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Decyl Glucosides

CIR EXPERT PANEL MEETING DECEMBER 12-13, 2011

Memorandum

To: CIR Expert Panel Members and Liaisons From: Monice M. Fiume MMF Senior Scientific Analyst/Writer Date: November 21, 2011 Subject: Draft Final Safety Assessment on Decyl Glucosides and Other Alkyl Glucosides as Used in Cosmetics

Included is the draft Final Safety Assessment on Decyl Glucosides and other Alkyl Glucosides as Used in Cosmetics. Nineteen ingredients are being reviewed.

At the September meeting, the Panel issued a tentative safety assessment with a conclusion of safe in the present practices of use and concentration when formulated to be non-irritating. No additional data have been received. Comments on the tentative safety assessment on decyl glucoside and other alkyl glucosides as used in cosmetics were received from the Council, and these comments have been addressed.

The Panel should be prepared to issue a final conclusion at this meeting.

Distributed for Comment Only -- Do Not Cite or Quote

CIR Panel Book Page 1 Distributed for Comment Only -- Do Not Cite or Quote History - Decyl Glucosides and Other Alkyl Glucosides

February 24, 2011: Scientific Literature Review The following unpublished data were included in the SLR: 1. Unpublished information on glucoside ingredients. Memo dated Dec 14, 2010. a. Cognis Care Chemicals. 2010. Data profile PLANTACARE 810 UP (Caprylyl/Capryl Glucoside); b. Cognis Care Chemicals. 2010. Data profile PLANTACARE 818 UP (Coco-Glucoside); c. Cognis Care Chemicals. 2010. Data profile PLANTACARE 1200 UP (Lauryl Glucoside); d. Cognis Care Chemicals. 2010. Data profile PLANTACARE 2000 JP (Decyl Glucoside); e. Consumer Product Testing Company. 1993. Repeat insult patch test of 5% active lauryl glucoside and decyl glucoside; f. Consumer Product Testing Company. 2005. Repeat insult patch test of coco- glucoside (1% active). 2. Concentration of use by FDA product category: glucoside ingredients. Memo dated Jan 7, 2011. 3. Updated concentration of use by FDA product category: Glucoside ingredients. Memo dated Jan 28, 2011

June 27-28, 2011: Draft Safety Assessment The following were received after the SLR was announced. The data have been incorporated into the report, and the comments have been addressed. 1. Comments on the Scientific Literature Review on Decyl Glucosides and Other Alkyl Glucosides as Used in Cosmetics. Memo dated March 23, 2011. 2. Concentration of use by FDA product category: Hexyldecyl d-Glucoside and Octadecyl d-Glucoside. Memo dated March 15, 2011. 3. In Vitro dermal penetration study: Caprylyl/Capryl Glucoside. Memo dated April 8, 2011

The Expert Panel noted the absence of dermal sensitization data at an active ingredient concentration of 11% and issued an insufficient data announcement requesting human dermal sensitization data (HRIPT) for decyl glucoside at 11% active ingredient, the maximum reported leave-on use concentration reported. If it is determined that the 11% reported use concentration of decyl glucoside is actually use at 11% with only <100% decyl glucoside, then appropriate modifications may be made to the testing protocol. Those submitting data should note that the percent active ingredient should be identified in all data submissions.

The Expert Panel requested clarification as to whether the reported use concentrations of decyl glucoside, as well as the other alkyl glucosides, relate to the active ingredient.

September 26-27, 2011: Draft Tentative Safety Assessment

A clarification as to whether the reported use concentration is reported as active ingredient was received – and the reporting is as active ingredient. The leave-on use at 11% active ingredient decyl glucoside was reported incorrectly.; the greatest leave-on use concentration is 5% lauryl glucoside.

The following unpublished data were received and included in the safety assessment:

- Updated concentration of use by FDA product category: Glucoside Ingredients. Memo dated Aug. 16, 2011. - AMA Laboratories, Inc. 2002. 100 Human subject repeat insult patch test skin irritation/sensitization evaluation (occlusive patch) of an indoor tanning preparation containing 0.5% Decyl Glucoside. AMA Ref No.: MSO2.R1PTC38440. 100.DERM.TRLI. - Product Investigations, Inc. 2005. Determination of the irritating and sensitizing propensities of a liquid foundation (containing 1.8%) Decyl Glucoside on human skin.

The Panel issued a Tentative Report with the conclusion of safe in the present practices of use when formulated to be non- irritating.

December 11-12, 2011: Draft Final Safety Assessment

CIR Panel Book Page 2 Decyl Glucoside and Other Alkyl Glucosides Data Profile* – Dec 2011 – Writer, Monice Fiume Rptd Dose, Inhalaiton Repro/Dev Tox Genotox Carcinogeni- city Dermal Irr/Sens Ocular Irritation Use Reported Method of Manufacture Toxicokinetic Data Tox – Animal Acute, Derrmal Tox – Animal Acute, Oral Animal Tox, Acute, Inhalation Tox – Animal Rptd Dose, Dermal Animal Tox, Rptd Dose, Oral Tox – Animal Decyl Glucoside X X X Arachidyl Glucoside X Butyl Glucoside C10-16 Alkyl Glucoside X X C12-18 Alkyl Glucoside C12-20 Alkyl Glucoside X C20-22 Alkyl Glucoside Caprylyl/Capryl Glucoside X X X X X X X X Distributed Caprylyl Glucoside X X X Cetearyl Glucoside X Coco-Glucoside X X X

Ethyl Glucoside X X X for Comment CIR Hexadecyl D‐Glucoside X Isostearyl Glucoside Panel Lauryl Glucoside X X X X

Myristyl Glucoside X Only Book Octadecyl D‐Glucoside X --

Page Octyldodecyl Glucoside Do Undecyl Glucoside Not

3 Alkyl Polyglucosides (APGs), General Info X X X X

Previously Reviewed Fatty Alcohols Yr. Rev. Cite

n-Butyl Alcohol 2008 X X X X X X X X or

Cetearyl Alcohol 1988 X X Quote Cetyl Alcohol 1988 X X X X X X X X Coconut Alcohol 2008 Isostearyl Alcohol 1988 X X X Myristyl Alcohol 1988 X X X X Octyl Dodecancol 1985 X X X X Stearyl Alcohol 1985 X X X X X X X

*“X” indicates that data were available in a category for the ingredient

1

Decyl Glucoside Search Strategy

constant search update every week using Keep Me Posted tool in SciFinder

Searched term Triton 100 using SciFinder – July 11, 2011 89 hits ordered 7 papers

SciFinder Search – April 7, 2011

History

Session began April 7, 2011 at 12:35 PM Distributed April 7, 2011 12:36 PM Explore substances by ID: glucoside initiated Explore complete Explore results for Comment CIR No answers

