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Pentaerythrityl Tetraisostearate and Other Pentaerythrityl Esters

CIR EXPERT PANEL MEETING

SEPTEMBER 26-27, 2011

August 26, 2011

MEMORANDUM

To: CIR Expert Panel and Liaisons From: Lillian C. Becker, M.S.

Scientific Analyst and Writer Subject: Draft Final Safety Assessment for Pentaerythrityl Tetraisostearate and

other pentaerythrityl tetraester ingredients used in cosmetics The Expert Panel issued a tentative safety assessment at the June, 2011 Panel meeting for pentaerythrityl tetraisostearate and related pentaerythrityl tetraesters with the conclusion that these ingredients were found to be safe as used. Comments from industry have been received and incorporated into the report. The Personal Care Products Council has redefined pentaerythrityl cocoate as a monoester. Since it no longer fits in with the tetraesters, it has been removed from the report. The tetracocoate ester remains. A summary of data for the possible metabolite/residutal monomer pentaerythirtol has been incorporated in the Toxicokinetics section. The Panel should review the draft final safety assessment and decide if the discussion and conclusion accurately reflect the Panel’s thinking. The Panel should issue a final safety assessment.

Distributed for Comment Only -- Do Not Cite or Quote

CIR Panel Book Page 1

History of Pentaerythrityl Tetraisostearate and Other Pentaerythrityl Tetraesters

February, 2011 – SLR announced. June, 2011 – The CIR Expert Panel issued a tentative report for pentaerythrityl tetraesters. The CIR

Expert Panel issued a safe as used in cosmetics conclusion for these ingredients. The Panel included two ingredients that had been previously reviewed in this group. The Panel also removed pentaerythrityl tetraacetate from this report. Since this report, pentaerythrityl cocoate has been redefined as a monoester and removed from this report. The possibility of these ingredients being cleaved and penetrating the skin was addressed. The 16 ingredients included in this safety assessment are:

Pentaerythrityl Tetraisostearate Pentaerythrityl Tetra C5-9 Acid Esters Pentaerythrityl Tetra C5-10 Acid Esters Pentaerythrityl Tetracaprylate/ Tetracaprate Pentaerythrityl Tetralaurate Pentaerythrityl Tetramyristate Pentaerythrityl Tetrastearate Pentaerythrityl Tetrabehenate Pentaerythrityl Tetracocoate Pentaerythrityl Tetraoleate Pentaerythrityl Tetraethylhexanoate Pentaerythrityl Tetraethylhexanoate/ Benzoate Pentaerythrityl Tetrabehenate/ Benzoate/ Ethylhexanoate Pentaerythrityl Tetrabenzoate Pentaerythrityl Tetraisononanoate Pentaerythrityl Tetrapelargonate

September, 2011 – The Panel considers a final report.



Search Strategy for Pentaerythrityl Tetraesters

Terms PubMed (1/2011)

ECETOC (1/2011)

SCCP & SCCN (1/2011)

IUCLID (1/2011)

IARC (1/2011)

HPVIS (1/2/2011)

Dogpile (1/2/2011)

Scifinder (6/27/2011)

HSDB

Pentaerythrityl Tetraacetate; 597-71-7; 2,2-Bis[(acetyloxy)methyl]-1,3-propanediol diacetate; tetra-O-acetylpentaerythritol; pentaerythrityl tetraacetate; 1,3-Propanediol, 2,2-bis[(acetyloxy)methyl]-, 1,3-diacetate; 1,3-Propanediol, 2,2-bis[(acetyloxy)methyl]-, diacetate; Pentaerythritol, tetraacetate; Normo-level; Normosterol; NSC 1841; Pentaerythrityl tetraacetate; Pentaerythrityl Tetra C5-9 Acid Esters; 67762-53-2; Carboxylic acids, C5-9, tetraesters with pentaerythritol; Fatty acids, C5-9, tetraesters with pentaerythritol; Pentaerythrityl Tetra C5-10 Acid Esters; 68424-31-7; Fatty acids, C5-10, esters with pentaerythritol; Pentaerythrityl Tetracaprylate/ Tetracaprate; 68441-68-9; Decanoic acid, mixed esters with octanoic acid and pentaerythritol; 68071-00-1; 69226-96-6; Pentaerythrityl Tetralaurate; 13057-50-6; Dodecanoic acid, 1,1'-[2,2-bis[[(1-oxododecyl)oxy]methyl]-1,3-propanediyl] Ester; Dodecanoic acid, 2,2-bis[[(1-oxododecyl)oxy]methyl]-1,3-propanediyl ester; Lauric acid, neopentanetetrayl ester; Pentaerythritol, tetralaurate; Pentaerythrityl tetralaurate; Pentaerythrityl Tetramyristate; 18641-59-3; Tetradecanoic acid, 2,2-bis[[(1-oxotetradecyl)oxy]methyl]-1,3-ropanediyl Ester; Myristic acid, tetraester with pentaerythritol; Pentaerythritol, tetramyristate; Pentaerythrityl Tetrastearate; 115-83-3; Octadecanoic acid, 1,1'-[2,2-bis[[(1-oxooctadecyl)oxy]methyl]-1,3-propanediyl] ester; Octadecanoic acid, 2,2-bis[[(1-oxooctadecyl)oxy]methyl]-1,3-propanediyl ester; Pentaerythritol, tetrastearate; Stearic acid, neopentanetetrayl ester; Stearic acid, tetraester with pentaerythritol; Pentaerythrityl tetrabehenate; 61682-73-3; Docosanoic acid, 1,1'-[2,2-bis[[(1-oxodocosyl)oxy]methyl]-1,3-propanediyl] ester; Docosanoic acid, 2,2-bis[[(1-odocosyl)oxy]methyl]-1,3-propanediyl ester; Pentaerythritol, tetradocosanoate ; Pentaerythrityl Tetracocoate; 92201-72-4; Fatty acids, C6-18, tetraesters with pentaerythritol; Pentaerythrityl Tetraoleate; 19321-40-5; 9-Octadecenoic acid (9Z)-, 1,1'-[2,2-bis[[[(9Z)-1-oxo-9-octadecenyl]oxy]methyl]-1,3-propanediyl] ester; 9-Octadecenoic acid (9Z)-, 2,2-bis[[[(9Z)-1-oxo-9-octadecenyl]oxy]methyl]-1,3-propanediyl ester; 9-Octadecenoic acid (Z)-, 2,2-bis[[(1-oxo-9-octadecenyl)oxy]methyl]-1,3-propanediyl ester, (Z,Z)-; Oleic acid, neopentanetetrayl ester; Pentaerythritol, tetraoleate; Pentaerythrityl Tetraisostearate; 62125-22-8; Isooctadecanoic acid, 1,1'-[2,2-bis[[(1-oxoisooctadecyl)oxy]methyl]-1,3-propanediyl] ester; Isooctadecanoic acid, 2,2-bis[[(1-oxoisooctadecyl)oxy]methyl]-1,3; Pentaerythrityl Tetraethylhexanoate; 7299-99-2; Hexanoic acid, 2-ethyl-, 1,1'-[2,2-bis[[(2-ethyl-1-oxohexyl)oxy]methyl]-1,3-propanediyl] ester; Hexanoic acid, 2-ethyl-, 2,2-bis[[(2-ethyl-1-oxohexyl)oxy]methyl]-1,3- propanediyl ester; Hexanoic acid, 2-ethyl-, neopentanetetrayl ester; Hexanoic acid, 2-ethyl-, pentaerythritol tetraester; Hexanoic acid, 2-ethyl-, tetraester with pentaerythritol; Pentaerythritol, tetrakis(2-ethylhexanoate); Pentaerythrityl Tetraethylhexanoate/Benzoate; Pentaerythrityl Tetrabehenate/ Benzoate/ Ethylhexanoate; Pentaerythrityl Tetrabenzoate; 4196-86-5; 1,3-Propanediol, 2,2-bis[(benzoyloxy)methyl]-, 1,3-dibenzoate; 1,3-Propanediol, 2,2-bis[(benzoyloxy)methyl]-, dibenzoate; Pentaerythritol, tetrabenzoate; Pentaerythrityl Tetraabietate; 127-23-1; 1-Phenanthrenecarboxylic acid, 1,2,3,4,4a,4b,5,6,10,10a-decahydro-1,4a-dimethyl-7-(1-methylethyl)-, 1,1'-[2,2-bis[[[[(1R,4aR,4bR,10aR)- 1,2,3,4,4a,4b,5,6,10,10a-decahydro-1,4a-dimethyl-7-(1-methylethyl)-1- phenanthrenyl]carbonyl]oxy]methyl]-1,3-propanediyl] ester, (1R,1'R,4aR,4'aR,4bR,4'bR,10aR,10'aR)-; 1-Phenanthrenecarboxylic acid, 1,2,3,4,4a,4b,5,6,10,10a-decahydro-1,4a-dimethyl-7-(1-methylethyl)-, 2,2-bis[[[[(1R,4aR,4bR,10aR)-1,2,3,4,4a,4b,5,6,10,10a-decahydro-1,4a-dimethyl-7-(1-methylethyl)-1-phenanthrenyl]carbonyl]oxy]methyl]-1,3-propanediyl ester, (1R,1'R,4aR,4'aR,4bR,4'bR,10aR,10'aR)-; 1-Phenanthrenecarboxylic acid, 1,2,3,4,4a,4b,5,6,10,10a-decahydro-1,4a-dimethyl-7-(1-methylethyl)-, 2,2-bis[[[[1,2,3,4,4a,4b,5,6,10,10a-decahydro-1,4a-dimethyl-7-(1-methylethyl)-1-phenanthrenyl]carbonyl]oxy]methyl]-1,3-propanediyl

4 hits 0 0 0 0



ester, stereoisomer; Podocarpa-8,12-dien-15-oic acid, 13-isopropyl-, neopentanetetrayl ester CAS Nos & INCI names Hits on P.

tetra C5-10 & C5-9 acid esters

CAS Nos. A few MSDS

Pentaerythitol and CAS No. (6/27/2011) 1 hit No hits No hits Pentaerythritol tetranitrate, PETN, and Cas No. 78-11-5 (7/2011)

4 hits 1 hit



INGREDIENT Data Profile for March, 2011. Writer ‐ Lillian Becker

ADME Acute toxicity Repeated dose

toxicity Irritation

Sensitiza-tion

Derm

al P

enetration

Log Kow

Use

Oral

Derm

al

Inhale

Oral

Derm

al

Inhale

Ocular

Irritation

Derm

al Irr. A

nimal

Derm

al Irr H

uman

Sensitization

Anim

al

Sensitization

Hum

an

Repro/D

evel to

xicity

Genotoxicity

Carcinogenicity

Phototoxicity

Pentaerythrityl Tetra C5-9 Acid Esters

X X X X X

Pentaerythrityl Tetra C5-10 Acid Esters

X

Pentaerythrityl Tetracaprylate/ Tetracaprate

X X

Pentaerythrityl Tetralaurate X

Pentaerythrityl Tetramyristate

Pentaerythrityl Tetrastearate X

Pentaerythrityl Tetrabehenate X X X

Pentaerythrityl Tetracocoate

Pentaerythrityl Tetraoleate

Pentaerythrityl isostearate

X X

Pentaerythrityl Tetraethylhexanoate

X

Pentaerythrityl Tetraethylhexanoate/ Benzoate

X X

Pentaerythrityl Tetrabehenate/ Benzoate/Ethylhexanoate

X X

Pentaerythrityl Tetrabenzoate

X X

Pentaerythrityl tetraisonate

X

Pentaerythrityl tetrapelargonate

X



Tran

scripts

1

Pentaerythrityl Tetraesters Minutes from June, 2011 Panel Meeting Dr. Belsito’s Team

DR. BELSITO: Okay, pentaerythrityl tetraisostearates. Okay. So, this is the first time we're looking at the report. There are 14 of them. Two – the tetraisononanoate and the tetrapelargonate have been previously reviewed, they were found safe as used, as was the cocoate, which was previously reviewed. And I guess one of the questions as we look at this is, do we want to include those 3 so 15 years from now when this group comes up, they all come up together? And then, we also looked at the rosinate and found that was insufficient, likely due to issues related more to the rosin than to the pentaerythrityl. But I always thought of the opinion, why not throw it back in and make, you know -- because there may be new data out on rosinate that we haven't looked at that would allow us to say the whole group is safe. So my feeling is, again, as we approach these let's be all-inclusive. If something has been reviewed before but actually belongs in the family, let's put it back in so that we're saving future generations from having to review the tetraisononanoate one year and then this entire family two years later. DR. BRESLAWEC: I think the -- we had considered doing that with the rosinate. And that my recollection is that the structure of the rosinate is so different because of its source. And I wish Bart was here, because he could actually remember better. That it really was that part of the molecule that was operative, if you will. MS. BECKER: Yeah. I got the impression that this -- when we were discussing this, that this should stay with the rosinate report and not get shifted over to here. MR. LIEBLER: I didn't see a structure of the rosinate. I don't know if it was in here and I missed it. What -- can you just describe it to me briefly what's it like? DR. BRESLAWEC: Sorry, I can't remember. We can get Bart in here and see if he -- DR. BELSITO: It was previously reviewed. Do we have -- would it be in the CIR Compendium, or do we have the book? It should be in there. MR. SNYDER: So on the list of ingredients, also, on Page 2? We list 14 ingredients, but the table has 15 ingredients. And so, the isostearate is missing from this list. DR. BRESLAWEC: Yes, the Council pointed that out to us. And they are correct, there are 15 ingredients and pentaerythrityl tetraisostearate was missing from that list. DR. BELSITO: And we are going to add in the isononanoate and the tetrapelargonate and the cocoate, those three? DR. BRESLAWEC: As you wish, right. DR. BELSITO: Well, I am not we. So, Curt? Paul, Dan? Are we going to add the three that were previously reviewed?



