppm = 1ppm = 1ppm = 1ppm = 1ppm = 4.75 1ppm = 6.55 3 3 3 3 3 Factor 3.03 mg/m 4.18 4.18 mg/m 4.75 mg/m mg/m mg/m mg/m3
Nonyl Myristyl Cetyl Stearyl Isostearyl Acetate Acetate Acetate Acetate Acetate
Cas No. 143-13-5 638-59-5 629-70-9 822-23-1 NL
Molecular 186.29 256.43 284.48 312.54 312.54 Weight (g/mol) Boiling 208-212 - - - - Point (°C) Density - - - - - (g/cm3) Vapor - - - - - pressure (mm Hg @ 20°C) Solubility - - - - - (g/100g water @ 20°C) Log Kow 4.3(EST) 6.76(EST) 7.74(EST) 8.72(EST) 8.65(EST) aConversion - - - - - Factor a Conversion factors were obtained from the NIOSH Online Pocket Guide to Chemical Hazards EST- Values were estimated using the EPI Suite, Version 4.0 program. - Not found
13
CIR Panel Book Page 85 Table 4. Physical and Chemical properties of the acid and alcohol ingredients.6
Acetic Sodium Potassium Magnesium Calcium Zinc Acid Acetate Acetate Acetate Acetate Acetate
Cas No. 64-19-7 127-09-3 127-08-2 142-72-3 62-54-4 557-34-6
Molecular 60.05 82.03 98.14 142.39 158.17 183.50 Weight (g/mol)
Boiling 118 (melt at (melt at (melt at (decomp. - Point (°C) 58oC) 292oC) 80oC) above 160oC) Density 1.05 - - - - - (g/cm3)
Vapor 14.8 7.08E-007 1.37E-008 1.79E-005 0.00548 6.57E-006 pressure (@25oC) (EST) (EST) (EST) (EST) (EST) (mm Hg @ 20°C) Solubility 100 100 (EST) 100 (EST) 100 (EST) 100 (EST) 30.3 (g/100g water @ 25°C) Log Kow -0.17 -3.72 -3.72 -1.38 (EST) -1.38 -1.28 (EST) (EST) (EST) (EST) aConversion 1ppm = Factor 2.46 mg/m3
Propyl Isopropyl Alcohol Alcohol
Cas No. 71-23-8 67-63-0
Molecular 60.1 60.1 Weight (g/mol)
Boiling 97.2 82.4 Point (°C)
Density 0.8035 0.7850 (g/cm3)
Vapor 14.9 33.0 pressure (mm Hg @ 20°C) Log Kow 0.25 0.05
aConversion 1ppm = 1ppm = Factor 2.46 2.46 3 mg/m mg/m3 a Conversion factors were obtained from the NIOSH Online Pocket Guide to Chemical Hazards 14
CIR Panel Book Page 86 Table 5. Current cosmetic product uses and concentrations for methyl acetate, propyl acetate, isopropyl acetate, t- butyl acetate, isobutyl acetate, nonyl acetate, cetyl acetate, stearyl acetate, propyl alcohol and isopropyl alcohol.11-13,91
Product Category 2009 uses (total 2007, 2009, 2010 (FDA 2009) number of products concentrations (%) in category; FDA (PCPC 2007; 2009; 2010) 2009)
Methyl Acetate
Noncoloring hair care products
Sprays/aerosol fixatives 1 (312) -
Nail care products Creams and lotions -(14) 11
Polish and enamel removers -(24) 45 - 60
Other -(138) 10
Total uses/ranges for Ingredient 1 10 - 60 Propyl Acetate Eye products Lotion -(254) 0.005
Nail care products
Basecoats and undercoats 2 (79) 10
Polish and enamel 26 (333) 1-39 Polish and enamel removers -(24) 10
Othera 6 (138) 7 Skin care products Body and hand sprays -(-) 0.8 Paste mask/mud packs -(441) 0.042
Total uses/ranges for Propyl Acetate 34 0.005-39 Isopropyl Acetate
Noncoloring hair care products
Tonics, dressings, etc. 2 (1205) -
Hair coloring products Dyes and colors 5 (2393) 2
Nail care products Polish and enamel -(333) 2
Polish and enamel removers 1(24) 0.5
Total uses/ranges for Isopropyl Acetate 8 0.5-2 t-Butyl Acetate
Nail care products Polish and enamel removers -(24) 10
Total uses/ranges for t-Butyl Acetate - 10 Isobutyl Acetate
Nail care products
Basecoats and undercoats 1 (79) 6 15
CIR Panel Book Page 87
Product Category 2009 uses (total 2007, 2009, 2010 (FDA 2009) number of products concentrations (%) in category; FDA (PCPC 2007; 2009; 2010) 2009)
Creams and lotions -(14) 34
Polish and enamel 3 (333) 45
Polish and enamel removers -(24) 35
Total uses/ranges for Isobutyl Acetate 4 6-45 Nonyl Acetate Bath products Bubble baths -(169) 0.0004 Total uses/ranges for Nonyl Acetate - 0.0004
Cetyl Acetate
Baby products
Lotions, oils, powders, etc. 2 (137) 0.07
Bath products
Soaps and detergents 3 (1665) 0.8-3
Other 1 (234) -
Eye products Eyebrow pencil -(144) 0.9
Eyeliner 2 (754) 3-4
Shadow 8 (1215) 3-8
Lotion 1 (254) -- Mascara -(499) 0.03
Other 4 (365) -
Fragrance products Colognes and toilet waters -(1377) 0.3 Perfumes -(666) 2
Powders 1 (221) -
Other 1 (566) -
Noncoloring hair care products
Conditioners 1 (1226) 0.3-0.9
Sprays/aerosol fixatives 1 (312) 2
Tonics, dressings, etc. 6 (1205) 2-7
Other 7 (807) - Hair Color Preparations Other hair coloring preparationsb -(168) 0.4
Makeup
Blushers 7 (434) 0.3-9
Face powders 9 (661) 2-8
Foundations 2 (589) 12
Lipstick 101 (1883) 3-12.6 *(Corrected from 3-17%) 71
16
CIR Panel Book Page 88
Product Category 2009 uses (total 2007, 2009, 2010 (FDA 2009) number of products concentrations (%) in category; FDA (PCPC 2007; 2009; 2010) 2009)
Makeup bases -(117) 2
Other 3 (485) - Nail care products Basecoats and undercoats -(79) 0.2 Polish and enamel removers -(24) 0.2 Personal hygiene products Underarm deodorants -(580) 0.9
Shaving products
Aftershave lotions 2 (367) -
Shaving cream 1 (122) 0.01-0.9
Shaving soap 1 (10) -
Skin care products
Cleansing creams, lotions, liquids, and pads 4 (1446) 0.3
Face and neck creams, lotions, etc. 7 (1583) 0.5-2
Body and hand creams, lotions, etc. 33 (1744) 0.9-9
Foot powders and sprays 3 (47) 0.9
Moisturizers 51 (2508) 2
Night creams, lotions, powder and sprays 2 (353) 0.9
Paste masks/mud packs 2 (441) -
Fresheners 1 (259) -
Other 5 (1308) -
Suntan products
Suntan gels, creams, liquids and sprays 4 (107) -
Indoor tanning preparations 1 (240) -
Total uses/ranges for Cetyl Acetate 277 0.01-17
Stearyl Acetate Bath products Soaps and detergents -(1665) 0.5
Makeup Face powders -(661) 0.4 Nail care products Basecoats and undercoats -(79) 0.02
Shaving products
Shaving soap 1 (10) -
Skin care products
Face and neck creams, lotions, etc. 1 (1583) - Body and hand creams, lotions, etc. -(1744) 0.3
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CIR Panel Book Page 89
Product Category 2009 uses (total 2007, 2009, 2010 (FDA 2009) number of products concentrations (%) in category; FDA (PCPC 2007; 2009; 2010) 2009)
Total uses/ranges for Stearyl Acetate 2 0.02-0.5 Isostearyl Acetate Fragrance products Perfumes -(666) 5 Noncoloring hair care products Shampoos -(1361) 0.002 Total uses/ranges for Isostearyl Acetate - 0.002-5 Acetic Acid Tonics, Dressings, and Other Hair Grooming Aids 1 Colognes and toilet waters - 0.0004 Hair conditioners - 0.07 Hair dyes and colors - 0.2 Other Hair Coloring Preparation 1 0.3 Nail polish and enamel - 0.0003 Bath Soaps and Detergents 9 0.01
Total uses/ranges for Acetic 11 - Acid Sodium Acetate Mascara - 0.003 Hair conditioners - 0.001-0.09 Shampoos - 0.002-0.1 Tonics, Dressings, and Other 0.008-0.07 Hair Grooming Aids - Hair dyes and colors - 0.5 Hair rinses - 0.07 Makeup bases - 0.002 Nail polish and enamel - 0.5 Other personal cleanliness 0.005-0.2 products - Other shaving preparation - 0.004 Skin cleansing - 0.003-0.004 Face and neck creams, lotions 0.0002-0.2 and powders - Body and hand creams, lotions 0.002-0.008 and powders - Moisturizing creams, lotions and 0.05 powders - Night creams, lotions and 0.0005 powders - 18
CIR Panel Book Page 90
Product Category 2009 uses (total 2007, 2009, 2010 (FDA 2009) number of products concentrations (%) in category; FDA (PCPC 2007; 2009; 2010) 2009)
Paste masks - 0.0002
Total uses/ranges for Sodium 64 - Acetate Potassium Acetate Nail creams and lotions - 3
Total uses/ranges for 0 - Potassium Acetate Magnesium Acetate Hair conditioners - 0.03 Permanent waves - 0.02 Shampoos - 0.02 Tonics, Dressings, and Other 0.02 Hair Grooming Aids - Hair rinses (coloring) 0.02 - Total uses/ranges for 0 - Potassium Acetate Calcium Acetate Cleansing 1 Face and Neck (exc shave) 1 Moisturizing 5
Total uses/ranges for 7 - Potassium Acetate
Zinc Acetate Mouthwashes and Breath Fresheners 1
Total uses/ranges for 1 - Potassium Acetate Propyl Alcohol Bath products Other -(234) 0.0001 Makeup Lipstick -(1883) 0.0001 Nail care products Cuticle softeners -(27) 0.0001 Creams and lotions -(14) 0.0001 Oral hygiene products Mouthwashes and breath fresheners -(74) 0.5 Skin care products Body and hand creams, lotions, etc. -(1744) 0.0001 19
CIR Panel Book Page 91
Product Category 2009 uses (total 2007, 2009, 2010 (FDA 2009) number of products concentrations (%) in category; FDA (PCPC 2007; 2009; 2010) 2009)
Total uses/ranges for Propyl Alcohol - 0.0001-0.5 Isopropyl Alcohol Baby products Lotions, oils, powders, etc. -(137) 0.2 Bath products Soaps and detergents 11(1665) 0.004-0.07 Oils, tablets, and salts 3 (314) 0.8 Bubble baths 1 (169) - Eye products Eyebrow pencil 2 (144) 3 Eyeliner 1 (754) 2 Shadow 1 (1215) 0.014 Mascara 12 (499) 0.3-3 Otherc 5 (365) 14 Fragrance products Colognes and toilet waters 1 (1377) 0.2-2 Perfumes -(666) 0.2-0.7 Other 2 (566) 0.02 Noncoloring hair care products Conditioners 184 (1226) 0.4-2 Sprays/aerosol fixatives 7 (312) 0.05-5 Hair straighteners - (178) 0.6 Permanent waves 2 (69) 0.8-2 Rinses 3 (33) 0.8-1 Shampoos 13 (1361) 0.2-8 Tonics, dressings, etc. 45 (1205) 0.6-41 Wave sets 1 (51) - Other 50 (807) 2 Hair coloring products Dyes and colors 758 (2393) 3-16 Tints 15 (21) 3 Shampoos 7 (40) - Color sprays/aerosol 1 (7) 4 Hair lighteners with color 2 (21) - Hair bleaches 8 (149) - Otherd 6 (168) 7 Makeup
20
CIR Panel Book Page 92
Product Category 2009 uses (total 2007, 2009, 2010 (FDA 2009) number of products concentrations (%) in category; FDA (PCPC 2007; 2009; 2010) 2009)
Blushers 1 (434) 0.05 Face powders -(661) 0.2 Foundations 15 (589) 0.002-5 Leg and body paints 3 (29) - Lipstick 1 (1883) 0.009-1 Makeup bases -(117) 0.02 Rouges 1 (102) - Makeup fixatives 2 (45) - Other 1 (485) 0.3 Manicuring preparations Basecoats and undercoats 71 (79) 5-25 Cuticle Softeners 1 (27) 0.04-17 Nail creams and lotions 1 (14) 5-23 Nail polish and enamel 292 (333) 6-18 Nail polish and enamel removers 4 (24) 8-35 Othere 40 (138) 15-100 Personal Cleanliness Other 3 (792) 0.3 Shaving preparations Aftershave lotion 1 Shaving cream 1 (122) Otherf 10-76 Skin care preparations Cleansing creams, lotions, liquids, and pads 8 (1446) 0.3-26 Face and neck creams, lotions, etc. 6 (1583) 0.1-1 Body and hand creams, lotions, etc. 10 (1744) 1 Body and hand sprays -(-) 0.08 Foot powders and sprays -(47) 6 Moisturizers 25 (2508) 0.04-0.2 Paste masks/mud packs 2 (441) 0.02-4 Fresheners 7 (259) 0.07-7 Other 10 (1308) 14 Suntan products Suntan gels, creams and liquids - (107) 0.06 Indoor tanning preparations 1 (240) - Total uses/ranges for Isopropyl Alcohol 1647 0.002-100
a 7% in a nail mender 21
CIR Panel Book Page 93 b 0.4% in a gradual hair color c14% in a eye lash tint d7% in a hair color remover e 50% in a nail surface sanitizer; 100% in a nail degreaser f76% in a razor burn/ingrown hair eliminator - Not found
22
CIR Panel Book Page 94 Table 6. LD50/LC50 values reported in the literature for methyl acetate, propyl acetate, isopropyl acetate, isobutyl acetate, butoxyethyl acetate, nonyl acetate, cetyl acetate, and isopropyl alcohol for various routes of exposure and test species.