Panel April 7, 2011 12:48 PM Explore substances by ID: 34625-23-5, 27214-60-4, 65309-84-4, 58846-77-8, 124828-32-6, 148406-76-2, 150679-30-4, 6801-88-3, 6801-92-9, 265312-14-9, 6801-86-1, Only Book 41444-56-8 initiated

Explore complete -- Page Explore results Do

Answer set 2 created with 6 answers from REGISTRY Not 4

April 7, 2011 12:57 PM Cite Explore substances by ID: 30285-48-4, 5391-18-4, 41444-57-9, 29836-26-8, 58846-77-8, 68515-73-1, 141464-42-8, 98283-67-1, 27836-64-2, 110615-47-9, 54549-26-7, 144982-05-8, 68515-73-1, 110615-47-9, 200413-69-0, 34625-23-5, 27214-60-4, 65309-84-4, 58846-77-8, 124828-32-6, 148406-76-2, 150679-30-4 initiated or Quote Explore complete Explore results Answer set 3 created with 13 answers from REGISTRY Saved 13 substance answers from Answer set 3 as 'Decyl glucoside 1' Retrieve reference information in 13 substances of Answer set 3 Answer set 4 created with 3,080 answers from CAPLUS 336 answers from MEDLINE Refine Answer set 4 by document type Book, Clinical Trial, Conference, Journal, Letter, Report, Review Answer set 5 created with 1,814 answers from CAPLUS 335 answers from MEDLINE Detailed display from Answer set 5 of Expanding Coverage of the Metabolome for Global Metabolite Profiling Saved 2149 reference answers from Answer set 5 as 'Decyl Gluc 1 Refines by pub type' Refine Answer set 4 by document type Patents only Answer set 6 created with 1,268 answers from CAPLUS April 7, 2011 1:03 PM Explore substances by ID: 6801-88-3, 6801-92-9, 265312-14-9, 6801-86-1, 41444-56-8, C12-18 Alkyl Glucoside, C12-20 Alkyl Glucoside, C12-20 Alkyl Glucoside, C20-22 Alkyl Glucoside, Cetearyl Glucoside, Coco- Glucoside, Octyldodecyl Glycoside initiated Explore complete Explore results Answer set 7 created with 5 answers from REGISTRY Saved 5 substance answers from Answer set 7 as 'decyl gluc 2' Combine the current substance answer set with saved answer sets initiated: decyl gluc 2 OR Decyl glucoside 1 at April 7, 2011 1:04 PM Answer set 8 created with 15 answers from REGISTRY Saved 15 substance answers from Answer set 8 as 'Decyl glucoside All'

Retrieve reference information in 15 substances of Answer set 8 Distributed Answer set 9 created with 3,080 answers from CAPLUS 336 answers from MEDLINE Saved 3416 reference answers from Answer set 9 as 'Decyl Glucoside All' for Comment CIR Refine Answer set 9 by document type

Panel Book, Clinical Trial, Conference, Journal, Preprint, Report, Review Answer set 10 created with Only Book 1,815 answers from CAPLUS

333 answers from MEDLINE -- Page Saved 2148 reference answers from Answer set 10 as 'Decyl Glucoside refined by document type' Do

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sugar surfactant Cite Answer set 11 created with 49 answers from CAPLUS Detailed display from Answer set 11 of Physical properties and inhibitory effects of three-component hybrid liposomes including sugar surfactants or Quote Detailed display from Answer set 11 of Alkylpolyglycoside: carbohydrate based surfactant Detailed display from Answer set 11 of Adsorption of n-Decyl-β-D-glucopyranoside and n-Decyl-β-D-maltopyranoside Mixtures at the Liquid-Vapor Interface Explore results Answer set 14 created with 16 answers from CAPLUS 131 answers from MEDLINE Detailed display from Answer set 14 of Irritant and sensitizing potential of eight surfactants commonly used in skin cleansers: an evaluation of 105 patients Full text accessed for Irritant and sensitizing potential of eight surfactants commonly used in skin cleansers: an evaluation of 105 patients from Dermatitis : contact, atopic, occupational, drug : official journal of the American Contact Dermatitis Society, North American Contact Dermatitis Group Volume: 21 Issue: 5 Pages: 262-8 2010 April 7, 2011 1:22 PM Explore references by research topic: decyl glucoside initiated, resulting in 2 candidates Explore complete Candidates Selected 413 references were found containing "decyl glucoside" as entered. Automatically removed 6 duplicate MEDLINE answer(s) Explore results Answer set 15 created with 399 answers from CAPLUS 8 answers from MEDLINE

April 7, 2011 1:23 PM Explore references by research topic: decyl glucoside initiated, resulting in 2 candidates Explore complete Candidates Selected 413 references were found containing "decyl glucoside" as entered. Automatically removed 8 duplicate MEDLINE answer(s) 929 references were found containing the concept "decyl glucoside". Automatically removed 8 duplicate MEDLINE answer(s)

Explore results Distributed Answer set 18 created with 915 answers from CAPLUS 6 answers from MEDLINE for Comment CIR Explore references by research topic: glucoside initiated, resulting in 2 candidates

Panel April 7, 2011 1:26 PM Explore references by research topic: glucoside initiated, resulting in 2 candidates Only Book Limiters

Book, Preprint, Clinical Trial, Report, Journal, Review, Conference -- Page April 7, 2011 1:27 PM Do

Explore references by research topic: 30285-48-4 initiated, resulting in 2 candidates Not 6

Limiters Cite Book, Preprint, Clinical Trial, Report, Journal, Review, Conference or

Explore complete Quote Candidates Selected 59 references were found containing "30285-48-4" as entered. Automatically removed 3 duplicate MEDLINE answer(s) Explore results Answer set 21 created with 48 answers from CAPLUS 8 answers from MEDLINE April 7, 2011 1:29 PM Explore references by research topic: 30285-48-4 5391-18-4 41444-57-9 29836-26-8 58846-77-8 68515-73-1 141464-42-8 98283-67-1 27836-64-2 110615-47-9 54549-26-7 144982-05-8 68515-73-1 110615-47-9 initiated, resulting in 0 candidate April 7, 2011 1:31 PM Explore references by research topic: irritancy of glucosides initiated, resulting in 4 candidates Explore complete Candidates Selected 25 references were found where the two concepts "irritancy" and "glucosides" were present anywhere in the reference. Explore results Answer set 22 created with 21 answers from CAPLUS 4 answers from MEDLINE Detailed display from Answer set 22 of Non-irritating cosmetic and pharmaceutical compositions for irritating agents retinoids and α- and β-hydroxy acids Detailed display from Answer set 22 of Application of surfactants. 51. Alkyl polyglucoside surfactants. 1 Detailed display from Answer set 22 of Lactobionic acid in a natural alkylpolyglucoside-based vehicle: assessing safety and efficacy aspects in comparison to glycolic acid April 7, 2011 1:34 PM Explore references by research topic: sensitization potential of surfactants initiated, resulting in 4 candidates Explore complete Candidates Selected 145 references were found containing the two concepts "sensitization potential" and "surfactants" closely associated with one another. Automatically removed 23 duplicate MEDLINE answer(s)