2

DR. KLAASSEN: Sure. DR. BELSITO: Okay. DR. BRESLAWEC: I do have a question on that. We do not have concentration of use information on that. And to get that, would require a lot of time and effort. Based on the fact that they have previously been reviewed, do you feel that you need to see that information on those three ingredients that have been previously considered safe or not? DR. BELSITO: I would like to see an update, sure. I mean -- DR. BRESLAWEC: Do you want concentration of use update or just VCRP data? That would be easier. DR. BERGFELD: We need both. DR. BRESLAWEC: Okay. DR. BELSITO: I think both would be nice. DR. KLAASSEN: Or how recent – what were they reviewed or how? DR. BRESLAWEC: Well, the pelargonate was very recent. DR. KLAASSEN: What were the three – DR. BRESLAWEC: I don't know about the others. DR. EISENMANN: (inaudible) DR. BELSITO: Microphone, Carol. DR. EISENMANN: Sorry. I think the coconate was when we -- they re-did coconut ingredients fairly recently, too, I think. So I think they're both fairly recent. I mean, I can do it but you probably won't have it for September. DR. BELSITO: Well, you know, if September is anything like this meeting, if we're going to have a big discussion about priorities I think one less ingredient to review might be a nice break. MS. BECKER: The pelargonic acid -- DR. KLAASSEN: The --- MS. BECKER: I'm sorry, the pelargonic acid was published in 2010. DR. BELSITO: Okay. MS. BECKER: And the cocoate was published in 2008. So, the data is probably at least a year older than that, that we have. DR. BELSITO: But if we're going to come out as a safe as used, then the as used will refer to the concentrations that were in our report. Correct?



3

DR. BRESLAWEC: Right. And for those, you'd have concentrations that -- DR. BELSITO: From '08 and '10 -- DR. BRESLAWEC: -- are from one and two years old or three years old, yeah. DR. BELSITO: But if then some interested party in the past two or three years has come out with a new use for these at a higher concentration, then I would assume they would fess up and say, here's -- DR. BRESLAWEC: Only if we did the survey or only if the survey was done. DR. BELSITO: Well, don't you send out these documents to your member companies and say, hey, we're reviewing this and these are going to be limits and this is what's going to go. So if you're currently using these at a higher limit, speak now or forever hold your peace. I mean, you know who responded to you the first time around, don't you, Carol? DR. EISENMANN: No. DR. BELSITO: You don't? DR. EISENMANN: Well, I do for a while, but then I don't keep it forever. DR. BELSITO: So, forever means less than six months? Or? DR. EISENMANN: No, I keep it until the report is finished and then it goes. Not the information, but the connection. DR. BELSITO: I see. DR. EISENMANN: Plus, you know, even if -- companies are always buying and selling different portions of their companies, so it changes. So, if I go back to the company they may not be using it anymore or they may have started using it or, you know, I would just start again and say, this is a new concentration of use survey on this ingredient. DR. KLAASSEN: Yeah, I think, you know, if you could get that information but without holding up this document too long, if you could just put in there at least for now the most current information that you have is two or three years old and just kind of state that this will be updated. I think we could continue the process and keep it going so we don't lose some momentum. DR. BELSITO: Okay. So we're saying while we're waiting for Dan to decide on the rosinates for us, we're saying add in all the others. If you want to bring it back to us in September, fine. Bring it back to us with the concentrations that were reported at the time of the original report with the idea that, you know, at best it's going to go final, then leaving another three months to potentially update concentration. So we have six months to begin the process of looking at what those concentrations are. Is that fair? The -- I mean, because otherwise, I mean, I think they're safe as



4

used. There was no other additional data that I felt needed to be added. DR. KLAASSEN: Right. DR. BELSITO: My only question was, do we add in the rosinate and try and evaluate that for safety? MR. LIEBLER: No. So, I just found the rosin acid structure, a series of rosin acid structures. What -- they are quite dissimilar from the fatty acid chains that we're considering here. They're actually fused six-member rings with various methyl alkyl substituents, and double bond arrangements. They're quite different. They would have different metabolism and, probably, properties. I think they would be the tail wagging the dog with these pentaerythrityl esters. So, I think the rosinates should be left out. And the other thing I was going to say before we get out of this is that I actually think the acetates should probably be left out. Because the acetate -- there are no uses for it. It's a very -- it's -- even though it's chemically analogous – DR. BELSITO: The tetraacetate? MR. LIEBLER: The tetraacetate, exactly. The tetraacetate is chemically analogous, but it's very different in terms of solubility, absorption, any other compounds. So, my suggestion would be to leave the tetraacetate out. DR. BELSITO: Okay. Who is reporting on this? I am. So, basically what you're telling me to do is, we're going to include -- we're going to exclude the tetraacetate from the 15 that were suggested for inclusion. We are going to include the isononanoate and the tetrapelargonate in the cocoate, but not the rosinate. And after doing that, we're going to ask Carol to begin the process of updating concentrations of use so that when we do this as a final in December or March of 2012, we can have those for the three we've already reviewed. And we're going safe as used and basically really not asking for anything other than the concentration update. Correct? Anything else on the tetraisostearates? Hearing nothing, let's take a little R&R, 10 minutes. I have 3:10, back at 3:20.

Dr. Marks’ Team

DR. MARKS: We're close to the quickest we've done today. Okay, next one, and I said pentaerythrityl, how do you say that? SPEAKER: Pentaerythrityl. DR. MARKS: Oh, I had it right, pentaerythrityl. SPEAKER: Yes. DR. MARKS: Tetraisosterate and other pentaerythrityl esters. Boy, how can we make that -- PET, do you like that? That's what you suggested, Tom, didn't you?



5

DR. SLAGA: (inaudible) DR. MARKS: Okay, this is the first time we've seen this draft report. Scientific literature review is announced in February of this year. There were three compounds that were reviewed before that were safe, and then we have one that was insufficient. And that's on page 9 under the introduction here, and then we have 14 ingredients which are listed. So, is this technically a reopen? And add -- DR. ANDERSEN: We weren't playing that way. This was a de novo effort, new literature review, et cetera. So, since we've gone through that stack, it really doesn't matter what's in -- if you decide to add the pentaerythrityl tetraisononanoate, it would end up having the word "amended" in its title, but I don't really care. The tetraisononanoate and the tetrapelargonate have both been recently reviewed if you want to just come out and reference them. If you want to add them to create a package of tetra esters, yourselves out. DR. HILL: Well, the question I had was: Did we capture the data that allowed those conclusions to be made in this particular report? Because I'm not sure we did. And there are huge gaps in the toxicology data if we don't have information from that source in here. But we can use information with that source without having compound in here, can't we? DR. ANDERSEN: Yes. DR. HILL: Okay. DR. ANDERSEN: Yeah, and that's what I was suggesting, that there's no reason not to just reference those recent safety assessments and bring forward whatever we bring forward. But it's unlikely that there's anything in those reports. Wilbur, you can check me on this for certainly the pelargonate report, was the most recent. I don't think there were data on the pentaerythrityl moiety in there. MR. JOHNSON: I don't recall. DR. ANDERSEN: Yeah, it was all focused on -- MR. JOHNSON: Inorganic acids. DR. ANDERSEN: -- the inorganic acid side of it. And I think it's going to be same with the isononanoic and the cydanonanoic acid report and the focus would have been all on that side of the molecule. DR. MARKS: Yes. DR. ANDERSEN: And the reminder on the pentaerythrityl rosinate, which was the pentaerythrityl compound for which insufficient data was included, the only reason for that conclusion was the rosinate part of the molecule. So, it's not an informed safety assessment at all. DR. MARKS: So, let's proceed in terms of the 14 ingredients listed on the top of page 9, is there one we want to use as a lead or do we want to use one of these previously reviewed esters as a lead? And then is there any of that 14 you want to eliminate?



6

DR. HILL: The only thing that I entertained for elimination were the ones that had benzoate esters. I just entertained the notion only because it brings in UV and photosensitization and that sort of issue that doesn't exist with the others. DR. MARKS: Yes, I had that question in my own, the photo of the benzoate since it absorbs light. DR. SHANK: Two hundred seventy-five. DR. MARKS: Two hundred seventy-five below what's -- but I thought it was a little higher, too, Ron, or is it just 275? I think it was up in the UV -- DR. SHANK: Well, benzoic acid -- DR. MARKS: Yes. DR. SHANK: -- is 275. I didn't go beyond that. DR. HILL: Well, it should be consistent with benzoic esters, I wouldn't expect it to be – DR. SHANK: Any different. These are not even soluble, are they? These are solids. Am I correct in that understanding? SPEAKER: These are salts? DR. SHANK: This is (inaudible)? DR. MARKS: Pardon? Yes, solid (inaudible) with very poor solubility in water and large molecule rates. DR. HILL: Except for tetraacetate, which is -- DR. SHANK: Right. DR. HILL: To me, wasn't sure why that was in here if there was a lot of toxicology data for it, then I thought it would be valuable, but it's not in use, according to our reports. Quite dissimilar in physical, chemical properties from the rest of them. DR. SHANK: Right. Unless it's already been reported, reviewed. I think it has. I would eliminate that one, the tetraacetate because it's quite different from the rest. DR. HILL: It's in the dictionary though? DR. SHANK: I assume it's in the dictionary. I didn't look it up. DR. HILL: Yes. Art's shaking his head yes. DR. MARKS: So, you would eliminate the tetraacetate, the first one in there? Ron Shank? DR. SHANK: Yes, because all the others are crystals or solids.



7

DR. MARKS: Yes. DR. SHANK: That one is not. Or that one is soluble. There's probably some absorption. I looked up the PK. What is it? DR. HILL: The molecular weight is only 300, and I think we have a log P, but I think we surmised that it would be in a range that would allow absorption whereas many of the others are a lot higher. DR. SHANK: Yes. DR. HILL: Well, all of the others, I think, are a lot higher. DR. SLAGA: Would eliminating that then be (inaudible)? DR. SHANK: Yes. DR. HILL: That's what I think. DR. MARKS: Okay. DR. HILL: But we really do need to capture those (inaudible) already reviewed in terms of whatever toxicology is available because there's not a lot to go on, otherwise -- DR. MARKS: Do we want to combine them, Ron, on the report? DR. ANDERSEN: Well, the downside is, doesn't that mean the fact that we are reopening the ones that are already put to bed? DR. MARKS: Yes. Alan said he didn't really care which way, right? DR. ANDERSEN: I think you can do it -- DR. HILL: If it's going to be safe, it doesn't matter, right? DR. ANDERSEN: Yes. 174 DR. MARKS: Yes. DR. ANDERSEN: The benefit of adding the tetraisononate and the tetrapelargonate is that now you have all of the tetra esters of pentaerythritol. DR. MARKS: Yes. DR. SHANK: Do we need any information on the pentaerythritol itself? Is that likely to be hydrolyzed off or is there so much (inaudible)? DR. HILL: I think I made a note in here that we didn't have any information on that tox. I doubt that significant quantities of that free molecule are made. Yes, I wrote in here need to add toxicology on pentaerythritol. DR. SHANK: I had that as a question. DR. MARKS: Is that any reason not to move forward? No, okay. So -



8

DR. SHANK: So, make it insufficient rather than safe. DR. MARKS: Well, that's what I -- DR. SHANK: (inaudible) forward. DR. HILL: I don't expect anything on the toxicology to cause any problems from pentaerythritol, and however we have any information, to suggest that that even's formed. I mean, I didn't see anything one way or another. DR. MARKS: In these previous reports in which the pentaerythritol, the isononate, and the pelargonate was that addressed at all in those reports? DR. HILL: This is a case where I ran out of time to finish my homework. DR. MARKS: So, those were determined to be safe. DR. SLAGA: Safe as used. DR. MARKS: And, of course, it's the same issue as for those two ingredients. DR. SLAGA: Right. DR. MARKS: And somehow either that was overlooked or -- DR. HILL: Well, we can find that out today, right? Find those reports and see if it's mentioned. I know this is not your report, Christina, and I'm looking at you and you're -- we get copies of those reports. MS. BURNETT: Alan, are you online or? DR. ANDERSEN: Well, I can access them electronically to look at it. I don't have any way of -- DR. HILL: Right, right. DR. ANDERSEN: Sending somebody back to the office, but -- DR. HILL: In general, is that issue (inaudible) and put to bed? DR. MARKS: So, there would be 13 ingredients in the top. We eliminate the tetraacetate, we're going to include the first two that have already been declared safe, the two tetras. How about the cocoate? Do we want to include that in this report or do we want to leave that freestanding? DR. SHANK: I would put it in. DR. MARKS: Okay, so that makes now a total of 16 compounds, and then are we going to just leave the rosinate separate because that's sufficient or do we include that in this and confirm the insufficient because