Species/Strain N Route LD50 or LC50* Signs of Toxicity Reference
Methyl Acetate Carworth- 5/group Oral-Gavage 6.97 ml/kg (6500 35 Wistar Rats (Male) mg/kg) Rats 10/group Oral >5000mg/kg 38 Albino rats 6/group Inhalation 16000 ppm (48,480 35 (Male) mg/m3) for 4 h did not cause mortality within 14 days. 32000 ppm (96,960 mg/m3) for 4 h caused 6/6 animals to die within 14 days. Rabbits 6/group Dermal >5000 mg/kg 38 Propyl Acetate Osborne- 5/sex/group Oral-Gavage 9370 mg/kg Depression soon 33 Mendel Rats 95%CI (7670-11,430) after treatment, rough fur, scrawny appearance Mice/NR NR Oral-Gavage 8300 mg/kg Depression soon 33 95% CI (7280-9460) after treatment Carworth- 5/group Oral-Gavage 9.8 ml/kg 36 Wistar Rats (Male) (8692.6 mg/kg) New Zealand 4/group Dermal >20 ml/kg 36 giant albino (Male) (>17,740 mg/m3) rabbits Albino rats 6/group Inhalation 8000 ppm (33,440 36 (Male) mg/m3) for 4 h caused 4/6 animals to die within 14 days Rabbits 10/group Dermal >5000 mg/kg 45 Isopropyl Acetate Carworth- 5/group Oral-Gavage 6750 mg/kg 34 Wistar Rats (Male) New Zealand 4/group Dermal >20 ml/kg 34 giant albino (Male) (>17440 mg/kg) rabbits Albino rats 6/group Inhalation 32,000 ppm (133,700 34 (Male) mg/m3) for 4 h caused 5/6 animals to die within 14 days Isobutyl Acetate Carworth- 5/group Oral-Gavage 15.4 ml/kg (13,400 35 Wistar Rats (Male) mg/kg) New Zealand 4/group Dermal >20 ml/kg 35 giant albino (Male) (~17,400 mg/kg) rabbits Albino rats 6/group Inhalation 8000 ppm (38,000 35 (Male) mg/m3) for 4 h caused 4/6 animals to die within 14 days
23
CIR Panel Book Page 95 Species/Strain N Route LD50 or LC50* Signs of Toxicity Reference
Butoxyethyl Acetate Carworth- 5/group Oral-Gavage 7.46 ml/kg 35 Wistar Rats (Male) (7000 mg/kg) New Zealand 4/group Dermal 1.58 ml/kg 35 giant albino (Male) (1500 mg/kg) rabbits Wistar rats 10/group Oral-Gavage 3000 mg/kg in males Kidney pathology; 37 2400 mg/kg in Hemoglobinuria females and hematuria New Zealand 6/group Dermal 1500 mg/kg Kidney pathology; 37 rabbits Hemoglobinuria and hematuria Wistar rats 10/group Inhalation 400 ppm (2,620 37 (Male and mg/m3) for 4 h did not Female) cause mortality. New Zealand 2/sex/group Inhalation 400 ppm (2,620 Transient 37 rabbits mg/m3) for 4 h did not hemoglobinuria and cause mortality. hematuria in rabbits only. Nonyl Acetate
Rat/NR NR Oral >5000 mg/kg 38
Rat/NR NR Dermal >5000 mg/kg 38
Cetyl Acetate
Rat/NR NR Oral-Gavage >5000 mg/kg 32
Rabbit/NR NR Dermal >5000 mg/kg 32
Acetic Acid
Rat/NR NR Oral-Gavage 0.4-3.2 ml/kg Kidney pathology; 32 Hemoglobinuria and hematuria Rat/NR NR Oral-Gavage 3310 mg/kg 41
Mouse/NR NR Oral 4960 mg/kg 42
Mice/NR NR Inhalation 5620 ppm for a 1 h 32 / 44 exposure Rat/NR NR Inhalation 11.4 mg/l for a 4h 42 exposure Rats/NR 6/group Inhalation 16000 ppm for a 4 Pharyngeal edema 32 hour exposure caused and chronic 1/6 animals to die. bronchitus Guinea pigs/NR NR Dermal > 3.2 ml/kg of 28% 40 acetic acid. > 20 ml/kg of a 5% acetic acid Rabbit/NR NR Dermal 1060 mg/kg 92
24
CIR Panel Book Page 96 Species/Strain N Route LD50 or LC50* Signs of Toxicity Reference
Mice/NR NR Intravenous 525 mg/kg of 10% 40 acetic acid (buffered with sodium hydroxide to pH 7.3) Sodium Acetate
Rat/NR NR Oral 3530 mg/kg 42
Rat/NR NR Inhalation >30 g/m3 42
Mouse/NR NR Subcutaneous 3200 mg/kg 42
Mice/NR NR Intravenous 380 mg/kg 93
Calcium Acetate
Rat/NR NR Oral 4,280 mg/kg 42
Mouse/NR NR Intravenous 52 mg/kg 42
Magnesium Acetate
Rat/NR NR Oral 8610 mg/kg 42
Mouse/NR NR Intravenous 111 mg/kg 42
Potassium Acetate
Rat/NR NR Oral 3250 mg/kg 42
Propyl Alcohol
Rat/NR NR Oral 1870 mg/kg 94
Rat/NR NR Inhalation 2000 mg/kg for 4 94 hours Isopropyl Alcohol
Rat/NR NR Oral 4420 – 5840 mg/kg Hind leg paralysis, 25 lack of coordination, respiratory depression, stupor Rabbit/NR NR Dermal 13,000 mg/kg 25
*Values in ( ) were calculated by CIR
25
CIR Panel Book Page 97 Table 7. Summary of the genotoxicity data available for the ingredients in this assessment.
Test substance Type of test, test species Dose* Result Reference In vitro tests Methyl Acetate Reverse mutation, 10 mg/plate Negative (w/ and 52 S. typhimurium, TA97, w/o metabolic TA98, TA100, TA1535, activation) TA1537 Propyl Acetate Reverse mutation, 10 mg/plate Negative (w/ and 27 S. typhimurium, TA98, w/o metabolic TA100, TA1535, activation) TA1537, TA1538 Mitotic aneuploidy, S. 1.23% (v/v) Negative (w/o 53 cerevisiae, D61.M metabolic activation) Isopropyl Acetate Reverse mutation, 10 mg/plate Negative (w/ and 52 S. typhimurium, TA97, w/o metabolic TA98, TA100, TA1535, activation) TA1537 t-Butyl Acetate Reverse mutation, 5 mg/plate Negative (w/ and 54 S. typhimurium, TA98, w/o metabolic TA100, TA102, TA1535, activation) TA1537 and E. coli WP2uvrA/pKM101 Acetic Acid Reverse mutation, 0.03% (v/v) Slight 60 E. coli; B/Sd-4/1,3,4,5; B/Sd-4/3,4 Sister Chromatid 10 mM Negative w/o 61 Exchange (SCE), metabolic Chinese hamster K1 cells activation Propyl Alcohol Forward mutation, S. 10% (v/v) Negative (w/ and 55 pombe, ade6-60/rad10- cytotoxic w/o metabolic 198,h- activation) Sister Chromatid 100 mM Negative (w/ and 56 Exchange (SCE), (6 mg/mL)┼ w/o metabolic Chinese hamster V79 activation) cells Sister Chromatid 0.1% (v/v) Negative (w/o 57 Exchange (SCE), metabolic Chinese Hamster Ovary activation) (CHO) cells Micronucleus Assay, 40 mg/mL Negative (w/o 58 Chinese hamster V79 metabolic cells activation) Isopropyl Alcohol Reverse mutation, 10 mg/plate Negative (w/ and 52 S. typhimurium, TA97, w/o metabolic TA98, TA100, TA1535, activation) TA1537 Sister Chromatid 100 mM Negative (w/ and 56 Exchange (SCE), (6 mg/mL)┼ w/o metabolic Chinese hamster V79 activation) cells In vivo tests Isopropyl Alcohol Micronuclei, bone 1173 mg/kg Negative 59 marrow erythrocytes of (IP) male and female ICR 2500 mg/kg mice (n=40/group) caused mortality 26
CIR Panel Book Page 98 *Doses are the highest ineffective dose. ┼ calculated by CIR w/ - with w/o - without
27
CIR Panel Book Page 99 Data Research Institute for Fragrance Materials, Inc. 50 Tice Boulevard Woodcliff Lake, New Jersey 07677 USA Phone: 201-689-8089 FAX: 201-689-8090
April 6, 2010
Dr. F. Alan Andersen Director Cosmetic Ingredient Review 1101 17th St., N.W. Suite 412 Washington, DC 20036-4702
RE: Isopropyl Acetate, Methyl Acetate, Propyl Acetate
Dear Alan:
We noted that the CIR Expert Panel will be reviewing some acetate ingredients. Three of these materials - Isopropyl Acetate, Methyl Acetate and Propyl Acetate are also used as fragrance ingredients. RIFM has sponsored some toxicity studies on Methyl Acetate and Propyl Acetate.
The attached draft reviews contain summaries of all the RIFM sponsored studies on these materials. Please note that the reference lists included in these documents reflect comprehensive reference lists that are contained in our database. We have provided surveyed fragrance exposure data for methyl acetate; the fragrance exposure for the other two materials was derived from default values. The 1979 published monograph on methyl acetate is also included.
Please let me know if there is anything more I can provide.
Sincerely,
Anne Marie Api, PhD Vice President, Human Health Sciences
AMA/caj Enc/4 cc: Greg Adamson Carol Eisenmann Kevin Renskers Ladd Smith CIR Panel Book Page 100 DRAFT AS OF APRIL 6, 2010
Fragrance Material Review on Isopropyl Acetate
J. SCOGNAMIGLIO 1, C.S. LETIZIA, A.M. API
Research Institute for Fragrance Materials, Inc.
50 Tice Boulevard, Woodcliff Lake, NJ 07677, U.S.A.
Running Title: Fragrance Material Review on Isopropyl Acetate
1Corresponding author
Telephone: 1-201-689-8089
Fax: 1-201-689-8090
Email: [email protected]
Research Institute for Fragrance Materials, Inc. Page 1 50 Tice Boulevard Woodcliff Lake, New Jersey, 07677 USA
CIR Panel Book Page 101 DRAFT AS OF APRIL 6, 2010
Abstract
A toxicologic and dermatologic review of Isopropyl acetate when used as a fragrance ingredient is presented. Isopropyl Acetate is a member of the fragrance structural group Aliphatic Acyclic Esters.
This review contains a detailed summary of only the RIFM sponsored toxicology and dermatology papers that are related to this individual fragrance ingredient and is not intended as a stand-alone document. A complete FMR will accompany the safety assessment of the entire
Aliphatic Acyclic Esters which will be published simultaneously with this document in the future.
Research Institute for Fragrance Materials, Inc. Page 2 50 Tice Boulevard Woodcliff Lake, New Jersey, 07677 USA
CIR Panel Book Page 102 DRAFT AS OF APRIL 6, 2010
Introduction
This document provides a summary of only the RIFM sponsored toxicology and dermatology papers that are related to isopropyl acetate when used as a fragrance ingredient. Isooropyl acetate (see Figure 1;
CAS Number 108-21-4) is a fragrance ingredient used in cosmetics, fine fragrances, shampoos, toilet soaps and other toiletries as well as in non- cosmetic products such as household cleaners and detergents. It is a colorless liquid with a fruity odor (Arctander, 1969).
The safety data on this material has never before been reviewed by the Research Institute of Fragrance Material (RIFM). While only the RIFM sponsored studies are contained in this document, the references included in this document reflect a comprehensive reference list for isopropyl acetate. More details have been provided for unpublished data.
