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GREEN
Pentaerythrityl Tetraisostearate and Other Pentaerythrityl Esters
CIR EXPERT PANEL MEETING
JUNE 27-28, 2011
Ad
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May 27, 2011
MEMORANDUM
To: CIR Expert Panel and Liaisons From: Lillian C. Becker, M.S.
Scientific Analyst and Writer Subject: Draft Report for Pentaerythrityl Tetraisostearate and other pentaerythrityl tetraester
ingredients used in cosmetics The Cosmetic Ingredient Review (CIR) announced the Scientific Literature Review (SLR) for pentaerythrityl tetraisostearate in February, 2011. Pentaerythrityl tetraisostearate is the lead ingredient of this safety assessment and related pentaerythrityl tetraester ingredients are included. Comments and unpublished data have been received from industry and incorporated into the report. These submissions are included in the “Unpublished Data” section of the Panel Book and include: 1 – Council comments
2 – FDA VCRP data
3 – Concentration of Use survey by PCPC for silica silylate
4 – An in-use safety evaluation to determine the ocular irritation potential and a RIPT of a cosmetic product (eyeliner containing 1.705% Pentaerythrityl Tetrabehenate) submitted by PCPC
5 – Two RIPTs of products containing Pentaerythrityl tetraisostearate or pentaerythrityl
tetracaprylate/tetracaprate submitted by PCPC
6 - A Contact allergenciity test of Pentaerythrityl Tetrabehenate/Benzoate/Ethylhexanoate and Pentaerythrityl TetraethylhexanoatelBenzoate
The Panel should review the Draft Report and decide: 1) if it is reasonable to include the other listed ingredients with pentaerythrityl tetraisostearate in this report and 2) whether any additional data are needed in order to reach a safety conclusion for pentaerythrityl tetraisostearate and other pentaerythrityl tetraester ingredients. If no additional data are required, then the Panel may issue a Tentative Report.
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CIR Panel Book Page 1
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CIR Panel Book Page 2
History of Pentaerythrityl Tetraisostearate and Other Pentaerythrityl Tetraesters
February, 2011 – SLR announced. June, 2011 – Panel considers Draft Report.
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CIR Panel Book Page 3
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)
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;
4 hits 0 0 0 0
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CIR Panel Book Page 4
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 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
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CIR Panel Book Page 5
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 toxicity
Genotoxicity
Carcinogenicity
Phototoxicity
Pentaerythrityl Tetraacetate X
Pentaerythrityl Tetra C5-9 Acid Esters
X 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 X
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CIR Panel Book Page 6
Rep
ort
Draft Report
Pentaerythrityl Tetraisostearate and Other Pentaerythrityl Esters as Used in Cosmetics
June 27, 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.; Curtis D. Klaassen, Ph.D.; Daniel C. Liebler, Ph.D.; Ronald A Hill, Ph.D. James G. Marks, Jr., M.D.; Ronald C. Shank, Ph.D.; Thomas J. Slaga, Ph.D.; and Paul W. Snyder, D.V.M., Ph.D. The CIR Director is F. Alan Andersen, Ph.D. This report was prepared by 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 "
cirinfo@cir-safety.org
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TABLE OF CONTENTS TABLE OF CONTENTS ............................................................................................................................................................................................................. i
INTRODUCTION ...................................................................................................................................................................................................................... 2
Chemistry .................................................................................................................................................................................................................................... 2
Definition and Structure......................................................................................................................................................................................................... 2
Physical and Chemical Properties .......................................................................................................................................................................................... 2
Method of Manufacture ......................................................................................................................................................................................................... 2
Impurities............................................................................................................................................................................................................................... 2
UV Absorption ...................................................................................................................................................................................................................... 3
USE ............................................................................................................................................................................................................................................. 3
Cosmetic ................................................................................................................................................................................................................................ 3
Non-Cosmetic ........................................................................................................................................................................................................................ 4
TOXICOKINETICS ................................................................................................................................................................................................................... 4
Absorption, Distribution, Metabolism, and Excretion ............................................................................................................................................................ 4
TOXICOLOGICAL STUDIES ................................................................................................................................................................................................... 4
Acute Toxicity ....................................................................................................................................................................................................................... 4
Dermal.............................................................................................................................................................................................................................. 4
Oral – Non-Human ........................................................................................................................................................................................................... 4
Inhalation ......................................................................................................................................................................................................................... 4
Other Dose Administration ............................................................................................................................................................................................... 4
Repeated Dose Toxicity ......................................................................................................................................................................................................... 4
Dermal – Non-Human ...................................................................................................................................................................................................... 4
Oral and Inhalation ........................................................................................................................................................................................................... 5
REPRODUCTIVE AND DEVELOPMENTAL TOXICITY ...................................................................................................................................................... 5
Genotoxicity ................................................................................................................................................................................................................................ 5
In Vitro .................................................................................................................................................................................................................................. 5
In Vivo................................................................................................................................................................................................................................... 5
CARCINOGENICITY ................................................................................................................................................................................................................ 5
Irritation and sensitization ........................................................................................................................................................................................................... 5
Irritation ................................................................................................................................................................................................................................. 5
Dermal – Non-Human ...................................................................................................................................................................................................... 6
Dermal and Mucosal -Human ........................................................................................................................................................................................... 6
Ocular ............................................................................................................................................................................................................................... 6
Sensitization .......................................................................................................................................................................................................................... 6
Dermal – Non-Human ...................................................................................................................................................................................................... 6
Dermal – Human .............................................................................................................................................................................................................. 6
Phototoxicity.......................................................................................................................................................................................................................... 6
SUMMARY ................................................................................................................................................................................................................................ 6
Tables .......................................................................................................................................................................................................................................... 8
REFERENCES ......................................................................................................................................................................................................................... 13
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CIR Panel Book Page 8
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INTRODUCTION This scientific literature review summarizes published and unpublished data relevant to the safety of pentaerythrityl
tetraisostearate and other pentaerythrityl tetraester compounds used as cosmetic ingredients. These 14 ingredients include:
• Pentaerythrityl Tetraacetate • 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
The functions of these ingredients include: hair conditioning agents; plasticizers; skin-conditioning agents – miscellaneous;
plasticizers; binders; skin-conditioning agents - occlusive; viscosity increasing agents - nonaqueous; and skin-conditioning agents – emollient.
Four related ingredients previously have been reviewed by the Cosmetic Ingredient Review (CIR) Expert Panel in 3 separate safety assessments.
• Pentaerythrityl tetraisononanoate and pentaerythrityl tetrapelargonate, were determined to be safe in the present practices of use and concentration.1
• Pentaerythrityl cocoate was determined to be safe as a cosmetic ingredient in the practices of use and concentration.2 • Pentaerythrityl rosinate, which has a similar core structure as the pentaerythrityl tetraesters, has also been reviewed
and an insufficient data conclusion was reached.3 Additional data needed include: (1) two genotoxicity assays, at least one in a mammalian system; if positive, then a 2-year dermal carcinogenicity study using National Toxicology Program (NTP) methods is needed; (2) dermal absorption; if significantly absorbed, then both a 28-day dermal toxicity study and a reproductive and developmental toxicity study may be needed; and (3) chemical properties, including structure and impurities. These data were considered necessary because information was lacking about the rosinate moiety in this ingredient and the potential impurities that may be present. The chemical structure of the pentaerythrityl moiety was provided but the structure/composition of the rosinate was not.
CHEMISTRY
Definition and Structure The pentaerythrityl tetraesters have a core pentaerythritol that is esterified with 4 monobasic 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. With the exception of pentaerythrityl tetraacetate, these ingredients have very poor solubility in water. These ingredients have large molecular weights. Pentaerythrityl tetra C5-9 acid esters has an estimated Log Pow of 16.7.
Method of Manufacture The pentaerythrityl tetraesters can be prepared readily from pentaerythritol by the usual alcohol esterification methods (e.g., by reaction with acids, acid chlorides, or acid anhydrides).4 For example, pentaerythritol tetrastearate can be manufactured by heating stearoyl chloride and pentaerythritol (4:1 ratio) at 100ºC, under 2 mmHg.5 The resulting product can then be recrystallized to form a pure product from chloroform. 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.6
Impurities Pentaerythritol tetraacetate was reported to be 98.0% pure.7 Pentaerythrityl tetra C5-9 acid esters was reported by one source to be 100% pure.8,9 Another source, however, reported 81% purity with the other 19% comprised of carboxylic acids and dipentaerythritol C5-9 hexaesters.10
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CIR Panel Book Page 9
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Figure 1. Pentaerythrityl tetraisostearate
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. For the related ingredient pentaerythrityl rosinate, a sample solution of 1.891 g in methanol, was scanned (by USP XXI method) using a UV-Vis spectrophotometer from 400 to 300 nm at 25°C.11,12 Absorbtivity at 360 (UVA) and 310 nm (UVB) were 0.02 and 0.2, respectively. A typical absorbtivity for a sunscreen scanned under the same conditions would have been 65.0.
USE Cosmetic
Data on ingredient usage are provided to the Food and Drug Administration’s (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.13,14 The total numbers of VCRP reported uses of pentaerythrityl tetraisostearate was 697 in leave-on and 9 in 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. In some cases, such as baby products, pentaerythrityl tetraisostearate was reported to the VCRP as used in 2 baby products, but no use concentration was reported in the Council survey. There were also 344 uses in products that come in contact with the mucus membrane and up to 55% in lipstick. 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 tetrastearate was reported to be used in 22 leave-on products and was reported to be used at 7%. Pentaerythrityl tetraethylhexanoate was reported to be used in 236 leave-on products at 0.06% - 50% and 7 rinse-off products at 1% - 20%. While pentaerythrityl tetraethylhexanoate was not reported by the VCRP to be used in non-coloring hair products, the Council survey reported a use concentration of 2%-20%, suggesting that this ingredient is used. 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 leave-on products. Pentaerythrityl tetralaurate is used in 1eye makeup preparation.
There were no reports to the VCRP or the Council survey of use for pentaerythrityl tetraacetate, pentaerythrityl tetra C5-9 acid esters, pentaerythrityl C5-10 acid esters, pentaerythrityl tetramyristate, pentaerythrityl tetracocoate, pentaerythrityl tetraoleate, and pentaerythrityl tetrabenzoate.
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CIR Panel Book Page 10
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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 in as indirect food additive that may be used to make packaging that comes in contact with
food.16 It may also be used in cellophane that come 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.
Should these ingredients enter the body by other routes, metabolism of the pentaerythrityl tetraesters in animals would be expected to occur initially, via esterases, leading to the corresponding free acids (e.g., stearic acid is a potential free acid metabolite of pentaerythrityl tetrastearate), partially esterified pentaerythritol (e.g., pentaerythrityl cocoate is potentially esterified metabolite of pentaerythrityl), 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.
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.20-22 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 at concentrations up to 5%.23
TOXICOLOGICAL STUDIES Various oral pentaerythrityl tetraesters have been tested in single dose toxicity studies and found to not be significantly toxic – the lowest reported LD50 was greater than 1 g/kg.
Acute Toxicity Dermal PENTAERYTHRITYL TETRA C5-9 ACID ESTERS There were no dermal studies discovered for pentaerythrityl tetraesters. Oral – Non-Human PENTAERYTHRITYL TETRAACETATE The oral LD50 of pentaerythrityl tetraacetate was reported to be 3500 mg/kg for mice.24 No toxic effects were noted. PENTAERYTHRITYL TETRA C5-9 ACID ESTERS
Sprague-Dawley rats (n = 5/sex) were orally administered pentaerythrityl tetra C5-9 acid esters (1940 mg/kg).8,9 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).25 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).8,9 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.26 No toxic effects were observed. Inhalation
There were no inhalation studies discovered for pentaerythrityl tetraesters. Other Dose Administration PENTAERYTHRITYL TETRAACETATE The intraperitoneal (i.p.) LD50 of pentaerythrityl tetraacetate was reported to be 4850 mg/kg for mice.24 No toxic effects were noted.
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.27 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
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CIR Panel Book Page 11
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controls after 13 weeks and 7% in the low dose group. No effect on body weight 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 affects. It was not clear if the decreased growth represented toxicity, but the effect was so slight that the NOAEL is considered to be 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.27 There were no effects noted in sperm morphology. Examination 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.28 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 In Vitro
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 micronulceated PECs or NCEs in the bone marrow of rats. 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.29 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.30 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.10 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.31
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.32 The test material was not cytotoxic to red blood cell formation nor did it induce increased micronucleated PECs or NCEs in the bone marrow.
CARCINOGENICITY There were no carcinogenicity studies discovered for pentaerythrityl tetraesters.
IRRITATION AND SENSITIZATION Irritation
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
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sensitizing to guinea pigs.
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.27 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.28 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.33 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%).33,34 The acetone control had the expected results. PENTAERYTHRITYL TETRAETHYLHEXANOATE/BENZOATE In a contact allergencity test of pentaerythrityl tetraethylhexanoate/benzoate (n = 107; 100%) using female albino Harley guinea pigs (n = 10, 5 control), no signs of irritation or sentisization were observed when challenged (1.8%-100%).34,35 The acetone control had the expected results. Dermal – Human PENTAERYTHRITYL TETRABEHENATE In a human repeated insult patch test (HRIPT; n = 107), an eyeliner containing pentaerythrityl tetrabehenate (1.705%) was tested.36 No irritation or sensitization were observed. PENTAERYTHRITYL TETRAISOSTEARATE In a HRIPT (n = 107) a lip gloss containing pentaerythrityl tetraisostearate (55%), no irritation or sensitization were observed.37 PENTAERYTHRITYL TETRACAPRYLATE/TETRACAPRATE In a HRIPT (n = 115) a cream blush containing pentaerythrityl tetracaprylate/tetracaprate (5%), no irritation or sensitization were observed.35
Phototoxicity There were no phototoxicity studies discovered for pentaerythrityl tetraesters.
SUMMARY This safety assessment reviews summarizes published and unpublished data relevant to the safety 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; plasticizers; binders; skin-conditioning agents - occlusive; viscosity increasing agents - nonaqueous; and skin-conditioning agents – emollient.
The total number of uses of pentaerythrityl tetraisostearate was 679 in leave-on and 9 in rinse-off products ranging from 0.1% - 55%. Pentaerythrityl tetracaprylate/tetracaprate was reported to be used in 23 leave-on products at 0.07% - 5%. Pentaerythrityl tetrastearate was reported to be used in 22 leave-on products and was reported to be used at 7%. Pentaerythrityl tetraethylhexanoate was reported to be used in 236 leave-on products at 0.06% - 50% and 7 rinse-off products at 1% - 20%. Pentaerythrityl tetraethylhexanoate/benzoate, pentaerythrityl tetrabehenate, pentaerythrityl tetralaurate are also reported to be used. There were no reports of use for pentaerythrityl tetraacetate, pentaerythrityl tetra C5-9 acid esters, pentaerythrityl C5-10 acid esters, pentaerythrityl tetramyristate, pentaerythrityl tetracocoate, pentaerythrityl tetraoleate, and pentaerythrityl tetrabenzoate. There were no mortalities to rats orally administered 1943 mg/kg pentaerythrityl tetra C5-9 acid esters. The oral LD50 of pentaerythrityl tetraacetate was reported to be 3500 mg/kg for mice. There were no mortalities 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 i.p. LD50 of pentaerythrityl tetraacetate was reported to be 4850 mg/kg for mice.
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The dermal NOAEL was 2000 mg/kg/day for rats over 13 weeks for pentaerythrityl tetra C5-9 acid esters. 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 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 PECs 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.
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TABLES
Table 1. Definitions, functions, and structures of pentaerythrityl ester ingredients in this safety assessment.38
Ingredient CAS No. Definition Function(s) Formula/structure Pentaerythrityl Tetraacetate 597-71-7
The tetraester of pentaerythritol and acetic acid.
Skin-conditioning agent - miscellaneous
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
wherein R represents an 13 carbon alkyl
chain
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Table 1. Definitions, functions, and structures of pentaerythrityl ester ingredients in this safety assessment.38
Ingredient CAS No. Definition Function(s) Formula/structure Pentaerythrityl Tetrastearate 115-83-3
The tetraester of pentaerythritol and stearic acid.
Binder; skin-conditioning agent - occlusive; viscosity increasing agent - nonaqueous
wherein R represents an 17 carbon alkyl
chain
Pentaerythrityl Tetrabehenate 61682-73-3
The tetraester of pentaerythritol and behenic acid.
Binder; skin-conditioning agent - occlusive; viscosity increasing agent - nonaqueous
wherein R represents a 21 carbon alkyl
chain
Pentaerythrityl Tetracocoate 92201-72-4
The tetraester of pentaerythritol and coconut fatty acid.
Binder; skin-conditioning agent - occlusive; viscosity increasing agent - nonaqueous
wherein
represents coconut fatty acid residues Pentaerythrityl Tetraoleate 19321-40-5
The tetraester of pentaerythritol and oleic acid.