Explore results Distributed Answer set 23 created with 121 answers from CAPLUS 1 answer from MEDLINE April 7, 2011 1:37 PM for Comment CIR Explore references by research topic: sensitization potential of surfactants initiated, resulting in 4 candidates

Panel Limiters Book, Preprint, Clinical Trial, Report, Journal, Review Only Book English

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112 references were found containing the two concepts "sensitization potential" and "surfactants" closely associated with one another. Not 7

Automatically removed 22 duplicate MEDLINE answer(s) Cite Explore results Answer set 25 created with or Quote 89 answers from CAPLUS 1 answer from MEDLINE Full text accessed for Comparative testing for the identification of skin- of nonionic sugar lipid from Regulatory Toxicology and Pharmacology Volume: 58 Issue: 2 Pages: 301-307 2010 Full text accessed for Irritant and of eight commonly used in skin cleansers: an evaluation of 105 patients from Dermatitis : contact, atopic, occupational, drug : official journal of the American Contact Dermatitis Society, North American Contact Dermatitis Group Volume: 21 Issue: 5 Pages: 262-8 2010 Detailed display from Answer set 25 of Zinc and its derivatives: their applications in cosmetic April 7, 2011 1:42 PM Explore references by research topic: sensitization potential of surfactants initiated, resulting in 4 candidates Limiters Book, Preprint, Clinical Trial, Report, Journal, Review English Explore complete Candidates Selected 112 references were found containing the two concepts "sensitization potential" and "surfactants" closely associated with one another. Automatically removed 22 duplicate MEDLINE answer(s) Explore results Answer set 26 created with 89 answers from CAPLUS 1 answer from MEDLINE Keep Me Posted profile 'sensitization potential of surfactants' created from Answer set 26 Refine Answer set 26 by research topic cosmetics Answer set 27 created with 3 answers from CAPLUS 1 answer from MEDLINE April 7, 2011 1:44 PM Explore references by research topic: irritation of surfactants initiated, resulting in 5 candidates

Limiters Distributed Book, Preprint, Clinical Trial, Report, Journal, Review English Explore complete Candidates Selected for Comment CIR 668 references were found containing the two concepts "irritation" and "surfactants" closely associated with one another.

Panel Automatically removed 169 duplicate MEDLINE answer(s) Explore results Only Book Answer set 28 created with

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Keep Me Posted profile 'irritation of surfactants' created from Answer set 28 Not 8

Refine Answer set 28 by research topic Cite cosmetics Answer set 29 created with or Quote 152 answers from CAPLUS 7 answers from MEDLINE Detailed display from Answer set 29 of Ocular Irritection: in vitro method for testing ocular irritancy Refine Answer set 29 by research topic glucoside Answer set 30 created with 1 answer from CAPLUS 1 answer from MEDLINE Detailed display from Answer set 30 of Photostability of naturally occurring whitening agents in cosmetic microemulsions Refine Answer set 28 by research topic glucoside Answer set 31 created with 3 answers from CAPLUS 1 answer from MEDLINE Detailed display from Answer set 31 of Evaluation of irritation potential of surfactant mixtures Exported Evaluation of irritation potential of surfactant mixtures in 'RIS' format as "Reference_04_07_2011_134818.ris" Exported Evaluation of irritation potential of surfactant mixtures in 'RIS' format as "Reference_04_07_2011_134835.ris" Exported Evaluation of irritation potential of surfactant mixtures in 'RIS' format as "Reference_04_07_2011_134854.ris" Session began April 7, 2011 at 1:50 PM April 7, 2011 1:50 PM Saved answer set 'Decyl Glucoside refined by document type' opened Answer set 32 created with 1,815 reference answers from CAPLUS 333 reference answers from MEDLINE April 7, 2011 1:54 PM Saved answer set 'Decyl Glucoside refined by document type' opened Answer set 34 created with 1,815 reference answers from CAPLUS

333 reference answers from MEDLINE Distributed Answer set 35 created with 4 answers from CAPLUS Detailed display from Answer set 35 of Comparative study of the ocular irritation potential of various alkyl polyglucoside surfactants Exported Comparative study of the ocular irritation potential of various alkyl polyglucoside surfactants in 'RIS' format as "Cho.ris" Exported Comparative study of the ocular irritation potential of various alkyl polyglucoside surfactants in 'RIS' format as "Cho.ris" for Comment CIR April 7, 2011 1:56 PM

Panel Saved answer set 'Decyl Glucoside refined by document type' opened Answer set 36 created with Only Book 1,815 reference answers from CAPLUS

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Saved answer set 'Decyl Glucoside refined by document type' opened Not 9

Answer set 37 created with Cite 1,815 reference answers from CAPLUS 333 reference answers from MEDLINE or Quote April 7, 2011 1:57 PM Saved answer set 'Decyl Glucoside All' opened Answer set 38 created with 3,080 reference answers from CAPLUS 336 reference answers from MEDLINE Refine Answer set 38 by document type Book, Clinical Trial, Conference, Journal, Preprint, Report, Review Answer set 39 created with 1,815 answers from CAPLUS 333 answers from MEDLINE April 7, 2011 1:58 PM Saved answer set 'Decyl glucoside All' opened Answer set 40 created with 15 substance answers from REGISTRY Retrieve reference information in 15 substances of Answer set 40 Answer set 41 created with 3,080 answers from CAPLUS 336 answers from MEDLINE Refine Answer set 41 by document type Book, Clinical Trial, Conference, Journal, Preprint, Report, Review Answer set 42 created with 1,815 answers from CAPLUS 333 answers from MEDLINE Keep Me Posted profile 'Glucosides Refined by Document Type' created from Answer set 42 April 7, 2011 2:01 PM Explore references by research topic: alkyl polyglucosides initiated, resulting in 2 candidates Explore complete Candidates Selected 2649 references were found containing the concept "alkyl polyglucosides".