The number of animals, sex and strain are always provided unless they are not given in the original report or paper. Any papers in which the vehicles and/or the doses are not given have not been included in this review.
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1. Identification
1.1 Synonyms: Acetic acid, 1-methylethyl ester
1.2 CAS registry number: 108-21-4
1.3 EINECS number: 203-561-1
1.4 Formula: C5 H10O2
1.5 Molecular weight: 102.13
1.6 Council of Europe (2000): Isopropyl acetate was included by
the Council of Europe in the list of substances granted A - may
be used in foodstuffs (COE No. 193)
1.7 FDA: Isopropyl acetate was approved by the FDA as GRAS (21
CFR 172.515)
1.8 FEMA (1965): Flavor and Extract Manufacturers' Association
states: Generally Recognized as Safe as a flavor ingredient -
GRAS 3 (2926)
1.9 JECFA (1997): The Joint FAO/WHO Expert Committee on Food
Additives (JECFA No. 305) concluded that the substance does
not present a safety concern at current levels of intake when
used as a flavouring agent.
Research Institute for Fragrance Materials, Inc. Page 4 50 Tice Boulevard Woodcliff Lake, New Jersey, 07677 USA
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FIGURE 1: Isopropyl Acetate
2. Physical properties
2.1 Physical form: Colorless liquid with a fruity odor
2.2 Boiling point: 85°C
2.3 Flash point: 62°F;CC
2.4 Henry's law (calculated): 0.000278 atm m3/mol @ 25°C
2.5 Log Kow (measured): 1.28
2.6 Vapor pressure (calculated): 60.8 mm Hg @ 25°C
2.7 Water solubility (calculated): 9268 mg/l @ 25°C
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3. Usage
Isopropyl acetate is a fragrance ingredient used in many fragrance compounds. It may be found in fragrances used in decorative cosmetics, fine fragrances, shampoos, toilet soaps and other toiletries as well as in non-cosmetic products such as household cleaners and detergents. The worldwide volume of use for Isopropyl acetate is in the region of 0.1 – 1 metric tons per year (IFRA, 2008). The reported volume is for the use of a fragrance ingredient used in fragrance compounds (mixtures) used in all finished consumer product categories. The volume of use is surveyed by
IFRA approximately every four years through a comprehensive survey of
IFRA and RIFM member companies. As such the volume of use data from this survey provides volume of use of fragrance ingredients for the majority of the fragrance industry.
The dermal systemic exposure in cosmetic products (see Table 1) is calculated based on the concentrations of the same fragrance ingredient in ten types of the most frequently used personal care and cosmetic products (anti-perspirant, bath products, body lotion, eau de toilette, face cream, fragrance cream, hair spray, shampoo, shower gel, and toilet soap). The concentration of the fragrance ingredient in fine fragrances has not been surveyed. The concentration of isopropyl acetate in the fragrance mixture used in Table 1 is a default value of 0.02%. Given the very low volume of use of this material, this default value is used for all
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10 consumer products. These concentrations are multiplied by the amount of product applied, the number of applications per day for each product type, and a “retention factor” (ranging from 0.001 to 1.0) to account for the length of time a product may remain on the skin and/or likelihood of the fragrance ingredient being removed by washing. The resultant calculation represents the total consumer exposure (mg/kg/day)
(Cadby et al. 2002, Ford et al. 2000).
This is a conservative calculation of dermal systemic exposure because it makes the unlikely assumption that a consumer will use these
10 products containing; which are all perfumed with the fragrance ingredient from a fine fragrance type of product (Cadby et al. 2002, Ford et al. 2000). The default value of 0.02% is used to calculate maximum daily exposure on the skin of 0.0005 mg/kg for high end users of these products (see Table 1).
A maximum skin level is then determined for consideration of potential sensitization. The exposure is calculated as the percent concentration of the fragrance ingredient applied to the skin based on the use of 20% of the fragrance mixture in the fine fragrance consumer product. The average maximum use level in formulae that goes into fine fragrances has not been reported. A default value of 0.2% is used, assuming use of the fragrance oil at levels up to 20% in the final product.
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Table 1: Calculation of the total human skin exposure from the use of multiple cosmetic products containing Methyl acetate Grams Applications Retention Mixture Ingredient Ingredient Product Type a b Applied per day factor /Product (%) /Mixture mg/kg/day Antiperspirant 0.5 1 1 0.01 0.02 0.0000 Bath Products 17 0.29 0.001 0.02 0.02 0.0000 Body Lotion 8 0.71 1 0.004 0.02 0.0001 Eau de Toilette 0.75 1 1 0.08 0.02 0.0002 Face Cream 0.8 2 1 0.003 0.02 0.0000 Fragrance Cream 5 0.29 1 0.04 0.02 0.0002 Hair Spray 5 2 0.01 0.005 0.02 0.0000 Shampoo 8 1 0.01 0.005 0.02 0.0000 Shower Gel 5 1.07 0.01 0.012 0.02 0.0000 Toilet Soap 0.8 6 0.01 0.015 0.02 0.0000 Total 0.0005 a Upper 97.5 percentile levels of the fragrance ingredient in the fragrance mixture used in these products was not surveyed; a default value of 0.02% was used b Based on a 60 kg adult
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4. Toxicology Data
4.1 Acute toxicity
No RIFM sponsored data available on this material.
4.2 Skin irritation
No RIFM sponsored data available on this material.
4.3 Mucous membrane (eye) irritation
No RIFM sponsored data available on this material.
4.4 Skin sensitization
No RIFM sponsored data available on this material.
4.5 Phototoxicity and photoallergy
No RIFM sponsored data available on this material.
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4.6 Absorption, distribution, metabolism
No RIFM sponsored data available on this material.
4.7 Repeated dose toxicity
No RIFM sponsored data available on this material.
4.8 Reproductive and developmental toxicity
No RIFM sponsored data available on this material.
4.9 Genotoxicity
No RIFM sponsored data available on this material.
4.10 Carcinogenicity
No RIFM sponsored data available on this material.
This individual Fragrance Material Review is not intended as a stand- alone document. Please refer to the Toxicologic and Dermatologic Assessment of Aliphatic Acyclic Esters (not published to date) for an overall assessment of this material.
Research Institute for Fragrance Materials, Inc. Page 10 50 Tice Boulevard Woodcliff Lake, New Jersey, 07677 USA
CIR Panel Book Page 110 DRAFT AS OF APRIL 6, 2010
Comprehensive Reference List for Isopropyl Acetate
Abraham M.H. , Whiting G.S. , Alarie Y. , Morris J.J. , Taylor P.J. , Doherty R.M. , Taft R.W. and Nielson G.D. (1990) Hydrogen bonding 12. A new QSAR for upper respiratory tract irritation by airborne chemicals in mice. Quantitative Structure -Activity Relationships, 9(1), 6-10. Agrawal M.R. and Winder C. (1996) Frequency and occurrence of LD50 values for materials in the workplace. Journal of Applied Toxicology, 16(5), 407-422. Alarie Y. , Schaper M. , Nielson G.D. and Abraham M.H. (1998) Structure- activity relationships of volatile organic chemicals as sensory irritants. Archives of Toxicology, 72(3), 125-140. Amoore J.E. and Hautala E. (1983) Odor as an aid to chemical safety : Odor thresholds compared with threshold limit values and volatilities for 214 industrial chemicals in air and water dilution. Journal of Applied Toxicology, 3(6), 272-290. Aoshima H. and Tenpaku Y. (1997) Modulation of GABA receptors expressed in Xenopus oocytes by 13-L-hydroxylinoleic acid and food additives. Bioscience Biotechnology Biochemistry, 61(12), 2051-2057. Augustinsson K.-B. and Ekedahl G. (1962) On the specificity of arylesterases. Acta Chemica Scandinavica, 16(part 1), 240-241 Austin S.G. and Schnatter A.R. (1983) A case-control study of chemical exposures and brain tumors in petrochemical workers. Journal of Occupational Medicine, 25(4), 313-320. Babeu L. and Vaishnav D.D. (1987) Prediction of biodegradability for selected organic chamicals. Journal ind. Microbiol., 2(2), 107-115. Bar V.F. and Griepentrog F. (1967) Die Situation in der gesundheitlichen Beurteilung der Aromatisierungsmittel fur Lebensmittel. (Where we stand concerning the evaluation of flavoring substances from the viewpoint of health). Medizin Ernahr., 8, 244-251. Bos P.M.J. , Zwart A. , Reuzel P.G.J. and Bragt P.C. (1992) Evaulation of the sensory irritation test for the assessment of occupational health risk. Critical Reviews in Toxicology, 21(6), 423-450. Bringmann G. and Kuhn R. (1977) Results of the damaging effects of water pollutants on Daphnia magna. Zeitschrift Wasser Abwasser- Forschung, 10(5), 161-166.
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CIR Panel Book Page 111 DRAFT AS OF APRIL 6, 2010
Bringmann G. and Kuhn R. (1978) Testing of substances for their toxicity threshold: Model organisms Microcytis (Diplocytis) aeruginosa and Scenedesmus quadricauda. International Association Theoretical Applied Limnology, 21, 275-284. Bringmann G. and Kuehn R. (1979) Comparison of toxic limiting concentrations of water contaminants toward bacteria, algae and protozoa in the cell-growth inhibition test. Gesundheitsingenieur Haustechnik Bauphysik Umwelttechnik, 100(8), 249-252. Bringmann G. and Kuhn R. (1980) Comparison of the toxicity threholds of water pollutants to bacteria, algae, and protozoa in the cell multiplication inhibition test. Water Research, 14(3), 231-241. DeCeaurriz J. , Desiles J.P. , Bonnet P. , Marignac B. , Muller J. and Guenier J.P. (1983) Concentration-dependent behavioral changes in mice following short-term inhalation exposure to various industrial solvents. Toxicology and Applied Pharmacology, 67(3), 383-389. Enslein K. , Tuzzeo T.M. , Borgstedt H.H. , Blake B.W. and Hart J.B. (1978) Prediction of rat oral LD50 from Daphnia magna LC50 and chemical structure. QSAR in Environmental Toxicology, 91-106. Grunbauer H.J.M. , deMeere A.L.J. and vanRooij H.H. (1986) Local composition models in pharmaceutical chemistry. III. Prediction of drug solubility in binary aqueous mixtures. International Journal of Pharmacology, 32(2-3), 187-198. Hau K.M. , Connell D.W. and Richardson B.J. (2000) Use of partition models in setting health guidelines for volatile organic compounds. Regulatory Toxicology and Pharmacology, 31(1), 22-29. Hellman T.M. and Small F.H. (1974) Characterization of the odor properties of 101 petrochemical using sensory methods. Journal Air Pollution Control Association, 24(10), 979-982. International Fragrance Association (2008). Worldwide Volume of Use Survey. Ishikawa S. and Hirao T. (1965) Studies on olfactory sensation in the larvae of the silkworm, Bombyx mori. III. Attractants and repellents of hatched larvae. Bull. Sericul. Exp. Sta., 20(1), 21-36. [Sanshi Shikenjo] Jaeschke H. and Wendel A. (1985) Manipulation of mouse organ glutathione contents I: Enhancement by oral administration of
Research Institute for Fragrance Materials, Inc. Page 12 50 Tice Boulevard Woodcliff Lake, New Jersey, 07677 USA
CIR Panel Book Page 112 DRAFT AS OF APRIL 6, 2010
butylated hydroxyanisole and butylated hydroxytoluene. Toxicology, 36, 77-85. Joint FAO/WHO Expert Committee on Food Additives (2000) Evaluation of certain food additives. Fifty-first report of the joint FAO/WHO expert committee on food additives. WHO Technical Reports, 891, 1-168. Juhnke I. and Luedmann D. (1978) Results of the study of 200 chemical compounds on acute fish toxicity using the Golden Orfe test. Zeitschrift fur Wasser und Abwasser-Forschung, 11, 161-164. Karelson M. , Sild S. and Maran U. (2000) Non-linear QSAR treatment of genotoxicity. Molecular Simulation, 24(4-6), 229-242. Kool H.J. , vanKreijl C.F. and Zoeteman B.C.J. (1982) Toxicology assessment of organic compounds in drinking water. Critical Reviews in Toxicology, 12(4), 307-357. Kupczewska-Dobeca M. , Socko R. and Czerczak S. (2006) RD(50) value as the criterion for setting maximum admissible levels of occupational exposure to irritants in Poland. International Journal of Occupational Safety and Ergonomics(JOSE), 12(1), 95-99. Kuwabara Y. , Alexeeff G.V. , Broadwin R. and Salmon A.G. (2007) Evaluation and application of the RD50 for determining acceptable exposure levels of airborne sensory irritants for the general public. Environmental Science & Technology, 115(11), 1609-1616. Liu M. , Grant S.G. , Macina O.T. , Klopman G. and Rosenkranz H.S. (1997) Structural and mechanistic bases for the induction of mitotic chromosomal loss and duplication ('malsegregation') in the yeast Saccharomyces cerevisiae: Relevance to human carcinogenesis and developmental toxicology. Mutation Research, 374(2), 209-231. McLaughlin R.S. (1946) Chemical burns of the human cornea. American Journal of Ophthalmology, 29(11), 1355-1362. Meulenberg C.J.W. and Vijverberg H.P.M. (2000) Empirical relations predicting human and rat tissue: Air partition coefficients of volatile organic compounds. Toxicology and Applied Pharmacology, 165(3), 206-216. Muller J. and Greff G. (1984) Research on the relations between toxicity of molecules of industrial interest and physicochemical properties: Irritation test of the upper respiratory tract applied to four families of chemicals. Food and Chemical Toxicology, 22(8), 661-664.