Binder; skin-conditioning agent - occlusive; viscosity increasing agent - nonaqueous
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.
Binder; skin-conditioning agent - occlusive; viscosity increasing agent - nonaqueous
wherein R represents a 17 carbon “iso”
alkyl chain
Pentaerythrityl Tetraethylhexanoate 7299-99-2
The tetraester of pentaerythritol and 2-ethylhexanoic acid.
Binder; skin-conditioning agent - occlusive; viscosity increasing agent - nonaqueous
wherein R represents a 1-ethylpentyl
chain
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Table 1. Definitions, functions, and structures of pentaerythrityl ester ingredients in this safety assessment.38
Ingredient CAS No. Definition Function(s) Formula/structure 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 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
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Table 2. Physical and chemical properties. Property Value Reference Pentaerythrityl Tetraacetate Physical Form Crystals 39 Molecular Weight g/mol 304.29 39 Density/Specific Gravity @ 20oC 1.183 ± 0.06 Estimated40 Vapor pressure mmHg @ 25oC 1.0 x 10-05 Estimated40 Melting Point oC 78-80 41 Boiling Point oC 155-160 9 Water Solubility g/L @ 25oC & pH 1-10 8.2 Estimated40 Pentaerythrityl Tetra C5-9 Acid Esters Molecular Weight g/mol 529 19 Boiling Point oC 858 Estimated19 Melting Point oC 150 42 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 42 Pentaerythrityl Tetracaprylate/ Tetracaprate No data found Pentaerythrityl Tetralaurate Molecular Weight g/mol 865.36 Estimated40 Density/Specific Gravity @ 20oC 0.943 ± 0.06 Estimated40 Vapor pressure mmHg @ 25oC 3.28 x 10-26 Estimated40 Melting Point oC 48.8-9 43 Boiling Point oC 808.8 ± 60.0 Estimated40 Water Solubility g/L @ 25 oC & pH 1 – 10 4 x 10-9 Estimated40 Pentaerythrityl Tetramyristate Molecular Weight g/mol 977.58 44 Density/Specific Gravity g/cm3 @ 20oC 0.931 ± 0.06 Estimated40 Melting Point oC 62 43 Boiling Point oC 875.8 ± 60.0 Estimated40 Water Solubility g/L @ 25 oC & pH 1-10 4.7 x 10-10 Estimated40 Pentaerythrityl Tetrastearate Molecular Weight g/mol 1201.99 Estimated40 Density/Specific Gravity @ 20 oC 0.915 ± 0.06 Estimated40 Vapor pressure mmHg @ 25oC 1.5 x 10-27 Estimated19 Boiling Point oC 998.5 ± 60.0 Estimated40 Melting Point oC 66-77 19 Water Solubility g/L @ 25 oC & pH 1-10 6.3 x 10-11 Estimated40 Pentaerythrityl Tetrabehenate Molecular Weight g/mol 1426.42 Estimated40 Density/Specific Gravity @ 20oC 0.904 ± 0.06 Estimated40 Boiling Point oC 1109.5 ± 60.0 Estimated 40 Pentaerythrityl Tetracocoate No data found Pentaerythrityl Tetraoleate Molecular Weight g/mol 1193.93 Estimated40 Density/Specific Gravity (temperature not provided) 0.926 ± 0.06 Estimated40 Boiling Point oC 996.0 ± 65.0 Estimated40 Water Solubility g/L (temperature and pH not provided) 2.5 x 10-10 Estimated 40 Pentaerythrityl Tetraisostearate No data found Pentaerythrityl Tetraethylhexanoate Molecular Weight g/mol 640.93 Estimated40 Density/Specific Gravity @ 20oC 0.978 ± 0.06 Estimated40 Boiling Point oC 647.7 ± 50.0 Estimated40 Water Solubility g/L @ 25oC & pH 1-10 4 x 10-6 Estimated40 Pentaerythrityl Tetraethylhexanoate/Benzoate No data found Pentaerythrityl Tetrabehenate/ Benzoate/ Ethylhexanoate
No data found
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Table 2. Physical and chemical properties. Property Value Reference Pentaerythrityl Tetrabenzoate Molecular Weight g/mol 552.57 Estimated40 Density/Specific Gravity @ 20oC 1.255 ± 0.06 Estimated40 Melting Point oC 105 45 Boiling Point oC 684.3 ± 55.0 Estimated40 Water Solubility g/L @ 25oC & pH 1-10 9.4 x 10-6 Estimated40
Table 3. Frequency of use according to duration and exposure.13,14
Use type Uses Concentration
(%) Uses Concentration
(%) Uses Concentration
(%) Uses Concentration
(%)
Pentaerythrityl tetracaprylate/tetracaprate
Pentaerythrityl tetralaurate
Pentaerythrityl tetrastearate
Pentaerythrityl tetrabehenate
Total/range 23 0.07-5 NR 1 22 7 NR 2-3 Duration of use
Leave-on 23 0.07-5 NR 1 22 7 NR 2-3 Rinse-off NR NR NR NR NR NR NR NR
Exposure type Eye area 1 3 NR 1 18 7 NR 2 Possible ingestion
NR NR NR NR NR NR NR 3 Inhalation 7 0.07-1 NR NR NR NR NR NR Dermal 23 0.07-5 NR 1 20 NR NR 2-3
Deodorant (underarm)
NR NR NR NR NR NR NR NR Hair-noncoloring 7 0.07-1 NR NR 2 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
Bath products NR NR NR NR 1 NR NR NR Baby 1 NR NR NR NR NR NR NR
Pentaerythrityl tetraisostearate
Pentaerythrityl tetraethylhexanoate
Pentaerythrityl tetraethylhexanoate/
benzoate
Pentaerythrityl tetrabehenate/benzoate/
ethylhexanoate Total/range 688 0.1-55 243 0.06-50 NR 40 1 NR
Duration of use Leave-on 679 0.1-55 236 0.06-50 4 40 1 NR Rinse-off 9 0.1 7 1-20 NR NR NR NR
Exposure type Eye area 105 0.2-36 41 3-15 4 40 1 NR
Possible ingestion 344 0.8-55 9 2-49 NR NR NR NR Inhalation NR NR NR NR NR NR NR NR Dermal 688 0.1-55 242 0.06-50 4 40 1 NR
Deodorant (underarm)
NR NR NR 0.1 NR NR NR NR
Hair-noncoloring NR NR NR 2-20 NR NR NR NR Hair – coloring NR NR NR NR NR NR NR NR
Nail NR 0.1 NR 5 NR NR NR NR Mucous
Membrane 344 0.8-55 9 2-49 4 40 NR NR
Bath products NR NR NR NR NR NR NR NR Baby 2 NR NR NR NR NR NR NR
NR – None reported
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REFERENCES
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30. 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.
31. 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.
32. 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.
33. 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.
34. 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.
35. 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.
36. 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.
37. TKL Research. 2010. Repeated insult patch test of a lip product containing 55% Pentaerythrityl Tetraisostearate. TKL Study No.: DS11O11O-3.
38. Gottschalck TE and Bailey JE eds. International Cosmetic Ingredient Dictionary and Handbook. 13th edition. Washington, D.C.:Personal Care Products Council; 2010.
39. Wolfrom ML, Bower RS, and Maher GG. A Simple Acetolysis of Nitrate Esters. Journal of the American Chemical Society. 1951;73:(2):874-875.
40. Advanced Chemistry Development (ACD/Labs) Software V11.02. Advanced Chemistry Development (ACD/Labs) Software V11.02. 2010. Toronto, ON:
41. Kamal A, Khan MN, Reddy KS, Srikanth YVV, and Krishnaji T. AI(OTf)3 as a highly efficient catalyst for the rapid acetylation of alcohols, phenols and thiophenols under solvent-free conditions. Tetrahedron Letters. 2011;48:(22):3813-3818.
42. 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.
43. Margaillan L and Savary P. Sur les esters de la pentaérythrite et des acides gras. Bulletin de la Société Chimique de France. 1947;188.
Distributed for Comment Only -- Do Not Cite or Quote
CIR Panel Book Page 21
15
44. Zeman A and Wörle R. Untersuchung von 2.4.6-substituierten s-Triazinen durch Gaschromatographie-Massenspektrometrie. Organic Mass Spectrometry. 1978;13:(1):248-251.
45. Laguna MF, Compan V, Díaz-Calleha R, Guzmán J, and Riande E. Dipole correleation and relaxation behavior of flexible bulky low molecular weight esters. Journal of Molecular Liquids. 2006;123:1-7.
Distributed for Comment Only -- Do Not Cite or Quote
CIR Panel Book Page 22
Data
TO:
FROM:
DATE:
Products CouncilCommitted to Safety,Quality & Innovation
F. Alan Andersen, Ph.D.Director - COSMETIC INGREDIENT REVIEW (CW)
John Bailey, Ph.D.Industry Liaison to the CIR Expert Panel
January 28, 2011
SUBJECT: Updated Concentration of Use by FDA Product Category: Pentaerythrityl TetraIngredients
1101 17th Street, N.W., Suite 3OO Washington, D.C. 20036-4702 202.331.1770 202.331.1969 (fax) www.personalcarecouncil.org
Personal Care’
Memorandum
Distributed for Comment Only -- Do Not Cite or Quote
CIR Panel Book Page 23
Concentration of Use by FDA Product CategoryPentaerythrityl Tetraisostearate, Pentaerythrityl Tetraabietate, Pentaerythrityl Tetraacetate, Pentaerythrityl
Tetrabehenate, Pentaerythrityl TetrabehenatefBenzoate/Ethylhexanoate, Pentaery thrityl Tetrabenzoate,Pentaerythrityl Tetra C5-9 Acid Esters, Pentaerythrityl Tetra CS-b Acid Esters, PentaerythritylTetracaprylate/Tetracaprate, Pentaerythrityl Tetracocoate, Pentaerythrityl Tetraethylhexanoate,
Pentaerythrityl TetraethylhexanoatefBenzoate, Pentaerythrityl Tetralaurate, Pentaerythrityl Tetramyristate,Pentaerythrityl Tetraoleate, Pentaerythrityl Tetrapelargonate and Pentaerythrityl Tetrastearate*
Ingredient Product Category Concentrationof Use
Pentaerythrityl Tetraisostearate Eyebrow pencil 8-15%
Pentaerythrityl Tetraisostearate Eyeliner 6-16%
Pentaerythrityl Tetraisostearate Eye shadow 2-36%
Pentaerythrityl Tetraisostearate Eye lotion 0.2-5%
Pentaerythrityl Tetraisostearate Mascara 0.2%
Pentaerythrityl Tetraisostearate Blushers (all types) 2-4%
Pentaerythrityl Tetraisostearate Face powders 1-4%
Pentaerythrityl Tetraisostearate Foundations 1%
Pentaerythrityl Tetraisostearate Lipstick 0.8-55%
Pentaerythrityl Tetraisostearate Other makeup preparations 8%
Pentaerythrityl Tetraisostearate Nail creams and lotions 0.1%
Pentaerythrityl Tetraisostearate Preshave lotions (all types) 0.8%
Pentaerythrityl Tetraisostearate Face and neck creams, lotions and powders 1-4%
Pentaerythrityl Tetraisostearate Body and hand creams, lotions and powders 1%
Pentaerythrityl Tetraisostearate Night creams, lotions and powders 0.2%
Pentaerythrityl Tetraisostearate Paste masks (mud packs) 0.1%
Pentaerythrityl Tetraisostearate Other skin care preparations 1-8%
Pentaerythrityl Tetrabehenate Eyeliner 2%
Pentaerythrityl Tetrabehenate Lipstick 3%
Pentaerythrityl Tetrabehenate/Benzoate! Lipstick 16%Ethylhexanoate
Pentaerythrityl Tetrabehenate/Benzoate! Face and neck cream, lotions and powders 2%Ethylhexanoate
Pentaerythrityl Tetrabehenate/Benzoate/ Moisturizing creams, lotions and powders 2%Ethylhexanoate
Page 1 of 3
Distributed for Comment Only -- Do Not Cite or Quote
CIR Panel Book Page 24
Pentaerythrityl Tetrabehenate/Benzoate/ Paste masks (mud packs) 0.5%Ethyihexanoate
Pentaerythrityl Tetracaprylate/ Tetracaprate Eye lotion 3%
Pentaerythrityl Tetracaprylate/ Tetracaprate Hair sprays (aerosol fixatives) 0.07-1%
Pentaerythrityl Tetracaprylate! Tetracaprate Tonics, dressings and other hair grooming 0.1%aids
Pentaerythrityl Tetracaprylate/ Tetracaprate Blushers (all types) 5%
Pentaerythrityl Tetracaprylate/ Tetracaprate Aftershave lotions 3%
Pentaerythrityl Tetracaprylate/ Tetracaprate Face and neck creams, lotions and powders 3%
Pentaerythrityl Tetracaprylate/ Tetracaprate Body and hand creams, lotions and powders 2%
Pentaerythrityl Tetraethylhexanoate Eye shadow 3-8%
Pentaerythrityl Tetraethylhexanoate Eye lotion 6-15%
Pentaerythrityl Tetraethylhexanoate Colognes and toilet waters 45%
Pentaerythrityl Tetraethylhexanoate Perfumes 50%
Pentaerythrityl Tetraethylhexanoate Powders (dusting and talcum) 0.1%
Pentaerythrityl Tetraethylhexanoate Other fragrance preparations 5%
Pentaerythrityl Tetraethylhexanoate Hair conditioners 2%
Pentaerythrityl Tetraethylhexanoate Permanent waves 20%
Pentaerythrityl Tetraethylhexanoate Blushers (all types) 3%
Pentaerythrityl Tetraethylhexanoate Face powders 2%
Pentaerythrityl Tetraethylhexanoate Foundations 4-12%
Pentaerythrityl Tetraethylhexanoate Lipstick 2-49%
Pentaerythrityl Tetraethylhexanoate Makeup bases 2-12%
Pentaerythrityl Tetraethylhexanoate Other makeup preparations 21-46%
Pentaerythrityl Tetraethylhexanoate Nail creams and lotions 5%
Pentaerythrityl Tetraethylhexanoate Bath soaps and detergents 20%
Pentaerythrityl Tetraethylhexanoate Deodorants (underarm) 0.1%
Pentaerythrityl Tetraethylhexanoate Aftershave lotions 2%
Pentaerythrityl Tetraethylhexanoate Skin cleansing (cold creams, cleansing 3-8%lotions, liquids and pads)
Pentaerythrityl Tetraethylhexanoate Face and neck creams, lotions and powders 2-24%
Page 2 of 3
Distributed for Comment Only -- Do Not Cite or Quote
CIR Panel Book Page 25
Pentaerythrityl Tetraethylhexanoate Body and hand creams, lotions and powders 3-12%
Pentaerythrityl Tetraethylhexanoate Moisturizing creams, lotions and powders 0.06-20%
Pentaerythrityl Tetraethylhexanoate Night creams, lotions and powders 5-6%
Pentaerythrityl Tetraethylhexanoate Paste masks (mud packs) 1-8%
Pentaerythrityl Tetraethylhexanoate Other skin care preparations 3-12%
Pentaerythrityl Tetraethylhexanoate Suntan gels, creams and liquids 3-16%
Pentaerythrityl Tetraethylhexano ate Other suntan preparations 21%
Pentaerythrityl Lipstick 40%Tetraethylhexanoate/B enzoate
Pentaerythrityl Tetrapelargonate Makeup bases 0.5%
Pentaerythrityl TetrastearateJ_Mascara 7%
*Ingredients found in the title of the table but not found in the table were included in the concentration of use survey,but no uses were reported.
Information collected in 2010Table prepared January 6, 2011
Table updated January 28, 2011 (Pentaerythrityl Tetraisostearate: added Preshave lotions)
Page 3 of 3
Distributed for Comment Only -- Do Not Cite or Quote
CIR Panel Book Page 26
TO:
iProducts Council
F. Alan Andersen, Ph.D.Director - COSMETIC INGREDIENT REVIEW (Cifi)
Committed to Safety,Quality & Innovation
FROM:
DATE:
John Bailey, Ph.D.Industry Liaison to the CW Expert Panel
February 24, 2011
SUBJECT: Clinical Studies of an Eyeliner Containing Pentaerythrityl Tetrabehenate
Clinical Research Laboratories, Inc. 2008. An in-use safety evaluation to determine the ocularirritation potential of a cosmetic product (eyeliner containing 1.705% PentaerythritylTetrabehenate). CRL Study Number: CRL169007.
Consumer Product Testing Co. 2008. Repeated insult patch test of an eyeliner containing 1.705%Pentaerythrityl Tetrabehenate. Experiment Reference Number: C08—1387.02.
1101 17th Street, N.W., Suite 300 Washington, D.C. 20036-4702 202.331.1770 202.331.1969 (fax) www.personalcarecouncil.org
Personal Care
Memorandum
Distributed for Comment Only -- Do Not Cite or Quote
CIR Panel Book Page 27
CLI ENT:
ATTENTION:
CthuicalResearchLaboratories, Inc.
