GREEN Pentaerythrityl Tetraisostearate and Other ... · PDF fileGREEN Pentaerythrityl Tetraisostearate and Other ... Pentaerythrityl Tetraisostearate and Other Pentaerythrityl

GREEN

Pentaerythrityl Tetraisostearate and Other Pentaerythrityl Esters

CIR EXPERT PANEL MEETING

JUNE 27-28, 2011

Ad

min

istra

tive

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 Comments and unpublished data have been received from industry and incorporated into the report. These submissions are included in the “Unpublished Data” section of the Panel Book and include: 1 – Council comments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.

Distributed for Comment Only -- Do Not Cite or Quote

CIR Panel Book Page 1



History of Pentaerythrityl Tetraisostearate and Other Pentaerythrityl Tetraesters

February, 2011 – SLR announced. June, 2011 – Panel considers Draft Report.



Search Strategy for Pentaerythrityl Tetraesters

Terms PubMed (1/2011)

ECETOC (1/2011)

SCCP & SCCN (1/2011

IUCLID (1/2011)

IARC (1/2011)

HPVIS (1,2/2011)

Dogpile (1,2/2011)

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



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



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



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 "

[email protected]

i

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



2

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



3

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.



4

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



5

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



6

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.



7

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.



8

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


chain



9


Ingredient CAS No. Definition Function(s) Formula/structure Pentaerythrityl Tetrastearate 115-83-3

The tetraester of pentaerythritol and stearic acid.



chain

Pentaerythrityl Tetrabehenate 61682-73-3

The tetraester of pentaerythritol and behenic acid.


wherein R represents a 21 carbon alkyl

chain

Pentaerythrityl Tetracocoate 92201-72-4

The tetraester of pentaerythritol and coconut fatty acid.


wherein

represents coconut fatty acid residues Pentaerythrityl Tetraoleate 19321-40-5

The tetraester of pentaerythritol and oleic acid.


wherein

represents an oleic acid (an Ω-9 unsaturated, 18 carbon fatty acid) residue

Pentaerythrityl Tetraisostearate 62125-22-8

The tetraester of isostearic acid and pentaerythritol.


wherein R represents a 17 carbon “iso”

alkyl chain

Pentaerythrityl Tetraethylhexanoate 7299-99-2

The tetraester of pentaerythritol and 2-ethylhexanoic acid.


wherein R represents a 1-ethylpentyl

chain



10


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



11

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



12

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



(%)

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



13

REFERENCES

1. Johnson Jr.WJ, Bergfeld, WF, Belsito DV, Hill RA, Klaassen CD, Liebler D, Marks Jr.J, Shank RC, Slaga TJ, and Snyder PW. Final report of the Cosmetic Ingredient Review Expert Panel n the safety assessment of pelargonic acid (aka nonanoic acid) and nonanoate esters. Washington, DC, Cosmetic Ingredient Review. 6-29-2010. pp. 1-77.

2. Dimante C, Bergfeld, WF, Belsito DV, Klaassen CD, Marks Jr.J, Shank RC, Slaga TJ, Snyder PW, and Andersen FA. Final report on the safety assessment of amended safety assessment of cocos nucifera (coconut) oil, coconut acid, hydrogenated coconut acid, hydrogenated coconut oil, ammonium cocomonoglyceride sulfate, butylene glycol cocoate, caprylic/capric/coco glycerides, cocoglycerides, coconut alcohol, coconut oil decyl esters, decyl cocoate, ethylhexyl cocoate, hydrogenated coco-glycerides, isodecyl cocoate, lauryl cocoate, magnesium cocoate, methyl cocoate, octyldodecyl cocoate, pentaerythrityl cocoate, potassium cocoate, potassium hydrogenated cocoate, sodium cocoate, sodium cocomonoglyceride sulfate, sodium hydrogenated cocoate, and tridecyl cocoate. Washington, DC, 2008. pp. 1-31.