Automatically removed 37 duplicate MEDLINE answer(s) Distributed Explore results Answer set 43 created with 2,610 answers from CAPLUS 2 answers from MEDLINE for CIR April 7, 2011 2:02 PM Comment

Panel Explore references by research topic: alkyl polyglucosides initiated, resulting in 2 candidates Limiters Only Book Book, Preprint, Clinical Trial, Report, Journal, Review

English -- Page

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10 Candidates Selected

359 references were found containing the concept "alkyl polyglucosides". Cite Automatically removed 34 duplicate MEDLINE answer(s) or

Explore results Quote Answer set 44 created with 323 answers from CAPLUS 2 answers from MEDLINE Keep Me Posted profile 'Alkyl Polygolucosides' created from Answer set 44 Detailed display from Answer set 44 of Profile of irritant patch testing with detergents: sodium lauryl sulfate, sodium laureth sulfate and alkyl polyglucoside Detailed display from Answer set 44 of Toxicology of alkyl polyglycosides Detailed display from Answer set 44 of Alkyl polyglycosides Detailed display from Answer set 44 of Alkyl polyglycosides Full text accessed for from Surfactant Science Series Volume: 98 Issue: Detergency of Specialty Surfactants Pages: 1-69 2001 Detailed display from Answer set 44 of Nonionic Surfactants: Alkyl Polyglucosides. [In: Surfactant Sci. Ser., 2000; 91] Exported 3 reference answers from Answer set 44 in 'RIS' format as "APGs.ris" Detailed display from Answer set 44 of Dermatological properties of alkyl polyglycosides Full text accessed for Dermatological properties of from Alkyl Polyglycosides Pages: 169-176 1997 Detailed display from Answer set 44 of Alkyl polyglycosides in personal care products Full text accessed for in personal care products from Alkyl Polyglycosides Pages: 71-98 1997 Detailed display from Answer set 44 of Using alkyl polyglycosides in personal-care products Detailed display from Answer set 44 of Alkylpolyglycosides - a new cosmetic concept for mildness and care Full text accessed for - a new cosmetic concept for mildness and care from Agro-Food-Industry Hi-Tech Volume: 5 Issue: 5 Pages: 20-8 1994 Detailed display from Answer set 44 of Alkyl polyglycosides: properties and applications Exported 6 reference answers from Answer set 44 in 'RIS' format as "APGs2.ris" April 7, 2011 2:18 PM

Keep Me Posted searches checked weekly 5-7-11: 1/5 references ordered Distributed for CIR Comment Panel Only Book -- Page Do Not 11 Cite or Quote

NLM STN Intl EU FDA ChemPortal Mis Toxline ECE conc c NTI Regis- RTE Merc SCC SIDS-HPV-I IAR EAFU GRA NIOS # uses -Pubme EU TO NTP OTC Misc data NL S try CS k S UCLID C S S H d C M date searched 11-2 Oct20 1-12 1-28-11 11-19-10 1-12-11 1-12 2-08 2-08 2-08 2-08 2-08 2-08 3 10 Decyl Glucoside x 2 0 x x no no no no no no no no no x Arachidyl Glucoside x 0 x x no no no no no no no no no no Butyl Glucoside no 1 0 x x no no no no no no no no no x C10-16 Alkyl Glucoside no 0 x x no no no no no no no no no x C12-18 Alkyl Glucoside no 0 x no no no no no no no no no no C12-20 Alkyl Glucoside x 0 x no no no no no no no no no no C20-22 Alkyl Glucoside no 0 no no no no no no no no no no Distributed Caprylyl/Capryl x x 3 x x no no no no no no no no no Glucoside

Caprylyl Glucoside x 0 x x x no no no no no no no no no x for

CIR 352 Cetearyl Glucoside x 0 x no no no no no no no no no no Comment

Panel Coco-Glucoside x 0 x no no no no no no no no no no Ethyl Glucoside x 2 0 x x no no no no no no no no no x Only Book Isostearyl Glucoside no 0 x x no no no no no no no no no no Lauryl Glucoside x 2 0 x x no no no no no no no no no x -- Page

Myristyl Glucoside x 1 0 x x no no no no no no no no no x Do

Octyldodecyl Glucoside no 0 x no no no no no no no no no no Not 12 Palm Kernel/Coco no no 0 x no no no (deleted from report) Cite Glucoside Undecyl Glucoside no 1 0 x x no no no no no no no no no x or Tradenames Search 639 0 Quote

In VCRP/but not INCI Hexadecyl D-Glucoside x no no no no no x (54549-27-8) Octadecyl D-Glucoside x no no no no no x (27836-65-3)

References Ordered Whit – 25 papers (11-23-10) NTIS – 3 documents (11-23-10)

Distributed for Comment Only -- Do Not Cite or Quote Search Terms

((DECYL OR ETHYL OR BUTYL OR CAPRYLYL OR UNDECYL OR LAURYL OR MYRISTYL OR ARACHIDYL OR CAPRYL OR ALKYL OR CETEARYL OR COCO OR (PALM AND KERNEL) OR ISOSTEARYL OR ISOOCTADECYL OR OCTYLDODECYL OR OCTYL OR DODECYL OR TETRADECYL OR EICOSYL) AND GLUCOSIDE) OR ((ETHYL OR BUTYL OR OCTYL OR DECYL OR UNDECYL OR DODECYL OR LAURYL OR MYRISTYL OR TETRADECYL OR ARACHIDYL OR EICOSYL OR ISOSTEARYL OR ISOOCTADECYL) AND GLUCOPYRANOSIDE) OR 30285-48-4 OR 5391-18-4 OR 41444-57-9 OR 29836-26-8 OR 58846-77-8 OR 68515-73-1 OR 141464-42-8 OR 98283-67-1 OR 27836-64-2 OR 110615-47-9 OR 54549-26-7 OR 144982-05-8 OR 68515-73-1 OR 110615-47-9 OR 200413-69-0 OR 34625-23-5 OR 27214-60-4 OR 65309-84-4 OR 58846-77-8 OR 124828-32-6 OR 148406-76-2 OR 150679-30-4 OR 6801-88-3 OR 6801-92-9 OR 265312-14-9 OR 6801-86-1 OR 41444-56-8

ORAMIX OR PLANTACARE OR PLANTAREN OR ORAMIX OR SUCRAPH OR AVANEL OR ORISTAR OR DESULF OR (TRITON AND SURFACTANT) OR SEPISOFT OR (TEGO AND CARE)

SCiFinder Seach Terms – 4-7-11

30285-48-4 5391-18-4 41444-57-9 29836-26-8 58846-77-8 68515-73-1 141464-42-8 98283-67-1 27836-64-2 110615-47-9 54549-26-7 144982-05-8 68515-73-1 110615-47-9 200413-69-0 34625-23-5 27214-60-4 65309-84-4 58846-77-8 124828-32-6 148406-76-2 150679-30-4

6801-88-3 6801-92-9 265312-14-9 6801-86-1 41444-56-8 C12-18 Alkyl Glucoside C12-20 Alkyl Glucoside C12-20 Alkyl Glucoside C20-22 Alkyl Glucoside Cetearyl Glucoside Coco- Glucoside Octyldodecyl Glycoside Alkyl Glucoside

CIR Panel Book Page 13 Minutes

Distributed for Comment Only -- Do Not Cite or Quote BELSITO TEAM – DECYL GLUCOSIDE – SEPT 2011

DR. BELSITO: Okay, and we'll move to the decyl glucoside. So, again, so, I'm happy. The reported concentrations of use are of active ingredients.