Final ReportAn Ln4ie Safety Evaluation to Determine the Ocular
Irritation Potential of a Cosmetic Product
TEST 1ATER1ALS:
(RL 1’ ‘I ‘1lF K’
BruLe I’.. I L1t;’f. t.I), • \
( iph I h:dmi Iii L’%tig41or
Dipluni.iLc HlLricu Board of Uphthalmo[ogy
Pr i4utjhiJi I’
\ .ag (iao. Ti’.eniL)rIIecl(ai kcsLarchSc Intist;OhI hahniiogist
REPORT DATE:
CRi
Michael J. , PhiLExecutive Vice President/COo
r Automatic Eyeliner Metallics
(o.:s JbO 5% hJy e
January 1$, 2008
371 Hoes Lane • Piscataway, NJ 08854 (732) 981-1616 • FAX (732) 951-0520
Distributed for Comment Only -- Do Not Cite or Quote
CIR Panel Book Page 28
s_i..ClinicalResearchLaboratories, Inc.
Good Clinical PracticeQuality Assurance Audit Statement
Clinical Stuth Number: CR1. 169007
Start Date: i)ecember 10. 2007
Coin pietion Date: January 8, 2008
The clinical study listed above was conducted in accordance with Clinical Research
Laboratories. Inc. Standard Operathig Procedures, which incorporate the principles of
Good Clinical Practice defined by applicable guidelines and regulations established by
U.S. Regulatory Agencies. The conduct of the study was monitored for compitanec. and
the associated records. iniuding source documents or raw data, were reviewed for
documentdtlon prLtrts rnd .iccuraey b3 a Project Manager/Stud’ l)ircctor and ot
Quality Assurance Represcntative. Standard Quality Assurance audit procedures for this
tina) report and tudv reiated Gocuinents were conducted.. as indicated he1ox.
...—, 4
Sihature of QA Aur j.ate /
Distributed for Comment Only -- Do Not Cite or Quote
CIR Panel Book Page 29
(juI .‘Vii,nbr: CRLl6YthPgg3 nJ 9
FINAL. REPORT
An In-Use Safety Evaluation to l)etermine the OcularIrritation Potential of a Cmic Product
PURPOSE
The purpose of this study was to evaluate the potential of eyeliner products to inducesubjec1i e ocular irritation including stinging, burning. itching. dryness andior foreign bodysensation. In addition, this study assessed objective ophthalmic findings including
lacrimation, eyelid integrity. palpebral and bulbar conjunctival irritation, conicalabuormalides. and contact lens changes during 4 weeks of normal use in contact lenswearers and seif-assesed sensilive eye non-contact lens wearers.
INVESTIGATORS
Bruce F Kanensiser. M.D.Diploma!.e American Board of OphthalmologyPresident/Medical Director
Yang Gao. M.D.Senior Medical Research ScientistJOphthalmologist
Clinical Research laboratories. Inc.371 Hoes LanePiscatawa. New Jersey 08854732-981-1616
SPONSOR
TEST MATERIALS
The following test materials were provided by and were received by Clinical
Research Laboratories. Inc. on November 30. 2007:
r\utinatic lIveliner LHICS
j’7_3
I (
Distributed for Comment Only -- Do Not Cite or Quote
CIR Panel Book Page 30
kn
(Ud) Vuner: C RH6901)7
PgJif9
STUDY l)ATES
i’his stuth wac initiated on December 10. 2007 and was completed on January 8, 2D08.
STUDY POPULATION
A total of 33 female subjects, ranging in age from 18 to 68 ears and in generally good
health. were selected cor the study (Panelist Demographics — Apnendi I). Seventeen
subjects (52%) wore contact lens wearers and 16 subjects (48%) were selfassessed sensitive
eve noncontact lens wearers. Subjects selected the desired test material shade (Test
Material Assignment --Appendix ii). Subjects who met all of the inclusion criteria and none
of the exclusion criteria listed in the study protocol were enrolled lbr participation.
STUDY EXECUTION
This study was conducted according to the attached study protocol, CRLI69007AC 1 0.
TEST RESULTS
Completed and Discontinued Subjects
A total of 32 subjects completed the study. One subject (#30) discontinued study
participation ür reasons unrelated to test material use.
Ophthalmic Examinations
Individual ophthalmic examination results appear in Table I.
Trace increases in redness of the palpebral conjunctivae were observed in only 2 subjects at
the Week 4 examination. In the opinion of the Investigator, these findings were not related
to the use of the test materials and were most probably caused by external factors such as
hair products. mechanical factors, environmental and/or seasonal factors. rphere were no
i-coons of uhjectivc irriunion. There were no increases in lacrirnatina. eyelid inflammation.
er bulb u njuncna1 trritation and no hangcs an visual aunts cornual tissue mtcgnts or
contact lenses were Dbserved,
Distributed for Comment Only -- Do Not Cite or Quote
CIR Panel Book Page 31
TEST RESULTS (Continued)
,u ::l1:!’pr L1U.159OO7Ptig 5 of 9
Questionnaires
A summary of questionnaire responses appears in Attachment II. A comparison offavorable and unfavorable responses i.e each question appears below.
• (11 ides as fora smooth even application 96.9% 3.1%
• COflilOriRbp1CationafldWear 95.3% 4.7%
• Lasi1 h1eneci for a soft, subtle effect 95 3% 4 7%
• Proi&s high ntnsy ujavoff and cover - 12 5%
. l1iily metallic eflèct 84.4% l56%
eaieft1duct 78 1% 21 9%
3Jdti1Lsnr w.ar’ — 43 8% ‘56 3%
4 Pl’tse rate th. transfer-retant quality of this product 78 1% 21 9%
5. Please rate the smear-resistant quality of this product 68.8% 1 31 .3%
6. P1ee rate the e-resistant ua1i!’of thproduct 75.0% 25.0%
7Pcasr4e th true colorofodu__ 828°o 172%
8 Pkise rate th htveht feelofp9duct durinwear 875% 12%
9. Please rate the ability if the product to provide a high 79
10. Please rate the ease of removal with conventional make-up 4( 15 6%remo er,norma1 method of removal
Fur seEms o sn eveo nurnter of resp the percentage of sub;ect.c choosing the top responses wen, oddee toeether and the
noj of uFrc c hoosing the bostoni responsc wen, added ogethei For questions with at: cdd numbee of c.nses. the peecent.agc
of subyc: ehOosa s cew.rai poitwe r sponse (such as ed”) were spUr e ua1y been poseivc and eegaee caegortes The
,r :‘ oin a cet.n,T neutral tpcutse (uh as “oceher”) was added to neaeve xmses
Daily Diaries
lhere were no comments recorded on the Daily Diary that were related to reactions or
symptoms perceived during use of the test material.
TEST RESULTS (Continued)
Ultra soft texture and anlication
Adverse Events
There were no adverse events reported during the study period.
Distributed for Comment Only -- Do Not Cite or Quote
CIR Panel Book Page 32
L-:...r o....
SfIiai lk’1: CR1. 169Off9
CONCLUSION
The onhtha1rnit vntiiatinn of Automatic. Eyeliner Metallics
# over a 4.week use period did not demonstrate a potential for eliciting ophthalmiciuitat ion. In this test population, the test material is clinicafly safe for use by contact lenswearers and eIi-assessed sensitive eye noneontact lens wearers
Distributed for Comment Only -- Do Not Cite or Quote
CIR Panel Book Page 33
Fi,J P-—
Table!
Ophthalmic Examination Results
UO l?1bcF Rji”IPage f1
4 10 0 0 (3 0/00 0
)halrne ‘caics appear n the attuchod study protocol.NA — Not AplthLa. sal is not a c nael lens earer
3
0100 0 0
0 0/0 0/0 0/0 0/0 0 0 1 0 0 0 00 0/0 0/0 0/1 1 0/1 0
0 0/0 0/0 0/0 010
ojo0/0 0/0 1 0/0 C) 0 0 0 1 NA NA
NA NA
0 05 0u 0 0 0 0 010 010 0/0 0/0 0 0 0 0 NA NA
—
7-
0Q 0/0 0 0 0’O N NA- 8 010 0 0 0101 0/0 0/0 010 0 0 0 0 NA NA
0 OINA NA
9 0 0 0 0 0/0 [010 0/0 0/0 0 0 0 0 NA NA10 0 0 0 0 0/0 J 010 0/0 0/0 0 0 0 0 0 0I I 0 0 0 0 0/0 0/0 0/0 0/0 0 0 0 0 0 0
0 0 0 0 0/0 0/0 0/0 0/0 0 0 0 0 Itooo tC)\A
14 C) 0 0 0 0/0 0/0 0/0 0/0 0 0 0 (3 (3 015 0 0 0 0 0/0 0/0 0/0 0/0 0 0 0 0 0 016 0 0 0 0 0/GOIOT1R 1/I 0 0 0 0 (3 017 0 0 0 0 0/0 0/0 0/0 0/0 0 0 0 0 NA NA18 0 0 0 0 0/0 0/0 0/0 0/0 0 (3 0 0 NA NA
—
0 öTh 0/0 010 t0 U —° 0 020 0 0 0 0 0/0 0/0 0/0 0/0 o TT 1 o 0 Th o21 oo010000-2°J922 0 0 0 0 0/0 0/0 0/0 0/0 0 0 0 0 N A NA
23 0 0 0 0 0/0 0/0 0/0 0/0 0 0 0 0 NA NA—n- 1 0 0/0 010 0/0 0 0 0 0 0 [ Th
Th-
oio 02600100 0/0 0/010/0 0/00 0 0 T NA NA27 0 O00 0/010/00/00/00 0 010 NANA28 0 0 0 0 0/0 j 0/0 0/0 0/0 0 0 0 0 0 0
m: JLL_0/0100 0/0 0/0 0 0 0 010 030 Discontinued Stud
—Th32100 (3 00/00/00/00/00 Ou00 0
L. 0/0 0/0 0 0R Right !yc1. Left Eye
Distributed for Comment Only -- Do Not Cite or Quote
CIR Panel Book Page 34
Appendix I
Subject 1)emographics
SASE Sfsessed Sensitive EyesD1SP ssah1e Soft (ntat Lenses
irnbo’: CRLl65O7Faf 8 of
I2
ECPD 22L)
-
3D
3 SB I 179414 RA j 229105 TI) 22974 S6 LC 22990 S7 AR 171198 SS 22651
FFFF
9
35 F33 F37 F28 F
55 22861 SASE 57 FJO NP 19222 DISP 24 F
11 CP 19477 i)ISP 50 F
12 JM 13991 SASL 67 F
13 131 20206 SASE 59 .114 KP 22765 DISP 19 F
15 OK 18318 DISP 35 I16 MP 12034 DISP 63 F11 HI 07278 SASF 31 F
18 RR ‘0112 SASE 49 F
19 1311 — 9736 DISP 64 F20 Ml 7825 DISP 40 F
21 CM 21380 DISP 38 F
22 AM 17302 SASE 35 F23 DD 04567 SASE 48 F24 BM 21427 DJSP 18 F25 SR 23160 DISP 26 Ir BM 03450 SASE 41 1
27 231 15 SASE 21 F
28 SP 21038 DIS? 31 F29 P 18216 DISP 26 F
30 PK 23028 DISP 43 F
31 MM 22843 DJSP 45 1
32 JP 21061 DISP 27 F33 MC 15840 - DISP 25 1
Distributed for Comment Only -- Do Not Cite or Quote
CIR Panel Book Page 35
Appendix 11
Test Material Assignment
Sx4uy YVunthr: CJLIt9(i’)Pg ! fQ
2 1PD 22109 CRL169007.2
3 Sf3 17941 1 CRL169007-3
4 RA 22910 CRL169007-4
5 — ID 22974 CRL1690075 -
6 LC 22990 CRL169007-67 AR 17119 CRL169007-7
8 SS 22651 CRL169007-8
9 SS 22861 CRL169007-910 NP 9222 C.RL169007-l0
11 CP 9477 CRLI69007-11 112 - JM 3991 CRL169007-12 2
13 BL 20206 C,RL169007l3 2
KP 22765 CRL169007i4 215 DK 18318 CRL169007-15 2
16 MP 12044 CRL169007-16 2
17 HF 07278 CRLI69007-17 2
18 RR 10112 (R1l690071 2
19 SF1 19736 CRLI69007-19 2
20 MT 17825 CRL169007-20 2
21 CM 21380 CRL169007-21 2
22 - M 17302 CRL169o07-22 2
23 Di) 04567 CRL169007-23 3
24 ]3M 21427 CRL16900724 3
2 SR 23160 (RL169007-25 3
26 13M 03450 CRL169007-26 3
27-
j Ki 23115 CRL169007.27 3
28 SP 21038 CRL169007-28 3
29 - NP 18216 CRL169007-29 3
30 PK 23028 CRL16900730 3
31 MM 22843 CRL169007-31 3
32 JP j21061 CRL169007-32 3
3_ - MC-
CRL16900733 3Pmduc Code;1 CR!.Ij)OO7 1U)$756 SJvr Shade O2i)
2- C1U P-: R1>3715? (‘ pprShad O22)
3 CR1 69007-3 R1)376R7 Gnld Shadc 02O)
Distributed for Comment Only -- Do Not Cite or Quote
CIR Panel Book Page 36
Count and PercentP69307 Eyeliner
Please indicate which eyeliner you had been using?
Count PercerLt
r Sade k021
Srade #C22)
ct (Shade #020)
Ultre soft texture and application
Exce’lent
Very Good
Fair
Ghdes easily for a smooth even application
Excellent
Very Good
Good
Comfortable application and wear
Excellent
Very Good
Good
Easily blended for a soft, subtle effect
Excellent
Very Good
Good
Provides high intensity color payoff and coverage
Excellent
Very Good
Goad
Far
11 34.38%
12 37.50 %
28.13%
32 100%
20 62.50%
ii 34.38%
1 3.13 %
Total Responses 32 100%
17 53.13%
13 40.63%
2 6.26 %
Total Responses 32 100%
19 59,38%
10 31.25%
3 9.38%
Total ReSponses 32 100%
17 53.13%
12 37.60%
3 9.38%
Total Responses 32 100%
15 46.88%
11 34.38%
4 12,50%
1 3.13%
1 3.13%
Total Responses 32 100%
Total Responses
January 8, 2008 Page ‘1 ot3
Distributed for Comment Only -- Do Not Cite or Quote
CIR Panel Book Page 37
Count and PercentP69307 Eyeliner
Highly metallic effect
Count Percent
Exceem
Very Good
Gooo
Fair
Total Ftesponses
16 5000%
10 3125%
2 5.25%
I 313%
3 3,35%
32 100%
2. Please rate the long-lasting wear of thts product.
ExceHem
Very good
Good
13 hours Or more
11-12 nours
3-10 hours
7-8 hours
6 hours or iess
10 31.25%
11 34.38%
8 25.00 96
8.38%
32 100%
8 2500%
1 3.13%
10 31.25%
11 3438%
2 6.25%
32 100%Total Responses
4. Please rate the transfer-resistant quality of this product
Excellent
Very good
Good
Far
Total Responses
10 31.25%
11 34.38%
8 2500%
3 3.38%
32 100%
5. Please rate the smear-resistant quality of this product.
Exceern
Very good
Good
rar
Total Responses
9 23.13%
8 2505 96
10 31.25%
5 15.63 %
32 100%
3. Now long did this eyeliner wear?.
Total Responses
Janary 8, 20’38 Page 2 of 3
Distributed for Comment Only -- Do Not Cite or Quote
CIR Panel Book Page 38
Count and PercentP69307 EyelIner
6. Please rate the smudge-resistant quality of this product.
Count Percent
Exceflent
Very good
Goca
Fair
_______
S. Please rate the lightweight feel of this product during wear.
Exc&lent
Very good
Gooa
Fa
Total Responses
7 21.88%
12 37.50%
10 31.25%
9.38%
‘100%
15 46.88%
-II 3438%
4 12.50%
2 6.25%
32 100%
9, Please rate the abUity if the product to provide a high precision
Excellent
Very good
Good
Fair
Responses 32
10. Please rate the ease of removal wth conventional make-up
removersinormal method of removal:
9 28.13%
13 40.63%
7 21.88%
2 6.25%
3.13 %
100%
Very eesv
Somewha: easy
Neither easy nor dftiO.!
Somewhat di1c.iI
Total Responses 32
21 66.63 %
6 18.75%
3 3.38%
2 6.25%
100%
Excellem
Very good
Fair
7. Please rate the stay true calor of this product.
Total Responses 32
12 37.50%
11 34.38%
7 2188%
2 6.25%
Total Responses 2 100%
Ji..ay8 2008 Page 3 of 3
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CIR Panel Book Page 39
Consumer Product Testing Co.