Research Institute for Fragrance Materials, Inc. Page 13 50 Tice Boulevard Woodcliff Lake, New Jersey, 07677 USA
CIR Panel Book Page 113 DRAFT AS OF APRIL 6, 2010
Munch J.C. (1972) Aliphatic alcohols and alkyl esters: Narcotic and lethal potencies to tadpoles and to rabbits. Industrial Medicine and Surgery, 41(4), 31-33. Munro I.C. and Kennepohl E. (2001) Comparison of estimated daily capita intakes of flavouring substances with no-observed-effect levels from animal studies. Food and Chemical Toxicology, 39(4), 331-354. Netzeva T.I. , Schultz W.T. , Aptula A.O. and Cronin M.T.D. (2003) Partial least squares modelling of the acute toxicity of aliphatic compounds to Tetrahymena pyriformis. SAR & QSAR in Environmental Research, 14(4), 265-283. Niemi G.J. , Veith G.D. , Regal R.R. and Vaishnav D.D. (1987) Structural features associated with degradable and persistent chemicals. Environmental Toxicology and Chemistry, 6, 515-527. Nishimura H. , Saito S. , Kishida F. and Matsuo M. (1994) Analysis of acute toxicity (LD50-value) of organic chemicals to mammals by solubility parameter (delta). 1. Acute oral toxicity to rats. Sangyo Igaku, 36(5), 314-323. [Japanese Journal Industrial Health] Papa E. , Battaini F. and Gramatica P. (2005) Ranking of aquatic toxicity of esters modelled by QSAR. Chemosphere, 58(5), 559-570. Person A. , Laurent A.-M. , Festy B. , Anguenot F. , Aigueperse J. and Hardy S. (1991) Atmospheric impact to indoor air organic volatile compounds (VOC) emitted by household products: Characterization of emissions and modeling of human exposure. Pollution Atmospherique, 33(130), 159-176. Pitt M.J. (1982) A vapour hazard index for volatile chemicals. Chem Ind., 20, 804-806. Poulin P. and Krishnan K. (1995) An algorithm for predicting tissue: Blood partition coefficients of organic chemicals from n-octanol:water partition coefficient data. Journal of Toxicology and Environmental Health, 46(1), 117-129. Price K.S. , Waggy G.T. and Conway R.A. (1974) Brine shrimp bioassay and seawater BOD of petrochemicals. Journal Water Pollution Control Federation, 46(1), 63-77. Prockop L. and Couri D. (1977) Nervous system damage from mixed organic solvents. National Institute Drug Abuse Research, Monograph Series 15, Ch.11, 185-198.
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Ran Y. , He Y. , Yang G. , Johnson J.L.H. and Yalkowsky S.H. (2002) Estimation of aqueous solubility of organic compounds by using the general solubility equation. Chemosphere, 48(5), 487-509. Roberts D.W. (1986) Qsar for upper-respiratory tract irritation. Chemico- Biological Interactions, 57, 325-345. Ruth J.H. (1986) Odor thresholds and irritation levels of several chemical substances: A review. American Industrial Hygiene Association Journal (AIHAJ), 47(3), A142-A151. Sakai S. and Asuka Y. (1959) On the carrier efficiency and joint toxic action of insecticidal solvents. Botyu-Kagaku, 22(I), 113-138. Schaper M. (1993) Development of a database for sensory irritants and its use in establishing occupational exposure limits. American Industrial Hygiene Association Journal (AIHAJ) (AIHAJ), 54(9), 488-544. Silverman L. , Schultz H.F. and First M.W. (1946) Further studies on sensory response to certain industrial solvent vapors. The Journal of Industrial Hygiene and Toxicolology, 28, 262-266. Smyth Jr. H.F. , Carpenter C.P. , Weil C.S. and Pozzani U.C. (1954) Range-finding toxicity data. List V. Archives of Ind. Hyg., 10, 61-68. Stull D.R. (1947) Vapor pressure of pure substances organic compounds. Industrial and Engineering Chemistry, 39(4), 517-540. Takagi K. and Takayanagi I. (1966) The effects of acetates of aliphatic alcohols on the cholinergic nerve structures and the acetylcholine receptor of the guinea-pig ileum. Journal of Pharmacy and Pharmacology, 18(11), 795-800. Testud F. and Descotes J. (1996) Aldehydes, Esters, Ketones, Ethers and Amines. In Human Toxicology, Chapter 25, 649-660. vonOettingen W.F. (1960) The aliphatic acids and their esters: Toxicity and potential dangers: The saturated monobasic aliphatic acids & their esters. Journal of the American Medical Association, Jan. 21, 28- 65. Whitehead L.W. , Ball G.L. , Fine L.J. and Langolf G.D. (1984) Solvent vapor exposures in booth spray painting and spray glueing, and associated operations. American Industrial Hygiene Association Journal (AIHAJ), 45(11), 767-772. Zeiger E. , Anderson B. , Haworth S. , Lawlor T. and Mortelmans K. (1992) Salmonella mutagenicity tests: V. Results from the testing of Research Institute for Fragrance Materials, Inc. Page 15 50 Tice Boulevard Woodcliff Lake, New Jersey, 07677 USA
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311 chemicals. Environmental and Molecular Mutagenesis, 19(suppl. 21), 2-141. Zeiger E. (1997) Genotoxicity Database. In Handbook Of Carcinogenic Potency Genotoxicity Databases, Chapter 5, 687-729. Zimmermann F.K. , Mayer V.W. , Scheel I. and Resnick M.A. (1985) Acetone, methyl ethyl ketone, ethyl acetate, acetonitrile and other polar aprotic solvents are strong inducers of aneuploidy in saccharomyces-cerevisiae. Mutation Research, 149(3), 339-352. Zimmermann F.K. , Scheel I. and Resnick M.A. (1989) Induction of chromosome loss by mixtures of organic solvents. Mutation Research, 224(2), 287-303.
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Fragrance Material Review on Methyl Acetate
J. SCOGNAMIGLIO 1, C.S. LETIZIA, A.M. API
Research Institute for Fragrance Materials, Inc.
50 Tice Boulevard, Woodcliff Lake, NJ 07677, U.S.A.
Running Title: Fragrance Material Review on Methyl Acetate
1Corresponding author
Telephone: 1-201-689-8089
Fax: 1-201-689-8090
Email: [email protected]
Research Institute for Fragrance Materials, Inc. Page 1 50 Tice Boulevard Woodcliff Lake, New Jersey, 07677 USA
CIR Panel Book Page 117 DRAFT AS OF APRIL 6, 2010
Abstract
A toxicologic and dermatologic review of Methyl Acetate when used as a fragrance ingredient is presented. Methyl Acetate is a member of the fragrance structural group Aliphatic Acyclic Esters.
This review contains a detailed summary of only the RIFM sponsored toxicology and dermatology papers that are related to this individual fragrance ingredient and is not intended as a stand-alone document. A complete FMR will accompany the safety assessment of the entire
Aliphatic Acyclic Esters which will be published simultaneously with this document in the future.
Research Institute for Fragrance Materials, Inc. Page 2 50 Tice Boulevard Woodcliff Lake, New Jersey, 07677 USA
CIR Panel Book Page 118 DRAFT AS OF APRIL 6, 2010
Introduction
This document provides a summary of only the RIFM sponsored toxicology and dermatology papers that are related to Methyl acetate when used as a fragrance ingredient. Methyl acetate (see Figure 1; CAS
Number 79-20-9) is a fragrance ingredient used in cosmetics, fine fragrances, shampoos, toilet soaps and other toiletries as well as in non- cosmetic products such as household cleaners and detergents. It is a colorless liquid with a pleasant, sweet, ethereal-fruity odor (Arctander,
1969).
The safety data on this material was last reviewed by Opdyke, 1979.
While only the RIFM sponsored studies are contained in this document, the references included in this document reflect a comprehensive reference list for methyl acetate. More details have been provided for unpublished data. The number of animals, sex and strain are always provided unless they are not given in the original report or paper. Any papers in which the vehicles and/or the doses are not given have not been included in this review.
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1. Identification
1.1 Synonyms: Acetic acid, methyl ester; Methyl ethanoate
1.2 CAS registry number: 79-20-9
1.3 EINECS number: 201-185-2
1.4 Formula: C3 H6O 2
1.5 Molecular weight: 74.08
1.6 Council of Europe (2000): Methyl acetate was included by the
Council of Europe in the list of substances granted A - may be
used in foodstuffs (COE No. 213)
1.7 FDA: Methyl acetate was approved by the FDA as GRAS (21
CFR 172.515)
1.8 FEMA (1965): Flavor and Extract Manufacturers' Association
states: Generally Recognized as Safe as a flavor ingredient -
GRAS 3 (2676)
1.9 JECFA (1997): The Joint FAO/WHO Expert Committee on Food
Additives (JECFA No. 125) concluded that the substance does
not present a safety concern at current levels of intake when
used as a flavouring agent.
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FIGURE 1: Methyl Acetate
2. Physical properties
2.1 Physical form: Colorless liquid with pleasant, sweet, ethereal-
fruity odor
2.2 Boiling point: 57°C
2.3 Flash point: <40°F;CC
2.4 Henry's law (calculated): 0.000175 atm m3/mol @ 25°C
2.5 Log Kow (measured): 0.18
2.6 Refractive index: 1.3549 @ 20°C
2.7 Specific gravity: 0.9020 @ 25°C
2.8 Vapor pressure (calculated): 52.7 mm Hg @ 25°C
2.9 Water solubility (calculated): 93900 mg/l (25°C)
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3. Usage
Methyl acetate is a fragrance ingredient used in many fragrance compounds. It may be found in fragrances used in decorative cosmetics, fine fragrances, shampoos, toilet soaps and other toiletries as well as in non-cosmetic products such as household cleaners and detergents. The worldwide volume of use for Methyl acetate is in the region of 0.1 – 1 metric tons per year (IFRA, 2008). The reported volume is for the use of a fragrance ingredient used in fragrance compounds (mixtures) used in all finished consumer product categories. The volume of use is surveyed by
IFRA approximately every four years through a comprehensive survey of
IFRA and RIFM member companies. As such the volume of use data from this survey provides volume of use of fragrance ingredients for the majority of the fragrance industry.
The dermal systemic exposure in cosmetic products (see Table 1) is calculated based on the concentrations of the same fragrance ingredient in ten types of the most frequently used personal care and cosmetic products (anti-perspirant, bath products, body lotion, eau de toilette, face cream, fragrance cream, hair spray, shampoo, shower gel, and toilet soap). The concentration of the fragrance ingredient in fine fragrances is obtained from examination of several thousand commercial formulations.
The upper 97.5 percentile concentration is calculated from the data obtained. This upper 97.5 percentile concentration is then used for all 10
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Ford et al. 2000).
This is a conservative calculation of dermal systemic exposure because it makes the unlikely assumption that a consumer will use these
10 products containing; which are all perfumed with the upper 97.5 percentile level of the fragrance ingredient from a fine fragrance type of product (Cadby et al. 2002, Ford et al. 2000). The 97.5 percentile use level in formulae for use in cosmetics in general has been reported to be
0.014% (IFRA, 2004), which would result in a maximum daily exposure on the skin of 0.0004 mg/kg/day for high end users (see Table 1).
A maximum skin level is then determined for consideration of potential sensitization. The exposure is calculated as the percent concentration of the fragrance ingredient applied to the skin based on the use of 20% of the fragrance mixture in the fine fragrance consumer product (IFRA, 2004). The average maximum use level in formulae that goes into fine fragrances has been reported to be 0.02% (IFRA, 2004); assuming use of the fragrance oil at levels up to 20% in the final product.