9

of the rosinate moiety? Now, up above, we eliminated the tetraacetate. I guess with this one, we could just eliminate this by saying leave the report stamped. DR. SHANK: Well, if this is a crystal -- DR. ANDERSEN: It is a (inaudible) ester. DR. MARKS: Yes. DR. ANDERSEN: The rosinate just doesn't fit this. DR. MARKS: Right, and the cocoate, that's not a tetraester, is it? DR. ANDERSEN: I think my guess would be yes. Bart and I had this discussion. It could be. DR. MARKS: Oh, okay, could be. DR. ANDERSEN: Yes, but a question of how much depends on just the stoichiometry of how it was made and how of it depends on the stearic influence? If you can make the tetra benzoate, I have to believe you can fill almost anything in there. DR. SHANK: Yes. DR. MARKS: Okay. Then that would be 16 -- DR. ANDERSEN: But the dictionary is silent -- DR. SHANK: Okay. DR. ANDERSEN: On whether it's a monoester, diester, trimester, tetraester. DR. SHANK: But it is it insoluble because we did not ask for much toxicity data because these things aren't soluble. DR. MARKS: Of course, once we include this and it's already been determined to be safe previously, presumably, that would continue whether it's a solid or not, right, Ron? So, even though in the discussion the reason we're saying the top 13 are safe because they are solid crystal materials which aren't going to be absorbed, if this one was amino and it was absorbed, it's already determined to be safe, presumably. DR. HILL: Yes, and it's an interesting question because if you have let's see three out of the four hydroxyls derivatized, then you still have a very (inaudible) molecule probably in occluded hydroxyl, but if you had just one of the four, now you have a long chain molecule with polar head group, it'd look a lot like an inositol a couple hydroxyls short. So, I think that had very different characteristics, I'm guessing. So, this is a case where I should have drilled down that report for that molecule and read it cover to cover, which I'm going to admit right this second I did not get to do. DR. MARKS: So, do we want to include the cocoate? DR. HILL: I think we should.



10

DR. MARKS: Yes. Is that okay, Ron Shank and Tom, and then so now we're up to 16. What do we want to do with the rosinate? That's not even a tetra, right? DR. ANDERSEN: Yes, I don't think it belongs in this report. We just wanted you to be aware that there was one for which a red flag had been raised. DR. MARKS: Okay. DR. ANDERSEN: But the red flag is tagged to the rosinate part. DR. MARKS: Safe, it would be a tentative report. DR. SHANK: Well. DR. MARKS: I'm sorry. DR. SHANK: What did we decide about data needed for erythritol? DR. MARKS: Well, we're defining that. DR. ANDERSEN: I'm still -- DR. SHANK: You're still (inaudible). Because it's not -- DR. ANDERSEN: Well, the question is whether it's relevant even or not. I mean, that's -- DR. SHANK: Yes. DR. ANDERSEN: There's no question that pentaerythritol or anything that gets into the body is going to be formed. That's one of the quick metabolites. DR. HILL: Well, do we know that because we don't have that question. We have a conjecture from this report. DR. SHANK: It's surmised that -- DR. HILL: It's surmised, but I'm not sure I agree with that surmise. DR. ANDERSEN: I think that (inaudible) with the esterase attackable? DR. HILL: The question is whether -- DR. SHANK: Sterically. DR. HILL: -- a sterically crowded molecule is accessible to esterases or not. DR. ANDERSEN: Good point. DR. HILL: My guess would be maybe not.



11

DR. ANDERSEN: Which would argue that it's (inaudible). DR. HILL: But that's my next question, do we have information one way or another to -- DR. ANDERSEN: So far, for the isononate report, there is nothing to inform that discussion. DR. HILL: And, I mean, and a related question is, and I gather it's an issue because these are crystalline, are there monoacyl, diacyl, triacyl impurities in any of these and is that concern -- and I think there's no concern. DR. SHANK: How about erythritol impurity? Not as a metabolite, because if it's solid, it won't pass through the skin, but this is made from erythritol, so that is an impurity. That could -- DR. HILL: And I don't know -- DR. SHANK: -- be pretty polar. DR. HILL: I just think in the back of my head without -- I don't think pentaerythritol presents any serious toxicological issues in the kinds of amounts that would be generated either with impurity or a metabolic generation, but I'm not sure. I just don't think so. DR. SHANK: Because these are used up to 50 percent. DR. HILL: Certainly, the molecular weights and lipophilicity suggests that they'll be some layers of the skin could be penetrated. And then the question is: Does that matter? Which is why I think one of the reasons I asked about pentaerythritol itself. DR. MARKS: Probably, you aren't defining anything in the pelargonate either. DR. ANDERSEN: Not so far. DR. MARKS: Yes. DR. ANDERSEN: But I think from just the part of the discussion in which you said gee, the benzoate tetraester ought to have some solid UV absorption data, and right now, we've got some (inaudible) maybe the absorption is at the lower end. If it's below solar UV cutoffs, but wouldn't we rather have those data? DR. SHANK: I don't see the need. SPEAKER: No, I don't. DR. ANDERSEN: Okay. DR. MARKS: So, I guess we're at this point, do we want to have an insufficient or the PET portion of this molecule, the toxicology, or do we want to just move forward with safe and feel that the toxicology of that pentaerythritol is unlikely to be a problem?



12

DR. SLAGA: Unlikely to be a problem because there's insolubility, right? DR. SHANK: Yes, though this is the pentaerythritol itself. DR. SLAGA: Oh, itself. DR. SHANK: Just not the -- DR. MARKS: Yeah, Ron brought up the issue of that. DR. HILL: Either metabolite or -- DR. SHANK: Well -- DR. HILL: I just don't -- DR. SHANK: I don't think it'd get through the skin to be metabolized, but it might be as an impurity. DR. HILL: There are esterases in the skin that can handle lipophilic substances, the molecular weights are not huge for some of these. DR. SHANK: Right, I don't think you'll get to viable skin. DR. HILL: Why do you think that? DR. SHANK: Because they're crystals. DR. HILL: But not once it's in a formulation. DR. SHANK: Well, my understanding is these are solids. DR. HILL: But once it's in some cream or some oil, it's not going to be solid anymore. DR. SHANK: Well, (inaudible)impurities. DR. HILL: As soon as it's in an oil-based formulation or an emulsion-based formulation, there's no reason to think it will stay solid. It's not like silica-based polymers. These will definitely dissolve in the oil. DR. ANDERSEN: You sure it can dissolve in water? DR. HILL: No, sir. DR. MARKS: And, certainly, some of them have a lot of uses, particularly on leave-on here in the hundreds. DR. HILL: Yes.



13

DR. MARKS: So, if you're saying that, we go right -- initially, it was can we indicate these are safe because they aren't being absorbed? Are we changing that now? DR. SHANK: Well, Ron Hill says they can be solubilized in formulation. So, I misunderstood. I thought that these were solids that are used in mudpacks and pastes and things that there would be no penetration of the stratum corneum. So, you don't have a toxicity to consider. If that's not the case, then I'll have to look at this all over again. DR. HILL: Yes, eye shadow, eyeliner, lotion, mascara, blushes, foundations, lipstick, lotions, creams, all of those. DR. MARKS: So, presumably, again, those were with (inaudible) tetra compounds that were already declared safe. Is there a lot more data to substantiate in terms of reproductive, so and 20 so forth, that we can rely on the data? DR. ANDERSEN: Well, there's nothing to fall out of the pentaerythritol isononate or the pentaerythritol tetrapelargonate reports to inform the pentaerythritol part of the molecule. Tons of data to inform the other side. DR. SHANK: Okay. DR. ANDERSEN: So, pentaerythritol is a concern those data are largely MIA. DR. HILL: And the answer is no, the ones I've just mentioned are not previously reviewed. DR. MARKS: So, we get into the read across of these tetras. Because I think, Ron Shank, you were feeling we could just arrive at a safe based on lack of penetration absorption. DR. SHANK: Right. DR. HILL: My thinking is that -- DR. SLAGA: Even if it was in a cream, wouldn't it still be relatively -- and it would still be -- DR. MARKS: Do we have any absorption data on the isononate and the pelargonate? DR. ANDERSEN: No. DR. MARKS: No. DR. ANDERSEN: The discussion of absorption for both of those related to log Ps of greater than 5 would be expectation that there wouldn't be significant dermal penetration. DR. SHANK: So, we end up in the same place. DR. ANDERSEN: (inaudible) less likely. DR. MARKS: Yes. So, that's, again, in the same rationale for these



14

others if we're going to use that. DR. SHANK: Yes. DR. HILL: And I don't -- DR. MARKS: Since we are going to combine that -- DR. HILL: Okay, I don't buy it. DR. MARKS: That would lend more credence to why we should combine these together. But I get a sense of a hesitancy to come to a conclusion of safe. And if we're going to do insufficient, then what do we need as our data points? DR. HILL: I'm just interested in stability data resistance that esterases and lipases. DR. SLAGA: But don't they have to be relatively solubilized to enzymes to do that? I -- DR. HILL: And I'm saying the molecular weights are such and that they're not that huge. I mean, they're several of them -- DR. SLAGA: Well, you have to (inaudible) sight of the enzyme to -- DR. HILL: There are lipases in the upper layers of skin in sebaceous glands and -- DR. SLAGA: Yes, but you still have to get into that. DR. HILL: And the log Ps are not that high and molecular weights are not that high., so, I think it's feasible. I don't think that presents any issues because I don't think there any issues with the amounts of pentaerythritol we're talking about. And, so, my sense was you'll probably find that we do lack any information on that at the present time. Of course, tomorrow, the other team, they may have done a little more homework and could answer those questions. DR. MARKS: Well, but we need to make a conclusion as to how we're going to move forward. So, are we going to go with safe or insufficient? And if we go with insufficient, do we want more on the pentaerythritol toxicology or do we go with safe and say it's unlikely to be significantly absorbed? DR. HILL: The problem that I have with the pentaerythritol is I'm pretty sure that information is out there to be captured, and we just didn't capture it in the report, which means we're not lacking the information; we just lack to bring homework. But on the other hand, if we question whether that's an issue in terms of an impurity of whether we have a mono-, di-, or triacyl, whether that's potential issues, then I think we lack some information. The lack of information on impurities, the lack of information on resistance to esterases and lipases. I think that's it for penetration and to any layers of the skin whatsoever. We could show lack of dermal penetration in art of use, that would be okay from where I sit, too.



15

DR. MARKS: Tom? DR. SLAGA: Well, I still would go with safe. DR. MARKS: Safe. Okay. Ron Shank? DR. SHANK: And that's taking tetraacetate out, right? DR. MARKS: Yes. Yes. DR. SHANK: I would go along with safe, too. As long as we include those other ones that have already been reviewed. DR. MARKS: Right. So, we would have 13 new ingredients and we would have the previous 3 that have been reviewed and are safe combined into one report. Do you want me to, Ron, call on your tomorrow and discuss your concerns? DR. SHANK: Yes, because that will give the people on the other group an opportunity to render an opinion. DR. MARKS: Sure. Ron Hill. I'm going to ask for you then to give -- even though, presumably, we're going to second a safe, we'll see, and we don't know what the other team decided. But concerns. They'll ask you to annunciate your concerns. DR. ANDERSEN: Ron, a question on the pentaerythritol issue. The search strategy is mapped out on Panel Books 4 and 5. Pentaerythritol is one of the search terms. So, thinking maybe there isn't stuff out there. You can look at what the search strategy was, but -- DR. HILL: If I had a computer, I would type pentaerythritol into Wikipedia and see because I think it's used in pharmaceutical formulations, or, I mean, it may be in food stuff. I guess -- DR. MARKS: Any rate, what we'll do is, , I'll call on you, and if you that tonight and get no concerns then -- DR. SHANK: Okay. DR. MARKS: You can just say no, I resign this. DR. SHANK: I will take it upon myself. DR. MARKS: So, we would issue a tentative report -- DR. ANDERSEN: Which I should have done before I got here. DR. MARKS: -- reopening 3 previous ingredients and adding 13 more with a conclusion that these are safe. Okay. Next is the aerosol precedent review. That's in Buff Book? This is the inhalation boilerplate? DR. SHANK: Yes. It's okay with me. DR. SLAGA: Looks good to me, too.