FINAL REPORT
CL lENT:
ATfENT1ON
TEST: Repeated Insult Patch TestProtocol No.: 1,01
TESTMATERTAL.: 1311’iER( -c,-L’,O
EXPERIMENTREFERENCE NUMBER: C08-l3$7.02
fZL24—
Riciard R..Eisenberg, Mi).Boxd Certified Dermatologist
-i
Soyfan, LN.Executive Vice President, Clinical Evaluations
ReporL 1)atc:
fl :epor r tiie kw ee ecWe ue ef tha pro, pnrlner&Sp, or eop aIo, to s actresa, an rercr the ext nc thett-ete a atoes nr ,i’ rembar of itS staff, ma” be ueed hi e ttnacthin wtth the amchsrng or sale of ary product or cease
ei wx;ea
70 xw 1:wh L:ne • irIk:td, Nc\v Jersey O7004214 (73 808-71 Ii • tax i973) 8Cff724
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CIR Panel Book Page 40
Consumer Product Testing Co.
JAL1TY ASSURANCE UNITSTATEMENT
Study No.: CO8l37O2
The objective of the Quality Assurance Unit (QAU) is to monitor the conduct and reporting of clinicalktboratory studies. These studies have been performed with adherence to the applicable ICH GuideLineE6 for Good Clinical Practice and requirements provided for in 21 CFR parts 50 and 56 and inaccordance to standard operating procedures and applicable protocols. The QAU maintains copies ofstudy protocols and standard operating procedures and has inspected this study. All data perdrient tothis study will he stored in the Consumer Product Testing Company archive, unless specified otherwise,in writing by the Sponsor.
Quality Assurance personnel involved:
uaiitv Assurance ate
The representative signature of the Quality Assurance Unit signifies that this study has been performedin accordance with standard operating procedures and study protocol as well as government regulationsregarding such procedures and protocols.
70 New Dutch ne * Pai fi<1d, Ne’V Jersey O700425 14 (973) 8O$7 111 • Fax (973 SO87234Clinicai Toxicology • knaIytieal Chemistry • Microbiology
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C08-1387.02Page 3
Objective; To determine by repetitive epiderrnal contact the potential of a test materialto induce primary or cumulative irritation and/or allergic contactsensitization.
Participants; One hundred thirteen (113) qualified subjects, male and female, ranging inae from 16 to 79 years, were selected for this evauation. One hundredseven (107) subjects completed this study. The remaining subjectsdiscontinued their participation for various reasons, none of which wererelated to the application of the test material.
Inclusion Criteria: a. Male and female subjects, age 16a and over,b. Absence of any visible skin disease which might be confused with a skin
reaction from the test materiaLc, Prohibition of use of topical or systemic steroids and/or antihistarninos
for at least se’en days prior to study initiation.th Completion of a Medical Histoiy form and the understanding and
signing of an Informed Consent form.e Considered reliable and capable of following directions.
Exclusion Criteria: a. Ill health.b. Under a doctor’s care or taking medication(s) which could influence the
outcome of the study.c. Females who are pregnant or nursing.d A history of adverse reactions to cosmetics or other persona! care
products.
Test Material: EYELINER
Study Schedule: gç1# 1nitiatiojgg gption Datç
20080110 March 19,2008 May 1,200820080114 ?1arch 24,2008 May 1, 2008
\Vith narental or guardian consent
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C0-i ;.wPage 4
Methodology: The upper back between the scapulae served as the treatment area.Approximately 0.2 g of the test material, or an amount sufficient to cover thecantact surface, was applied to the l x 1” absorbent pad portion of a clearadhesive dressing*. This was then applied to the appropriate treatment site toform a semi-occlusive patch.
induction Phase:
Patches were applied three (3) times per week (eg., Monday, Wednesday,and Friday) for a total of nine (9) applications. The site was marked toensure the continuity of patch application. Following supervised removaland scoring of the first Induction patch, participants were Instructed toremove all subsequent Induction patches at home, twenty-four hours afterapplication. The evaluation of this Site was made again just prior to reanplication. If a participant was unable to report for an assigned test day, one(1) makeup day was permitted. This day was added to the Induction period.
With the exception of the first supervised Induction Patch reading, if any testsite exhibited a moderate 2-level) reaction during the Induction Phase.application was moved to an adjacent area. Applications were discontinuedfor the remainder of this test phase, if a moderate (2-Icvofl reaction wasobserved on this new test site. Applications would also be discontinued ifmarked (3-level) or severe (4-level) reactivity was noted.
Rest periods consstcd of twenty-four hours following each Tuesday and‘Thursday removal, and forty-eight hours following each Saturday removal.
Cbal1cnte Phase:
Approximately two (2) weeks after the final Induction patch application, aChallenge patch was applied to a virgin test site adjacent to the originalInduction patch site, following the same procedure described for Induction.The patch was removed and the site scored at the clinic twenty-four andseventy-two hours post-application.
*Nlauufactured by l’ruMed Technologies, Inc., Burnsvillc, MN
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CIR Panel Book Page 43
38702Page 5
Evaluation Criteria (Ervtbcrna and additional Dermal SeQuclac):
0 No visible skin reaction £ Edema0.51+ Barely perceptible D Dryness
I = Mild S Staining2 Mcderate 1> = Papules3 = Marked V Veshles4 = Severe 13 BuIlae
U Ulcerationpeading
Erythema was scored numerically according to this key. If present.additional Dermal Sequelae were indicated by the appropriate letter code anda numericai value for severity.
Results: The results ot each participant are appended (Table i)
Obsenrations remained negative throughout the test intervai.
Subject demographics are presented in Table 2.
Summary: Under the conditions of this study, test material. EYELINERid not indicate a potential
for dermal irritation or allergic contact sensitization.
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CIR Panel Book Page 44
Table 1Ptnel #20080110
Individual Results
c08-i 387.02Page 6
EYELINER
SubjectNumhr 24’hr ‘-4
—--——--Tnduction Phase—-------—-------3.__ 4 54____7.g - 9
Virgin ChaflengeSite
24*hr 72hr
19 0 0 0 0
20 0 0 0 0
21 0 0 0 0
22 0 0 0 023 0 0 0 024 0 0 0 025 0 0 0 0
26 0 0 0 027 0 0 0 0
28 0 0 0 0
o 0
o 00 0
00
0
0
0
0
o 0 0 0 0 0o 0 0 0 0 00 0 0 0 0S4 0S
0 00 00 0
o o0 00 00 0
o 00 0
0 0o 0
0 0o 0
I
j
0 0 0 0 0 0 0 00 0 0 0 0 0 0. 00 0 0 0 0 0 0 0
-DD NOT COMPLETh STUDY-----—5 0 0 0 0 0 0 0 0 06 0 0 0 0 0 0 0 0 07 0 0 0 0 0 0 0 0 08 0 0 0 0 0 0 0 0 09 0 0 0 0 0 0 0 0 010 0 0 0 0 0 0 0 0 011 0 0 0 0 0 0 0 0 0 0 0 012 0 0 0 0 0 0.0 0 0 0 0 013 0 0 0 0 0 0 0 0 0 0 0 014 0 0 0 0 0 0 0 0 0 0 0 015 0 0 0 0 0 0 0 0 0 0 0 016 0 0 0 0 0 0 0 0 0 0 0 017 0 0 0 0 0S+ 0S+ 05*. Os+ 0 0 018 0 0 0 0 0 0 0 0 0 0 0 0
0 0 0 0 0 0 0 0o 0 0 0 0 0 0 00 0 0 0 0 0 0 00 0 0 0 0 0 0 00 0 0 0 0 0
----DD NOT COMPLETE STUDYo 0 0 0 0 0 0 0
29 0 0 0 0 0 0 0 0 0 0
24* Supervised rrnova1 of 1 1nductio and Challenge PatchS Stainiig
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CIR Panel Book Page 45
Tabic I(continued)
Panel 20O801 10
Individual Results
C08- I 38702Page 7
EYELINER
Virgin ChallengeSubject ---————-—-———--Induction Phse—---——-——--- Siteur24*hr i__ 2 3 4 5 6 7 8 9
- 24hr2Jm
24 Supevisd rcmova of 1u induction and ChI1cnge Patch= Observations ro.orded 48 hours post challenge application. Subject
unabic to rpor& as scbcdued
30 0 0 0 0 0 0 0 0 0 0 0 031 0 0 0 0 0 0 0 0 0 0 0 032 0 0 0 0 0 0 0 0 0 0 0 033 0 0 0 0 0 0 0 0 0 0 0 034 0 0 0 0 0 0 0 0 0 0 0 035 0 0 0 0 0 0 0 0 0 0 0 036 0 0 0 0 0 0 0 0 0 0 0 037 0 0 --— ——------DIDNOTCOMPLETESTUDY—-—----—-—--—------38 0 0 0 0 0 0 0 0 0 0 0 039 0 0 0 0 0 0 0 0 0 0 0 040 0 0 0 0 0 0 0 0 0 0 041 0 0 0 0 0 0 0 0 0 0 0 042 0 0 0 0 0 0 0 0 0 0 0 0,4 0 0 0 0 0 0 00 0 0 0 044 0 0 0 0 0 0 0 0 0 0 0 045 0 0 0 0 0 0 0 0 0 0 0 046 0 0 0 0 0 0 0 0 0 0 0 047 0 0 0 0 0 0 0 0 0 0 0 048 0 0 0 0 0 0 0 0 0 0 0 049 0 0 0 0 0 0 0 0 0 0 0 050 0 0 0 0 0 0 0 0 0 0 0 05’ 0 0 0 0 0 0 0 0 0 0 0 052 0 0 0 0 0 0 0 0 0 0 0 053 0 0 0 0 0 0 0 0 0 0 0 054 0 0 0 0 0 0 0 0 0 0 0 055 0 0 0 0 0 0 0 0 0 0 0 056 0 0 0 0 0 0 0 0 0 0 0 057 0 0 0 0 0 0 0 0 0 0 0 0
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CIR Panel Book Page 46
C08-l 387.02Page 8
Table I(continued)
Panel #20080114
Individual Results
FXP1JNER (-
Virgin ChallengcSubje ——---—----lnduction Phase——-——-—---——----------— Siteub244htJ__ 3.. 4 _j 7 8 9 244hr72 hr
1 0 0 0 0 0 0 0 0 0 0 0 02 0 0 C) 0 0 0 0 0 0 0 0 03 0 0 0 0 0 0 0 0 0 0 0 04 0 0 0 0 0 0 0 0 0 0 0 05 0 0 0 0 0 0 0 00 0 0 06 0 0 0 0 0 OS,. 0 0 0 0 0 07 0 0 0 0 0 0 0 0 9 0 0 08 0 0 0 0 0 0 0 0 0 0 0 09 ---—
- —DID NOT COMPLETE STUDY————-—-——-—--10 0 0 0 0 0 0 0 0 0 0 0 0ii 0 0 0 0 0 0 0 0 0 0 0 012 0 0 0 0 0 0 0 0 0 0 0 013 0 0 0 0 0 0 0 0 0 0 0 014 0 0 0 0 0 0 0 0 0 0 0 015 0 0 0 0 0 0 0 0 0 0 0 016 0 0 0 0 0 0 0 0 0 0 0 017 0 0 0 0 0 0 0 0 0 0 0 018 0 0 0 0 0 0 0 0 0 0 0 019 0 0 0 0 0 0 0 0 0 0 0 020 0 0 0 0 0 0 0S1 S1 o o o21 0 0 0 0 0 0 0 0 0 0 0 022 0 0 0 0 0 0 0 0 0 0 0 023 0 0 0 0 0 0 0 0.0 0 0 024 0 0 0 0 0 0 0 0 0 0 0 025 0 0 0 0 o o 0S 0 0S4 0 0 026 0 0 0 0 0 0 Ô 0 0 0 0 02; 0 0 0 0 0 0 0 0 0 0 0 028 (1 0 0 0 0 0 0 0 0 0 0 029 0 0 0 0 0 0 0 0 0 0 0 0
24 — PatchS Stuining
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CIR Panel Book Page 47
C0-1 38 702Page 9
Table 1(continued)
Panel #20O01l4
kdividual Results
EYELINER—
Virgin ChaIlngeSubject -———-————--—lnduction Phasc—-—-----—————-— SiteNumber 24*hr 1 3 4 5 6 7 8 9 24*hr72
30 0 0 0 0 0 0 0 0 0 0 0 031 0 0 0 0 0 0 0 .0 0 0 0 032 0 0 0 0 0 0 0 0 0 0 0 033 0 0 0 0 0 0 0 0 0 0 0 034 0 0 0 0 0 0 0 0 0 0 035 0 0 0 0 0 0 0 0 0 0 0 036 0 0 0 0 0 0 0 0 0 0 o o37 0 0 0 0 0 0 0 0 0 0 0 038 0 0 0 0 0 0 0 0 0 0 0 039 0 0 0 0 0 0 0 0 0 0 -DNC—
(1 0 0 0 0 0 0 0 0 0 0 041 0 0 0 0 0 0 0 0 0 0 0 042 0 0 0 0 0 0 0 0 0 0 (1 043 0 0 0 0 0 0 0 0 0 0 0 044 0 0 0 0 0 0 0 0 0 0 0 045 0 —————-——----—---—DlDNOTCOMPLP1’ESTUDY—————-—--——46 0 0 0 0 0 0 0 0 0 0 0 047 0 0 0 00 0 0 0 0 0 0 048 0 0 0 0 0 0 0 0 0 0 0 049 0 0 0 0 0 0 0 0, 0 0 0 050 0 0 0 0 0 0 0 0 0 0 0 051 0 0 0 0 0 0 0 0 0 0 0 052 0 0 0 0 0 0 0 0 0 0 0 053 0 0 0 0 0 0 0 0 0 0 0 054 0 0 0 0 C) 0 0 0 0 0 0 055 0 0 0 0 0 0 0 0 0 0 0 056 0 0 0 0 0 0 0 0 00 0 0
24 Supcrvis rcnoval of t Induction and Clailenge Patchm Addtonzi1 n;akeup cky granted at tha discretion ofthe clinic supervisor
DNC I)id not comnew stucyS = Staining
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CIR Panel Book Page 48
Table 2Panel #20080110
C08-i 387.02Page 10
Subjee: —_______________________________
Nun Jnftials Age Sx
1 BL 69 F2 DO 72 F3 RD 52 M4 Al) 44 F5 3W 21 F6 AM 76 M7 ED 47 F8 DR 38 F9 RM 38 F10 PG 46 F11 DP 65 F12 JL 44 M13 flL 61 M14 NJ 52 Fis AR 41 F16 LP 25 F17 LM 70 F18 AC 38 F19 AL 51 M20 MV 26 F21 PL 49 F22 ES 55 F23 AL 25 M24 RL 67 M25 JP 72 M26 MF 16 F27 AA 24 F28 MK 41 F29 MD 43 F
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CIR Panel Book Page 49
Table 2(continued)
Panel 2O08O1 10
ic-cp
C08- I 37.02Page I I
SubjectNumber Initials ge Sx
30 Ri 37 F31 PW 48 M32 MC 32 F33 MR 53 F34 CC 71 M35 WV 49 M36 1? 26 F’37 JC 33 F38 DB 52 F39 JL 33 F40 BS 76 M41 FM 55 F’42 MM 55 F43 N 63 F44 CC 75 F45 AF 77 F46 SC $4 F47 YC 44 F48 JY 49 M49 05 79 F50 AD 56 F51 JD 59 M52 DS 77 M53 BR 49 F54 ZA 48 F55 CD 68 F56 LV 54 F57 MB 77 F
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CIR Panel Book Page 50
Table 2(continued)
Panel #20080114
eiDa
CO81 387.02Page 12
SuectNumber Initials ASe Sex
I JB 76 M2 PT 71 M3 WT 69 F4 JO 67 M5 LC 49 F6 GB 43 F7 LB 42 F8 WI 68 M9 NG 38 M10 PC 71 F11 RO 47 F12 ML 53 F13 TL 68 M14 JD 43 F15 CB 72 F16 AP 45 F17 PA 60 M18 EJ 67 F19 LB 37 F20 SG 67 M21 HR 60 M22 OS 30 F23 MC 41 M24, 3K 40 F25 GK 69 F26 PC 60 F27 FR 45 M2$ FR 79 F29 HR 72 F
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CIR Panel Book Page 51
Table 2(continued
Panel #20080114
ctL)ata
CO81 38702Page 13
SubjectNumber Initials Ae Sex
—- .-....................rn.—”
30 HS 65 F31 1.5 44 F32 SD 73 M33 KS 66 F34 IlK 79 F35 KH 39 F36 AP 43 M37 MP 39 M38 KF 70 F39 DH 50 M40 513 49 F41 KM 34 M42 GT 36 F43 LP 73 M44 PD 71 F45 LA 36 F46 MP 56 M4? EW 75 F48 HW 57 F49 JK 37 F50 .LO 64 F51 AD 47 F52 ME 48 M53 MB 49 F54 JO 28 F55 BR 61 F56 CZ 43 F
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CIR Panel Book Page 52
TO:
iProducts Counci
F. Alan Andersen, Ph.D.Director - COSMETIC INGREDIENT REVIEW (Cifi)
Committed to Safety,Quality & Innovation
FROM:
DATE:
John Bailey, Ph.D.Industry Liaison to the CIR Expert Panel
March 11,2011
SUBJECT: HRIPTs on a Product Contining Pentaerythrityl Tetraisostearate, and a ProductContaining Pentaerythrityl Tetracaprylate/Tetracaprate
TKL Research. 2010. Repeated insult patch test of a lip product containing 55% PentaerythritylTetraisostearate. TKL Study No.: DS11O11O-3.