MS. FIUME: Yes, that's what Carol has said. And the decyl glucoside concentration was not 11 percent. I believe it was.5. No, 2 percent in leave-on products.

DR. BELSITO: But I saw that noted someplace, but then when I looked at the concentration here for decyl glucoside -- okay, so, it's leave-on, 2 percent.

MS. FIUME: And that is in a hair product.

SPEAKER: Yes.

DR. BELSITO: But then below it, it says eye area percent. "Exposure type, eye area, 6."

MS. FIUME: That's in eye makeup remover, so that's not leave-on.

DR. BELSITO: Eye makeup removers. How does a woman use an eye makeup remover? Don't they usually just wipe it and then they may rinse it with soap and water? No?

MS. FIUME: You rinse it with water.

SPEAKER: Water.

MS. FIUME: You wipe it and then rinse with water.

MS. WEINTRAUB: With water.

DR. BELSITO: You do rinse with water?

MS. FIUME: Yes.

DR. BELSITO: Okay. You can see I've never used eye makeup. I thought they just put it on a cotton ball and went like that.

MS. WEINTRAUB: Then you rinse it off.

DR. BELSITO: Then you rinse it off. Okay.

DR. LIEBLER: You mean you weren't one of the guys at the football games with your whole body painted and just one letter with all your buddies? (Laughter)

DR. ANSELL: Yes, but you never rinse that off.

(Laughter)

SPEAKER: Well, that rinses off with beer, so.

DR. ANSELL: That's right.

DR. BELSITO: Okay, so, eye makeup removers are a rinse-off. Okay, thank you for that clarification. Okay, well, in that case, I mean, safe as used, and we have to deal with the respiratory issue again and penetration enhancement. That's always easy to do, penetration enhancement. Respiration issue, what do we have here? We have sprays, .8, .5, .6. Deodorants, .6, not reporting. Sprays, the highest sprays, looks like is going to be 8 percent for lauryl glucoside. Is that right?

MS. FIUME: It looks like it eights it.

DR. BELSITO: So, under the cosmetic use section, we're going with the boilerplate that we developed for

CIR Panel Book Page 14 Distributed for Comment Only -- Do Not Cite or Quote whatever that compound we developed it for. So, a few of the ingredients are reported to be used on page 3, Panel Book 26. Spray or powder forms, it's not known if any product containing these ingredients are actually sprays or powders. "Particle size of aerosol hairsprays and pumps," that needs to be changed. What is the compound that we did the boilerplate for?

DR. LIEBLER: I think alkyl PEG sulfosuccinates, right?

DR. BELSITO: I think. Yes, so, it was, in practice, aerosols have 95 to 99 percent of their particle diameters and the 10 to 110 µm range or micron range.

DR. LIEBLER: Right.

DR. BELSITO: Therefore, most aerosol products are deposited in a nasopharyngeal region and are not respirable. So, get rid of the particle size of aerosol hairsprays and pump hairsprays and use that language from the sulfosuccinate report. And then that leaves us with a discussion, which hasn't been formulated yet, so, how do we deal with 8 percent? Is that what I said?

MS. FIUME: Before the --

DR. BELSITO: Lauryl glucoside in a spray.

MS. FIUME: Yes.

DR. BELSITO: That may be used in a spray. We're not sure.

DR. ANDERSEN: The 8 percent is definitely a spray.

DR. BELSITO: Okay.

DR. ANDERSEN: It was a hair color spray. The other uses that are in the potential spray category, we just have --

DR. BELSITO: Right.

DR. ANDERSEN: The deodorants, the suntan products, we don't have a clue whether they're in sprays.

DR. BELSITO: Okay, so --

DR. ANDERSEN: Zero inhalation tox data.

DR. BELSITO: Right.

DR. ANSELL: We have ocular data showing material is not irritating, the decyl. We have no concern about systemic toxicity. Non-geotoxic, repro.

DR. ANDERSEN: Really, the only hanging piece of information are those case studies. Patch-testing with decyl glucoside in patients who had reactions to a bunch of products was positive for decyl glucoside and.5 to 10 percent.

DR. ANSELL: So, even though that's a rinse-off product, the data request --

DR. BELSITO: No, it has leave-on uses, too. Two percent.

DR. ANDERSEN: But in terms of the leave-on uses, you've got sensitization testing --

DR. BELSITO: Yes.

DR. ANDERSEN: More than adequate for the leave-on. Although, the question is inhalation --

DR. BELSITO: Right.

CIR Panel Book Page 15 Distributed for Comment Only -- Do Not Cite or Quote SPEAKER: Yes.

DR. ANDERSEN: So, everything else that Jay went through is not positive.

DR. ANSELL: But it all goes to the inhalation assessment.

DR. ANDERSEN: I agree. Yes, again, the only thing that there's any kind of a flag of those case reports, everything else is just (inaudible).

DR. BELSITO: Well, we have no inhalation data.

DR. ANDERSEN: No inhalation.

DR. LIEBLER: This is another one of those ones where I think all the available data suggests to me that there's no reason to worry about inhalation except that we don't have an explicit inhalation study.

DR. BELSITO: Okay, so, how do we craft a boilerplate for this and all of the other ingredients that are going to fall under the same thing?

DR. LIEBLER: Right.

DR. BELSITO: Where there are reported uses that could result inhalation, where we have no data that gives us concern for anything else, but we have no inhalation tox data. How do we draft that? Do we say the expert panel waved its magic wand and --

DR. LIEBLER: No, okay, so, actually --

DR. BELSITO: -- control this without creating --

DR. LIEBLER: I think it's systemic toxicity because, I mean, as Curt pointed out earlier, there are two ways in which an inhaled compound can be important. One is it's a gateway to systemic and the other is, is in lung target organ toxicity.

So, first of all, from the systemic point of view, there's not going to be enough absorption to the lungs to contribute to systemic toxicity, particularly given the systemic toxicities. So, absorption to the lung, a systemic toxicity due to absorption, due to an inhalation is unlikely to be significant. So, that's the first part.

And then the second part is, even though despite an absence of inhalation toxicity data, a lack of systemic toxicity, a lack of ocular toxicity, and minimal --

DR. ANSELL: Exposure, minimal exposure.