16

DR. MARKS: Lillian isn't here. The only thing I question when I read it, and it'll be in my book, this is on page 14 of buff book one. DR. SLAGA: Yes. DR. MARKS: I guess words like "around 38 micromillimeters," I guess that was whether "around," and then there was "most" and then "typically" and "generally," and I guess I kind of wondered whether those are sort of vague ways. Like, "However, the particle sizes produced by cosmetic aerosols are typically not respirable." Now, if they aren't "typically," what happens to the ones that are? And in the re-review, its summary, it says "because aerosols from these products are generally not respirable." Well, if I'm using "generally," how about the ones that are? Am I worried about that? So, I don't know, can react to that. To me, when I read those, I was thinking okay, well, they may not be most of the time, but it's like if you drove a car, if your brakes typically work, how about once when they don't work? I think Toyota, that was what made the news. (Laughter) So, I guess that's wordsmithing, but I had a little bit of a question about that. MR. BOYER: Well, I wrote this. DR. MARKS: Oh, good, we have the author here. MR. BOYER: And, basically, it started with the older or boilerplate as the basis and sort of preserve some of that language. And we were at a disadvantage because we didn't have copies of all of the references that this information was based on. Since then, we've got reference that suggests that aerosols in hairsprays in any case averaged about 38 microns, the distribution looks like it does not extend below about 10 microns or so. So, that looks pretty good. We've got another reference that came in just last Friday from Germany that more or less supports that distribution. Now, that's from hairsprays. It's not for the antiperspirant sprays. Those tend to be much, much finer. So, I mean, it's difficult to talk about aerosols in a general way because it depends so much on not only the median or the average particle size, but it also depends on the distribution and the variation of the particle sizes and so forth. So, for the purpose of the boilerplate, were going for the generalities, we're going for the basic principles, for which there's a very large body of literature out there as the basis. And we can clear up some of the ambiguities by looking at the primary references. DR. MARKS: Okay. Without being overly reactive when I saw that, did I have some respiratory irritation when I read that? DR. SLAGA: Not a perfect world. DR. MARKS: Not a perfect world, yes, for sure. I guess when we say okay, we're going to say that this is safe and we're just going to put on a respiratory or inhalation boilerplate, if I were reading this, would I feel reassured? We need Rachel in here maybe. But at any rate, I'll let you -- was I overly sensitive when I read that? DR. SLAGA: Well, the "around" and -- DR. MARKS: Yes, the "around," I put approximately.



17

DR. SLAGA: That's above or below. I mean that's an average. SPEAKER: You have a range. DR. MARKS: Yes. DR. SLAGA: It's a range. DR. MARKS: That one, you addressed. Okay. DR. ANDERSEN: It's interesting, the different perspectives. DR. MARKS: Yes. DR. ANDERSEN: As I look at it from the side of the devices where the evaluation was what do you have to do in order to create respirable particles? It's hard. So, I kind of relax on a look at an aerosol can with hairspray in it or a pump that's going to produce spray and is (inaudible) technology standpoint. DR. MARKS: And I guess I might go back to it instead of the way it's worded under discussion, however, the particles sizes, there are not enough particles of the sizes that are respiratory or something. I don't know. It's sort of saying okay, there may be a few that are down there, but they're not enough to make any difference. That was -- DR. HILL: Well, some mention of the distribution -- DR. MARKS: Yes, that might be helpful. DR. HILL: -- (inaudible) be there. DR. MARKS: Okay. DR. HILL: But it says 99 percent will be in the (inaudible), that's it. DR. MARKS: Right. DR. HILL: That captures it. DR. MARKS: Yes. Okay. Let's see, inaudible). Let's move onto the priority list.

DAY 2

DR. BELSITO: Okay. So, the pentaerthrityl tetraisostearate group, this -- some of these have been previously reviewed and found safe as used, and then there are a number of other related chemicals that were asked to look at at this meeting. And my team felt that in the -- that if you look at the 15 ingredients that are listed in the report that would be new, not 14 as the report states, the pentaerthrityl isostearate is missing from that list on page 2, Panel Book page 9. Of those we felt that all of them could be included with the exception of the tetraacetate. Dan felt that the tetraacetate molecule might be wagging that dog's tail, unless you've changed your mind?



18

DR. LIEBLER: Well, no, it's just -- it's much lower molecular weight, much different in solubility than the other compounds, which are longer chain. DR. BELSITO: Okay, so we would do all of them except the tetraacetate and include the isostearate missing from that list. My group is also under the feeling that even though there were others that have been reviewed and approved, we should make sensible groups, and, therefore, even though these may not be up for re-review, wanted to add back into this group the pentaerthrityl tetraisononanoate and the tetrapelargonate, as well as the cocoate. The rosinate raises issues separate and has always provided problems, so we would not include the rosinate. That would need to be done under a rosin group. So, we'd include 14 of the 15 that were originally proposed, not the tetraacetate, and the 4 -- or 3 ingredients that have been previously found to be safe, but we would keep the rosinate out of this group and go with a safe as used conclusion. DR. BERGFELD: And that's a motion? DR. BELSITO: That's a motion. DR. MARKS: We second that motion. This would be a tentative report, then. DR. BERGFELD: A tentative report. Any other discussion? DR. BELSITO: Yes, I'd like Ron Hill to comment. He had some concerns and just so the Panel hears this. DR. HILL: Yeah, the question that we didn't have any data to address was are their either impurities, monoacyl, diacyl, triacyl, that are present in the products as produced, or can either lipases or esterases in the upper layers of skin cleave these? I don't know that there are any deleterious consequences of that cleavage, but if the cleavage was down to a monoacyl or diacyl, a possibility where these could be have as analogues of diglycerides. And so we don't have any information as to whether that cleavage can occur by esterases or lipases, we don't have any information as to diacyl, monoacyl, triacyl impurities in the products. And whether that has any relevance to anything is unclear. And I didn't make that as an insufficiency, but rather a literature search need yesterday that we were going to try to identify what's known about that. DR. BERGFELD: Dan. DR. LIEBLER: So, maybe Ron and I should develop a parking lot of unanswered interesting questions about metabolism of chemicals of the skin. This would be one of the entries. DR. HILL: And also that the report didn't have anything about pentaerythrityl toxicology in there which is perhaps not even relevant. So, the question was, is it relevant? Actually, since yesterday I got a little information because my sense was that there isn't a toxicology problem with pentaerthrityl and this information seems to confirm that. DR. BERGFELD: Thank you. So, we're going to move on. We voted?



19

DR. ANDERSEN: No. DR. BERGFELD: No, we didn't vote. Okay, I'm sorry. I got all taken up with the discussion. All those in favor then of this approval? Thank you very much, unanimous.



Rep

ort

Final Report

Pentaerythrityl Tetraisostearate and Other Pentaerythrityl Esters as Used in Cosmetics

September 26, 2011 The 2011 Cosmetic Ingredient Review Expert Panel members are: Chair, Wilma F. Bergfeld, M.D., F.A.C.P.; Donald V. Belsito, M.D.; Ronald A. Hill, Ph.D.; Curtis D. Klaassen, Ph.D.; Daniel C. Liebler, Ph.D.; James G. Marks, Jr., M.D.; Ronald C. Shank, Ph.D.; Thomas J. Slaga, Ph.D.; and Paul W. Snyder, D.V.M., Ph.D. The CIR Director is F. Alan Andersen, Ph.D. This report was prepared by Lillian Becker, Scientific Analyst/Writer.

© Cosmetic Ingredient Review 1101 17th Street, NW, Suite 412 " Washington, DC 20036-4702 " ph 202.331.0651 " fax 202.331.0088 "

[email protected]



ii

TABLE OF CONTENTS TABLE OF CONTENTS .................................................................................................................................................................................................................. ii

ABSTRACT ...................................................................................................................................................................................................................................... 1

INTRODUCTION ............................................................................................................................................................................................................................. 1

CHEMISTRY .................................................................................................................................................................................................................................... 1

Definition and Structure .............................................................................................................................................................................................................. 1

Physical and Chemical Properties ............................................................................................................................................................................................... 1

Method of Manufacture ............................................................................................................................................................................................................... 1

Impurities ..................................................................................................................................................................................................................................... 2

UV Absorption ............................................................................................................................................................................................................................. 2

USE .................................................................................................................................................................................................................................................... 2

Cosmetic ...................................................................................................................................................................................................................................... 2

Non-Cosmetic .............................................................................................................................................................................................................................. 3

TOXICOKINETICS .......................................................................................................................................................................................................................... 3

Absorption, Distribution, Metabolism, and Excretion ................................................................................................................................................................ 3

TOXICOLOGICAL STUDIES ......................................................................................................................................................................................................... 3

Acute Toxicity ............................................................................................................................................................................................................................. 3

Dermal .................................................................................................................................................................................................................................... 3

Oral – Non-Human ................................................................................................................................................................................................................. 3

Inhalation ................................................................................................................................................................................................................................ 3

Repeated Dose Toxicity ............................................................................................................................................................................................................... 4

Dermal – Non-Human ............................................................................................................................................................................................................ 4

Oral and Inhalation ................................................................................................................................................................................................................. 4

REPRODUCTIVE AND DEVELOPMENTAL TOXICITY .......................................................................................................................................................... 4

GENOTOXICITY ............................................................................................................................................................................................................................. 4

In Vitro ......................................................................................................................................................................................................................................... 4

In Vivo ......................................................................................................................................................................................................................................... 4

CARCINOGENICITY ...................................................................................................................................................................................................................... 5

IRRITATION AND SENSITIZATION ........................................................................................................................................................................................... 5

Irritation ....................................................................................................................................................................................................................................... 5

Dermal – Non-Human ............................................................................................................................................................................................................ 5

Dermal and Mucosal -Human ................................................................................................................................................................................................ 5

Ocular ..................................................................................................................................................................................................................................... 5

Sensitization ................................................................................................................................................................................................................................. 5

Dermal – Non-Human ............................................................................................................................................................................................................ 5

Dermal – Human .................................................................................................................................................................................................................... 5

Phototoxicity ................................................................................................................................................................................................................................ 5

SUMMARY ...................................................................................................................................................................................................................................... 5

DISCUSSION ................................................................................................................................................................................................................................... 6

CONCLUSION ................................................................................................................................................................................................................................. 6

TABLES ............................................................................................................................................................................................................................................ 8

REFERENCES ................................................................................................................................................................................................................................ 14



1

ABSTRACT The Cosmetic Ingredient Review Expert Panel reviewed the safety of 16 pentaerythrityl tetraester compounds used in cosmetics, including the widely used pentaerythrityl tetraisostearate. The functions of these ingredients include: hair conditioning agents; skin-conditioning agents – miscellaneous; binders; skin-conditioning agents - occlusive; viscosity increasing agents - nonaqueous; and skin-conditioning agents – emollient. The Panel reviewed available animal and human data related to these ingredients along with previous safety assessments of the fatty acid moieties. The Panel concluded that of pentaerythrityl tetraisostearate and the other pentaerythrityl tetraester compounds were safe as cosmetic ingredients in the practices of use and concentration as given in this safety assessment.

INTRODUCTION This tentative safety assessment summarizes published and unpublished data relevant to the safety of pentaerythrityl

tetraisostearate and other pentaerythrityl tetraester compounds used in cosmetics. These 16 ingredients are:

Pentaerythrityl tetraisostearate Pentaerythrityl tetra C5-9 acid esters Pentaerythrityl tetra C5-10 acid esters Pentaerythrityl tetracaprylate/tetracaprate Pentaerythrityl tetralaurate Pentaerythrityl tetramyristate Pentaerythrityl tetrastearate Pentaerythrityl tetrabehenate Pentaerythrityl tetracocoate

Pentaerythrityl tetraoleate Pentaerythrityl tetraethylhexanoate Pentaerythrityl tetraethylhexanoate/ benzoate Pentaerythrityl tetrabehenate/

benzoate/ethylhexanoate Pentaerythrityl tetrabenzoate Pentaerythrityl tetraisononanoate Pentaerythrityl tetrapelargonate

The functions of these ingredients include: hair conditioning agents; skin-conditioning agents – miscellaneous; binders; skin-

conditioning agents - occlusive; viscosity increasing agents - nonaqueous; and skin-conditioning agents – emollient. Two of these ingredients previously were reviewed by the Cosmetic Ingredient Review (CIR) Expert Panel in another safety

assessment. Pentaerythrityl tetraisononanoate and pentaerythrityl tetrapelargonate, were determined to be safe in the present practices of use and concentration.1 These 2 ingredients were added to this report to so that all of the reviewed pentaerythrityl tetraesters would be in one report.

In addition, the CIR Expert Panel has issued safety assessments of most of the component fatty acid component of these ingredients, including coconut, isostearic, oleic, lauric, myristic, and stearic acids. These are the esterase metabolites that would result from pentaerythrityl tetracocoate, pentaerythrityl tetraisostearate, pentaerythrityl tetraoleate, pentaerythrityl tetralaurate, pentaerythrityl tetramyristate, and pentaerythrityl tetrastearate, respectively. In previous safety assessments, CIR determined that these fatty acids are safe in the present practices of cosmetic use.2-4 Benzoic acid (a metabolite of pentaerythrityl tetrabenzoate, pentaerythrityl tetraethylhexanoate/benzoate, and pentaerythrityl tetrabehenate/benzoate/ethylhexanoate) was determined by the CIR Expert Panel to be safe for use in cosmetic formulations in the present practices of use and concentration at the CIR Expert Panel meeting on June 27-28, 2011. This revised the earlier safety assessment of Benzoic Acid.5

CHEMISTRY

Definition and Structure The pentaerythrityl tetraesters have a core pentaerythritol moiety that is esterified with 4 monobasic fatty acids. For example, pentaerythrityl tetraisostearate consists of a pentaerythritol core, esterified with 4 stoichiometric equivalents of isostearic acid (Figure 1).

The CAS Nos., definitions, functions, and structures of these ingredients are provided in Table 1.