Clinical Research Laboratories, Inc. 2006. Repeated insult patch test of a blush product containing 5%Pentaerythrityl Tetracapryl ate/Tetracaprate. CRL Study Number: CRL8 5006-1
1101 17th Street, N.W., Suite 300 Washington, D.C. 20036-4702 202.331.1770 202.331.1969 (fax) www.personalcarecouncil.org
Persona Care
Memorandum
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CIR Panel Book Page 53
RESEARCH
SUMMARY REPORT
TKL Study No.: DS1IO11O-3
Date of Report: November 24, 2010
Study Title; Repeated Insult Patch Test
Study Sponsor:
TKL Protocol No.: TKL-1000
Sponsor Reference No.:
Study Objective: To assess the sensitization potential of topically appliedstudy material.
Study Design: Standard RIPT methodology with nine 24-hourinduction applications and a single 24-hour challengeapplication following a 10- 15 day rest period.
Principal Investigator: Jonathan S. Dosik, MD - Dermatologist
Director, Dermatologic Safety Testing: Kathleen Georgeian
Manager, Dermatologic Safety Testing; Michelle Medina
Corporate Office: TKL Research, Inc365 W. Passaic StreetRochelle Park, NJ 07662
Study Site: TKL Research, Inc1 Palmer TerraceCarlstadt, NJ 07072
Study Dates: Date Study Initiated: October 6, 2010Date Study Completed: November 12, 2010
Study Material:
SPL Code and Category Amount Applied Patch Condition
Lip Gloss 0.2 g Occlusive
C’4c.’,1 55/o 7e-a)ojI-ccr-q4
D TKL Clinical Trials Division 0 TKL Clinical Site Division MTKL Recruitment Managenenf UWianCorporate Office: 365W. Passaic Street, Roct’eiIe Park, NJ 07662 Phone: 201•587’OSQfJ wtkireseafLcarn
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CIR Panel Book Page 54
SUMMARY REPORT (Continued)
TKL Study No.: DS11O11O-3
Page 2 of3
Number of Subjects: Enrolled: 1 14 Completed: 107
Discontinued: 7
Lost to follow-up: 6Protocol violation: I(Subject scratchedpatch area)
Listing of Attached Tables:
Appendix I Summary Tables
Appendix II Data Listings
SUMMARY AND CONCLUSION:
There were no adverse events reported.
Subject No. 001 showed evidence of pre-sensitization at the patch site at the ]st Induction Reading.The patch site had a reaction of definite erythema, definite edema (++). The subject was no longerpatched with the product and was lost to follow-up at the 5Ih Induction Reading.
A summary of response data is provided in Table 3, Appendix I. Individual dermatological responsegrades are provided in Data Listing 3 and residual readings in 3A, Appendix II.
Under the conditions employed in this study, there was no evidence of sensitization being induced bySPL Code
STATEMENT OF QUALITY CONTROL:
The Quality Control Unit of the Dermatological Safety Department conducted a 100% review of all
study-related documents. The protocol was reviewed prior to the start of the study, and the medical
screening forms and informed consent documents were reviewed in-process of the study. The regulatory
binder and study data were reviewed post-study to ensure accuracy. The study report was reviewed and
accurately reflects the data for this study.
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CIR Panel Book Page 55
SUMMARY REPORT (Continued)
TKL Study No.: DS11O11O-3
Page 3 of 3
SIGNATURES:
I have read this report and confirm that to the best of my knowledge it accurately
describes the conduct and results ofthe study.
JonathiiJ S.osiZ4D Date,
DermatoVgistlPrincipal Investigator
________
Kathleen Georgeian Date
Director, Derrnatologic Safety Testing
Michelle Medina Date
Manager, Dermatologic Safety Testing
1gpKript’MC\Beailty Avenues’DSI 101 10-3-R
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CIR Panel Book Page 56
APPENDIX I
SUMMARY TABLES
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CIR Panel Book Page 57
TKL Study No. DSIIOI 10Page 1 of I
Table I Summary of Subject Enrollment and Disposition
N (%)
Subjects enrolled114
Subjects completed induction phase 108 (94.7)
Subjects completed all phases107 (93.9)
Total subjects discontinued7 (6.1)
Lost to follow-up6 (5.3)
Protocol violation1 (0.9)
Note: All percentages are relative to total subjects enrolled.
See data listing I for further detail.
Generated on 11/15/10:16:53 by DISPSMY.SAS / Uses: FINAL
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TKL Study No. DSI 10110 Page 1 of 1
Table 2: Summary of Subject DemographicsAll Enrolled Subjects
Age
N(%) l8to44 36(31.6)
N (%)45 1o64 48(42.1)
N (%) 65 and up 30 (26.3)
Mean (SD) 52.7 (13.5)
Median 51.7
Range 20.8 to 75.5
Gender
N(%)Male 15(13.2)
N (%) Female 99 (86.8)
Race
Black 3 (2.6)
Caucasian 95 (83.3)
Hispanic 16(14.0)
See data listing 2 for further detail.
Generated on 11/15/10:16:53 by DEMOSMY.SAS / Uses: DEMOGS
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CIR Panel Book Page 59
TM. Study No. DSIIO1IO Page! of!
Table 3: Summary of Dermatologic Response Grades
Number of Subjects by Product
Product =
Induction Reading Challenge Phase
Make
Response 1 234 5 6 7 8 9 Up 48hr 72hr 96hr(*)
- 106 106 III 111 106 107 104 104 106 19 107 107
7 I 1 1 0 0 0 0 0 0 0 0 0
+ 1 0 0 0 0 0 0 0 0 0 0 0
+-t- 1 0 0 0 0 0 0 0 0 0 0 0
Total evaluable 109 107 112 111 106 107 104 104 106 19 107 107
Number absent 4 5 0 1 3 2 4 4 2 0 0
Number discontinued 1 1 1 I 5 5 6 6 6 7 7
Patch not applied 0 1 I I 0 0 0 0 1) 0 0
Maximum Elicited Response During InductionAll Subjects Completing Induction (N=l 08)
Response n(%) Subjects
-106 (98.1%)
7 1 (0.9%)
E 1 (0.9%)
(*) when required
See Table 3.1 for Key to Symbols and Scores
Generated on I 1115/i 0:16:53 by SUMMARYSAS/USES: RESPONSE, PRODLIST, FINAL
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CIR Panel Book Page 60
TKL Study No. DS1IOIIO
Table 3.1: Key To Symbols and Scores
Score or Response or
Symbol Description of Reaction
Erythema Results
No reaction
Minimal or doubtful response, slightly different from surrounding normal skin
+ Definite erytheina, no edema
±+ Definite eryihema, definite edema
+++ Definite erythema, definite edema and vesiculation
Additional Comments
X Reading not performed due to missed Visit or subject discontinuation
D Damage to epidermis: oozing, crusting andlor superficial erosions
E Markedlsevere erythema
I Itching
p Papular response >50%
pv Papulovesicular response >50%
S Spreading of reaction beyond patch site
NP Not patched due to reaction achieved
PD Patch dislodged
N9G No ninth grading
NA Not applied
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CIR Panel Book Page 61
TKL Study No. DSI 10110
Table 3.1: Key To Symbols and Scores
Score or Response or
Symbol Description of Reaction
Erythema Results
-No reaction
Minimal or doubtful response, slightly different from surrounding nommi skin
+ Definite erythema, no edema
Definite erythema, definite edema
Definite erythema, definite edema and vesiculation
Additional Comments
X Reading not performed due to missed visit or subject discontinuation
D Damage to epidermis: oozing, crusting and’or superficial erosions
E Marked/severe erythema
I Itching
p Papular response >50%
pv Papulovesicular response >50%
S Spreading of reaction beyond patch site
NP Not patched due to reaction achieved
PD Patch dislodged
N9G No ninth grading
NA Not applied
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CIR Panel Book Page 62
APPENDIX II
DATA LISTINGS
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CIR Panel Book Page 63
TKL STUDY NO. DSI 10110Page 1 of 4
Data Listing 1: Subject Enrollment and Disposition
Study DatesLast
Reading Completion Days in
Subject No. Screened 1st Applic Chall Applic Ended Status Study
001 10/06/10 10/06/10 --10/20/10 14 L 15
002 10/06/10 10/06/10 11/09/10 11/12/10 C C 38
003 10/06/10 10/06/10 11/09/10 11/12/10 C C 38
004 10/06/10 10/06/10 11/09/10 11/12/10 C C 38
005 10/06/10 10/06/10 11/09/10 11/12/10 C C 38
006 10/06/10 10/06/10 11/09/10 11/12/10 C C 38
007 10106/10 10/06/10 11/09/10 11/12/10 C C 38
008 10/06/10 10/06/10 11,09/10 11/12/10 C C 38
009 10/06/10 10/06/10 11/09/10 11/12/10 C C 38
010 10/06/10 10/06/10 11/09/10 11/12/10 C C 38
011 10/06/10 10/06/lU 11/09/10 11/12/10 C C 38
012 10/06/10 10/06/10 11/09/10 Il’l2!10 C C 38
013 10/06/10 10/06/10 11/09/10 11/1210 C C 38
014 I0/06/l0 10/06/10 11/09/10 11/12/10 C C 38
015 10/06/10 10/06/10 11/09/10 l1112/l0 C C 38
016 10/06/10 10/06/10 11/09/10 11/12/10 C C 38
017 10/06/10 10/06/10 11/09/10 11/12/10 C C 38
018 10/06/10 10/06/10 11/09/10 11/12/10 C C 38
019 10/06/10 10/06/10 11/09/10 11/12/10 C C 38
020 10/06/10 10/06)10 11/09/10 11/12/10 C C 38
021 10/06/10 10/06110 11/09/10 11/12/10 C C 38
022 10/06/10 10/06/10 11/09/10 11/12/10 C C 38
023 10/06/10 10/06/10 11/09/10 11/12/10 C C 38
024 10/06/10 10/06/10 11/09/10 11/12/10 C C 38
025 10/06/10 10/06/10 11/09/10 11/12/10 C C 38
026 10/06/10 10/06/10 1/09/10 11/12/10 C C 38
027 10/06/10 10/06/10 11/09/10 11/12/10 C C 38
028 10/06/10 10/06/10 11/09/10 11/12/10 C C 38
029 10/06/10 10/06/10 11/09/10 11/12/10 C C 38
030 10/06/10 10/06/10 11/09/10 11/12/10 C C 38
031 10/06/10 10/06/10 11/09/10 11/12/10 C C 38
Key:Last Reading # (1=lnduction Phase. C=Challenge Phase)
Completion Status (C’=Completed. LLost to follow-up, S=Voluntary withdrawal, VProtocol violation, AE=Adverse
event. O=Other)
Generated on 11/15110:16:53 by DISPLIST. SAS / Uses: DEMOGS, RESPONSE, FINAL
Distributed for Comment Only -- Do Not Cite or Quote
CIR Panel Book Page 64
TKL STUDY NO. DSI 10110Page 2 of 4
Data Listing I Subject Enrollment and Disposition
Study DatesLast
Reading Completion Days in
Subject No. Screened 1st Applic Chall Applic Ended 4 Status Study
032 10/06/10 10/06/10 11/09/10 11/12/10 C C 38
033 10/06/10 10/06/10 11/09/10 11/12/10 C C 38
034 10/06/10 10/06/10 11/09/10 11112/10 C C 38
035 10106/10 10/06/10 11/09/10 11/12/10 C C 38
036 10/06/10 10/06/10 11/09/10 1112/10 C C 38
037 10/06/10 10/06/10 l1/09i’lO 11/12/10 C C 38
038 10/06/10 10/06/10 11/09/10 11/12/10 C C 38
039 10/06/10 10/06/10 11/09/10 11/12/10 C C 38
040 10/06/10 10/06/10 11/09/10 11/12/10 C C 38
041 10/06/10 10/06110 11/09/10 11/12/10 C C 38
042 10/06/10 10/06/10 11/09/10 11/12/10 C C 38
043 10/06/10 10/06/10 11/09/10 11/12/10 C C 38
044 10/06/10 10/06/10 11/09/10 11/12/10 C C 38
045 10/06/10 10/06/10 --10118/10 14 V 13
046 10/06/10 10106/10 11/09/10 11/12/10 C C 38
047 10/06/10 10/06/10 11/09/10 11/12/10 C C 38
048 10/06/10 10/06/10 --10/22/10 16 L 17
049 10/06/10 10/06/10 11/09/10 11/12/10 C C 38
050 10/06/10 10/06/10 11/09/10 11/12/10 C C 38
051 10/06/10 10/06/10 11109/10 11112/10 C C 38
052 10/06/10 10/06/10 11/09/10 11/12/10 C C 38
053 10/06/10 10/06/10 11/09/10 11/12110 C C 38
054 10/06/10 10/06/10 11/09/10 11/12/10 C C 38
055 10/06/10 10/06/10 11/09/10 11/12/10 C C 38
056 10/06/10 10/06/10 11/09/10 11/12/10 C C 38
057 10/06/10 10/06/10 11/09/10 11/12/10 C C 38
058 10/06/10 10/06/10 11/09/10 11/12/JO C C 38
059 10/06/10 10/06/10 11/09/10 11/12/10 C C 38
060 10/06/10 10/06/10 11/09/10 11/12/10 C C 38
061 10/06/10 10/06/10 11/09/10 11/12/10 C C 38
062 10/06/10 10/06/10 --10/18/10 14 L 13
Key:Last Reading # (1Induction Phase, C=Challenge Phase)
Completion Status (C=Completed, L=Lost to follow-up, SVo1untary withdrawal, VProtocol violation, AEAdverse
cvent, O=Other)
Generated on 11/15/10:16:53 by D1SPLIST.SAS / Uses: DEMOGS, RESPONSE, FINAL
Distributed for Comment Only -- Do Not Cite or Quote
CIR Panel Book Page 65
TKL STUDY NO. DSI1OI1OPage 3of 4
Data Listing I: Subject Enrollment and Disposition
Study DatesLast
Reading Completion Days in
Subject No. Screened IstApplic Chall Applic Ended Status Study
063 10106/10 10106)10 11109/10 11/12/10 C C 38
064 10/06/10 10/06/10 11)09/10 11/12/10 C C 38
065 10/06/JO 10/06/10 11/09110 11)12/10 C C 38
066 10/06/10 10/06/10 -- 10/15/10 14 L 10
067 10/06/10 10/06/10 11/09/10 11/12/10 C C 38
068 10/06/10 10/06/10 11/09)10 11/12/10 C C 38
069 10/06/10 10/06/10 -- 10/11/10 10 L 6
070 10/06/10 10/06/10 11/09/10 11/12/10 C C 38
071 10/06110 10)06/10 --11/09)10 19 L 35
072 10/06110 10/06/10 11/09/10 11/12/10 C C 38
073 10/06/10 10/06/10 11/09/10 11/12/10 C C 38
074 10/06/10 10/06/10 11/09/10 11/12/10 C C 38
075 10/06/10 10/06/10 11/09/10 11/12/10 C C 38
076 10106/10 10/06/10 11/09/10 11/12/10 C C 38
077 10/06/10 10/06/10 11/09/10 11/12/10 C C 38
078 10/06/10 l0)06,’lO 11/09/10 11)12/10 C C 38
079 10/06/10 10/06/10 11109/10 11/12/10 C C 38
080 10)06)10 10/06/10 11/09/10 11/12/10 C C 38
081 10/06/10 10/06/10 11/09/10 11/12/10 C C 38
082 10/06/10 10/06/10 11/09/10 11/12/10 C C 38
083 10/06,10 10/06/10 11/09/10 11,12/10 C C 38
084 10/06/10 10/06/10 11/09/10 11/12/10 C C 38
085 10/06/10 10/06/10 11/09/10 11/12/10 C C 38
086 10/06/10 10/06/10 11/09/10 11/12/10 C C 38
087 10/06/10 10)06/10 11)09/10 11’12/10 C C 38
088 10/06/10 10/06/10 11/09,110 11/12110 C C 38
089 10/06/10 10/06/10 11/09/10 11/12/10 C C 38
090 10/06/10 10/06/10 11/09/10 11/12/10 C C 38
091 10/06/10 10/06/10 11/09/10 11/12/10 C C 38
092 10/06/10 10/06/10 11)09/10 11/12/10 C C 38
093 10/06/10 10/06/10 11/09/10 11/12/10 C C 38
Key:Last Reading # (Ilnduction Phase, C=Challenge Phase)
Completion Status (C=Completed, LLost to fo11owup, SVoluntary withdrawal, V=Protocol violation, AEAdverse
event, O=Other)
Generated on 11/15/10:16:53 by DISPLIST.SAS / Uses: DEMOGS. RESPONSE, FINAL
Distributed for Comment Only -- Do Not Cite or Quote
CIR Panel Book Page 66
TKL STUDY NO. DSI 10110Page 4 of 4
Data Listing 1: Subject Enrollment and Disposition
Study DatesLast
Reading Completion Days in
Subject No. Screened 1st Applic ChaH Applic Ended / Status Study
094 10/06/10 10/06/10 11/09110 11/12/10 C C 38
095 10106/10 10/06.10 11/09/10 11112,10 C C 38
096 10/06/10 10/06/10 11/09/10 11/12/10 C C 38
097 10/06/10 10/06/10 11/09110 11/12/10 C C 38
098 10/06/10 10/06/10 11/09/10 11/12/10 C C 38
099 10/06/10 10/06’lO 11/09/10 11/12/10 C C 38
300 10/06/10 10/06/10 11/09/10 11112/10 C C 38
101 10’06I10 10/06/10 11109/10 11’12/10 C C 38
102 10/06/10 10/06/10 11/09/10 11/12/10 C C 38
103 10/06/10 10/06/10 11/09/10 11/12/10 C C 38
104 10/06/10 10/06110 11/09/10 11/12/10 C C 38
105 10/06/10 10/06/10 11/09110 11/12/10 C C 38
106 10/06/10 10/06/10 11/09/10 11/12/10 C C 38
107 10/06/10 10/06/10 11/0910 11/12/10 C C 38
108 10/06/10 10/06/10 11/09/10 11/12/10 C C 38
109 10/06/10 10/06/10 11/09/10 11/12/10 C C 38
110 30/06/10 10/06/10 11/09/10 11/12/10 C C 38
III 10/06/10 10/06/10 11/09/10 11/12/10 C C 38
112 1O.’06/10 10106/10 11/09/10 11/12/10 C C 3X
113 10/06/10 10/06/10 11/09/10 11/12/10 C C St
114 10/06/10 10/06/10 11/09/10 11/12110 C C 3t
Key:Last Reading # (1=Induction Phase, CChal1cnge Phase)
Completion Status (CComp1eted. L=Lost to follow-up. SVoluntary withdrawal, VProtoco1 violation, AEAdverse
event, OOther)
Generated on 11/15/10:16:53 by DISPLIST.SAS / Uses: DEMOGS. RESPONSE, FINAL
Distributed for Comment Only -- Do Not Cite or Quote
CIR Panel Book Page 67
TKLSTUDYNO.DSIIO1IOPage lof 3
Data Listing 2: Subject Demographics
Subject No. Age Gender Race
001 53,8 Female Caucasian
002 47.3 Female Caucasian
003 74.2 Female Caucasian
004 57.0 Female Caucasian
005 66.8 Female Caucasian
006 71.4 Female Caucasian
007 40.7 Female Caucasian
008 74.1 Female Caucasian
009 27.3 Female Caucasian
010 30.3 Female Caucasian
011 69.5 Female Caucasian
012 43.1 Female Caucasian
013 55.1 Male Caucasian
014 49.9 Female Caucasian
015 54.0 Female Hispanic
016 50.7 Male Caucasian
017 51.9 Female Flispanic
018 55.8 Male Hispanic
019 68.3 Male Caucasian
020 54.0 Female Caucasian
021 49.6 Male Black
022 38.4 Female Hispanic
023 64.5 Female Caucasian
024 71.8 Male Caucasian
025 46.7 Female Hispanic
026 33.6 Female Caucasian
027 48.3 Female Caucasian
028 41.8 Female Caucasian
029 45.4 Female Caucasian
030 44.7 Female Caucasian
031 44.8 Female Hispanic
032 70.7 Male Caucasian
033 53.4 Female Caucasian
034 57.4 Female Caucasian
035 52.1 Female Caucasian
036 44.0 Female Caucasian
037 57.9 Female Caucasian
Generated on 11/15/10:16:53 by DEMOLIST,SAS / Uses: DEMOGS
Distributed for Comment Only -- Do Not Cite or Quote
CIR Panel Book Page 68
TKLSTUDYNO,DSI1OIIOPage 2o1 3
Data Listing 2: Subject Demographics
Subject No.