3. Andersen FA. Amended final report on the safety assessment of pentaerythrityl rosinate. International Journal of Toxicology. 1998;17:(suppl. 4):83-94.

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

5. Youngs CG. Preparation of esters and anhydrides from long chain fatty acid chlorides. Journal of the American Oil Chemists' Society. 1958;35:416-417.

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

7. TCI America. Pentaerythritol tetraacetate. http://www.tciamerica.com/catalog/P0757.html. 2011.

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

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

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

11. Personal Care Products Association formerly Cosmetic, Toiletry and Fragrance Association CTFA. Safety test data on Pentaerythrityl Rosinate. Washington, DC, Personal Care Products Council. 1995. pp. 1-19. Unpublished data submitted by CTFA, September 12, 1995.

12. Personal Care Products Council. Safety test data on Pentaerythrityl Rosinate . Washington, DC, Personal Care Products Association. 1995. pp. 1-106. Unpublished data submitted by the Personal Care Products Association.

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

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

15. Shiokawa Y, Matsumoto S, Sato Y, Kato K, and Kitamura M. Process for the production of polyol ester and ester-containing lubricating oil. 1-6-1998. 578,994:(5,705,459):

16. U.S.Food and Drug Administration. Indirect food additives: Paper and paperboard components. 2009. 21CFR176.170:Date accessed 4/2011. http://edocket.access.gpo.gov/cfr_2009/aprqtr/21cfr176.170.htm

17. U.S.Food and Drug Administration. Indirect food additives: Polymers-Subpart B Substances for Use as Basic Components of Single and Repeated Use Food Contact Surfaces Sec. 177.1590 Polyester elastomers. 2009. 21 CFR 177.1590:Date accessed 4/2011. http://edocket.access.gpo.gov/cfr_2009/aprqtr/21cfr177.1590.htm

18. U.S.Food and Drug Administration. Defoaming agents used in the manufacture of paper and paperboard. 2010. 21CFR176.210:Date accessed 4/2011. http://www.accessdata.fda.gov/scripts/cdrh/cfdocs/cfCFR/CFRSearch.cfm?fr=176.210

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

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



14

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

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

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

24. Mungiu OC, Oita N, Papa V, Botez E, and Panaitescu AM. Experimentarea farmacologica a unui derivat acetilat de glucoza. Societatea de Medici si Natrualisti. 1924;86:322-324.

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

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

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

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

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

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.



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.



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



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



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



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



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



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



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 /



(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 (



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,



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.



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



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



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



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)



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 %


19 59,38%

10 31.25%

3 9.38%

Total ReSponses 32 100%

17 53.13%

12 37.60%

3 9.38%


15 46.88%

11 34.38%

4 12,50%

1 3.13%

1 3.13%


Total Responses

January 8, 2008 Page ‘1 ot3



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



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%


Ji..ay8 2008 Page 3 of 3



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



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



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



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



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.



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



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



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



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



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



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



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



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



TO:

iProducts Counci

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

Committed to Safety,Quality & Innovation

FROM:

DATE:


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


Persona Care

Memorandum



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



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.



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



APPENDIX I

SUMMARY TABLES



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



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



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



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



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



APPENDIX II

DATA LISTINGS



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




Data Listing I Subject Enrollment and Disposition

Study DatesLast


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



TKL STUDY NO. DSI1OI1OPage 3of 4

Data Listing I: Subject Enrollment and Disposition

Study DatesLast


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




Data Listing 1: Subject Enrollment and Disposition

Study DatesLast


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



TKLSTUDYNO.DSIIO1IOPage lof 3

Data Listing 2: Subject Demographics

Subject No. Age Gender Race

001 53,8 Female Caucasian

002 47.3 Female Caucasian











013 55.1 Male Caucasian


015 54.0 Female Hispanic


017 51.9 Female Flispanic

018 55.8 Male Hispanic



021 49.6 Male Black

















Generated on 11/15/10:16:53 by DEMOLIST,SAS / Uses: DEMOGS



TKLSTUDYNO,DSI1OIIOPage 2o1 3


Subject No.