Physical and Chemical Properties The physical and chemical properties of the pentaerythrityl tetraester ingredients in this safety assessment are provided in

Table 2. The pentaerythrityl tetraesters, as a group, are solid crystalline materials. These ingredients have very poor solubility in water and have large molecular weights (too large to pass through the dermal layer). Pentaerythrityl tetra C5-9 acid esters has an estimated Log Pow of 16.7.

Method of Manufacture

Pentaerythrityl tetraesters can be prepared from pentaerythritol by alcohol esterification methods (e.g., by reaction with acids, acid chlorides, or acid anhydrides).6 For example, pentaerythritol tetrastearate can be manufactured by heating stearoyl chloride and pentaerythritol (4:1 ratio) at 100ºC, under 2 mmHg.7 The resulting product can then be recrystallized from chloroform to form a pure product. A greener, biocatalytic process developed specifically for the manufacture of esters for use in the formulation of cosmetic ingredients (i.e., for producing cosmetic grade esters), also has the potential for the manufacture of these ingredients.8



2

Figure 1. Pentaerythrityl tetraisostearate

Impurities Pentaerythrityl tetra C5-9 acid esters was reported by one source to be 100% pure.9,10 Another source, however, reported 81% purity with the other 19% comprised of carboxylic acids and dipentaerythritol C5-9 hexaesters.11

UV Absorption While no UV absorption data on the ingredients in this safety assessment were available, most of the ingredients included in

this review would not be expected to have any meaningful ultraviolet (UV) absorption (i.e. no detectable absorption in the UVA and UVB bands). The alkyl carboxyl groups found in most of these ingredients would be expected to absorb in the UVC band, as would the non-conjugated alkenyl groups of pentaerythrityl tetraoleate. However, the aromatic, conjugated carboxyl groups present in pentaerythrityl tetrabenzoate, pentaerythrityl tetraethylhexanoate/benzoate, and pentaerythrityl tetrabehenate/benzoate/ethylhexanoate would be expected to have some meaningful UV absorption.

USE Cosmetic

Data on ingredient usage are provided to the Food and Drug Administration (FDA) Voluntary Cosmetic Registration Program (VCRP) and a survey conducted by the Personal Care Products Council (Council) has collected use concentrations for ingredients in this group.1-4 The total number of VCRP reported uses of pentaerythrityl tetraisostearate was 532 for leave-on and 9 for rinse-off products and the Council survey found that pentaerythrityl tetraisostearate was used at 0.1% - 55% (highest concentration in lipstick) in leave-on products and 0.1% in paste masks (mud packs) a rinse-off product. Table 3 summarizes the VCRP and Council survey data for all ingredients in this group. Pentaerythrityl tetracaprylate/tetracaprate was reported to be used in 23 leave-on products at 0.07% - 5%. Pentaerythrityl tetraethylhexanoate was reported to be used in 224 leave-on products at 0.06% - 50% and 17 rinse-off products at 1% - 20%. Pentaerythrityl tetraethylhexanoate/benzoate was reported to be used in 4 leave-on products at 40%. Pentaerythrityl tetrabehenate was reported to be used at 2% – 3% in 8 leave-on products. Pentaerythrityl tetrapelargonate is reported to be used in one hair product by the VCRP and at 0.5% in makeup bases. Pentaerythrityl tetrabehenate/benzoate/ethylhexanoate was reported to be used in 7 leave-on products at 2% to 16% and in rinse-off products at 0.5% to 16%. Pentaerythrityl tetrastearate was reported to be used at 7%. The VCRP has no uses reported for these ingredients. VCRP reported 1 leave-on use of pentaerythrityl tetralaurate. The Council reported that pentathrityl tetraisononanoate is used in leave on produts at 1% to 2% in eye lotion and body and hand lotions. There were no reports to the VCRP or the Council survey of use for pentaerythrityl tetra C5-9 acid esters, pentaerythrityl C5-10 acid esters, pentaerythrityl tetramyristate, pentaerythrityl tetracocoate, pentaerythrityl tetraoleate, and pentaerythrityl tetrabenzoate. Pentaerythrityl tetracaprylate/tetracaprate is used in hair sprays and could be inhaled. The average particle size of aerosols from aerosol hair sprays is around 38 μm, with particle sizes > 60 µm and >80 μm reported for aerosol and pump hair sprays,



3

respectively. These particle sizes are considerably larger than the sizes of respirable particles (≤10 µm). Thus, most aerosol particles inhaled during hair spray use are deposited in the nasopharyngeal region, and do not enter the deeper, absorptive surfaces of the lungs.

Non-Cosmetic Pentaerythrityl tetraesters are used in lubricating oils of jet engines, low-temperature use grease, heat-resistant engine oil, and

refrigerator oil.15 Pentaerythrityl tetrastearate is an indirect food additive that may be used to make food packaging.16 It may also be used in

cellophane that comes in contact with food with a limit of 0.1%.17 Pentaerythrityl fatty acids may be used as defoaming agents in paper and paperboard intended for food use.18

TOXICOKINETICS

Absorption, Distribution, Metabolism, and Excretion There were no experimental data discovered on the toxicokinetics of pentaerythritol tetraesters. However, due to the large size of the molecules and the low Pow of pentaerythrityl tetra C5-9 acid esters, it is not expected that these ingredients would penetrate the skin. For example, pentaerythrityl tetrapelargonate has a log P > 5, a molecular weight > 500, and low solubility so is not likely to penetrate the skin.

Should these ingredients enter the body by other routes, metabolism of the pentaerythrityl tetraesters in mammals would be expected to occur initially, via esterases, to the corresponding free acids (e.g., stearic acid is a potential free acid metabolite of pentaerythrityl tetrastearate), partially esterified mono-, di-, and triesters, (e.g. pentaerythrityl stearate, etc.) and free pentaerythritol.19 These tetraesters may be subject to slower rates of enzymatic hydrolysis due to steric hindrance. However, metabolite formation would be expected to happen at some point over a period of time. The free pentaerythritol and free acids can be further metabolized or conjugated to polar products that are excreted in the urine.

Available data on pentaerythritol do not raise toxicological concern. For example: The oral LD50 for mice and guinea pigs was 25,500 and 11,300 mg/kg, respectively.20 Rats survived oral doses up to 16,000 mg/kg. Rats fed pentaerythitol (0.2. 1.0, and 5%) in the dry diet for 90 days had severe diarrhea, enlarged cecums and increased cecum to body weight ratios in high dose group and no effects were observed in the mid and low dose groups. Inhalation exposure of rats to pentaerythitol dust (11 mg/m3) for a single 6-h period caused no effects. Rats, guinea pigs and dogs inhaling pentaerythitol dust (8 g /m3) for 6 h/d for 90 days had no observed adverse effects. Also, orally administered pentaerythritol (1000 mg/kg/d) for 28 days was not toxic to F344 rats.21 In addition, pentaerythitol tetranitrate, is used as an in vivo nitrate delivery system for patients as a prophylaxis of attacks of angina pectoris.22

A literature search did not uncover any data on possible mono-, di-, or triesters of pentaerythritol. However, as noted earlier, coconut, isostearic, oleic, lauric, myristic, and stearic acids are the free fatty acid, esterase metabolites that would result from pentaerythrityl tetracocoate, pentaerythrityl tetraisostearate, pentaerythrityl tetraoleate, pentaerythrityl tetralaurate, pentaerythrityl tetramyristate, and pentaerythrityl tetrastearate, respectively. In previous safety assessment, CIR has determined that these fatty acids are safe in the present practices of cosmetic use.2-4 Benzoic acid (a metabolite of pentaerythrityl tetrabenzoate, pentaerythrityl tetraethylhexanoate/benzoate, and pentaerythrityl tetrabehenate/benzoate/ethylhexanoate) was determined by the CIR Expert Panel to be safe for use in cosmetic formulations in the present practices of use and concentration at the CIR Expert Panel meeting on June 27-28, 2011.23 This revised the earlier safety assessment of Benzoic Acid.5

TOXICOLOGICAL STUDIES Various oral pentaerythrityl tetraesters have been tested in single dose toxicity studies and found to not be significantly toxic – the lowest reported oral LD50 was greater than 1 g/kg. Pentaerythrityl tetra C5-9 acid esters had a NOAEL of 2000 mg/kg/day for rats for 13 weeks.

Acute Toxicity Dermal There were no dermal studies discovered for pentaerythrityl tetraesters. Oral – Non-Human PENTAERYTHRITYL TETRA C5-9 ACID ESTERS

Sprague-Dawley rats (n = 5/sex) were orally administered pentaerythrityl tetra C5-9 acid esters (1940 mg/kg).9,10 There were no deaths. One male had unformed stool at 4 h after administration. Necropsy was unremarkable at 15 days. Sprague-Dawley rats (n = 5/sex) had no deaths or clinical signs after oral gavage of pentaerythrityl tetra C5-9 acid esters (1940 mg/kg; 2.0 ml/kg).24 Necropsy was unremarkable at 15 days. PENTAERYTHRITYL TETRA C5-10 ACID ESTERS Wistar rats (n = 5/sex) were orally administered pentaerythrityl tetra C5-10 acid esters (5000 mg/kg).9,10 There were no deaths or clinical signs. Necropsy was unremarkable at 14 days. PENTAERYTHRITYL TETRABENZOATE The oral LD50 for pentaerythrityl tetrabenzoate was reported to be 1158 mg/kg in rats.25 Inhalation

There were no inhalation studies discovered for pentaerythrityl tetraesters.



4

Repeated Dose Toxicity Dermal – Non-Human PENTAERYTHRITYL TETRA C5-9 ACID ESTERS Pentaerythrityl tetra C5-9 acid esters (0, 800, 2000 mg/kg, neat) were dermally administered to clipped backs of Sprague-Dawley rats (n = 10/sex) for 5 days/week for 13 weeks.26 The test material was not covered but collars were used to prevent grooming of the area. The dermal bioavailability of the test article was 2% to 6%. Males in the high dose group weighed 10% less than the controls after 13 weeks and 7% in the low dose group. No effect on body weights occurred in females. There were no other signs of systemic toxicity. There was minimal skin irritation, mostly flaking with slight erythema, was observed in both treatment groups. Microscopic examination of the skin revealed very minor epidermal hyperplasia and chronic inflammation of the dermis. No differences were seen in sperm morphology at necropsy. Ovaries, testes, epididymides, uterus, and vagina showed no adverse effects. The NOAEL was 2000 mg/kg/day. Oral and Inhalation

There were no oral or inhalation studies discovered for pentaerythrityl tetraesters.

REPRODUCTIVE AND DEVELOPMENTAL TOXICITY Dermally applied pentaerythrityl tetra C5-9 acid esters had no effects on male or female reproductive organs in rats. There were no teratogenic effects up to 2000 mg/kg. PENTAERYTHRITYL TETRA C5-9 ACID ESTERS Pentaerythrityl tetra C5-9 acid esters (0, 800, 2000 mg/kg) were dermally administered to clipped backs of Sprague-Dawley rats (n = 10/sex) for 5 days/week for 13 weeks.26 There were no effects noted in sperm morphology. Gross necropsy and histopathology of the ovaries, testis, epididymides, uteruses, and vaginas were unremarkable. Pentaerythrityl tetra C5-9 acid esters (0, 800 or 2000 mg/kg/d) were applied to the clipped backs of Sprague-Dawley rats (n = 20) on days 0 – 19 of gestation.27 Neither maternal parameters (food consumption, body weight gains) monitored throughout gestation (days 0-19) nor reproductive parameters (number of implants, resorptions, or viable fetuses) were adversely affected by the test substance. No evidence of teratogenicity was observed by external examination of fetuses. Mean fetal body weights and crown-rump distances were similar in all groups.

GENOTOXICITY Pentaerythrityl tetra C5-9 acid esters and pentaerythrityl tetrabenzoate were not genotoxic in reverse mutation assays at 5000 µg/plate.

Aerosolized pentaerythrityl tetra C5-9 acid was not cytotoxic to red blood cell formation nor did it induce increased polychromatic erythrocytes PCEs or NCEs in the bone marrow of rats.

In Vitro PENTAERYTHRITYL TETRA C5-9 ACID ESTERS In a reverse mutation assay of pentaerythrityl tetra C5-9 acid esters (33.3, 100, 333, 1000, 3330, 5000 µg/plate) using Salmonella typhimurium (TA98, TA100, TA1535, TA1537) and Escherichia coli (WP2uvrA) with and without metabolic activation, the results were negative.28 Positive controls were 2-aminoanthracene and benzo[a]prene with metabolic activation. Positive controls, without metabolic activation, were sodium azide, 2-nitrofluorene and ICR-191. The controls had the expected results. In a reverse mutation assay using E. coli (WP2uvrA), pentaerythrityl tetra C5-9 acid esters (33.3, 100, 333, 1000, 3330, 5000 µg/plate) with and without metabolic activation, was not cytotoxic or mutagenic.29 The positive controls (2-aminoanthracen and 4-nitroquinoline-N-oxide) and negative vehicle controls (ethanol) had the expected results. In a microsome reverse mutations assay using S. typhimurium (TA98, TA100, TA1535, TA1537) and E. coli (WP2uvrA), pentaerythrityl tetra C5-9 acid esters (33.3, 100, 333, 1000, 3330, 5000 µg/plate) was not mutagenic with or without metabolic activation.11 PENTAERYTHRITYL TETRABENZOATE In a mutagenicity assay of pentaerythrityl tetrabenzoate (0.05 ml/plate) using S. typhimurium strains (TA97, TA98, TAl00, TAl535, and TA1537) was negative.30

In Vivo PENTAERYTHRITYL TETRA C5-9 ACID ESTERS A micronucleus assay was performed on male Sprague-Dawley rats (n = 10) that were exposed to aerosolized pentaerythrityl tetra C5-9 acid esters (0.5 mg/L) for 6 h/d, 5 d/week, for 2 weeks.31 The test material was not cytotoxic to red blood cell formation nor did it induce increased micronucleated polychromatic erythrocytes (PCE) or normochormatic erythrocytes (NCE) in the bone marrow.