__________
Age Gender Race
038 46.6 Female Caucasian
039 65.2 Male Caucasian
040 51.3 Female Caucasian
041 44.8 Female Caucasian
042 46.4 Female Caucasian
043 43.4 Female Caucasian
044 43.4 Female Caucasian
045 47.9 Female Caucasian
046 41.2 Female Caucasian
047 29.9 Female Hispanic
048 33.4 Female Hispanic
049 51.6 Female Caucasian
050 42.4 Female Caucasian
051 47.5 Female Caucasian
052 37.8 Female Caucasian
053 20.8 Female Caucasian
054 71.2 Female Caucasian
055 44.5 Female Caucasian
056 32.8 Female Caucasian
057 68.5 Female Caucasian
058 56.3 Female Caucasian
059 36.5 Female Caucasian
060 57.7 Female Caucasian
061 51.0 Female Caucasian
062 40.0 Female Caucasian
063 68.6 Male Caucasian
064 65.9 Female Caucasian
065 70.4 Female Caucasian
066 24.8 Female Black
067 75.1 Female Caucasian
068 43.8 Female Caucasian
069 37.2 Female Caucasian
070 43.2 Female Caucasian
071 54.8 Female Caucasian
072 66.3 Female Caucasian
073 65.2 Female Caucasian
074 67.4 Female Caucasian
Generated on 11/15/10:16:53 byDEMOLIST.SAS /Uses: DEMOGS
Distributed for Comment Only -- Do Not Cite or Quote
CIR Panel Book Page 69
TKLSTUDYNO.DSIIOIIOPage 3of 3
Data Listing 2: Subject Demographics
Subject No. Age Gender Race
075 53.6 Male Caucasian
076 57.0 Female Caucasian
077 61.2 Male Hispanic
078 67.5 Female Caucasian
079 45.8 Female Caucasian
080 46.4 Female Caucasian
081 53.1 Female Hispanic
082 64.0 Female Hispanic
083 70.9 Male Caucasian
084 70.6 Female Caucasian
085 71.3 Female Caucasian
086 71,9 Female Caucasian
087 62.5 Female Caucasian
088 32.1 Female Hispanic
089 42.4 Female Caucasian
090 23.6 Male Caucasian
091 37.8 Female Caucasian
092 45.8 Female Caucasian
093 49.1 Female Caucasian
094 51.7 Female Caucasian
095 75.5 Female Hispanic
096 39.6 Female Black
097 39.8 Female Hispanic
098 72.1 Female Caucasian
099 50.4 Female Caucasian
100 42.2 Female Caucasian
101 26.0 Male Caucasian
102 41.5 Female Caucasian
103 69.1 Female Caucasian
104 64.6 Female Caucasian
105 46.6 Female Caucasian
106 67.9 Female Caucasian
107 70.3 Male Caucasian
108 74.9 Female Caucasian
109 48.1 Female Hispanic
I 10 52.6 Female Caucasian
111 70.0 Female Caucasian
112 58.4 Female Caucasian
113 57.5 Female Caucasian
114 63.6 Female Hispanic
Generated on 1 1/15,10:16:53 by DEMOLIST.SAS / Uses: DEMOGS
Distributed for Comment Only -- Do Not Cite or Quote
CIR Panel Book Page 70
TKL Study No. DS1IOIIOPage I of 5
Data Listing 3: Dermatologic Response Grades
By Product and Subject
Product
Induction Reading Challenge Phase
SubjectNo. 1 2 3 4 5 6 7 8 9 MU 4Shr 72hr 96hr(*)
001 NP NP NP X X X X X X X
002 - X -- -
- -
003 --
- -- -
004 - X - -- -
005 - - - -- -
006 - - - -- - -
007 - - - -- - -
008 -- - - -
-
009 - - --
-
010 7 - - - - --
011 4 9 7 --
012 - X -
013 - -- -
- --
014 -- - - - -
-
015 - - --
- -
016 - - -- -
- -
017 - - -- - - -
018 - -- - - - -
019 - - -- - - -
020 - -- - - -
-
021 - -- - - -
022 - -- -
- -
023 - -- -
- -
See Table 3.1 for Key to Symbols and Scores
MU = Make-up reading for missed induction visit
(*) When required
Generated on 11/15/10:16:53 by DETAILSAS/USES: RESPONSE, PRODLTST
Distributed for Comment Only -- Do Not Cite or Quote
CIR Panel Book Page 71
TKL Study No. DSI 10110Page 2 of 5
Data Listing 3: Dermatologic Response Grades
By Product and Subject
Product
induction Reading Challenge Phase
SubjectNo. 1 2 3 4 5 6 7 8 9 MU 48hr 72hr 96hr(*)
024 -- -
-- -
- - -- -
025 -- -
-- -
--
--
-
026 -- -
-- -
--
--
027 - -- - - -
-- -
- -
028 - - - -- -
- - --
-
029 --
- X - - - - -- - -
030 --
- - - X --
- --
-
031 -- - -
--
- --
--
032 --
- --
- - - --
-
033 - -- -
- -- - -
- -
034 - -- - -
- - -- -
035 -- -
- - --
-- -
036 -- - -
-- -
- -
037 - --
- --
--
- -
038 - --
- -- - -
- -
039 --
- -- - -
-
- -
040 --
- - -- -
--
--
041 - - -- - X - -
-- -
042 -- -
-- - -
--
--
043 --
- - - - X -- - - -
044 -- -
- - - X - - -- -
045 -- - - X X X X X X X
046 - -- - -
- --
--
-
(*) When required
Generated on I 1/15/10:16:53 by DETAIL.SAS/USES: RESPONSE, PRODLJST
Distributed for Comment Only -- Do Not Cite or Quote
CIR Panel Book Page 72
4
TKL Study No DS1IOI 10Page 3of 5
Data Listing 3: Dermatologic Response Grades
By Product and Subject
Product
Induction Reading Challenge Phase
SubjectNo. 1 2 3 4 5 6 7 8 9 MU 48hr 72hr 96hr(*)
047-
-- - - -
- -
048 - - - - X - X X X X X
049 -- -
- - - --
- -
050 -- -
- -- -
- --
-
051 - - - - -- - -
-- -
052 - - -- -
- - - -- -
053 -- -
- -- - - -
- -
054 - - -- -
- - - -- -
055 - - - - - - - --
-
056 -- -
- -- -
- -- -
057 -- -
- -- - - -
- -
058 X - - --
-- - - -
059 - - -- -
- -- -
--
060 - -- - - - -
--
-
061 - -- -
- -- -
-- -
062 X -- - X X X X X X X
063 -- - -
- -- -
-- -
064 - -- -
- -- -
-- -
065 - X -- - -
- -- -
- -
066 X --
- X X )( X X X X
067 - -- -
- -- -
-- -
068 - -- - - - -
- --
-
069 X X X X X X X X X X X
(*) When required
Generated on 11 / 15/10:16:53 by DETAIL.SAS/IJSES: RESPONSE, PRODLIST
Distributed for Comment Only -- Do Not Cite or Quote
CIR Panel Book Page 73
TKLStudyNo.DSIIOIIOPage 4o1 5
Data Listing 3: Dermatologic Response Grades
By Product and Subject
Product =
Induction Reading Challenge Phase
Subject
_______
No. 1 2 3 4 5 6 7 8 9 MU 48hr 72hr 96hr(*)
070 --
-
071 --
--
--
- - N9G X X
072-
-- -
-- - -
073 --
--
-- - -
074 - -- -
- --
075 --
--
--
- --
076 --
- --
- --
077 --
- --
--
078 - --
--
--
079 -X -
-
--
080 - -
-
-
081 -
--
--
-
082 - -- -
--
- -
083 -- -
- - --
- -
084 - - - -- -
- -
085 --
-- -
--
-
086 --
- --
--
-
087 -- -
--
--
-
088 - - --
--
- X - N9G
089-
-- -
X --
--
-
090 --
- X -- -
--
091 -- - - -
-- - N9G
092 -
(*) When requiredGenerated on 11/15/10:16:53 by DETAIL.SAS/USES: RESPONSE, PRODLIST
Distributed for Comment Only -- Do Not Cite or Quote
CIR Panel Book Page 74
TKL SludyNo. DSI 10110Page 5 of 5
Data Listing 3: Dermatoogic Response Grades
By Product and Subject
Product =
Induction Reading Challenge Phase
SubjectNo. 1 2 3 4 5 6 7 8 9 MU 48hr 72hr 96hr(*)
093 --
--
- --
--
--
094 --
--
--
--
--
095 -- -
- - -- -
-
096 --
-- - - -
--
--
097 --
-- -
-X -
--
--
098 -
-- - -
-- -
--
099 --
- -- -
--
--
100 -- - - -
-- -
--
-
101 --
- --
-- x -
--
102 - -- - - -
- --
--
103 --
- --
--
- --
-
104 --
--
--
- X -- - -
105 -- -
--
--
--
106 -- -
--
--
-
--
107 -- - - -
- -- -
--
108 -- -
- - - --
--
109 -- -
- --
--
-- -
110 - --
--
--
--
--
111 - -- - -
X -- - -
--
112 -- -
- --
--
-
- -
113 --
--
--
-X - -
- -
114 X --
--
--
-- - - -
(*) When required
Generated on 1],’15!10:16:53 by DETATL.SAS/USES: RESPONSE, PRODLIST
Distributed for Comment Only -- Do Not Cite or Quote
CIR Panel Book Page 75
TKL STUDY NO. DSJ 10110Page 1 of I
Data Listing 3A: Residual Readings
by Product and Subject
Product =
Induction Reading
SubjectNo. 1 2 3 4 5 6 7 8 9
001 -t ± 7
Generated on 11/15/10:16:53 by RESIDSAS / Uses: RESID, PRODLIST
Distributed for Comment Only -- Do Not Cite or Quote
CIR Panel Book Page 76
c
Clinical
• ResearchLaboratories. Inc.
Fina1 Report
Repeated Insult Patch Test
CLIENT: -
ATTENTI4)N
TEST MATERIAL. Cream ifiushc Pc:yi4YI • iQ I
CRL STUDY NUMER: CR1 64
—UTUOR1ZED SIGNATUIES: — /
nice E Kanengier M Michael uscatieU, Ph,R
President/Medic tor Executive iePresa*ntICOO
Georg.J”-$e ler, M DD1pionae American Board
of Dermatology
REPORT DATE: September 15, 20011
371 Hoes Lane’ Pscataway, NJ 08854• (732) 981-1616 • FAX (732) 981-0520
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CIR Panel Book Page 77
ClinicalResearchLaboratories. Inc.
G..d Clinical PracticeQuality Assurance Audit Statement
Clinical Study Number: CRL85006-l
Start Date: July 26, 2006
Completion Date: September 1, 2006
The clinical study listed above was conducted in accordance with Clinical Research
Laboratories, Inc. Standard Operating Procedures, which incorporate the principles of
Good Clinical Practice defined by applicable guidelines and regulations established by
U.S. Regulatory Agencies. The conduct of the study was monitored for compliance, and
the associated records, including source documents or raw data, were reviewed for
documentation practices and accuracy by a Project Manager/Study Director andlor a
Quality Assurance Representative. Standard Quality Assurance audit procedures for this
final rpø’ort and study related documents were conducted, as indicated below.
Signature of QA itor Date
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CIR Panel Book Page 78
Final ReportClient:Study Nurnbr: C’kLut,o-i
Page 3 of 13
FINAL REPORT
REPEATED INSULT PATCH TEST
PURPOSE
The purpose of this study was to determine the dermal irritation and sensitization
potential of a test material.
INVESTIGATIVE SITE
Clinical Research Laboratories, Inc.371 Hoes LanePiscataway, New Jersey 08854732-981-1616
TEST MATERIAL
The following test material was provided by and was received by
Clinical Research Laboratories, Inc. on July 20, 2006:
II Test Material Test Condition Patch Type
I Cream Blush I Test as received Occlusive*
The test material was coded with the following CRL identification number:
CRL85006- 1
STUDY DATES
This study was initiated on July 26, 2006 and was completed on September 1, 2006.