DR. SNYDER: This is where we need to know the -- we need to have our foundation of information based on particle size distribution of the category whether it's pump spray, whether it's a deodorant, or whether it's a aersolated spray so we know that we're talking less than 1 percent or 1 to 2 percent or what it is, the comfort level of potential doesn't mean it is, but I can't --

DR. BELSITO: Five percent of 8 percent --

DR. ANSELL: Or (inaudible). I don't see that it's fundamentally different than what we do with a 90-day oral study and lack of dermal irritation and molecular weight all kind of aggregating to convince us that, you know, we're not concerned. The inhalation route has different issues, it doesn't -- you know, first (inaudible) metabolism, the root of absorption, but I think when we look at the data and we say very short exposures to low concentrations absent irritation, absent systemic issues, I would not argue that we have no inhalation data. We have a lot of data which you relied upon to make a reasonable assessment.

DR. LIEBLER: Well, we have the other types that I just mentioned that, together with the very brief and small inhalation exposure, could lead the panel to conclude that the risk of lung toxicity, inhalation toxicity is not significant.

DR. SNYDER: Not biologically condemning. Toxicology.

CIR Panel Book Page 16 Distributed for Comment Only -- Do Not Cite or Quote DR. LIEBLER: So, we have this recurring situation, as Don just pointed out, where we have a compound and we have an ingredient that has really minimal toxicities, maybe some irritation on skin on some individuals, and that depends on the formulation and so forth. We have no inhalation tox data, but there's a potential for some inhalation of the compound. So, that's what we need a boilerplate for. And, I mean, I'd be happy to try and draft some tentative language to work on that. I don't think we have time to talk about that before we're done today, but, tomorrow, I don't know if we're going to have time in the agenda to get into that.

DR. BELSITO: Well, I think, I mean, we really need to. I mean, this is --

SPEAKER: We have to.

DR. BELSITO: This is going out as a final.

SPEAKER: Yes.

MS. FIUME: It'll be tentative.

DR. BELSITO: Tentative, right, but, I mean, we need a fairly good boilerplate for our discussion because it's going to be happening over and over again, and something that maybe we can cross out or add in, but what are all the points that we, as a panel, want to consider when we have inhalation exposures and there is no inhalation toxicities?

So, it would, A, be nice if we could find for those inhalation exposures what the relevant particle size would be. That would be nice. Certainly, breaking out inhalation exposures into deodorant and deodorant exposures into aerosol, non-aerosol would be nice. General absence of other toxicologic endpoints is what I hear Dan saying. Low concentration of use always helps, but then what's low? Define "low."

DR. ANDERSEN: I mean, that's --

DR. KLAASSEN: Another very important one is when the chemical was given orally or what have you, it didn't produce a lung toxicity. I mean, the target organ is not liver entry.

SPEAKER: Lung.

DR. KLAASSEN: It's not lung entry.

DR. LIEBLER: Yes, right. Yes, many classic lung toxins that are activated, certain furans, naphthalene, regardless of the route of administration, it goes to the lung and causes toxicity there.

DR. KLAASSEN: Right.

DR. LIEBLER: And that's what we're basically talking about.

DR. BELSITO: But I hate to beat a dead horse, but microwave popcorn eaters did not have a problem with fibrosing alveolitis. So, the diacetyl, when it was ingested, did not create problems in the lungs.

DR. KLAASSEN: Well, it's probably the dose.

MS. WEINTRAUB: Sometimes, you get different kinds of funny reactions that occur in the lungs when something needs to come out.

DR. KLAASSEN: Oh, yes, like pouring gas. I mean, that's different, but what you're doing is producing hydrochloric acid. Most of the things that produce lung entry from inhalation are either extremely reactive, like ozone, or chlorine gas, or you have the compounds that really are systemically toxic to the lungs, which they get into the lung through the blood or either way. For example, some of the herbicides, and some of the cells in the lung metabolize the compound to a toxic compound with the naphthalene, et cetera, and that what causes the toxicity.

So, everything that I can think of, now, it'd be interesting to look at the data on the diacetyl what really has been done in laboratory animals, since that was first detected in Missouri, but I would guess or I'd be surprised if diacetyl isn't being forming a -- how is that working probably, Dan? Do you know?

CIR Panel Book Page 17 Distributed for Comment Only -- Do Not Cite or Quote DR. LIEBLER: I'm not sure.

DR. BELSITO: It's an allergic reaction, isn't it? It's a immunologic reaction specific to the lung that results in fibrosing alveolitis.

DR. KLAASSEN: Yes, I don't know if anybody knows the mechanism.

DR. BELSITO: Right.

DR. KLAASSEN: I mean, a compound like that, you might imagine acetylating proteins --

SPEAKER: Right.

DR. KLAASSEN: To form some immunogen that then triggers an immune response that leads to this, but I don't know if there's enough mechanistic information --

DR. BELSITO: I don't think there is.

DR. KLAASSEN: -- I just don't know that. I haven't (inaudible) literature on that guy, so.

DR. ANDERSEN: Coming back though to the profile that Dan was trying to describe, I think while, I mean, this one, you may not have complete information, but let's say that we did recognize the importance of having more detailed information on particle size, here, we have a particular kind of product, a hair color spray, and I'd like to know what that distribution is. And if we knew that, that would probably inform a discussion, but let's then just say, for example, that it is in the 3 percent of the particle size is a respirable. Then going down the path that Dan went through, we would argue that that can't be a significant route of systemic exposure because it's just too low a percentage, and that chemical would then be absorbed through the lungs. So, systemic exposure isn't the issue for that product.

Now, let's look at the other question. What about the lung tissue itself? And if we then look through what's in there and there's low demonstrated systemic toxicity, which is true for most, and I put the caveat of well, there's also as part of that they looked at the lungs and nothing was wrong, low reproductive, low genotox, low ocular, and if you go down through the mantra of systems that were tested, and there's an absence of toxicant responses, then we can infer that lung tissue is also not going to be damaged, and that route, as best I can tell, is the way to tie it together. Yes, it's an inference. You'd like to have the actual data showing that whatever is inhaled didn't do anything, but --

DR. ANSELL: Well, no, I think that's fine and we'd be happy to try to find additional data, but we keep talking about 3 or 5 percent, and as if this is 3 or 5 percent applied dermally or 3 or 5 percent in (inaudible). No, it's 3 to 5 percent of interior aerosolized to a few grams per cubic meter that are respired for minutes, and if we start doing that with a respiration rate of.02 cubic meters per minute, all of a sudden, we're getting into background levels.

DR. ANDERSEN: Well, I think that, arguably, could be added to this mantra as a way of saying where's the beef?

DR. ANSELL: Yes.