5

CARCINOGENICITY There were no carcinogenicity studies discovered for pentaerythrityl tetraesters.

IRRITATION AND SENSITIZATION Pentaerythrityl tetra C5-9 acid esters were mildly irritating in rats at 800 mg/kg when administered dermally for 13 weeks.

Product testing with an eyeliner containing pentaerythrityl tetrabehenate at 1.705% for 4 weeks did not cause irritation. Pentaerythrityl tetrabehenate/benzoate/ethylhexanoate at 16.6% and pentaerythrityl tetraethylhexanoate/benzoate at 100%

were not sensitizing to guinea pigs. In 3 HRIPTs of cosmetic products, pentaerythrityl tetrabehenate, pentaerythrityl tetraisostearate, and pentaerythrityl tetracaprylate/tetracaprate were not sensitizing at 1.705%, 55%, and 5%, respectively.

Irritation Dermal – Non-Human PENTAERYTHRITYL TETRA C5-9 ACID ESTERS Pentaerythrityl tetra C5-9 acid esters (0, 800, 2000 mg/kg) were dermally administered to clipped backs of Sprague-Dawley rats (n = 10/sex) for 5 days/week for 13 weeks.26 Minimal skin irritation, mostly flaking with slight erythema, was observed in both treatment groups. Microscopic examination of the skin revealed very minor epidermal hyperplasia and chronic inflammation of the dermis. Pentaerythrityl tetra C5-9 acid esters (0, 800 or 2000 mg/kg/d) were applied to the clipped back of Sprague-Dawley rats (n = 20) on days 0 – 19 of gestation.27 The test substances at both doses produced slight skin irritation (erythema and flaking) at the application site. Dermal and Mucosal -Human

There were no human dermal or mucosal irritation studies discovered for pentaerythrityl tetraesters. Ocular PENTAERYTHRITYL TETRABEHENATE Subjects (n = 30) used an eyeliner containing pentaerythrityl tetrabehenate (1.705%) daily for 4 weeks.32 Trace increases in redness of the palpebral conjunctivae was observed in 2 subjects at week 4. The authors decided that this was unrelated to the test substance. The subjects did not report any irritation. There were no increases in lacrimation, eye lid inflammation, or bulbar conjunctova1 irritation and no changes in visual acuity, corneal tissue integrity or contact lenses were observed.

Sensitization Dermal – Non-Human PENTAERYTHRITYL TETRABEHENATE/BENZOATE/ETHYLHEXANOATE In a skin contact allergenicity test of pentaerythrityl tetrabehenate/benzoate/ethylhexanoate (16.6%) using female albino guinea pigs (n = 10 test, 5 control), no signs of irritation or sensitization were observed when challenged (16.6% and 50%).32,33 The acetone control had the expected results. PENTAERYTHRITYL TETRAETHYLHEXANOATE/BENZOATE In a contact allergenicity test of pentaerythrityl tetraethylhexanoate/benzoate (100%) using female albino Harley guinea pigs (n = 10, 5 control), no signs of irritation or sensitization were observed when challenged (1.8%-100%).33,34 The acetone control had the expected results. Dermal – Human PENTAERYTHRITYL TETRACAPRYLATE/TETRACAPRATE In a HRIPT (n = 115) a cream blush containing pentaerythrityl tetracaprylate/tetracaprate (5%), no irritation or sensitization were observed.34 PENTAERYTHRITYL TETRABEHENATE In a human repeated insult patch test (HRIPT; n = 107), an eyeliner containing pentaerythrityl tetrabehenate (1.705%) was tested.35 There were irritation or sensitization observed. PENTAERYTHRITYL TETRAISOSTEARATE In a HRIPT (n = 107) a lip gloss containing pentaerythrityl tetraisostearate (55%), no irritation or sensitization were observed.36 PENTAERYTHRITYL TETRACAPRYLATE/TETRACAPRATE

Phototoxicity There were no phototoxicity studies discovered for the pentaerythrityl tetraesters included in this report.

SUMMARY This is a safety assessment of pentaerythrityl tetraisostearate and other pentaerythrityl tetraester compounds used as cosmetic

ingredients. The functions of these ingredients include: hair conditioning agents; plasticizers; skin-conditioning agents – miscellaneous; binders; skin-conditioning agents - occlusive; viscosity increasing agents - nonaqueous; and skin-conditioning agents – emollient.



6

The total number of reported uses of pentaerythrityl tetraisostearate was 532 in leave-on and 9 in rinse-off products and that pentaerythrityl tetraisostearate was used at 0.1% - 55% in leave-on products and 0.1% in paste masks (mud packs) a rinse-off product. Pentaerythrityl tetracaprylate/tetracaprate was reported to be used in 26 leave-on products at 0.07% - 5%. Pentaerythrityl tetraethylhexanoate was reported to be used in 224 leave-on products at 0.06% - 50% and 17 rinse-off products at 1% - 20%. Pentaerythrityl tetraethylhexanoate/benzoate was reported to be used in 4 leave-on products at 40%. Pentaerythrityl tetrabehenate was reported to be used at 2% – 3% in 8 leave-on products. Pentaerythrityl tetrapelargonate is reported to be used in one hair product by the VCRP and at 0.5% in makeup bases. Pentaerythrityl tetrastearate was reported to be used at 7% and pentaerythrityl tetraisononanoate at 1% - 2%. The VCRP has no uses reported for these ingredients. VCRP reports 1 use of pentaerythrityl tetralaurate. There were no reports to the VCRP or the Council survey of use for pentaerythrityl tetra C5-9 acid esters, pentaerythrityl C5-10 acid esters, pentaerythrityl tetramyristate, pentaerythrityl tetracocoate, pentaerythrityl tetraoleate, and pentaerythrityl tetrabenzoate. There was no mortality to rats orally administered 1943 mg/kg pentaerythrityl tetra C5-9 acid esters. There was no mortality to rats orally administered pentaerythrityl tetra C5-9 acid esters at 1940 mg/kg and pentaerythrityl tetra C5-10 acid esters at 5000 mg/kg. The oral LD50 for pentaerythrityl tetrabenzoate was reported to be 1158 mg/kg in rats.

The dermal NOAEL was 2000 mg/kg/d for female rats and > 2000 mg/kg/d over 13 weeks for pentaerythrityl tetra C5-9 acid esters. Dermally applied pentaerythrityl tetra C5-9 acid esters at 2000 mg/kg had no effects on male or female reproductive organs in rats. There were no teratogenic effects up to 2000 mg/kg. Pentaerythrityl tetra C5-9 acid esters and pentaerythrityl tetrabenzoate were not genotoxic in reverse mutation assays.

Aerosolized pentaerythrityl tetra C5-9 acid was neither cytotoxic to red blood cell formation nor did it induce increased micronulceated PCEs or NCEs in the bone marrow of rats.

Pentaerythrityl tetra C5-9 acid esters were mildly irritating in rats at 800 mg/kg when administered dermally for 13 weeks. Using an eyeliner containing pentaerythrityl tetrabehenate at 1.705% for 4 weeks did not cause irritation.

Pentaerythrityl tetrabehenate/benzoate/ethylhexanoate at 16.6% and pentaerythrityl tetraethylhexanoate/benzoate at 100% were not sensitizing to guinea pigs.

Pentaerythrityl tetrabehenate in an eyeliner, pentaerythrityl tetraisostearate in a lip gloss, and pentaerythrityl tetracaprylate/tetracaprate in a cream blush were not sensitizing at 1.705%, 55%, and 5%, respectively.

DISCUSSION

The Expert Panel noted gaps in the available safety data for the pentaerythrityl tetraester compounds in this safety assessment. The available data on many of the ingredients are sufficient, however, and similarity between structures suggested that the available data may be read across to address the entire group. In addition, these ingredients have similar functions in cosmetics.

Safety assessments have been completed that support the safety for most of the component fatty acid components of these ingredients, including coconut, isostearic, oleic, lauric, myristic, and stearic acids. These are the esterase metabolites that would result from cleavage of pentaerythrityl tetracocoate, pentaerythrityl tetraisostearate, pentaerythrityl tetraoleate, pentaerythrityl tetralaurate, pentaerythrityl tetramyristate, and pentaerythrityl tetrastearate, respectively. Likewise, benzoic acid (a metabolite of pentaerythrityl tetrabenzoate, pentaerythrityl tetraethylhexanoate/benzoate, and pentaerythrityl tetrabehenate/benzoate/ethylhexanoate) was determined by the Panel to be safe for use in cosmetic formulations in the present practices of use and concentration. Were all of the ester linkages to be cleaved from any of these ingredients, pentaerythritol would be produced as well, but there are no toxicological alerts for this alcohol. Some products in which these ingredients are used may be aerosols, and the potential for inhalation of pentaerythrityl tetraester compounds exists. The Panel noted that inhalation toxicity data are not available for these ingredients. However, the particle sizes produced by cosmetic aerosols typically are not respirable. The Panel noted limited systemic toxicity data, including reproductive and developmental toxicity and carcinogenicity endpoints. Systemic toxicity was not considered to be a significant concern because these ingredients are characterized by a large molecular size, and, most importantly, have low solubility, making dermal penetration unlikely.

CONCLUSION The CIR Expert Panel concluded that the following ingredients are safe in the present practices of use and concentration

described in this safety assessment:

Pentaerythrityl Tetraisostearate Pentaerythrityl Tetra C5-9 Acid Esters* Pentaerythrityl Tetra C5-10 Acid Esters* Pentaerythrityl Tetracaprylate/Tetracaprate Pentaerythrityl Tetralaurate Pentaerythrityl Tetramyristate* Pentaerythrityl Tetrastearate Pentaerythrityl Tetrabehenate

Pentaerythrityl Tetracocoate* Pentaerythrityl Tetraoleate* Pentaerythrityl Tetraethylhexanoate Pentaerythrityl Tetraethylhexanoate/Benzoate Pentaerythrityl Tetrabehenate/

Benzoate/Ethylhexanoate Pentaerythrityl Tetrabenzoate* Pentaerythrityl Tetraisononanoate



7

Pentaerythrityl Tetrapelargonate

Were ingredients in this group not in current use (identified with an *) 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.



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TABLES

Table 1. Definitions, functions, and structures of pentaerythrityl ester ingredients in this safety assessment.37

Ingredient CAS No. Definition Function(s) Formula/structure Pentaerythrityl Tetra C5-9 Acid Esters 67762-53-2

The tetraester of branched and linear C5-9 acids with pentaerythritol.

Hair conditioning agent; plasticizer; skin-conditioning agent - miscellaneous

wherein R represents a 4-8 carbon alkyl

chain Pentaerythrityl Tetra C5-10 Acid Esters 68424-31-7

The tetraester of C5-10 acids with pentaerythritol.

Plasticizer

wherein R represents a 4-9 carbon alkyl

chain Pentaerythrityl Tetracaprylate/ Tetracaprate 68441-68-9

The tetraester of pentaerythritol and a blend of caprylic and capric acids.

Skin-conditioning agent - occlusive; viscosity increasing agent - nonaqueous

wherein R represents a 7 or 9 carbon

alkyl chain Pentaerythrityl Tetralaurate 13057-50-6

The tetraester of pentaerythritol and lauric acid.

Binder; skin-conditioning agent - occlusive; viscosity increasing agent - nonaqueous

wherein R represents an 11 carbon alkyl

chain Pentaerythrityl Tetramyristate 18641-59-3

The tetraester of pentaerythritol and myristic acid.

Skin-conditioning agent - occlusive; viscosity increasing agent - nonaqueous


chain Pentaerythrityl Tetrastearate 115-83-3

The tetraester of pentaerythritol and stearic acid.



chain



9


Ingredient CAS No. Definition Function(s) Formula/structure Pentaerythrityl Tetrabehenate 61682-73-3

The tetraester of pentaerythritol and behenic acid.


wherein R represents a 21 carbon alkyl

chain Pentaerythrityl Tetracocoate 92201-72-4

The tetraester of pentaerythritol and coconut fatty acid.


wherein represents coconut fatty acid residues

Pentaerythrityl Tetraoleate 19321-40-5

The tetraester of pentaerythritol and oleic acid.


wherein represents an oleic acid (an Ω-9

unsaturated, 18 carbon fatty acid) residue Pentaerythrityl Tetraisostearate 62125-22-8

The tetraester of isostearic acid and pentaerythritol.


wherein R represents a 17 carbon “iso”

alkyl chain Pentaerythrityl Tetraethylhexanoate 7299-99-2

The tetraester of pentaerythritol and 2-ethylhexanoic acid.


wherein R represents a 1-ethylpentyl

chain Pentaerythrityl Tetraethylhexanoate/Benzoate

The tetraester of pentaerythritol and a blend of ethylhexanoic and benzoic acids.