* Occlusive Strip with Flexcon® (TruMed Technologies Inc., Bumsville, Minnesota)
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CIR Panel Book Page 79
Final Reni,rl
Client:Study Number: cRL8SOO6-1Page 4 of13
PANEL SELECTION
Each subject was assigned a permanent CRL identification number. All subjects signed
an Informed Consent Form in compliance with 21 CFR Part 50: “Protection of Human
Subjects” and a HIPAA Authorization Form in compliance with 45 CFR Parts 160 and
164. All subjects completed a Subject Profile/Medical History Form provided by
Clinical Research Laboratories, Inc. prior to the study (Subject Demographics -
Appendix 1). Subjects who met the following criteria were impaneled:
• Male and female panelists between the ages of 18 and 70;
• Subjects who have completed a Panelist Profile/Medical History;
• Subjects who are in general good health as determined by a Panelist Profile/Medical
History;
• Subjects who do not exhibit any skin diseases that might be confused with a skin
reaction from the test material;
• Subjects willing to sign an Informed Consent Form in conformance with 21 CFR
Part 50: “Protection of Human Subjects’;
• Subjects who have completed a HIPAA Authorization Form in conformance with 45
CFR Parts 160 and 164;
• Females who are not pregnant or lactating;
• Subjects who demonstrate dependability and intelligence in following directions;
• Subjects who are not currently using any systemic or topical corticosteroids, anti
inflammatory drugs or antihistamines.
TEST METHOD
Prior to the application of the patch, the test area was wiped with 70% isopropyl alcohol
and allowed to dry. The test material, which was prepared as described in the Test
Material section of the report, was applied to the upper back (between the scapulae) and
was allowed to remain in direct skin contact for a period of 24 hours.
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CIR Panel Book Page 80
Final RenortClient:Stud, Number: CRL8SOO6-l
Page 50113
TEST METHOD (Continued)
Patches were applied to the same site on Monday, Wednesday, and Friday for a total of 9
applications during the Induction Period. This schedule may have been modified to
allow for missed visits or holidays, if a subject was unable to report on an assigned test
date, the test material was applied on 2 consecutive days during the Induction Phase
andlor a makeup day was added at the end of the Induction Phase.
The sites were graded by a CRL technician for dermal irritation 24 hours after removal of
the patches by the subjects on Tuesday and Thursday and 48 hours after removal of the
patches on Saturday, unless the patching schedule was altered as described above.
The sites were graded according to the following scoring system:
Dermal Scoring Scale
O No visible skin reaction+ Barely perceptible erythema1+ Mild erythema2+ Well defined erythema3+ Erythema and edema4+ Erythema and edema with vesiculation
If a ‘2+” reaction or greater occurred, the test material was applied to an adjacent virgin
site. If a ‘2+” reaction or greater occurred on the new site, the subject was not patched
again during the Induction Phase but was challenged on the appropriate day of the study.
At the discretion of the Study Director, patch sites with scores less than a ‘2+” may have
been changed.
Following approximately a 2-week rest period, the challenge patches were applied to
previously untreated test sites on the back. After 24 hours, the patches were removed by
a CRL technician and the test sites were evaluated for dermal reactions. The test sites
were re-evaluated at 48 and 72 hours. Subjects exhibiting reactions during the Challenge
Phase of the study may have been asked to return for a 96-hour reading.
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CIR Panel Book Page 81
Final Renatclient:Study Number: CRL85006-?Page 6 of 13
RESULTS
This study was initiated with 119 subjects. Four subjects discontinued study
participation for reasons unrelated to the test material. A total of 115 subjects completed
the study.
Individual dennal scores recorded during the Induction and Challenge Phases appear in
Table I.
CONCLUSION
Based on the test population of 115 subjects and under the conditions of this study, the
test material identified as Cream Blush did not demonstrate a clinically
significant potential for eliciting dermal irritation or sensitization.
RETENTION
Test materials and all original forms of this study will be retained by Clinical Research
Laboratories, Inc. as specified in CRL Standard Operating Procedure 30.6C, unless
designated otherwise by the Sponsor.
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CIR Panel Book Page 82
TABLE I
Summary of Dermal Scores
Final R,’nert
Client: -
Study Number: CRL8500ó-lPage 7of 13
Cream Blush
:tion Scores a ‘haHflQ&Øre3:.r24
5 6 7 8 - Hour llodi Hbur
I
1 0 o 0 0 0 0 0 0 00
2 0 0 0 0 0 0 0 0 0 0 0 0
3 0 0 0 0 0 0 0 0 0 0 0 0
4 0 0 0 0 0 0 0 0 0 0 0 0
5 0 0 0 0 0 0 0 0 0 0 0 0
6 0 0 0 0 0 0 0 0 0 0 0 0
7 0 0 0 0 0 0 0 0 0 0 0 0
8 0 0 0 0 0 0 0 0 0 0 0 0
9 0 0 0 0 0 0 0 0 0 0 0 0
10 0 0 0 0 0 0 0 0 0 0 0 0
11 0 0 0 0 0 0 0 0 0 0 0 0
12 0 0 0 0 0 0 0 0 0 0 0 0
13 0 0 0 0 0 0 0 0 0 0 0 0
14 0 0 0 0 0 0 0 0 0 0 0 0
15 0 0 0 0 0 0 0 0 0 0 0 0
16 0 0 0 0 0 0 0 0 0 0 0 0
17 0 0 0 0-0 0 0 0 0 0 0 0
18 0 0 0 0 0 0 0 0 0 0 0 0
19 0 0 0 0 0 0 0 0 0 0 0 0
20 0 0 0 0 0 0 0 0 0 0 0 0
21 0 0 0 0 0 0 0 0 0 0 0 0
22 0 0 0 0 0 0 0 0 0 0 0 0
23 0 0 0 0 0 0 0 0 0 0 0 0
24 0 0 0 0 0 0 0 0 0 0 0 0
25 0 0 0 0 0 0 0 0 0 0 0 0
Nurnb12
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CIR Panel Book Page 83
TABLE I(Continued)
Summary of Dermal Scores
Final Rp”Client:Study Nu,nber: cRL8500o-lPage 8 of 13
.4 Cream Blush 1Wtductkm Scores ____
____
4 567
27 0 0 0 0 0 0 0 0 0 0 0 0
28 0 0 0 0 0 0 0 0 0 0 0 0
29 0 0 0 0 0 0 0 0 0 0 0 0
30 0 0 0 0 0 0 0 0 0 0 0 0
31 0 0 0 0 0 0 0 0 0 0 0 0
32 0 0 0 0 0 0 + 0 0 0 0 0
33 0 0 0 0 0 0 0 0 0 0 0 0
34 0 0 0 0 0 0 0 0 0 0 0 0
35 0 0 0 0 0 0 0 0 0 0 0 0
36 0 0 0 0 0 0 0 0 0 0 0 0
37 0 0 0 0 0 0 0 0 0 0 0 0
38 0 0 0 0 0 0 0 0 0 0 0 0
39 0 0 0 0 0 0 0 0 0 0 0 0
40 0 0 0 0 0 0 0 0 0 0 0 0
41 0 0 0 0 0 0 0 0 0 0 0 0
42 0 0 0 0 0 0 0 0 0 0 0 0
43 0 0 0 0 0 0 0 0 0 0 0 0
44 0 0 0 0 0 0 0 0 0 0 0 0
45 0 0 0 0 0 0 0 0 0 0 0 0
46 0 0 0 0 0 0 0 0 0 0 0 0
47 0 0 0 0 ± 0 0 0 0 0 0 0
48 0 0 0 0 0 0 0 0 0 0 0 0
49 0 0 0 0 0 0 0 0 0 0 0 0
50 0 0 0 0 0 0 0 0 0 0 0 0
0 026 0 0
3
0 0 0 0
9
S
48 72
-—
Ilour
0 00
hour0
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CIR Panel Book Page 84
Final Rennet
TABLE 1(Continued)
Summary of Dermal Scores
Client:Studj Number: cRL8500O-lPage 9of13
Test Material: j Cream Blush
Subject Induction Scores Challenge Scores
Number 1 2 3 4 5 J 6 7 824 48 72
Hour Hour Hour
51 0 0 0 0 0 0 0 0 0 0 0 0
52 0 0 0 0 0 0 0 0 0 0 0 0
53 0 0 0 0 0 0 0 0 0 0 0 0
54 0 0 0 0 0 0 0 0 0 0 0 0
55 0 0 0 0 0 0 0 0 0 0 0 0
56 0 0 0 0 0 0 0 0 0 0 0 0
57 0 0 0 0 0 0 0 0 0 0 0 0
58 0 0 0 0 0 0 0 0 0 0 0 0
59 0 0 0 0 0 0 0 0 0 0 0 0
60 0 0 0 0 0 0 0 0 0 0 0 0
61 0 0 0 0 0 0 0 0 0 0 0 0
62 0 0 0 0 0 0 0 0 0 0 0 0
63 0 0 0 0 0 0 0 0 0 0 0 0
64 0 0 0 0 0 0 0 0 0 0 0 0
65 0 0 0 0 0 0 0 0 0 0 0 0
66 0 0 0 0 0 0 0 0 0 0 0 0
67 0 Discontinued
68 0 0 0 0 0 0 0 0 0 0 0 0
69 0 0 0 0 0 0 0 0 0 0 0 0
70 0 0 0 0 0 0 0 0 0 0 0 0
71 0 0 0 0 0 0 0 0 0 0 0 0
72 0 0 0 0 0 0 0 0 0 0 0 0
73 0 0 0 0 0 0 0 0 0 0 0 0
74 0 0 0 0 0 0 0 0 0 0 0 0
75 0 0 0 0 0 0 0 0 0 0 0 0
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Fi,,aI Ree’art
TABLE I(Continued)
Summary of Dermal Scores
Client:Study Number: CRL85006-lPage IOofi3
Cream B’ush
76 0 0
4
0 0 0 0
6 7 8’1 9 -
- 24 4S 72 -
I Hour Hour Hour
0
jige Scores
0 0 0 0 0
77 0 0 0 0 0 0 0 0 0 0 0 0
78 0 0 0 0 0 0 0 0 0 0 0 0
79 0 0 0 0 0 0 0 0 0 0 0 0
80 0 0 0 0 0 0 0 0 0 0 0 0
81 0 0 0 0 0 0 0 0 0 0 0 0
82 0 0 0 0 0 0 0 0 0 0 0 0
83 0 0 Discontinued
84 0 0 0 0 0 0 0 0 0 0 0 0
85 0 0 0 0 0 0 0 0 0 0 0 0
86 0 0 0 0 0 0 0 0 0 0 0 0
87 0 Discontinued
88 0 0 0 0 0 0 0 0 0 0 0 0
89 0 0 0 0 0 0 0 0 0 0 0 0
90 0 0 0 0 0 0 0 0 0 0 0 0
91 0 0 0 0 0 0 0 0 0 0 0 0
92 0 0 0 0 0 0 0 0 0 0 0 0
93 0 0 0 0 0 0 0 0 0 0 0 0
94 0 0 0 0 0 0 0 0 0 0 0 0
95 0 0 0 0 0 0 0 0 0 0 0 0
96 0 0 0 0 0 0 0 0 0 0 0 0
97 0 0 0 0 0 0 0 0 0 0 0 0
98 0 0 0 0 0 0 0 0 0 0 0 0
99 0 0 0 0 0 0 0 0 0 0 0 0
100 0 0 0 0 0 0 0 0 0 0 0 0
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CIR Panel Book Page 86
TABLE I(Continued)
Summary of Dermal Scores
Flual Re’’”Client:Study Number: CRL85006-lPage II oJ13
1: J Cream Blush
I 2 Li
i Sceres:
5 6
‘1haIIenge Scores24 48
&j7 Hour Hour72
Hour
101 0 0 0 0 0 0 0 0 0 0 0 0
102 0 0 0 0 0 0 0 0 0 0 0 0
103 0 0 0 0 0 0 0 0 0 0 0 0
104 0 0 0 0 0 0 0 0 0 0 0 0
105 0 0 0 0 0 0 0 0 0 0 0 0
106 0 0 0 0 0 0 0 0 0 0 0 0
107 0 0 0 0 0 0 0 0 0 0 0 0
108 0 0 0 0 0 0 0 0 0 0 0 0
109 0 0 0 0 0 0 0 0 0 0 0 0
110 0 0 0 0 0 0 0 0 0 0 0 0
111 0 0 0 0 0 0 0 0 0 0 0 0
112 0 0 0 0 0 0 0 0 0 0 0 0
113 0 0 0 0 0 0 0 0 0 0 0 0
114 0 0 0 0 0 0 0 0 0 0 0 0
115 0 0 0 0 0 0 0 0 0 0 0 0
116 0 0 0 0 0 0 0 0 0 0 0 0
117 0 0 0 Discontinued
118 0 0 0 0 0 0 0 0 0 0 0 0
119 0 0 0 0 0 0 0 0 0 0 0 0
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CIR Panel Book Page 87
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CIR Panel Book Page 88
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Distributed for Comment Only -- Do Not Cite or Quote
CIR Panel Book Page 89
TO:
FROM:
DATE:
‘Products CouncilCommitted to Safety,Quality & Innovation
F. Alan Andersen, Ph.D.Director - COSMETIC INGREDIENT REVIEW (CIR)
John Bailey, Ph.D.Industry Liaison to the CIR Expert Panel
May 2, 2011
SUBJECT: Contact Allergenicity: Pentaerythrityl Tetrabehenate/Benzoate/Ethylhexanoate andPentaerythrityl TetraethylhexanoatelBenzoate
Anonymous. 2011. Safety data (contact allergenicity in guinea pigs) of PentaerythritylTetrabenzoate/Benzoate/Ethylhexanoate and Pentaerythrityl Tetraethylhexanoate/Benzoate.
11011 7th Street, N.W., Suite 300 Washington, D.C. 20036-4702 202.331.1770 202.331.1969 (fax) www.personalcarecouncil.org
Personal Care
Memorandum
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CIR Panel Book Page 90
SAFETY DATA OF
PENTAERYTHRITYLTETRABEHENATEJBENZOATEJETHYLIIEXANOATE
ANDPENTAERYTIIRITYL
TETRAETHYLHEXANOATE/BENZOATE
April 28th, 2011
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CIR Panel Book Page 91
Index
PENTAERYTHRITYLTETRABEIIENATE[BENZOATE[ETHYLHEXANOATE
- 1. Contact Allergenicity
PENTAERYTITRITYLTETRAETIIYLHEXANOATE/BENZOATE
1. Contact Allergenicity
‘1
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CIR Panel Book Page 92
C
PENTAERYTHRITYLTETRABEIIENATE/BENZOATtIETHYLHEXANOATE
1. Contact allergenicity
Contact allergenicity of PENTAERYTHRITYL TETRABEHENATEfBENZOATEJETHYLHEXANOATE was evaluated by adjuvant & patch test method*. The test method and results were summarized as follows.
* Sato Y., et al., Contact Dermatitis, 7, 225-237, 1981
Date of the first exposure (induction phase): June 8, 2010Test laboratory: Nihon Bioresearch Inc.Animals: Species, and strain: Ten female Hartley strain albino guinea pigs
Age and body weight at the beginning of the study: 8 weeks of age;341-385 g
Animal room environment: Each animal was individually housed in stainless steel cage.Room temperature and the humidity were maintained at 20-26°C and40-77.5%. Light cycle was 12 hr on and 12 hr off per day.
PENTAERYTHRITYL
I: PENTAERYTHRITYI TETRABEHENATE/BENZOATE/TETRABEHENATE/
BENZOATE/ ETHYLHEXANOATE;16.6% and 50% inETHYLHEXANOATE
Acetone,
________________________ ________________________
AcetonePENTAERYTHRITYLTETRABEHENATE/
BENZOATE/Acetone ETHYLHEXANOATE;
16.6% and 50% inAcetone,
________________________ ________________________
Acetone
Method:Test group: Fifleen animals were divided into two groups, 10 treated with PENTA
ERYTHRITYL TETRABEHENATEIBENZOATE/ETHYLHEXANOATE(Group I) and 5 treated with acetone as control group (Group II). The nuchalarea of guinea pigs was clipped and shaved free ofhair, and about 3 X 4 cm ofthe area was treated as follows.
Induction: 1) On the first day, 0.1 mL of emulsified *FCA(E..FCA), prepared from equalvolumes of FCA and distilled water, was injected intradermally at the 4
Test materials and test groups:
Test materialsNumber 0:Groupsanimals Induction phase Challenge phase
10
PENTAERYTHRITYLTETRABEHENATE/
BENZOATE/ETHYLHEXANOATE;
16.6% in Acetone
II: Acetone (Control)
2
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CIR Panel Book Page 93
corners of a shaved 3 )< 4 cm nuchal area. A criss-cross lattice of abrasionswas made at each site of injection.* Freund’s Complete Adjuvant2) A 0.1 mL aliquot of the test material was applied occiusively for 24 hrs onthe injection sites ofE-FCA on Group I animals. The plaster was removed andthis application was repeated for the following 2 days. Control animals (GroupII) were treated with acetone.3) One week following the injection, 50 mg of 10% sodium lauryl sulfate inpetrolatum was applied to the nuchal area.4) On the next day, 0.2 mL of test materials was applied on Group I animalsocclusively for 48 hrs. Control animals (Group II) were treated with acetone.