DR. ANDERSEN: Yes, we haven't written that yet. That's what I think people --

DR. ANSELL: I also think if you start looking at inhalation data, it's going to be very complicated because you don't do an inhalation study where the animal isn't being exposed to respirable --

DR. BELSITO: Okay, so, the boilerplate in the cosmetic use section will definitely be changed. I think we're happy with that. We're going to go with the safest use conclusion for this. We're going to ask the CIR staff and the scientific committee of the PCPC and maybe include Dan, since he already volunteered to do this, but no one is going to do it tonight, to talk back and forth over the next however many days, 30 days or 90 days before all of these issues come back to us in December, and come up with some type of boilerplate that we're going to deal with these chemicals when we have inhalation data.

DR. ANDERSEN: I can see Monice's response already. I'm not uncomfortable with putting a first version of

CIR Panel Book Page 18 Distributed for Comment Only -- Do Not Cite or Quote that discussion in a tentative document that we will issue.

DR. BELSITO: Sure.

DR. ANDERSEN: I think I can get pretty complete.

DR. BELSITO: Okay.

DR. ANDERSEN: And then you guys can polish it.

DR. BELSITO: Correct, that's what I'm asking. What I'm saying is that we're not going to get there today. I think everyone, at least speaking for myself, is too exhausted to be thinking --

DR. KLAASSEN: And we've got five more documents.

DR. BELSITO: Clearly, we've got six more documents, Curt.

SPEAKER: And the aerosol discussion.

DR. BELSITO: And an aerosol discussion --

DR. ANDERSEN: Which we've been having all along, so.

DR. BELSITO: -- which is really what we're doing.

DR. ANDERSEN: So, no, thank you.

DR. SNYDER: One last comment. So, there's two footnotes here, and which I think we should try to eliminate it so that includes some (inaudible) that is not known whether or not reported in a product, a spray, same thing with deodorants. We need to know that because I think that when we end up with those large percentages in a category that we don't know whether or not that truly is inhalation, could provide inhalation exposure. That's one of the more refined data we need from this use table.

DR. BELSITO: Well, I think that's what we've been saying all along.

DR. SNYDER: Yes.

DR. BELSITO: Those product categories, we'd like it split out into aerosol, non-aerosol.

DR. SNYDER: Well, it's got to pump spray, whatever, yes.

DR. ANSELL: Well, let's take it back home, take it back home and talk about this. It's quite possibly what we're really talking about, difference between 1 and 50 is a microgram.

DR. BELSITO: So, but wait a minute, let's just go back to Paul's point for a second. So, you would like it split three ways, aerosol, non-vaporized or whatever.

DR. LIEBLER: Non-spray.

DR. BELSITO: Non-spray, pump, aerosol non-spray. You would like all three categories?

DR. SNYDER: Well, that's because of the data that we presented this morning. In the pump spray --

DR. BELSITO: Less likely, right.

DR. SNYDER: -- less likely, and then the aerosol spray is 1 to 2, but then we heard the deodorant is even different again because it had a greater proportion of the particles that could review less. So, I think that we have to be careful. We want to make sure we are asking specifically what we want from the standpoint of --

DR. BELSITO: Okay, so, what you would like would be non-aerosol, aerosol pump, aerosol spray?

CIR Panel Book Page 19 Distributed for Comment Only -- Do Not Cite or Quote DR. SNYDER: Correct. At this point. Okay, that's what you said.

DR. LIEBLER: Yes.

MS. FIUME: Dr. Belsito, before you move on, the conclusion, safe as used or safe as used while formulated to be non-irritating?

DR. LIEBLER: I'd guess the latter.

DR. BELSITO: Yes, non-irritating.

DR. SNYDER: Are you sure about that? Because I thought we had concentration use that was lower than the other (inaudible). Is that not correct?

DR. BELSITO: Yes. I don't know, I think we do have the data. I guess what still bothers me at the bottom of my heart is I know that Carol is beating the bushes and asking them to do active ingredients, but when we have compounds that are not present at 100 percent, and, quite honestly, and they're irritating and that's an issue, and I know you're 100 percent certain that the concentrations of use that you're seeing in the studies and/or reported are the real ones, and I feel --

DR. SNYDER: Then why do we caveat our conclusions as reportedly used?

DR. BELSITO: But this is just one more caveat, but our real concern is irritation. I don't know.

DR. SNYDER: Right. I mean, I hear you.

DR. BELSITO: Well, we have the data. If all of the data is correct, we have the data to suggest that as used is not sensitized.

DR. SNYDER: Right.

DR. BELSITO: And non-irritating.

DR. SNYDER: I just don't want to go to path that every report we caveat on when --

DR. BELSITO: All right.

DR. SNYDER: Because if we'd rather have the data --

DR. BELSITO: Safe as used.

DR. SNYDER: Yes.

MS. FIUME: So, slightly irritating is okay in both of those?

DR. SNYDER: Right.

MS. FIUME: And human irritation studies, at like percent active ingredient, lauryl glucoside, it was slightly irritating in 13 patch tests. That's a glucoside percent active ingredient with slightly irritating 13 percent.

DR. BELSITO: Let me look in my notes here.

MS. FIUME: All right.

DR. BELSITO: No, I had when formulated not to be irritating is my conclusion.

DR. LIEBLER: The reason I said that is because when I see sometimes irritating, sometimes it's not and it's close to the concentration of use --

SPEAKER: Right.

CIR Panel Book Page 20 Distributed for Comment Only -- Do Not Cite or Quote DR. LIEBLER: Then any particular product could be irritating depending on how it's formulated. That's why I put that in.

DR. BELSITO: And penetration enhancement in the discussion, as well.

MARKS TEAM – DECYL GLUCOSIDE – SEPT 2011

So let's move on them while we're waiting to Decyl Glucoside group. It's in the Pink Book. In June, the panel issued an insufficient data announcement. We've received new data. There was concern about the sensitization. I think we could move forward now with a tentative safety assessment, safe as formulated to be non-irritating. Comments?

DR. HILL: I have a comment in that the new data does not include the ingredient of greatest concern, which was a long chain branched decyl glucoside. The data that was supplied as far as I can tell doesn't have any such because the sensitization potential of its C12-16 APG. And then they did some additional studies and didn't show up anything but it seemed that the greatest alerts in terms of data we had the last time was from branching -- long-branch chain. Specifically, C18 branched.

DR. MARKS: Now I --

DR. HILL: And then the other question I had was -- pardon to interrupt but just thought I'd toss this out in the same because it's the same issue -- is in the discussion it says the concern with the potential exists for dermal irritation but I thought the main concern was sensitization, not irritation. And so I was surprised that that showed up that way.

DR. MARKS: As in Monice's memorandum it was primarily dermal sensitization and decyl glucoside concentration at 11 percent. And in point the new data received in leave-ons it's really at five percent. So we have that concern is now addressed. There was no sensitization at five percent with laurel and decyl glucoside.