Hair conditioning agent; skin-conditioning agent - emollient

wherein R represents a 1-ethylpentyl

chain or benzene



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Ingredient CAS No. Definition Function(s) Formula/structure Pentaerythrityl Tetrabehenate/ Benzoate/ Ethylhexanoate

The tetraester of Pentaerythritol with a blend of behenic, benzoic and ethylhexanoic acids.

Hair conditioning agent; skin-conditioning agent - emollient

wherein R represents a 21 carbon alkyl chain, benzene, or a 1-ethylpentyl chain

Pentaerythrityl Tetrabenzoate 4196-86-5

The tetraester of pentaerythritol and benzoic acid.

Binder; skin-conditioning agent - emollient; viscosity increasing agent - nonaqueous

Pentaerythrityl Tetraisononanoate 137636-04-5

The tetraester of pentaerythritol and a branched chain nonanoic acid

Skin-conditioning agent – occlusive; viscosity increasing agent – nonaqueous

RCO- represents the isononanoic acid

radical Pentaerythrityl Tetrapelargonate 14450-05-6

Tetraester of pentaerythritol and pelargonic acid

Fragrance ingredient; skin – conditioning agent – emollient

RCO- represents the pelargonic acid

radical

Table 2. Physical and chemical properties. Property Value Reference Pentaerythrityl Tetra C5-9 Acid Esters Molecular Weight g/mol 529 19 Boiling Point oC 858 Estimated19 Melting Point oC 150 38 Vapor pressure mmHg @ 25oC 1.6 x 10-21 Estimated19 Log Pow 16.7 Estimated19 Water Solubility g/L @ 25 oC (pH not provided) 3.4 10-15 Estimated19 Pentaerythrityl Tetra C5-10 Acid Esters Molecular Weight g/mol 613 19 Vapor pressure mmHg @ 25oC 7.03 x 10-21 Estimated19 Water Solubility g/L @ 25 oC (pH not provided) 3.6 x 10-14 Estimated19 Boiling Point oC 835 Estimated19 Melting Point oC 150 38 Pentaerythrityl Tetracaprylate/ Tetracaprate No data found



11

Table 2. Physical and chemical properties. Property Value Reference Pentaerythrityl Tetralaurate Molecular Weight g/mol 865.36 Estimated39 Density/Specific Gravity @ 20oC 0.943 ± 0.06 Estimated39 Vapor pressure mmHg @ 25oC 3.28 x 10-26 Estimated39 Melting Point oC 48.8-9 40 Boiling Point oC 808.8 ± 60.0 Estimated39 Water Solubility g/L @ 25 oC & pH 1 – 10 4 x 10-9 Estimated39 Pentaerythrityl Tetramyristate Molecular Weight g/mol 977.58 40 Density/Specific Gravity g/cm3 @ 20oC 0.931 ± 0.06 Estimated39 Melting Point oC 62 40 Boiling Point oC 875.8 ± 60.0 Estimated39 Water Solubility g/L @ 25 oC & pH 1-10 4.7 x 10-10 Estimated39 Pentaerythrityl Tetrastearate Molecular Weight g/mol 1201.99 Estimated39 Density/Specific Gravity @ 20 oC 0.915 ± 0.06 Estimated39 Vapor pressure mmHg @ 25oC 1.5 x 10-27 Estimated19 Boiling Point oC 998.5 ± 60.0 Estimated39 Melting Point oC 66-77 19 Water Solubility g/L @ 25 oC & pH 1-10 6.3 x 10-11 Estimated39 Pentaerythrityl Tetrabehenate Molecular Weight g/mol 1426.42 Estimated39 Density/Specific Gravity @ 20oC 0.904 ± 0.06 Estimated39 Boiling Point oC 1109.5 ± 60.0 Estimated 39 Pentaerythrityl Tetracocoate No data found Pentaerythrityl Tetraoleate Molecular Weight g/mol 1193.93 Estimated39 Density/Specific Gravity (temperature not provided) 0.926 ± 0.06 Estimated39 Boiling Point oC 996.0 ± 65.0 Estimated39 Water Solubility g/L (temperature and pH not provided) 2.5 x 10-10 Estimated 39 Pentaerythrityl Tetraisostearate No data found Pentaerythrityl Tetraethylhexanoate Molecular Weight g/mol 640.93 Estimated39 Density/Specific Gravity @ 20oC 0.978 ± 0.06 Estimated39 Boiling Point oC 647.7 ± 50.0 Estimated39 Water Solubility g/L @ 25oC & pH 1-10 4 x 10-6 Estimated39 Pentaerythrityl Tetraethylhexanoate/Benzoate No data found Pentaerythrityl Tetrabehenate/ Benzoate/ Ethylhexanoate

No data found Pentaerythrityl tetrabenzoate Molecular Weight g/mol 552.57 Estimated39 Density/Specific Gravity @ 20oC 1.255 ± 0.06 Estimated39 Melting Point oC 105 40 Boiling Point oC 684.3 ± 55.0 Estimated39 Water Solubility g/L @ 25oC & pH 1-10 9.4 x 10-6 Estimated39 Pentaerythrityl tetraisononanoate Molecular weight g/mol 697.04 41 Pentaerythrityl tetrapelargonate Molecular Weight g/mol 697.04 42 Density/Specific Gravity @ 20oC 0.969 42 Melting Point oC 12 42 Boiling Point oC 699.1± 50 42 Water Solubility g/L @ 25oC & pH 1-10 7.7 x 10-7 42 Vapor pressure mmHg@ 25oC 2.16E-19Torr 42



12

Table 3. Frequency of use according to duration and exposure.

Use type Uses Concentration

(%) Uses Concentration



(%)

Pentaerythrityl tetracaprylate/tetracaprate

Pentaerythrityl tetralaurate

Pentaerythrityl tetrastearate

Pentaerythrityl tetrabehenate

Total/range 23 0.07-5 1 NR NR 7 8 2-3 Duration of use

Leave-on 23 0.07-5 1 NR NR 7 8 2-3 Rinse-off NR NR NR NR NR NR NR NR

Diluted for (bath) use

NR NR

Exposure type Eye area 1 3 1 NR NR 7 4 2

Incidental ingestion

NR NR NR NR NR NR NR 3 Incidental

inhalation-sprays 9 0.07-1 NR NR NR NR 1 NR

Incidental inhalation-powders

1 NR NR NR

Dermal contact 17 0.07-1 1 NR NR NR 8 2 Deodorant (underarm)

NR NR NR NR NR NR NR NR Hair-non-coloring 9 0.07-1 NR NR NR NR NR NR

Hair-coloring NR NR NR NR NR NR NR NR Nail NR NR NR NR NR NR NR NR

Mucous Membrane

NR NR NR NR NR NR NR 3

Baby 1 NR NR NR NR NR NR NR

Pentaerythrityl tetraisostearate

Pentaerythrityl tetraethylhexanoate

Pentaerythrityl tetraethylhexanoate/

benzoate

Pentaerythrityl tetrabehenate/benzoate/

ethylhexanoate Total/range 541 0.1-55 241 0.06-50 4 40 7 0.5-16

Duration of use Leave-on 532 0.1-55 224 0.06-50 4 40 7 2-16 Rinse-off 9 0.1 17 1-20 NR NR NR 0.5-16


NR NR NR NR NR NR NR NR

Exposure type Eye area 104 0.2-36 41 3-15 NR NR NR NR


344 0.8-55 10 2-49 4 40 5 16

Incidental inhalation-sprays

5 NR 4 0.1-50 NR NR NR NR

Incidental inhalation-powders

47 17 0.1-2 NR NR NR NR

Dermal 306 0.1-36 230 0.06-50 NR NR 2 0.5-2 Deodorant (underarm)

NR NR NR 0.1 NR NR NR NR

Hair-noncoloring NR NR 1 2-20 NR NR NR NR Hair – coloring NR NR NR NR NR NR NR NR

Nail 1 0.1 NR 5 NR NR NR NR Mucous

Membrane 227 0.8-55 10 2-49 4 40 5 16

Baby products NR NR NR NR NR NR NR NR

Pentaerythrityl

tetrapelargonate Pentaerythrityl

tetraisononanoate

Total/range 1 0.5 NR 1-2 Duration of use

Leave-on 1 0.5 NR 1-2 Rinse-off NR NR NR NR


NR NR NR NR

Exposure type Eye area NR NR NR 2


NR NR NR NR

Incidental inhalation-sprays

NR NR NR NR

Inhalation inhalation-powers

NR NR NR NR

Dermal contact NR 0.5 NR 1-2



13

Table 3. Frequency of use according to duration and exposure.

Use type Uses Concentration




(%) Deodorant (underarm)

NR NR NR NR

Hair-non-coloring 1 NR NR NR Hair-coloring NR NR NR NR

Nail NR NR NR NR Mucous

Membrane NR NR NR NR

Baby NR NR NR NR NR – None reported Note: Because each ingredient may be used in cosmetics with multiple exposure types, the sum of all exposure type uses may not equal the sum total uses.



14

REFERENCES 1. Johnson Jr.WJ, Bergfeld, WF, Belsito DV, Hill RA, Klaassen CD, Liebler D, Marks Jr.J, Shank RC, Slaga TJ, and Snyder PW. Final report of the Cosmetic

Ingredient Review Expert Panel n the safety assessment of pelargonic acid (aka nonanoic acid) and nonanoate esters. Washington, DC, Cosmetic Ingredient Review. 6-29-2010. pp. 1-77.

2. Andersen FA. Final report on the safety assessment of coconut oil, coconut acid, hydorgenated coconut acid, and hydrogenated coconut oil. Journal of the American College of Toxicology. 1986;8(3):103-121.

3. Andersen FA. Final report on the safety assessment of isostearic acid. Journal of the American College of Toxicology. 1983;2(7):61-74.

4. Andersen FA. Final report on the safety assessment of oleic acid, lauric acid, palmitic acid, myristic acid, and stearic acid. International Journal of Toxicology. 1987;6(3):321-401.

5. Andersen FA. Final report on the safety assessment of benzyl alcohol, benzoic acid, and sodium benzoate. International Journal of Toxicology. 2001;20(Suppl 3):23-50.

6. Marrian SF. The chemicalreactions of pentaerythritol and its derivatives. Chemical Reviews. 1947;42(1):149-202.

7. Youngs CG. Preparation of esters and anhydrides from long chain fatty acid chlorides. Journal of the American Oil Chemists' Society. 1958;35416-417.

8. Thum O and Oxenbøll M. Biocatalysis - A sustainable method for the production of emollient esters. SÖFW Journal. 2008;134(1-2):44-47.

9. Environmental Protection Agency (EPA). Test results - acute toxicity, pentaerythrityl tetra C5-10 acid esters, study 1. 1987. http://iaspub.epa.gov/oppthpv/Public_Search.PublicTabs?SECTION=1&epcount=2&v_rs_list=25025425,25014754. Unpublished data submited to the High Production Volume Information System (HPVIS); Date accessed 2/2011.

10. Environmental Protection Agency (EPA). Test results - acute toxicity, pentaerythrityl tetra C5-10 acid esters, study 2. 1. http://iaspub.epa.gov/oppthpv/Public_Search.PublicTabs?SECTION=1&epcount=2&v_rs_list=25025425,25014754. Report No. Study 2. Unpublished data submitted to the High Production Volume Information System (HPVIS) NO DATE PROVIDED; Date accessed 2/2011.

11. Environmental Protection Agency (EPA). Genetic toxicity in vitro: (6772-53-2) Carboxylic acids, C5-9, tetraesters with pentaerythritol, Study 3. 1000. http://iaspub.epa.gov/oppthpv/quicksearch.display?pChem=101091. Unreferenced study submitted to the High Production volume Information System (HPVIS); NO DATE PROVIDED; Date accessed 2/2011.

12. Personal Care Products Council. [Pentaerythrityl tetraisononanoate and pentaerythrityl tetrapelargonate] Use concentration data from industry survey. 9-17-2009. pp.1-6. Unpublished data submitted by the Personal Care Products Council. Date Accessed 12-17-2009

13. Personal Care Products Council. Concentration of use by FDA product category pentaerythrityl tetraisostearate, pentaerythrityl tetraabietate, pentaerythrityl tetraacetate, pentaerythrityl tetrabehenate, pentaerythrityl tetrabehenate/benzoate/ethylhexanoate, pentaery thrityl tetrabenzoate, pentaerythrityl tetra C5-9 acid esters, pentaerythrityl tetra C5-10 acid esters, pentaerythrityl tetracaprylate/tetracaprate, pentaerythrityl tetracocoate, pentaerythrityl tetraethylhexanoate, pentaerythrityl tetraethylhexanoate/benzoate, pentaerythrityl tetralaurate, pentaerythrityl tetramyristate, pentaerythrityl tetraoleate, pentaerythrityl tetrapelargonate and pentaerythrityl tetrastearate. 2011. pp. 1-3. Unpublished data submitted by the Personal Care Products Council.