Challenge: Three weeks after the first induction, 0.01 mL of test materials was topicallyapplied on the flank of animals of each group clipped free of hair.
Assessment: The reaction with respect to erythema, esehar formation, and edema werescored at 24 and 48 hours after challenge according to the criteria as followingscoring.
Scoring criteria of skin reaction:
________
Skin reaction Score(1) Erythema formationNo erythema 0Very slight erythema (barely perceptible) 1Well defined erythema 2Moderate to severe erythema 3Severe erythema (beet redness) to slight eschar formation 4(injuries in depth)
(2) Edema formationNo edema 0Slight edema 1Moderate edema 2Severe edema (raised more than 1 mm and extending beyond 3area of exposure)
Evaluation of skin reaction (scoring):
Moderate to severe erythema 3
Severe erythema (beet redness) to slight eschar formation(injuries in depth) and severe edema (more than 1 mm and 4extending beyond area of exposure)
Severity of erythema and edema formation
No Erythema
Very slight erythema (barely perceptible)Well defined erythema
Score
0
1
2
When the score of skin reaction was 2 and over, the reaction was judged as positive.
3
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CIR Panel Book Page 94
Results and conclusion:No reactions were observed in all the animals of both groups challenged with 16.6 and50% PENTAERYTHRITYL TETRABEHENATE/BENZOATE/ETIIYLHEXANOATE in Acetone as shown in Table 1. It is concluded that PENTAERYTHRITYLTETRABEHENATE/BENZOATE/ETIIYLHEXANOATE does not possess sensitizingpotential under the test conditions.
Table 1 Contact aflergenicity ofPENTAERYTHRITYL TETRABEHENATE/BENZOATE/ETHYLHEXANOATE
Induction 16.6% AcetonePENTAERYTHRITYL
. TETRABEHENATE/. BENZOATE/ETIIYL
HEXANOATE. PENTAERYTHRITYL PENTAERYTHRITYL
TETRABEHENATE/ TETRA.BEHENATE/Challenge , BENZOATE/ETHYL- BENZOATE/ETHYL
HEXANOATE FIEXANOATE16.6 and 50% 16.6 and 50%
Number of animal 10 5Sensitization rateHours after challengeapplication,
24 0/10 0/548 0/10 0/5
a): number of positive animals! number of animals
4
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CIR Panel Book Page 95
PENTAERYTBRITYLTETRAETHYLHEXANOATEJBENZOATE
1. Contact allergenicityContact allergenicity of PENTAERYTHRITYL TETRAETHYLHEXANOATEJBE
NZOATE was evaluated by the shortened adjuvant & patch test method*. The test methods and results were summarized as follows.
*: Yanagi M., et al., Contact Dermatitis, 44: 140-145, 2001
Date of the first exposure (induction phase): July 23, 2003Test laboratory:Animals: Species, and strain: Ten female Hartley strain albino guinea pigs.
Age and body weight at the beginning of the study: 8 weeks of age;427.2-479.0 g
Animal room environment: Each animal was individually housed in stainless steel cage.Room temperature and the humidity were maintained at 20-26°C and40-70%. Light cycle was 12 hr on and 12 hr offper day.
Test materials and test groups:
Number Test materialsGroups of
animals Induction phase Challenge phase
PENTAERYTHRITYLPENTAERYTHRITYLI: PENTAERYTIIRITYL TETRAETHYLHEXATETRAETHYLHEXATETRAETHYLHEXA- 5 NOATE/BENZOATE;NOATE/BENZOATE;NOATEIBENZOATE 1.8, 3.6, 7.2, 18, 36, 50,100%. 72 and 100% inEtOH
PENTAERYTHRITYLTETRAETHYLHEXA
II: EtOH (Control) 5 EtOll NOATE/BENZOATE;1.8, 3.6, 7.2, 18, 36, 50,72 and 100% in EtOH
Methods:Test group: Ten animals were divided into two group, in each group. One group was
for the treatment with PENTAERYTHRITYL TETRAETHYLHEXANOATEFBENZOATE (Group I) and the other was for the control (Group II).
Induction phase: On the first day (Day 0), 0.1 mL of emulsified FCA* (E-FCA) preparedfrom equal volumes of FCA and distilled water was injected intradermally at the 4corners of a shaved 3 x 4 cm nuchal area of all the animals. A criss-cross lattice ofabrasions was made at each injection site. 0.1 mL ofthe test material was applied tothe injection sites on Group I animals for 72 Irs. On the 7th day after theapplication, 0.4 mL of the test material was occlusively applied for 48 Irs on thenewly abraded nuchal area. Control animals (Group II) were treated with EtOH.
*: Freund’s Complete Adjuvant
5
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CIR Panel Book Page 96
Challenge phase: On the 14th day, 0.01 mL of test materials was topically applied on theclipped back of animals in each group.
Assessment: The reaction with respect to erythema, eschar formation, and edema werescored at 24 and 48 hours after challenge according to the criteria as followingscoring.
Scoring criteria of skin reaction:
___________
Skin reaction Score(1) Erythema formationNo erythema 0Very slight erythema (barely perceptible) 1Well defined erythema 2Moderate to severe erythema 3Severe erythema (beet redness) to slight esehar formation 4(injuries in depth)
(2) Edema formationNo edema 0Slight edema 1Moderate edema 2Severe edema (raised more than 1 mm and extending beyond 3area of exposure)
Evaluation of skin reaction (scoring):
Severity of erythema and edema formation
Well defined erythema 2Moderate to severe erythema 3Severe erythema (beet redness) to slight eschar formation(injuries in depth) and severe edema (more than 1 mm and 4extending beyond area of exposure)
No Erythema
Very slight erythema (barely perceptible)_________
Score
0
1
When the score of skin reaction was 2 and over, the reaction was judged as positive.
Results and conclusion:No reactions were observed in all the animals of both groups challenged with 1.8, 3.6,7.2, 18,36,50,72 and 100% PENTAERYTHRITYLTETRAETHYLHEXANOATE
/BENZOATE in EtOH as shown in Table 1. It is concluded that PENTABRYTIIRITYL TETRAETHYLHEXANOATE/BENZOATE does not possess sensitizing potential under the test conditions.
6
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CIR Panel Book Page 97
Table 1 Contact allergenicity ofPENTAERYTHRITYL ThTRABEHENATE/BENZOATEInduction 100% EtOH
PENTAERYTHRITYLTETRABEHENATE/
BENZOATEPENTAERYTHRITYL PENTABRYTIIRJTYLTETRABEHENATE/ TETRABEHENATE/Challenge
BENZOATE BENZOATE1.8- 100% 1.8- 100%
Number of animal 5 5Sensitization rateHours after challengeapplication
24 0/5 0/548 0/5 0/5
a): number of positive animals! number of animals
7
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CIR Panel Book Page 98
Date of signature: 2011/4/28
8
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CIR Panel Book Page 99
13057506 PENTAERYTHRITYL TETRALAURATE 03G - Other Eye Makeup Preparations 1
9.99E+08 PENTAERYTHRITYL TETRABEHENATE/BENZOATE/ETHYLHEXANOATE 07E - Lipstick 5
9.99E+08 PENTAERYTHRITYL TETRABEHENATE/BENZOATE/ETHYLHEXANOATE 07G - Rouges 1
9.99E+08 PENTAERYTHRITYL TETRABEHENATE/BENZOATE/ETHYLHEXANOATE
12C - Face and Neck (exc shave) 1
PENTAERYTHRITYL TETRAISOSTEARATE 03A - Eyebrow Pencil 3
PENTAERYTHRITYL TETRAISOSTEARATE 03B - Eyeliner 2
PENTAERYTHRITYL TETRAISOSTEARATE 03C - Eye Shadow 78
PENTAERYTHRITYL TETRAISOSTEARATE 03D - Eye Lotion 3
PENTAERYTHRITYL TETRAISOSTEARATE 03F - Mascara 6
PENTAERYTHRITYL TETRAISOSTEARATE 03G - Other Eye Makeup Preparations 13
PENTAERYTHRITYL TETRAISOSTEARATE 04E - Other Fragrance Preparation 3
PENTAERYTHRITYL TETRAISOSTEARATE 07A - Blushers (all types) 48
PENTAERYTHRITYL TETRAISOSTEARATE 07B - Face Powders 51
PENTAERYTHRITYL TETRAISOSTEARATE 07C - Foundations 21
PENTAERYTHRITYL TETRAISOSTEARATE 07E - Lipstick 344
PENTAERYTHRITYL TETRAISOSTEARATE 07F - Makeup Bases 1
PENTAERYTHRITYL TETRAISOSTEARATE 07I - Other Makeup Preparations 38
PENTAERYTHRITYL TETRAISOSTEARATE 12B - Depilatories 4
PENTAERYTHRITYL TETRAISOSTEARATE 12C - Face and Neck (exc shave) 10
PENTAERYTHRITYL TETRAISOSTEARATE 12D - Body and Hand (exc shave) 9
PENTAERYTHRITYL TETRAISOSTEARATE 12F - Moisturizing 39
PENTAERYTHRITYL TETRAISOSTEARATE 12G - Night 1
PENTAERYTHRITYL TETRAISOSTEARATE 12H - Paste Masks (mud packs) 5
PENTAERYTHRITYL TETRAISOSTEARATE 12I - Skin Fresheners 1
PENTAERYTHRITYL TETRAISOSTEARATE 12J - Other Skin Care Preps 4
PENTAERYTHRITYL TETRAISOSTEARATE 13B - Indoor Tanning Preparations 2
PENTAERYTHRITYL TETRAISOSTEARATE 13C - Other Suntan Preparations 2
PENTAERYTHRITYL TETRAETHYLHEXANOATE 03A - Eyebrow Pencil 1
PENTAERYTHRITYL TETRAETHYLHEXANOATE 03B - Eyeliner 2
PENTAERYTHRITYL TETRAETHYLHEXANOATE 03C - Eye Shadow 6
PENTAERYTHRITYL TETRAETHYLHEXANOATE 03D - Eye Lotion 17
PENTAERYTHRITYL TETRAETHYLHEXANOATE 03E - Eye Makeup Remover 3
PENTAERYTHRITYL TETRAETHYLHEXANOATE 03G - Other Eye Makeup Preparations 12
PENTAERYTHRITYL TETRAETHYLHEXANOATE 04E - Other Fragrance Preparation 1
PENTAERYTHRITYL TETRAETHYLHEXANOATE 05G - Tonics, Dressings, and Other Hair Grooming Aids 1
PENTAERYTHRITYL TETRAETHYLHEXANOATE 07A - Blushers (all types) 6
PENTAERYTHRITYL TETRAETHYLHEXANOATE 07B - Face Powders 14
PENTAERYTHRITYL TETRAETHYLHEXANOATE 07C - Foundations 5
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CIR Panel Book Page 100
PENTAERYTHRITYL TETRAETHYLHEXANOATE 07E - Lipstick 9
PENTAERYTHRITYL TETRAETHYLHEXANOATE 07H - Makeup Fixatives 1
PENTAERYTHRITYL TETRAETHYLHEXANOATE 07I - Other Makeup Preparations 3
PENTAERYTHRITYL TETRAETHYLHEXANOATE 09C - Other Oral Hygiene Products 1
PENTAERYTHRITYL TETRAETHYLHEXANOATE 11E - Shaving Cream 1
PENTAERYTHRITYL TETRAETHYLHEXANOATE 12A - Cleansing 6
PENTAERYTHRITYL TETRAETHYLHEXANOATE 12C - Face and Neck (exc shave) 54
PENTAERYTHRITYL TETRAETHYLHEXANOATE 12D - Body and Hand (exc shave) 10
PENTAERYTHRITYL TETRAETHYLHEXANOATE 12F - Moisturizing 47
PENTAERYTHRITYL TETRAETHYLHEXANOATE 12G - Night 19
PENTAERYTHRITYL TETRAETHYLHEXANOATE 12H - Paste Masks (mud packs) 7
PENTAERYTHRITYL TETRAETHYLHEXANOATE 12J - Other Skin Care Preps 14
PENTAERYTHRITYL TETRAETHYLHEXANOATE 13B - Indoor Tanning Preparations 1
PENTAERYTHRITYL TETRAETHYLHEXANOATE 13C - Other Suntan Preparations 2
PENTAERYTHRITYL TETRAETHYLHEXANOATE/BENZOATE 07E - Lipstick 4
PENTAERYTHRITYL TETRALAURATE 03G - Other Eye Makeup Preparations 1
PENTAERYTHRITOL TETRASTEARATE 03F - Mascara 18
PENTAERYTHRITOL TETRASTEARATE 05G - Tonics, Dressings, and Other Hair Grooming Aids 2
PENTAERYTHRITOL TETRASTEARATE 07I - Other Makeup Preparations 1
PENTAERYTHRITOL TETRASTEARATE 10E - Other Personal Cleanliness Products 1
PENTAERYTHRITYL TETRACAPRYLATE/TETRACAPRATE 01B - Baby Lotions, Oils, Powders, and Creams 1
PENTAERYTHRITYL TETRACAPRYLATE/TETRACAPRATE 03D - Eye Lotion 1
PENTAERYTHRITYL TETRACAPRYLATE/TETRACAPRATE 05B - Hair Spray (aerosol fixatives) 7
PENTAERYTHRITYL TETRACAPRYLATE/TETRACAPRATE 07C - Foundations 1
PENTAERYTHRITYL TETRACAPRYLATE/TETRACAPRATE 12D - Body and Hand (exc shave) 1
PENTAERYTHRITYL TETRACAPRYLATE/TETRACAPRATE 12F - Moisturizing 8
PENTAERYTHRITYL TETRACAPRYLATE/TETRACAPRATE 12G - Night 3
PENTAERYTHRITYL TETRACAPRYLATE/TETRACAPRATE 12J - Other Skin Care Preps 1
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Personal Care Products CouncilCommitted to Safety,Quality & Innovation
Memorandum
TO: F. Alan Andersen, Ph.D.Director - COSMETIC INGREDIENT REVIEW (CIR)
FROM: John Bailey, Ph.D.Industry Liaison to the CIR Expert Panel
DATE: March 22, 2011
SUBJECT: Comments on the Scientific Literature Review on Pentaerythrityl Tetraester Compoundsas Used in Cosmetics
p.1 - It would be helpful if the text of the Chemistry section would include a discussion of propertiesthat influence dermal absorption. For some of these compounds, molecular weight andoctanol/water partition coefficient suggest that they would not be absorbed across the skin. Thespeculation on metabolic pathways should only be presented in the Toxicokinetic section.
p.3 - For indirect food additives, why is the focus only on Pentaerythrityl Tetrastearate?21CFR176.210 indicates that fatty acid esters of pentaerythritol can be used as defoamingagents in paper and paperboard intended for food use.
p.3 - The Toxicokinetic section should include a discussion about how chemical properties may affectthe ability of these ingredients to be absorbed through the skin.
p.3 - The oral gavage study of Pentaerythrityl Tetra C5-9 Acid Esters should not be in the Dermalexposure section.
p.3-4 - Please delete the Human subsections under Acute and Repeated Dose Exposure as studiesexamining systemic effects following human exposure are not routinely completed for cosmeticingredients.
p.4 - In the dermal study of Pentaerythrityl Tetra C5-9 Acid Esters, please indicate that the material(tested undiluted) applied to the backs of the rats was not covered and that collars were used toprevent the rats from ingesting the material.
p.4 - Please include the doses in the summary of the Reproductive and Developmental Toxicity section.p.4-5 - As the studies on Pentaerythrityl C5-9 Acid Esters and Pentaerythrityl Tetrabenzoate were both
reverse mutation assays, it is not clear why separate sentences are needed in the summary of thein vitro Genotoxicity subsection. The summaries of the in vitro and in vivo genotoxicitysubsections should be combined into one summary of the Genotoxicity section.
p.5 - Please provide the doses or concentrations tested in the Genotoxicity section.p.5 - Under the Dermal - Non-Human Sensitization subsection it says: “There were no human dermal
sensitization studies discovered...” Under the Dermal - Human Sensitization subsection it says:“There were no non-human dermal sensitization studies discovered...”
1101 17th Street, N.W., Suite 3OO Washington, D.C. 20036-4702 202.331.1770 I 202.331.1969 (fax) www.personcilcarecouncil.org
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CIR Panel Book Page 102
p.5-6 - Please delete the Mucosal and Ocular Sensitization subsections. Having these subsectionssuggests that the CIR Expert Panel expects mucosal and ocular sensitization data. There are nostandard study protocols developed to determine potential mucosal and ocular sensitization.
p.6 - In the Summary, please list the ingredients with no reported uses.p.6 - “No teratogenic effects at 2000 mg/kg.” is not a complete sentence. Please include the species
and the route of exposure.p.6 - In what species and over what time duration was Pentaerythrityl Tetra C5-9 Acid Esters found to
be mildly irritating?p.7-9, Table 1 - Please provide the reference(s) for Table 1.
2
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CIR Panel Book Page 103