__________

Age Gender Race





























066 24.8 Female Black









Generated on 11/15/10:16:53 byDEMOLIST.SAS /Uses: DEMOGS



TKLSTUDYNO.DSIIOIIOPage 3of 3


Subject No. Age Gender Race



077 61.2 Male Hispanic









086 71,9 Female Caucasian










096 39.6 Female Black














I 10 52.6 Female Caucasian





Generated on 1 1/15,10:16:53 by DEMOLIST.SAS / Uses: DEMOGS



TKL Study No. DS1IOIIOPage I of 5

Data Listing 3: Dermatologic Response Grades

By Product and Subject

Product


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



TKL Study No. DSI 10110Page 2 of 5



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



4

TKL Study No DS1IOI 10Page 3of 5



Product



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



TKLStudyNo.DSIIOIIOPage 4o1 5



Product =


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



TKL SludyNo. DSI 10110Page 5 of 5

Data Listing 3: Dermatoogic Response Grades


Product =



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



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



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



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



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)



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.



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.



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.



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



TABLE I(Continued)


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



Final Rennet

TABLE 1(Continued)


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



Fi,,aI Ree’art

TABLE I(Continued)


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



TABLE I(Continued)


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



z

-

-

Zø

t.,

——

——

——

——

—.

Oo

-aa

UI

00

aU

I0

0U

I

fD

1

CC

CC

CC

CC

——

——

——

——

——

C—

C—

—C

CC

CJ

Ccc

D-

D—

-4.

4-

—C

—t’

JL

.Jt

tJ4

-G

OG

O-

t

J—

——

—cG

O

J—

——

4

—G

OJU

iC

-

Q,

UI

UI

Ui

Ui

UI

UI

UI

....

UI

©00

—U

I—

00

—U

i

——

CC

CC

CC

CC

CC

—C

—C

——

C

-=



t00

0000

0000

00

0000

00-4

-4-3

-3—

.1-3

-3-3

Oa

‘J(M

Z00-3

UI

00

-3U

i0

0-4

Ui

00-3

——

n—

C—

-‘

CC

C-

C—

©—

C-

CC

CC

CC

C—

C—

——

——

CC

3O

\Ot’

J—

300(

CJ

—0

0-

$00

C—

—t)

—a-3

—0

00

0

CI)

——

——

——

——

——

——

——

——

._

——

00

00-3

UI

—00

-U

I.

(J

2<

<C

>H

—

c

CC

CC

CC

CC

C—

——

CC

C—

——

—C

C—

C—

—

00

CO

O C0O

O00

00—

Q0O

OC

Q-)Q

0—

-CN

4 —C

JC

CC

00”-1

rD_4r

-



TO:

FROM:

DATE:

‘Products CouncilCommitted to Safety,Quality & Innovation

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


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.


Personal Care

Memorandum



SAFETY DATA OF

PENTAERYTHRITYLTETRABEHENATEJBENZOATEJETHYLIIEXANOATE

ANDPENTAERYTIIRITYL

TETRAETHYLHEXANOATE/BENZOATE

April 28th, 2011



Index

PENTAERYTHRITYLTETRABEIIENATE[BENZOATE[ETHYLHEXANOATE

- 1. Contact Allergenicity

PENTAERYTITRITYLTETRAETIIYLHEXANOATE/BENZOATE

1. Contact Allergenicity

‘1



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



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



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



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



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



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



Date of signature: 2011/4/28

8



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



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



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



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



Documents

GREEN Pentaerythrityl Tetraisostearate and Other ... · PDF fileGREEN Pentaerythrityl Tetraisostearate and Other ... Pentaerythrityl Tetraisostearate and Other Pentaerythrityl