14. U.S.Food and Drug Administration. FDA database. Cosmetic production fomulation and frequency of use data submitted to the Voluntary Cosmetic Registration Program (VCRP). 2010. Washington, DC: FDA.Data submitted in response to FOIA request.

15. Shiokawa Y, Matsumoto S, Sato Y, Kato K, and Kitamura M; inventor. Process for the production of polyol ester and ester-containing lubricating oil. 5,705,459. 1-6-1998.

16. U.S.Food and Drug Administration. Indirect food additives: Paper and paperboard components. 2009. 21CFR176.170: http://edocket.access.gpo.gov/cfr_2009/aprqtr/21cfr176.170.htm

17. U.S.Food and Drug Administration.Indirect food additives: Polymers-Subpart B Substances for Use as Basic Components of Single and Repeated Use Food Contact Surfaces Sec. 177.1590 Polyester elastomers. http://edocket.access.gpo.gov/cfr_2009/aprqtr/21cfr177.1590.htm.

18. U.S.Food and Drug Administration.Defoaming agents used in the manufacture of paper and paperboard. http://www.accessdata.fda.gov/scripts/cdrh/cfdocs/cfCFR/CFRSearch.cfm?fr=176.210.

19. American Chemistry Council's Aliphatic Esters Poyol Esters Task Force. High Production Volume (HPV) Chemical Challenge Program; Test plan for the polyol esters category of the aliphatic esters chemicals. 2010. Report No. 201-16833B. pp. 1-41.

20. Keplinger ML and Kay JH. Oral and inhalation toxicity studies on pentaerythritol. Journal of Applied Pharmacology. 1964;6351.

21. Hayashi S, Toyoda K, Furuta K, Uneyama C, Kawanishi T, Imaida K, and Takahashi M. Twenty-eight-day repeated dose toxicity test of pentaerythritol in F344 rats. Eisei Shikenjo Hokoku. 1992;11032-36.

22. Kosmicki MA. Long-term use of short- and long-acting nitrates in stable angina pectoris. Current Clincal Pharmacology. 2009;4(2):132141.



15

23. Johnson Jr.WJ, Bergfeld, WF, Belsito DV, Hill RA, Klaassen CD, Liebler D, Marks Jr.J, Shank RC, Slaga TJ, Snyder PW, and Andersen FA. 2011. Tentative amended safety assessment: Benzyl alcohol, and benzoic acid and its salts and benzyl ester.

24. Environmental Protection Agency (EPA). Acute toxicity: (67762-53-2) Carboxilyic acids, C5-9, tetraesters with pentaerythritol, Study 1. 1999. http://iaspub.epa.gov/oppthpv/Public_Search.PublicTabs?SECTION=1&epcount=2&v_rs_list=25014643,25025073. pp. 1- Unpublished data submitted to the High Production Volume Information System (HPVIS); Date accessed 2/2011.

25. Nihon Iyaku Joho Senta. Pentaerythritol tetranitrate. In: Nihon Iyakuhin Shu [Drugs in Japan]. Tokyo, Japan: Nippon Iyaku Joho Senta; 1974:1105-1106.

26. Environmental Protection Agency (EPA). Repeated-dose toxicity: (67762-53-2) Carboxylic acids, C5-9, tetraesters with pentaerythritol, Study 1. 1985. http://iaspub.epa.gov/oppthpv/quicksearch.display?pChem=101091. pp. 1- Unpublished data submitted to the High Production Volume Information System (HPVIS); Date accessed 2/2011.

27. Environmental Protection Agency (EPA). Reproductive toxicity: (67762-53-2) Carboxylic acids, C5-9, tetraesters with pentaerythritol, Study 1. 1986. http://iaspub.epa.gov/oppthpv/quicksearch.display?pChem=101091. Unpublished data submitted to the High Production Volume Information System (HPVIS); Date accessed 2/2011.

28. Environmental Protection Agency (EPA). Genetic Toxicity in vitro: (6772-53-2) Carboxylic acids, C5-9, tetraesters with pentaerythritol, Study 1. 1999. http://iaspub.epa.gov/oppthpv/quicksearch.display?pChem=101091. Unpublished data submitted to the High Production Volume Information System (HPVIS); Date accessed 2/2011.

29. Environmental Protection Agency (EPA). Genetic Toxicity in vitro: (6772-53-2) Carboxylic acids, C5-9, tetraesters with pentaerythritol, Study 2. 1999. http://iaspub.epa.gov/oppthpv/quicksearch.display?pChem=101091. Unpublished data submitted to the High Production Volume Information System (HPVIS); Date accessed 2/2011.

30. Zeiger E, Anderson B, Haworth S, Lawlor T, and Mortelmans K. Salmonella mutagenicity test V. Results from the testing of 311 chemicals. Environmental and Molecular Mutagenesis. 1992;19(21):2-141.

31. Environmental Protection Agency (EPA). Genetic toxicity in vivo: (67662-53-2) Carboxilic acids, C5-9, tetraesters with pentaerythritol, Study 1. 1991. http://iaspub.epa.gov/oppthpv/quicksearch.display?pChem=101091. Unpublished data submitted to the High Production Volume Information System (HPVIS); Date accessed 2/2011.

32. Clinical Research Laboratories. 2008. An in-use safety evaluation to determine the ocular irritation potential of a cosmetic product (eyeliner containing 1.705% Pentaerythrityl Tetrabehenate). CRL Study Number: CRL169007. Unpublished data submitted by the Personal Care Products Council.

33. Anonymous. 2011. Safety data (contact allergenicity in guinea pigs) of Pentaerythrityl Tetrabenzoate/Benzoate/Ethylhexanoate and Pentaerythrityl Tetraethylhexanoate/Benzoate. Unpublished data submitted by Personal Care Products Council. 10 pages.

34. Clinical Research Laboratories Inc. 2006. Repeated insult patch test of a blush product containing 5% Pentaerythrityl Tetracaprylate/Tetracaprate. CRL Study Number: CRL85006-1. Unpublished data submitted by the Personal Care Products Council.

35. Consumer Product Testing Co. 2008. Repeated insult patch test of an eyeliner containing 1.705% Pentaerythrityl Tetrabehenate. Experiment Reference Number: C08—1387.02. Unpublished data submitted by the Personal Care Products Council.

36. TKL Research. 2010. Repeated insult patch test of a lip product containing 55% Pentaerythrityl Tetraisostearate. TKL Study No.: DS11O11O-3. Unpublished data submitted by the Personal Care Products Council.

37. Gottschalck TE and Bailey JE eds. International Cosmetic Ingredient Dictionary and Handbook. 13th ed. Washington, D.C.: Personal Care Products Council; 2010.

38. U.S.Food and Drug Administration. Estimation Programs Interface Suite™ for Microsoft® Windows. 2011. 4.0:Washington, DC, USA: United States Environmental Protection Agency, Washington, DC, USA.

39. Advanced Chemistry Development (ACD/Labs) Software V11.02. Advanced Chemistry Development (ACD/Labs) Software V11.02. 2010. Toronto, ON:

40. Margaillan L and Savary P. Sur les esters de la pentaérythritite et des acides gras. Bulletin de la Société Chimique de France. 1947;188.

41. ChemDraw [computer program]. 2002. Cambridge, MA: Cambridge Soft Corporation.

42. Scientific and Technical Information Network (STN).Pentaerythrityl tetrapelargonate. Registry file. http://stnweb.cas.org. Date Accessed 9-7-2009.



Personal Care Products CouncilCommitted to Safety,Quality & Innovation

Memorandum

TO: F. Alan Andersen, Ph.D.Director - COSMETIC INGREDIENT REVIEW (CR)

FROM: John Bailey, Ph.DEi—Industry Liaison to the CR Expert Panel

DATE: July 14, 2011

SUBJECT: Comments on the Tentative Safety Assessment: Pentaerythrityl Tetraesters as Used inCosmetics

p.4. .- In the Physical and Chemical Properties section, it would be helpful to state what is meant bylarge molecular weights.

p.5 - As Pentaerythrityl Tetraacetate has been removed from the report, please delete the followingsentence. “Pentaerythritol tetraacetate was reported to be 98.0% pure.”

p.5 - As the information about Pentaerythrityl Rosinate has been removed from the introduction, pleaseconsider removing the information about Pentaerythrityl Rosinate from the UV absorption.section.

p.5, Use, p. 14, Table 3 - In the text, rather than stating that there were “344 uses in products that comein contact with the mucous membranes”, it would more helpful to state that there were 344lipstick uses reported to the VCRP. In Table 3, the 344 uses are not associated with the mucousmembrane category. It is not necessary to indicate that Pentaerythrityl Tetraisostearate has amaximum reported use concentration of 55% twice in the first paragraph of the Use section.Please revise the last sentence of the first paragraph to: “Pentaerythrityl Tetralaurate wasreported to be used in one eye makeup preparation” (this use is not in Table 3). Where did theuse concentration for Pentaerythrityl Tetralaurate of 1% come from as it is not included in theCouncil concentration of use survey? Perhaps in Table 3, “1” should only be in the Usescolumn. In the third paragraph of the Use section, please give the type of products theconcentrations represent. Please check the VCRP again, the most recent version has one use ofPentaerythrityl Tetrapelargonate in hair tonics, dressings and other hair grooming aids reported.As the reference stayed the same, why are the VCRP use numbers in Table 3 different in theTentative report compared to the numbers in this Table in the draft provided to the CR ExpertPanel for the June, 2011 Pane meeting?

p.6 - The summary under Toxicological Studies should be moved under the Acute Exposure heading.It should be revised to read as follows: “A number of pentaerythrityl tetraester ingredients havebeen tested in single dose oral toxicity studies. The ingredients were not significantly toxic; thelowest reported oral LD50 was greater than 1 glkg.”

11011 7th Street, N.W., Suite 300 Washington, D.C. 20036-4702 202.331.1770 202.331.1969 (fax) www.personalcarecouncil.org



p.6 - If the LD5O for Pentaerythrityl Tetrabenzoate was 1158 mg/kg in rats, a number of deaths mustbeen have observed in this study (reference 24). Therefore, it is not appropriate to state that“No toxic effects were observed.”

p.7 - In the summary of the Reproductive and Developmental Toxicity section, please include thespecies used in the teratogenicity study.

p.8 - The summary under the Irritation subheading also summarizes sensitization data. Therefore, thissummary should be moved under the Irritation and Sensitization heading.

p.8 - In the Summary, please revise the following: “This safety assessment reviews summarizes....”p.8 - Rather than stating that Pentaerythrityl Tetralaurate is used in 1 eye makeup preparation, please

state that it was reported to be used in 1 eye makeup preparation. The 1% use concentration forPentaerythrityl Tetralaurate should be deleted as this value was not included in the Councilconcentration of use survey.

p.9 - As Pentaerythrityl Tetraacetate is no longer in this report, please delete the following sentencesfrom the Summary. “The oral LD50 pentaerythrityl tetraacetate was reported to be 3500 mg/kgfor mice.” “The i.p. LD50 of pentaerythirtyl tetraacetate was reported to be 4850 mg/kg formice.”

p.9 - Please include the dose of Pentaerythrityl Tetra C5-9 Acid Esters that had no effects onreproductive organs in rats.

p.9 - Please indicate that formulations containing 1.705% Pentaerythrityl Tetrabehenate, 55% : ..

Pentaerythrityl Tetraisostearate or 5% Pentaerythrityl Tetracaprate/Caprylate were not V

sensitizing in HRIPTs. :p.9 - It is not clear what is meant by “toxicological alerts”. If this means that the CJR Expert Panel V

VV

V

considered safety data on pentaerythritol and were not concerned, references should be given V

V

VV :.

for the studies (or reviews) examined. If this is based solely on the structure of pentaerythritol, VV

V

V it would be better to state that there were no “structural alerts” identified. V

VV:

V

V

p.9 - To consistent with the draft inhalation boilerplate language, please delete: “so exposure of the V

VVV

V

lungs is not possible.”

2



Personal Care iProducts CouncilCommitted to Safety,Quality & Innovation

TO:

FROM:

DATE:

Memorandum

F. Alan Andersen, Ph.D.Director - COSMETIC INGREDIENT REVIEW (CIR)

John Bailey, Ph.D.Industry Liaison to the Cifi Expert Panel

July 5,2011

SUBJECT: Revised Definition: Pentaerythrityl Cocoate

The definition for Pentaerythrityl Cocoate has been revised to indicate that this ingredient is amonoester. The monograph proof is attached.

11011 7th Street, N.W., Suite 3O0 Washington, D.C. 20036-4702 202.331.1770 202.331.1969 (fax) www.personalcarecouncil.org



07/05/2011

Monograph Proof-P

18057: PENTAERYTHRITYL COCOATE

INCI Monograph ID: 18057

Flags: ReadyToPublish

JPN Translation:

CN Translation:

Definition: Pentaerythrityl Cocoate is themonoester of Coconut Acid (q.v.) andpentaerythritol.

Information Sources: CIR: [S], JCLS

Chemical Class: C504- Esters

Reported Function: F572- Skin-Conditioning Agent - Miscellaneous

Ingredient Sources: Plant; Synthetic

International Cosmetic Ingredient Dictionary and Handbook Monograph Proof • 1



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