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Table 1: Calculation of the total human skin exposure from the use of multiple cosmetic products containing Methyl acetate Grams Applications Retention Mixture Ingredient Ingredient Product Type a b Applied per day factor /Product (%) /Mixture mg/kg/day Antiperspirant 0.5 1 1 0.01 0.014 0.0000 Bath Products 17 0.29 0.001 0.02 0.014 0.0000 Body Lotion 8 0.71 1 0.004 0.014 0.0001 Eau de Toilette 0.75 1 1 0.08 0.014 0.0001 Face Cream 0.8 2 1 0.003 0.014 0.0000 Fragrance Cream 5 0.29 1 0.04 0.014 0.0001 Hair Spray 5 2 0.01 0.005 0.014 0.0000 Shampoo 8 1 0.01 0.005 0.014 0.0000 Shower Gel 5 1.07 0.01 0.012 0.014 0.0000 Toilet Soap 0.8 6 0.01 0.015 0.014 0.0000 Total 0.0004 a Upper 97.5 percentile levels of the fragrance ingredient in the fragrance mixture used in these products b Based on a 60 kg adult
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4. Toxicology Data
4.1 Acute toxicity (see Table 2)
Table 2: Summary of acute toxicity studies NO. ANIMALS/ ROUTE SPECIES LD REFERENCES DOSE GROUP 50 Oral Rat 10 > 5 g/kg RIFM 1976a Dermal Rabbit 6 > 5 g/kg RIFM 1976a
Oral studies
The acute oral LD 50 of methyl acetate in rats was reported to be
> 5 g/kg. Animals were dosed at 5 g/kg and observed for 14
days. One of ten rats died on day 1. Clinical signs of toxicity
included only slight lethargy (RIFM 1973a).
Dermal Studies
The acute dermal LD 50 of methyl acetate in rabbits was reported
to be > 5 g/kg. Rabbits were dosed at 5 g/kg and observed for
14 days. Mortality was observed in 1 of 6 rabbits on day 13.
Diarrhea was observed in 1 of 10 animals. Slight to moderate
erythema was observed in 7 animals while slight edema was
present in 4 animals (RIFM 1973a).
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4.2 Skin irritation
Human studies (see Table 3)
Table 3: Summary of human irritation studies RESULTS METHOD DOSE (%) VEHICLE REFERENCES Reactions Frequency Maximization 10 Petrolatum 0 0% RIFM 1976b
In a human maximization test pre-screen, 10% methyl acetate in
petrolatum was applied to the backs of 25 healthy subjects for 48
hours under occlusion. No subject experienced any irritation (RIFM
1976b).
Animal studies
No RIFM sponsored data available on this material.
4.3 Mucous membrane (eye) irritation
No RIFM sponsored data available on this material.
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4.4 Skin sensitization
Human studies
Induction studies (see Table 4)
Table 4: Summary of human skin sensitization studies RESULTS METHOD CONCENTRATION REFERENCES Reactions Frequency 10% Maximization 0/25 0% RIFM 1976b (6900 μg/cm2)
Maximization studies
Human maximization tests according to Magnusson and Kligman
(1966) and Kligman and Epstein (1975) were carried out with
methyl acetate in petrolatum on various panels of volunteers.
Application was under occlusion to the same site on the
forearms or backs of all subjects for five alternate-day 48-hour
periods. Patch sites were pre-treated for 24 hours with 2.5%
aqueous sodium lauryl sulfate (SLS) under occlusion. Following
a 10 – 14 day rest period, challenge patches were applied under
occlusion to fresh sites for 48 hours. Challenge applications
were preceded by a 60 minute SLS treatment. Reactions were
read at patch removal and again at 24 hours thereafter. The
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following results were obtained: No sensitization reactions
were observed in any of the 25 subjects tested.
Animal studies
No RIFM sponsored data available on this material.
4.5 Phototoxicity and photoallergy
No RIFM sponsored data available on this material.
4.6 Absorption, distribution, metabolism
No RIFM sponsored data available on this material.
4.7 Repeated dose toxicity
No RIFM sponsored data available on this material.
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4.8 Reproductive and developmental toxicity
No RIFM sponsored data available on this material.
4.9 Genotoxicity
No RIFM sponsored data available on this material.
4.10 Carcinogenicity
No RIFM sponsored data available on this material.
This individual Fragrance Material Review is not intended as a stand- alone document. Please refer to the Toxicologic and Dermatologic Assessment of Aliphatic Acyclic Esters (not published to date) for an overall assessment of this material.
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Comprehensive Reference List for Methyl Acetate
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Sciences, 22(1B), 468-469.
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polar aprotic solvents are strong inducers of aneuploidy in saccharomyces-cerevisiae. Mutation Research, 149(3), 339 -352
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Fragrance Material Review on Propyl Acetate
J. SCOGNAMIGLIO 1, C.S. LETIZIA, A.M. API
Research Institute for Fragrance Materials, Inc.
50 Tice Boulevard, Woodcliff Lake, NJ 07677, U.S.A.
Running Title: Fragrance Material Review on Propyl Acetate
1Corresponding author
Telephone: 1-201-689-8089
Fax: 1-201-689-8090
Email: [email protected]
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Abstract
A toxicologic and dermatologic review of Propyl acetate when used as a fragrance ingredient is presented. Propyl Acetate is a member of the fragrance structural group Aliphatic Acyclic Esters.
This review contains a detailed summary of only the RIFM sponsored toxicology and dermatology papers that are related to this individual fragrance ingredient and is not intended as a stand-alone document. A complete FMR will accompany the safety assessment of the entire
Aliphatic Acyclic Esters which will be published simultaneously with this document in the future.
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Introduction
This document provides a summary of only the RIFM sponsored toxicology and dermatology papers that are related to propyl acetate when used as a fragrance ingredient. Propyl acetate (see Figure 1; CAS
Number 109-60-4) is a fragrance ingredient used in cosmetics, fine fragrances, shampoos, toilet soaps and other toiletries as well as in non- cosmetic products such as household cleaners and detergents. It is a colorless, water-white liquid with mild, fruity, fresh, ethereal, pear-like odor (Arctander, 1969).
The safety data on this material has never before been reviewed by the Research Institute of Fragrance Material (RIFM). While only the RIFM sponsored studies are contained in this document, the references included in this document reflect a comprehensive reference list for propyl acetate. More details have been provided for unpublished data. The number of animals, sex and strain are always provided unless they are not given in the original report or paper. Any papers in which the vehicles and/or the doses are not given have not been included in this review.
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1. Identification
1.1 Synonyms: Acetic acid, propyl ester; n-Propyl acetate
1.2 CAS registry number: 109-60-4
1.3 EINECS number: 203-686-1
1.4 Formula: C5 H10O2
1.5 Molecular weight: 102.13
1.6 Council of Europe (2000): Propyl acetate was included by the
Council of Europe in the list of substances granted A - may be
used in foodstuffs (COE No. 192)
1.7 FDA: Propyl acetate was approved by the FDA as GRAS (21
CFR 172.515)
1.8 FEMA (1965): Flavor and Extract Manufacturers' Association
states: Generally Recognized as Safe as a flavor ingredient -
GRAS 3 (2925)
1.9 JECFA (1997): The Joint FAO/WHO Expert Committee on Food
Additives (JECFA No. 126) concluded that the substance does
not present a safety concern at current levels of intake when
used as a flavouring agent.
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FIGURE 1: Propyl Acetate
2. Physical properties
2.1 Physical form: Colorless, water-white liquid with mild, fruity,
fresh, ethereal, pear-like odor
2.2 Boiling point: 102°C
2.3 Flash point: 55°F;CC
2.4 Henry's law (calculated): 0.000309 atm m3/mol @ 25°C
2.5 Log Kow (measured): 1.24
2.6 Specific gravity: 0.888
2.7 Vapor pressure (calculated): 25 mm Hg @ 20°C
2.8 Water solubility (calculated): 10060 mg/l @ 25°C
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3. Usage
Propyl acetate is a fragrance ingredient used in many fragrance compounds. It may be found in fragrances used in decorative cosmetics, fine fragrances, shampoos, toilet soaps and other toiletries as well as in non-cosmetic products such as household cleaners and detergents. The worldwide volume of use for Propyl acetate is in the region of 0.1 – 1 metric tons per year (IFRA, 2008). The reported volume is for the use of a fragrance ingredient used in fragrance compounds (mixtures) used in all finished consumer product categories. The volume of use is surveyed by
IFRA approximately every four years through a comprehensive survey of
IFRA and RIFM member companies. As such the volume of use data from this survey provides volume of use of fragrance ingredients for the majority of the fragrance industry.
The dermal systemic exposure in cosmetic products (see Table 1) is calculated based on the concentrations of the same fragrance ingredient in ten types of the most frequently used personal care and cosmetic products (anti-perspirant, bath products, body lotion, eau de toilette, face cream, fragrance cream, hair spray, shampoo, shower gel, and toilet soap). The concentration of the fragrance ingredient in fine fragrances has not been surveyed. The concentration of propyl acetate in the fragrance mixture used in Table 1 is a default value of 0.02%. Given t he very low volume of use of this material, this default value is used for all
10 consumer products. These concentrations are multiplied by the
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CIR Panel Book Page 151 DRAFT AS OF APRIL 6, 2010 amount of product applied, the number of applications per day for each product type, and a “retention factor” (ranging from 0.001 to 1.0) to account for the length of time a product may remain on the skin and/or likelihood of the fragrance ingredient being removed by washing. The resultant calculation represents the total consumer exposure (mg/kg/day)
(Cadby et al. 2002, Ford et al. 2000).
This is a conservative calculation of dermal systemic exposure because it makes the unlikely assumption that a consumer will use these
10 products containing; which are all perfumed with the fragrance ingredient from a fine fragrance type of product (Cadby et al. 2002, Ford et al. 2000). The default value of 0.02% is used to calculate maximum daily exposure on the skin of 0.0005 mg/kg for high end users of these products (see Table 1).
A maximum skin level is then determined for consideration of potential sensitization. The exposure is calculated as the percent concentration of the fragrance ingredient applied to the skin based on the use of 20% of the fragrance mixture in the fine fragrance consumer product (IFRA, 2004). The average maximum use level in formulae that goes into fine fragrances has not been reported. A default value of 0.2% is used, assuming use of the fragrance oil at levels up to 20% in the final product.
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Table 1: Calculation of the total human skin exposure from the use of multiple cosmetic products containing Propyl acetate Grams Applications Retention Mixture Ingredient Ingredient Product Type a b Applied per day factor /Product (%) /Mixture mg/kg/day Antiperspirant 0.5 1 1 0.01 0.02 0.0000 Bath Products 17 0.29 0.001 0.02 0.02 0.0000 Body Lotion 8 0.71 1 0.004 0.02 0.0001 Eau de Toilette 0.75 1 1 0.08 0.02 0.0002 Face Cream 0.8 2 1 0.003 0.02 0.0000 Fragrance Cream 5 0.29 1 0.04 0.02 0.0002 Hair Spray 5 2 0.01 0.005 0.02 0.0000 Shampoo 8 1 0.01 0.005 0.02 0.0000 Shower Gel 5 1.07 0.01 0.012 0.02 0.0000 Toilet Soap 0.8 6 0.01 0.015 0.02 0.0000 Total 0.0005 a Upper 97.5 percentile levels of the fragrance ingredient in the fragrance mixture used in these products was not surveyed; a default value of 0.02% was used b Based on a 60 kg adult
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4. Toxicology Data
4.1 Acute toxicity (see Table 2)
Table 2: Summary of acute toxicity studies NO. ANIMALS/ ROUTE SPECIES LD REFERENCES DOSE GROUP 50 Dermal Rabbit 10 > 5 g/kg RIFM 1978a
Oral studies
No RIFM sponsored data available on this material.
Dermal Studies
The acute dermal LD 50 of propyl acetate in rabbits was reported
to be > 5 g/kg. Rabbits were dosed at 5 g/kg and observed for
14 days. Mortality was observed in 2 of 10 rabbits, one on day
5 and the other on day 12. Signs of toxicity included difficulty
in movement due to sore feet, yellow exudates at the nose,
mucus in stool, body hot, lethargy, diarrhea, and emaciation.
Slight to moderate erythema and edema was observed in all
animals (RIFM 1978a).
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4.2 Skin irritation
Human studies (see Table 3)
Table 3: Summary of human irritation studies RESULTS METHOD DOSE (%) VEHICLE REFERENCES Reactions Frequency Maximization 2 Petrolatum 0 0% RIFM 1978b
In a human maximization test pre-screen, 2% propyl acetate in
petrolatum was applied to the backs of 25 healthy subjects for 48
hours under occlusion. No subject experienced any irritation (RIFM
1978b).
Animal studies
No RIFM sponsored data available on this material.
4.3 Mucous membrane (eye) irritation
No RIFM sponsored data available on this material.
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4.4 Skin sensitization
Human studies
Induction studies (see Table 4)
Table 4: Summary of human skin sensitization studies RESULTS METHOD CONCENTRATION REFERENCES Reactions Frequency 2% Maximization 0/25 0% RIFM 1978b (1380 μg/cm2)
Maximization studies
Human maximization tests according to Magnusson and Kligman
(1966) and Kligman and Epstein (1975) were carried out with
propyl acetate in petrolatum on various panels of volunteers.
Application was under occlusion to the same site on the
forearms or backs of all subjects for five alternate-day 48-hour
periods. Patch sites were pre-treated for 24 hours with 2.5%
aqueous sodium lauryl sulfate (SLS) under occlusion. Following
a 10 – 14 day rest period, challenge patches were applied under
occlusion to fresh sites for 48 hours. Challenge applications
were preceded by a 60 minute SLS treatment. Reactions were
read at patch removal and again at 24 hours thereafter. The
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following results were obtained: No sensitization reactions
were observed in any of the 25 subjects tested.
Animal studies
No RIFM sponsored data available on this material.
4.5 Phototoxicity and photoallergy
No RIFM sponsored data available on this material.
4.6 Absorption, distribution, metabolism
No RIFM sponsored data available on this material.
4.7 Repeated dose toxicity
No RIFM sponsored data available on this material.
4.8 Reproductive and developmental toxicity
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No RIFM sponsored data available on this material.
4.9 Genotoxicity
No RIFM sponsored data available on this material.
4.10 Carcinogenicity
No RIFM sponsored data available on this material.
This individual Fragrance Material Review is not intended as a stand- alone document. Please refer to the Toxicologic and Dermatologic Assessment of Aliphatic Acyclic Esters (not published to date) for an overall assessment of this material.
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Comprehensive Reference List for Propyl Acetate
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Arndt R. and Krisch K. (1973) Catalytic properties of an unspecific carboxylesterase (E1) from rat-liver microsomes. European Journal of Biochemistry, 36, 129-134. Baker R.A. , Massey ED and Smith G. (2004) An overview of the effects of tobacco ingredients on smoke chemistry and toxicity. Food and Chemical Toxicology, 42S, S53-S83. Baker R.R. , Pereira da Silva JR and Smith G. (2004a) The effect of tobacco ingredients on smoke chemistry. Part I: Flavourings and additives. Food and Chemical Toxicology, 42S, S3-S37. Baldi G. (1953) Occupational pathology of amyl, butyl and propyl acetates. La Medicina del Lavoro, 44(11), 469-474. Bar V.F. and Griepentrog F. (1967) Die Situation in der gesundheitlichen Beurteilung der Aromatisierungsmittel fur Lebensmittel. (Where we stand concerning the evaluation of flavoring substances from the viewpoint of health). Medizin Ernahr., 8, 244-251. Barry B.W. (1983) Properties that Influence Percutaneous Absorption. In Dermatological Formations: Percutaneous Absorption, Chapter 4, 127- 233. Basak S.C. , Gieschen D.P. and Magnuson V.R. (1984) A quantitative correlation of the LC50 values of esters in Pimephales promelas using physicochemical and topological parameters. Environmental Toxicology and Chemistry, 3(2), 191-199. Bearden A.P. and Schultz T.W. (1998) Comparison of tetrahymena and pimephales toxicity based on mechanism of action. SAR & QSAR in Environmental Research, 9(3-4), 127-153. Bos P.M.J. , Zwart A. , Reuzel P.G.J. and Bragt P.C. (1992) Evaulation of the sensory irritation test for the assessment of occupational health risk. Critical Reviews in Toxicology, 21(6), 423-450. Brandao J.C. , Bohets H.H.L. , VanDeVyver I.E. and Dierickx P.J. (1992) Correlation between the in vitro cytotoxicity to cultured fathead minnow fish cells and fish lethality data for 50 chemicals. Chemosphere, 25(4), 553-562. Bringmann G. and Kuhn R. (1977) Results of the damaging effects of water pollutants on Daphnia magna. Zeitschrift Wasser Abwasser- Forschung, 10(5), 161-166. Bringmann G. and Kuhn R. (1978) Testing of substances for their toxicity threshold: Model organisms Microcytis (Diplocytis) aeruginosa and
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Scenedesmus quadricauda. International Association Theoretical Applied Limnology, 21, 275-284. Bringmann G. and Kuehn R. (1979) Comparison of toxic limiting concentrations of water contaminants toward bacteria, algae and protozoa in the cell-growth inhibition test. Gesundheitsingenieur Haustechnik Bauphysik Umwelttechnik, 100(8), 249-252. Bringmann G. and Kuhn R. (1980) Comparison of the toxicity threholds of water pollutants to bacteria, algae, and protozoa in the cell multiplication inhibition test. Water Research, 14(3), 231-241. Chen D. , Yin C. , Wang X. and Wang L. (2004) Holographic QSAR of selected esters. Chemosphere, 57(11), 1739-1745. Conkle J.P. , Camp B.J. and Welch B.E. (1975) Trace composition of human respiratory gas. Archives of Environmental Health, 30, 290- 295. Couri D. and Nachtman J.P. (1977) Toxicology of alcohols, ketones and esters--inhalation. National Institute Drug Abuse Research, 15, 112- 123. Cronin M.T.D. , Dearden J.C. and Dobbs A.J. (1991) QSAR studies of comparative toxicity in aquatic organisms. The Science of the Total Environment, 109/110, 431-439. Cronin M.T.D. (1996) Quantitative structure-activity relationship (QSAR) analysis of the acute sublethal neurotoxicity of solvents. Toxicology in Vitro, 10(2), 103-110. Dahl A.R. , Miller S.C. and Petridou-Fischer J. (1987) Carboxylesterases in the respiratory tracts of rabbits, rats and Syrian hamsters. Toxicology Letters, 36, 129-136. DeWolf W. , Lieder P.H. and Walker J.D. (2004) Application of QSARs: Correlation of acute tocicity in the rat following oral or inhalation exposure. QSAR Comb. Sci., 23(7), 521-525. Dierickx P.J. (1998) Increased cytotoxic sensitivity of cultured FHM fish cells by simultaneous treatment with sodium dodecyl sulfate and buthionine sulfoximine. Chemosphere, 36(6), 1263-1274. Eldred D.V. , Weikel C.L. , Jurs P.C. and Kaiser K.L. (1999) Prediction of fathead minnow acute toxicity of organic compounds from molecular structure. Chemical Research in Toxicology, 12(7), 670-678. Fischer A.A. (1981) Perfume dermatitis. III. The search for nonsensitizing perfumes. Cutis, 27(1), 13, 16, 17, 20, 22, 62. Research Institute for Fragrance Materials, Inc. Page 16 50 Tice Boulevard Woodcliff Lake, New Jersey, 07677 USA
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Flury F. and Wirth W. (1933) Solvent toxicology. Archives Gewerbepath. Gewerbehyg., 5, 1-90. Frantik E. , Hornychova M. and Horvath M. (1994) Relative acute neurotoxicity of solvents: Isoeffective air concentrations of 48 compounds evaluated in rats and mice. Environmental Research, 66(2), 173-185. Gombar V.K. and Wadhwa L. (1982) Quantitative structure-activity relationships: IV use of molecular negentropy as structural parameter. Arzneimittel-Forschung (Drug Research), 32(2), 715-719. Gunatilleka A.D. and Poole C.F. (1999) Models for estimating the non- specific aquatic toxicity of organic compounds. Anal. Commun., 36(6), 235-242. Hau K.M. , Connell D.W. and Richardson B.J. (1999) Quantitative structure-activity relationships for nasal pungency thresholds of volatile organic compounds. Toxicological Sciences (formerly Fundamental & Applied Toxicology), 47, 93-98. Hau K.M. , Connell D.W. and Richardson B.J. (2000) Use of partition models in setting health guidelines for volatile organic compounds. Regulatory Toxicology and Pharmacology, 31(1), 22-29. Hellman T.M. and Small F.H. (1974) Characterization of the odor properties of 101 petrochemical using sensory methods. Journal Air Pollution Control Association, 24(10), 979-982. Heymann E. (1980) Carboxylesterases and Amidases. In Enzymatic Basis Detoxication, 2, Chapter 16, 291-323. Holmberg B. and Malmfors T. (1974) The cytotoxicity of some organic solvents. Environmental Research, 7(2), 183-192. Holmberg B. , Jakobson I. and Malmfors T. (1974a) The effect of organic solvents on erythrocytes during hypotonic hemolysis. Environmental Research, 7(2), 193-205. International Fragrance Association (2008). Worldwide Volume of Use Survey. Ishikawa S. and Hirao T. (1965) Studies on olfactory sensation in the larvae of the silkworm, Bombyx mori. III. Attractants and repellents of hatched larvae. Bull. Sericul. Exp. Sta., 20(1), 21-36. [Sanshi Shikenjo] Ishikawa M. , Ito O. , Ishizaki S. , Kurobayashi Y. and Fujita A. (2004) Solid-phase aroma concentrate extraction (SPACE(TM)): A new Research Institute for Fragrance Materials, Inc. Page 17 50 Tice Boulevard Woodcliff Lake, New Jersey, 07677 USA
CIR Panel Book Page 162 DRAFT AS OF APRIL 6, 2010
headspace technique for more sensitive analysis of volatiles. Flavour and Fragrance Journal, 19(3), 183-187. Jenner P.M. , Hagan E.C. , Taylor J.M. , Cook E.L. and Fitzhugh O.G. (1964) Food flavorings and compounds of related structure. I. Acute oral toxicity. Food and Cosmetics Toxicology, 2(3), 327-343. Johnson R. , Macina O.T. , Graham C. , Rosenkranz H.S. , Cass G.R. and Karol M.H. (1997) Prioritizing testing of organic compounds detected as gas phase air pollutants: Structure-activity study for human contact allergens. Environmental Health Perspectives, 105(9), 986-992. Jordan W.P. and Dahl M.V. (1971) Contact dermatitis to a plastic solvent in eyeglasses. Archives of Dermatology , 104, 524-528. Juhnke I. and Luedmann D. (1978) Results of the study of 200 chemical compounds on acute fish toxicity using the Golden Orfe test. Zeitschrift fur Wasser und Abwasser-Forschung, 11, 161-164. Juttner F. (1992) Flavor compounds in weakly polluted rivers as a means to differentiate pollution sources. Water Science and Technology, 25(2), 155-164. Kamlet M.J. , Doherty R.M. , Taft R.W. , Abraham M.H. , Veith G.D. and Abraham D.J. (1987) Solubility properties in polymers & biological media. 8. an analysis of the factors that influence toxicities of organic nonelectrolytes to the golden orfe fish Environmental Science & Technology, 21, 149-155. Kamlet M.J. , Doherty R.M. , Abraham M.H. and Taft R.W. (1988) Solubility properties in biological media. 12. Regarding the mechanism of nonspecific toxicity or narcosis by organic nonelectrolytes. Quantitative Structure -Activity Relationships, 7, 71-78. Karelson M. , Sild S. and Maran U. (2000) Non-linear QSAR treatment of genotoxicity. Molecular Simulation, 24(4-6), 229-242. Kennedy Jr. G.L. and Graepel G.J. (1991) Acute toxicity in the rat following either oral or inhalation exposure. Toxicology Letters, 56(3), 317-326. Khedouri E. , Warne P.J. and West G.B. (1976) Anti-inflammatory activity of esters of acetic acid. Journal of Pharmacy and Pharmacology, 28, 839-840. Knoppel H. and Schauenburg H. (1989) Screening of household products for the emission of volatile organic compounds. Environment International, 15(1-6), 413-418.
Research Institute for Fragrance Materials, Inc. Page 18 50 Tice Boulevard Woodcliff Lake, New Jersey, 07677 USA
CIR Panel Book Page 163 DRAFT AS OF APRIL 6, 2010
Knudsen J.T. , Tollsten L. and Bergstrom L.G. (1993) Review article number 76: Floral scents-a checklist of volatile compounds isolated by head-space techniques. Phytochemistry, 33(2), 253-280. Kupczewska-Dobeca M. , Socko R. and Czerczak S. (2006) RD(50) value as the criterion for setting maximum admissible levels of occupational exposure to irritants in Poland. International Journal of Occupational Safety and Ergonomics(JOSE), 12(1), 95-99. Levin H. (1989) Building materials and indoor air quality. Occupational Medicine, State of the Art Reviews, 4(4), 667-693. Y-X-Liang, B-Q.Gang and X.-Q.Gu (1995) The development of occupational exposure limits for chemical substances in China. Regulatory Toxicology and Pharmacology, 22(2), 162-171. Lipnick R.L. (1988) A quantitative structure-activity relationship study of Overton's data on the narcosis and toxicity of organic compounds to the tadpole, Rana temporaria. ASTM Spec. Technical Publication, 1007(11th Vol.), 468-489. Liu M. , Grant S.G. , Macina O.T. , Klopman G. and Rosenkranz H.S. (1997) Structural and mechanistic bases for the induction of mitotic chromosomal loss and duplication ('malsegregation') in the yeast Saccharomyces cerevisiae: Relevance to human carcinogenesis and developmental toxicology. Mutation Research, 374(2), 209-231. Magee P.S. (1991) Complex factors in hydrocarbon/water, soil/water and fish/water partitioning. The Science of the Total Environment, 109/110, 155-178. Martin T.M. and Young D.M. (2001) Prediction of the acute toxicity (96-h LC50) of organic compounds to the fathead minnow (Pimephales promelas) using a group contribution method. Toxicology In Vitro, 14(10), 1378-1385. Maruzzella J.C. , Chiaramonte J.S. and Garofalo M.M. (1961) Effects of vapours of aromatic chemicals on fungi. Journal of Pharmaceutical Sciences, 50(8), 665-668. Maruzzella J.C. and Bramnick E. (1961a) The antibacterial properties of perfumery chemicals. Soap, Perfumery and Cosmetics, 7 43-745. Maruzzella J.C. , Garofalo M.M. and Chiaramonte J.S. (1961b) How vapors of aromatic chemicals affect bacteria. American Perfumer, 76(2), 35-39.
Research Institute for Fragrance Materials, Inc. Page 19 50 Tice Boulevard Woodcliff Lake, New Jersey, 07677 USA
CIR Panel Book Page 164 DRAFT AS OF APRIL 6, 2010
Meulenberg C.J.W. and Vijverberg H.P.M. (2000) Empirical relations predicting human and rat tissue: Air partition coefficients of volatile organic compounds. Toxicology and Applied Pharmacology, 165(3), 206-216. Muller J. and Greff G. (1984) Research on the relations between toxicity of molecules of industrial interest and physicochemical properties: Irritation test of the upper respiratory tract applied to four families of chemicals. Food and Chemical Toxicology, 22(8), 661-664. Munch J.C. (1972) Aliphatic alcohols and alkyl esters: Narcotic and lethal potencies to tadpoles and to rabbits. Industrial Medicine and Surgery, 41(4), 31-33. Munro I.C. and Kennepohl E. (2001) Comparison of estimated daily capita intakes of flavouring substances with no-observed-effect levels from animal studies. Food and Chemical Toxicology, 39(4), 331-354. Nendza M. and Wenzel A. (2006) Discriminating toxicant classes by mode of action. 1. (Eco)toxicity Profiles. Environmental Science and Pollution Research, 13(3), 192-203. Netzeva T.I. , Schultz W.T. , Aptula A.O. and Cronin M.T.D. (2003) Partial least squares modelling of the acute toxicity of aliphatic compounds to Tetrahymena pyriformis. SAR & QSAR in Environmental Research, 14(4), 265-283. Nielsen G.D. (1991) Mechanisms of activation of the sensory irritant receptor by airborne chemicals. Critical Reviews in Toxicology, 21(3), 183-208. Nishimura H. , Saito S. , Kishida F. and Matsuo M. (1994) Analysis of acute toxicity (LD50-value) of organic chemicals to mammals by solubility parameter (delta). 2. Acute oral toxicity to mice. Sangyo Igaku, 36(6), 421-427. Nishimura H. , Saito S. , Kishida F. and Matsuo M. (1994a) Analysis of acute toxicity (LD50-value) of organic chemicals to mammals by solubility parameter (delta). 1. Acute oral toxicity to rats. Sangyo Igaku, 36(5), 314-323. [Japanese Journal Industrial Health] Papa E. , Battaini F. and Gramatica P. (2005) Ranking of aquatic toxicity of esters modelled by QSAR. Chemosphere, 58(5), 559-570. Paustenbach D.J. and Leung H.-W. (1993) Technique for Assessing the Health Risks of Dermal Contact with Chemicals in the Environment. In Health Risk Assessment, Chapter 23, 343-385.
Research Institute for Fragrance Materials, Inc. Page 20 50 Tice Boulevard Woodcliff Lake, New Jersey, 07677 USA
CIR Panel Book Page 165 DRAFT AS OF APRIL 6, 2010
Pavan M. , Netzeva T. and Worth A.P. (2006) Validation of a QSAR model for acute toxicity. SAR & QSAR in Environmental Research, 17(2), 147-171. Pitt M.J. (1982) A vapour hazard index for volatile chemicals. Chem Ind., 20, 804-806. Poulin P. and Krishnan K. (1995) An algorithm for predicting tissue: Blood partition coefficients of organic chemicals from n-octanol:water partition coefficient data. Journal of Toxicology and Environmental Health, 46(1), 117-129. Price K.S. , Waggy G.T. and Conway R.A. (1974) Brine shrimp bioassay and seawater BOD of petrochemicals. Journal Water Pollution Control Federation, 46(1), 63-77. Querci V. and Mascia D. (1970) Enzymelogical and histological findings on liver damage in experimental acetate intoxication. La Medicina del Lavoro, 61(10), 524-530. Ran Y. , He Y. , Yang G. , Johnson J.L.H. and Yalkowsky S.H. (2002) Estimation of aqueous solubility of organic compounds by using the general solubility equation. Chemosphere, 48(5), 487-509. Ren S. (2002) Predicting three narcosis mechanisms of aquatic toxicity. Toxicology Letters, 133(2-3), 127-139. Research Institute for Fragrance Materials, Inc, (1978a). Report on human maximization studies. Report to RIFM. Unpublished report 1787 from Kligman A.M. October 20 October 20A Research Institute for Fragrance Materials, Inc, (1978b). Acute toxicity studies in rats, mice, rabbits, and guinea pigs. Report to RIFM. Unpublished report 1699 from Moreno O.M. October 04 Roberts D.W. (1986) Qsar for upper-respiratory tract irritation. Chemico- Biological Interactions, 57, 325-345. Ruth J.H. (1986) Odor thresholds and irritation levels of several chemical substances: A review. American Industrial Hygiene Association Journal (AIHAJ), 47(3), A142-A151. Sakurai H. (2000) Recommendation of occupational exposure limits. Journal of Occupational Health, 42, 213-228. Salvito D.T. (2004) The limitations of commonly used ecotoxicity QSARs - experiments in model validation. SETAC 25th Annual Meeting in North America, 14-18 November, Portland, Oregon, 358.
Research Institute for Fragrance Materials, Inc. Page 21 50 Tice Boulevard Woodcliff Lake, New Jersey, 07677 USA
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Schaper M. (1993) Development of a database for sensory irritants and its use in establishing occupational exposure limits. American Industrial Hygiene Association Journal (AIHAJ) (AIHAJ), 54(9), 488-544. Schnabel K.-O. , Belitz H.-D. and vonRanson C. (1988) Investigations on the structure-activity-relationships of odorous substances. Communication I. Detection thresholds and odour qualities of aliphatic and alicyclic compounds containing oxigen functions. Z.Lebensmittelunters. u.-Forsch, 187(3), 215-223. Schultz T.W. (1997) Tetratox: Tetrahymena pyriformis population growth impairment endpoint. A surrogate for fish lethality. Toxicology Methods, 7, 289-309. Selisko O. , Ackermann H. and Kupke A. (1962) Relation of the toxicity of some homologous esters to their rates of saponification. Ernahrungsforschung, 7(2), 211-215. Shirazi M.A. and Lowrie L. (1990) A probabilistic statement of the structure activity relationship for environmental risk analysis. Archives of Environmental Contamination and Toxicology, 19, 597-602. Smith J.S. , Macina O.T. , Sussman N.B. , Karol M.H. and Maibach H.I. (2000) Experimental validation of a structure-activity relationship model of skin irritation by esters. Quantitative Structure -Activity Relationships, 19(5), 467-474. Smyth Jr. H.F. , Carpenter C.P. , Weil C.S. , Pozzani U.C. , Striegel J.A. and Nycum J.S. (1969) Range-finding toxicity data: List VII. American Industrial Hygiene Association Journal (AIHAJ), 30(5), 470-476. StGeorge A.V. (1937) The pathology of the newer commercial solvents. American Journal of Clinical Pathology, 7, 69-77. Staudinger J. and Roberts P.V. (2001) A critical compilation of Henry's law constant temperature dependence relations for organic componds in dilute aqueous solutions. Chemosphere, 44(4), 561-576. Stofberg J. and Grundschober F. (1987) Consumption ratio and food predominance of flavoring materials. Perfumer and Flavorist, 12(4), 27-68. Stokinger H.E. , Ashe H.B. , Baier E.J. , Coleman A.L. , Elkins H.B. , Grabois B. , Hayes Jr. W.J. , Jacobson K.H. , MacFarland H.N. , Reindollar W.F. , Scovill R.G. , Smith R.G. and Zavon M.R. (1963) Threshold limit values for 1963, Adopted at the 25th Annual Meeting of the American Conference of Governmental Industrial Hygienists. Journal of Occupational Medicine, 5(10), 491-498.
Research Institute for Fragrance Materials, Inc. Page 22 50 Tice Boulevard Woodcliff Lake, New Jersey, 07677 USA
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Stull D.R. (1947) Vapor pressure of pure substances organic compounds. Industrial and Engineering Chemistry, 39(4), 517-540. Takagi K. and Takayanagi I. (1966) The effects of acetates of aliphatic alcohols on the cholinergic nerve structures and the acetylcholine receptor of the guinea-pig ileum. Journal of Pharmacy and Pharmacology, 18(11), 795-800. Taylor J.M. , Jenner P.M. and Jones W.I. (1964) A comparison of the toxicity of some allyl, propenyl, and propyl compounds in the rat. Toxicology and Applied Pharmacology, 6(4), 378-87. Uehori R. , Nagata T. , Kimura K. , Kudo K. and Noda M. (1987) Screening of volatile compounds present in human blood using retention indices in gas chromatography. Journal of Chromatography A, 411, 251-257. Vaughan C.D. (1988) Solubility effects in product, package, penetration, and preservation. Cosmetics and Toiletries, 103, 47-69. Veith G.D. , De Foe D. and Knuth M. (1985) Structure-activity relationships for screening organic chemicals for potential ecotoxicity effects. Drug Metabolism Reviews, 15(7), 1295-1303. vonOettingen W.F. (1960) The aliphatic acids and their esters: Toxicity and potential dangers: The saturated monobasic aliphatic acids & their esters. Journal of the American Medical Association, Jan. 21, 28- 65. Wilkins C.K. and Larsen K. (1995) Identification of volatile (micro)biological compounds from household waste and building materials by thermal desorption-capillary gas chromatography-mass spectroscopy. Journal of High Resolution Chromatography, 18(6), 373-377. Williams A.A. , Lewis M.J. and May H.V. (1983) The volatile flavour components of commercial port wines. Journal of the Science of Food and Agriculture, 34, 311-319. Zimmermann F.K. , Mayer V.W. , Scheel I. and Resnick M.A. (1985) Acetone, methyl ethyl ketone, ethyl acetate, acetonitrile and other polar aprotic solvents are strong inducers of aneuploidy in saccharomyces-cerevisiae. Mutation Research, 149(3), 339-352. Zimmermann F.K. , Scheel I. and Resnick M.A. (1989) Induction of chromosome loss by mixtures of organic solvents. Mutation Research, 224(2), 287-303.
Research Institute for Fragrance Materials, Inc. Page 23 50 Tice Boulevard Woodcliff Lake, New Jersey, 07677 USA
CIR Panel Book Page 168 Persona Carei ProductsCounci Committedto Safety, Quality& Innovation Memorandum
TO: F. Alan Andersen, Ph.D. Director COSMETIC INGREDIENT REVIEW (CIR)
FROM: John Bailey, Ph.D. Industry Liaison to the CW Expert Panel
DATE: June 21, 2010
SUBJECT: Comments on the Draft Report on the Acetate Ingredients for the June 28-29, 2010 CIR Expert Panel Meeting
It is not clear if the reference lists in the RTFMsummaries on Methyl Acetate, Propyl Acetate and Isopropyl Acetate were reviewed for relevant information. The following potentially relevant references were identified. Methyl Acetate Derrnal 50LD in rabbits (>5g/kg) (RIFM 1973a) (there is also an oral study) Please check the following reference for Methyl Acetate as it was one of the substances included in EPA’s mandated testing for dermal absorption. Fasano WJ, McDougal JN. 2008. In vitro dermal absorption rate testing of certain chemicals of interest to the Occupational Safety and Health Administration: summary and evaluation of USEPAs mandated testing. Regul Toxicol Pharmacol. 51(2):181-94. Nakaaki K., Fikabori S., Tada 0. 1980 An experimental study of percutaneous absorption of some organic solvents. Journal Sci. Labour, 56(12), 1-9. Propyl Acetate Dermal 50LD in rabbits (>5 glkg) (RIFM 1978a) (2/10 died) Kennedy Jr. G.L. and Graepel G.J. 1991. Acute toxicity in the rat following either oral or inhalation exposure. Toxicology Letters, 56(3), 317-326. Isopropyl Acetate
DeCeaurriz J. , Desiles J.P. , Bonnet P. , et al. 1983. Concentration-dependent behavioral changes in mice following short-term inhalation exposure to various industrial solvents. Toxicol Appi Pharmacol, 67(3), 383-389. p.1 - It should be made clear that CIR does not review the safety of ingredients used only as a fragrance. If there are other reported functions, the C]R Expert Panel may review the safety of the ingredient. p.S - Please add Butoxyethyl Acetate to the list of ingredients for which no use information was available.
1101 N.W., D.C. 17th Street, Suite 30O Washington, 20036-4702CIR Panel Book202.331.1770 Page 169 202.331.1969 (fax) www.personalcarecouncil.org p.5 - Please provide a reference for the statement that Isopropyl Alcohol is an approved ingredient for topical antimicrobial OTC drug products. p.5 - The fact that Acetic Acid and some of its salts are GRAS is already stated in the first paragraph of the Non-Cosmetic use section. Therefore, this information can be deleted from the last paragraph of this section. p.8, 18 - As there is an ADME section under Clinical Assessment of Safety, it is not clear why the human ADME information on methanol is presented on p.8. p.9 - The following should be deleted from the summary of the Animal Toxicology section: “and in humans exposed to isopropyl alcohol.” p.9 - What compound resulted in 6/6 rats dying after a 4 hour exposure to 32000 ppm? p.10 - In the Acetic Acid inhalation study (reference 48), in which organ(s) was hyperplasia observed? p.11 - In the description of the Acetic Acid 2-4 month drinking water study, what is meant by “no toxic effects”? As reference 30 is dated 1960, this study may not have included histopathologic examination of major organs. p.11 - In what species did Sodium Acetate have a “maximum toleration level of 80mM”? p.12 - In the summary of the Dermal Irritation section, please include the concentrations that are considered irritants. The information on humans should not be in the Animal section. p.13 - The summary of the Ocular Irritation section states: “The metal acetate ingredients have been labeled minor irritants in animal studies.” - but there are no studies of the metal acetate ingredients presented in this section. p.13 - What concentration of Isopropyl Alcohol is considered a severe ocular irritant? p.15-16 - What route of exposure and when during gestation were mice, rats and rabbits treated with Acetic Acid, and mice treated with Sodium Acetate in the developmental studies (reference 24). At what concentration was Sodium Acetate nonteratogenic to chick embryos? p.16-18 - Perhaps the heading of the Carcinogenicity section should be changed to Chronic Exposure/Carcinogenicity, as there is no information in the summary of this section on carcinogenicity. If the heading is not changed, the summary should be rewritten to include information regarding carcinogenicity. p.16 - The 10 month study of Buthoxyethyl Acetate should be moved to the subchronic section. Chronic studies are generally considered to be 1 year or longer. p.17 - In the rat chronic inhalation study of Isopropyl Alcohol, were the incidences of interstitial cell adenomas of the testes significantly different from controls at all exposure concentrations? p.17 - In the t-butyl acetate study, were adenomas and or carcinomas of the renal tubules observed in female rats? p.18 - The following does not make sense. “The percutanous uptake rate of Butoxyethanol into blood varied from 127 to 1892 pmol.” Either this is the total uptake in pmol, or the units are incorrect. Please correct “30-mm lunch” to “30-minute lunch”. p.18 - The sentence on formate levels after methanol exposure should not be presented under the Isopropyl Alcohol subheading. p.19 - Please provide more information about the maximization study (incorrectly called HRIPT in the subject line of the submission memo) of the lipstick containing 12.6% Cetyl Acetate, including the number of subjects and the type of study. p.21, 25, 26 - Please indicate that the material tested in reference 79 was a hair dye base and it
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CIR Panel Book Page 170 contained both 2.85% Isopropyl Alcohol and 1.95% Isopropyl Acetate (it currently states that two different formulations were tested - this is not correct). Please state that this study was an HRIPT. p.21 - Information about Methyl Alcohol is presented for a second time under the subheading for t butyl alcohol. Where is the information on t-butyl alcohol? p.22 - How may subjects were included in the single insult occlusive patch test of 100% stearyl alcohol? Where did this information come from? It currently says “from the CIR final report on myristyl alcohol” - stearyl alcohol is not in that report. p.13 - How many subjects were included in the Acetic Acid dermal ilTitation study? p.23 - If the effects described in the occupational study of Butoxyethanol were not attributable to Butoxyethanol, this information should not be included in this report. p.24 - The following statement is misleading because based on log 0K the larger acetic esters may not readily penetration the skin. “Acetic ester in general, readily, penetrate the skin and mucous membranes...” p.24 - A summary of the cosmetic use information still needs to be added to the Summary section. 0.25 - Inclusion of butoxyethanol among the ingredients “found safe as used by the CW Expert Panel” is not correct as the CIR Expert Panel limited use of this ingredient to 10% in hair and nail products (50% in nail polish removers). That butoxyethanol was found safe as used is stated twice on this page (second paragraph and first paragraph under the Alcohols subheading). p.25 - The sentence on dermal penetration of longer chain esters should be presented in the Summary with the rest of the ADME information. p.25 - In the summary information regarding Isopropyl Alcohol it would be helpful to state that it is used as a vehicle and control in human sensitization studies and it is not considered to be a sensitizer. p.26 — The Discussion section needs to be rewritten based on comments from the CIR Expert Panel. Please delete the gibberish at the end of the first paragraph. If the unpublished information is acknowledged in the Discussion section, the information from RIFM should also be mentioned. p.26 - The study on the lipstick containingl2.6% Cetyl Acetate was actually a maximization study rather than a human repeat insult patch test. p.30, references 71 and 72 - RTFMhas clarifiedJune 21, 2010 the references for the human maximization studies of Methyl Acetate and Propyl Acetate. Reference 72 should be: Research Institute for Fragrance Materials, mc, (1976a). Report on human maximization studies. Report to RIFM. Unpublished report 1797 from Kligman A.M. May 18. Reference 71 should be: Research Institute for Fragrance Materials, mc, (1978a). Report on human maximization studies. Report to RIFM. Unpublished report 1787 from Kligman A.M. October 20 October 20A. p.48 - The footnote to Table 5 states that some concentration data came in 2009 and some in 2010, while the heading of the last column of the table says 2007 and 2009. The table heading is actually correct (until the 2010 information on Acetic Acid and its salts is completed) as use information for Methyl Acetate through Butyl Acetate was provided in 2007 (reference 19).
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CIR Panel Book Page 171 PersonalCare ProductsCouncil Committedto Safety, Quality& innovation Memorandum
TO: F. Alan Andersen, Ph.D. Director - COSMETIC INGREDIENT REVIEW (CIR)
FROM: John Bailey, Ph.D. Industry Liaison to the CIR Expert Panel
DATE: July 26, 2010
SUBJECT: Comments on the Tentative Report on the Acetates
p.1, Abstract - Nail polish remover is a product category rather than a function. The conclusion does not deal well with the ingredients that have no reported uses or use concentrations. This conclusion could be interpreted to mean that Butoxyethyl Acetate and Calcium Acetate can be used in the product categories and concentrations reported for Isopropyl Alcohol. p.2 What is mean by “an industry shift began two years ago”? This is from a 2004 reference. Does it mean in 2002? Or does it mean 2008? p.3 - It would be helpful to state the ingredients for which no uses and no uses concentrations were reported. p.3 - Is the spray product sentence necessary as there are inhalation data to support the use of these ingredients in products for which inhalation may be a route of exposure. p.4 - Please provide a reference for the sentence that indicates that Zinc Acetate is an approved OTC skin protectant. p.5 - In what species was Acetic Acid absorbed from the gastrointestinal tract and the lungs? p.7 - In the description of the metabolism of butoxyethanol, please change “These data suggest..” to “These data show...”. Butoxyacetic acid is the major metabolite of butoxyethanol. p.7 - In the summary of the Animal Toxicology section, what doses of Acetic Acid and the smaller solvent acetates resulted in central nervous system depression. p.8 - The following sentence is not clear. Should it be one species or both rats and mice? “An oral 50LD of 3530 mg/kg in rats in mice was observed with sodium acetate.” p.10 - In what species was the functional observation battery completed? If it was in rats, the results should be presented a paragraph in which the results in rats are presented, rather than in the first sentence of the paragraph about the results in mice. p.11 - It is not clear why the summary of the Dermal Irritation section includes the following sentence. “Acetic acid, at 10% concentration, has been labeled a minor skin irritant in humans.” Where is this information coming from as it is not included in the Acetic Acid subsection? Please change “contributed” to “attributed”. p.11 - A Propyl Acetate subheading appears to be missing after the Dermal Irritation summary.
11011 7th Street, N.W., Suite 300 Washington, D.C. 20036-4702 202.331.1770 202.331.1969 (fax) www.personalcarecouncil.org CIR Panel Book Page 172 p.13 - Please provide the type of exposure e.g., gavage, dietary, drinking water, used in the developmental toxicity studies of acetic acid. Please state the gestation days the animals were treated, if a standard protocol was used, please state the protocol. p.13 - Please provide the route and gestation days of treatment for the developmental study of Sodium Acetate. What concentrations of Sodium Acetate were used in the chick embryo study? p.14 - How old were the offspring when the behavioral tests were completed in the rat study of Propyl Alcohol? p.14 - In the summary of the Genotoxicity section, it would be helpful to state which alkyl acetates were tested. p.15 - The summary of the Carcinogenicity section does not include a single word about the carcinogenicity potential of the ingredients included in this report. p.15 - The 10 month study of Butoxyethyl Acetate should be moved to the subchronic exposures section. Chronic studies are generally considered to be 12 months and longer. Did the study authors say anything about the carcinogenicity potential of Butoxyethyl Acetate? p.16 - In the oral study of t-butyl alcohol in rats, were any tumors found in females? p.18 - Please change”a 12.6% lipstick formulation” to “a lipstick containing 12.6% Cetyl Acetate”. p.20 - Please revise the following sentences. “According to unpublished data, a 80.74% spray concentration caused did not exhibit any potential for dermal sensitization in 9 human subjects.” “According to unpublished HRIPT study on 109 test subjects, a 2.85% hair dye base formulation of isopropyl alcohol and 1.95% isopropyl acetate caused no dermal sensitization in humans.” (The hair dye base contained 2.85% Isopropyl Alcohol and 1.95% Isopropyl Acetate - the way it is written now suggests the base was diluted to 2.85% before testing.) p.21 - The summary of the rabbit irritation data on t-Butyl Alcohol should not be presented in the Clinical section. p.23 - If the effects in employees exposed to low levels of Butoxyethanol were attributed to exposure to an amine, it is not necessary to present this summary in this report. p.25 - Is it necessary to present the following twice on this page? “The alcohol metabolites, ethyl alcohol, butyl alcohol, t-butyl alcohol, butoxyethyl alcohol (with qualifications), myristyl alcohol, cetyl alcohol, stearyl alcohol and isostearyl alcohol have been found safe as used by the CIR Expert Panel.” p.25 - What is the lowest concentration of Acetic Acid that is considered a severe ocular irritant? p.26-27 - No uses or concentrations of use have been reported for Butoxyethyl Acetate. Therefore, the meaning of: “However, the Panel determined that the concentration of Butoxyethyl Acetate that would be required to generate appreciable quantities of butoxyethanol through metabolic pathways is well above the present use concentrations of Butoxyethyl Acetate.” is not clear. p.27 - This report is missing the Conclusion section. The post June meeting announcement listed the following conclusion: “Methyl Acetate, and the following acetate esters and relevant metabolites: Propyl Acetate, Isopropyl Acetate, t-Butyl Acetate, Isobutyl Acetate, Butoxyethyl Acetate, Nonyl Acetate, Myristyl Acetate, Cetyl Acetate, Stearyl Acetate, Isostearyl Acetate, Acetic Acid, Sodium Acetate, Potassium Acetate, Magnesium Acetate, Calcium Acetate, Zinc Acetate, Propyl Alcohol, and Isopropyl Alcohol, are safe in the practices of use and concentration as given in the safety assessment.” With the footnote: 1Were ingredients in this group not in used in “ current use to be the future, the expectation is that they would be used in
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CIR Panel Book Page 173 product categories and at concentrations comparable to others in the group.” Based on this conclusion is the CIR Expert Panel saying that Butoxyethanol Acetate and Calcium Acetate (two ingredients with no uses or use concentrations reported) can be used in product categories and at concentrations reported for Isopropyl Alcohol e.g., 100% in nail products, 76% in a shaving product? Perhaps the footnote needs to be modified to indicate that Butoxyethyl Acetate should be used like the other small alkyl acetates and Calcium Acetate like other metal acetates and the use patterns of the long chain alkyl acetates should be similar. p.30,Reference 44 - Please change this reference to: Research Institute for Fragrance Materials, mc, (1978). Report on human maximization studies. Report to RWM. Unpublished report 1787 from Kligman A.M. October 20 October 20A. RIEM made a mistake in their summary document, which they corrected. The corrected summary document is now on the I drive. Citing a human study to a report on acute toxicity studies in rats, mice, rabbits and guinea pigs did not make sense. p.31, Reference 32 - Please change this reference to: Research Institute for Fragrance Materials, mc, (1976). Report on human maximization studies. Report to RIFM. Unpublished report 1797 from Kligman A.M. May 18 RIEM made a mistake in their summary document, which they corrected. The corrected summary document is now on the I drive. Citing a human study to a report on acute toxicity studies in rats, mice, rabbits and guinea pigs did not make sense.
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CIR Panel Book Page 174