DR. HILL: Right. But I was surprised reading that memo because I didn't think the concern was necessarily with decyl glycoside at all. I mean, there was an irritation question about that one and that was resolved, but I'm not sure it was ever real in the first place. But then the sensitization, there were some structure activities or there were trends in terms of structure activity that suggested longer chain and branching might cause the sensitization problem. We didn't get any data addressing that best I can tell. That was a concern I raised several times in several different ways that shows up in the transcript.

MS. FIUME: If I could first address the decyl glucoside actually was the concern. Dr. Belsito had mentioned that they were doing testing in the North American Contact Dermatitis Group on decyl glucosides, so there was nothing in the report and that's why he wanted to see decyl glucoside at 11 percent.

DR. HILL: Oh, yes. I remember that.

DR. MARKS: That's actually on --

DR. HILL: That was what Dr. Belsito raised.

DR. MARKS: Yes. And I didn't have quite the concern that Dr. Belsito -- if you look on page 10 in the transcripts, actually at the top of the page, it's exactly as Monice said. You'll see that Dr. Belsito is referring to decyl glycoside at 11 percent. And that's -- he either wanted to have an HRIPT with decyl glycoside but now we know it's not at that concentration.

DR. HILL: Well, I would be comfortable with everything if we had a non-sensitizing disclaimer in our discussion of conclusion, but we don't have that in there best I can tell.

DR. BERGFELD: Are you proposing that you put in the discussion that the longer chain ingredients could be sensitizers? Is that what you're saying? A potential sensitizer?

DR. HILL: Yeah. So there's an LL -- I know it's just an LLNA. The bottom of Panel Book 33, page 10. "One C12-C18 glucoside C14 glucoside and C18 branch glucoside might cause skin sensitization so the concentration

CIR Panel Book Page 21 Distributed for Comment Only -- Do Not Cite or Quote is at 8.4 percent, 5.9 percent and 0.43 percent, respectively. And then they came back and used C12-C16. So my question was C18 branched because there's nothing in those C12 -- I don't know APG, what all is in there. We typically don't get a full analysis of all the components present in that sort of thing.

MS. FIUME: Excuse me, Dr. Hill, on Panel Book, pages 45 and 46 --

DR. HILL: Yeah.

MS. FIUME: -- there are some irritation data and sensitization data on the 18 branch glucoside. Does that answer your question or no?

DR. HILL: Hang on.

DR. SLAGA: What was the problem?

MS. BURNETT: In animals.

MS. FIUME: I think there's also a human on the bottom of -- see our Panel Book, page 46.

SPEAKER: It's the human data. All right, so. C18 branch, okay. Okay, so irritation but no positive reactions that challenge, blah blah blah. Yeah, I'm fine. Yes. I'm good now.

DR. MARKS: So are we to the point, team, that we, as I mentioned earlier, we can support a motion that this is safe when formulated? These ingredients are safe when formulated to be non-irritating and a tentative safety assessment would be issued?

DR. HILL: Mm-hmm.

DR. SLAGA: Agreed.

DR. MARKS: Okay. Any other comments? Thanks, Monice.

DR. HILL: I find it's interesting because we don't see anything on the humans but we are seeing multiple occasions. The LLNA is showing positive reaction so I'm not an expert on LLNA. I need to gain some expertise on that.

DR. MARKS: Well, the local lymph node assay, if you look in that transcript also I was relying on at that end Dr. Belsito didn't like that assay particularly even though it's a standard assay.

DR. HILL: I remember that.

DR. MARKS: Which is widely accepted, particularly in Europe.

FULL PANEL – DECYL GLUCOSIDE – SEPT 2011

DR. BELSITO: In June we issued an insufficient data announcement for this group of 17 alkyl glucosides, one of which is decyl, and we wanted further classification on the actual use concentration of the active ingredient for decyl glucoside or sensitization data at the level of 11 percent that appeared to be the highest concentration of the active ingredient. Since then we've gotten clarification that in fact it wasn't 11 percent decyl glucoside, it was 11 percent of the commercial product which represents only 0.5 percent decyl glucoside. Based on that information and Carol's ongoing attempts when getting concentration of use to assure that its active ingredient, the only comment I would make is please put that on the tables that it is active ingredient.

DR. EISENMANN: To clarify, it was in the wrong product category. It's a rinse-off product and the 11 percent is still there but it's in a rinse-off.

DR. BELSITO: Right.

DR. EISENMANN: It was active, but it was in the wrong product category.

CIR Panel Book Page 22 Distributed for Comment Only -- Do Not Cite or Quote DR. BELSITO: Based on that, we found that the alkyl glucosides were safe as used when formulated to being non-irritating as our conclusion. We need the usual respiratory issues inserted into the use section and the discussion section. It is a penetration enhancer and that would need to be in the discussion section as well.

DR. BERGFELD: That's a motion?

DR. BELSITO: That's a motion.

DR. MARKS: Second.

DR. BERGFELD: Jim, second. Is there any other discussion that's worthy of being discussed this morning here?

DR. SHANK: I would like to add the reference that Dr. Snyder has on stress and male reproductive toxicity in rabbits as it applies to this one as well.

DR. BERGFELD: Thank you for that reminder. Is there anything else? Seeing no one wanting to discuss this particular ingredient, I'll call for the question. All those in favor indicate by raising your hands. Unanimous.

CIR Panel Book Page 23 Report

Distributed for Comment Only -- Do Not Cite or Quote

Draft Final Safety Assessment

Decyl Glucosides and Other Alkyl Glucosides As Used in Cosmetics

December 13, 2011

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

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

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TABLE OF CONTENTS

Abstract ...... 1 Introduction ...... 1 Chemistry ...... 1 Definition and Structure ...... 1 Impurities, Constituents, and Physical and Chemical Properties ...... 2 Method of Manufacture ...... 2 Use ...... 2 Cosmetic ...... 2 Non-Cosmetic ...... 3 Toxicokinetics ...... 3 Absorption, Distribution, Metabolism, and Excretion ...... 3 Dermal ...... 3 Oral ...... 4 Absorption Enhancement ...... 4 Toxicological studies ...... 4 Single Dose (Acute) Toxicity ...... 4 Dermal ...... 4 Oral ...... 5 Repeated Dose Toxicity ...... 5 Dermal ...... 5 Oral ...... 6 Reproductive and Developmental Toxicity ...... 6 Dermal ...... 7 Oral ...... 7 In Vitro Estrogenicity Assays ...... 7 Genotoxicity ...... 7 Carcinogenicity ...... 7 Irritation and Sensitization ...... 7 Dermal Irritation and Sensitization ...... 7 Ocular Irritation ...... 8 Summary ...... 8 Discussion...... 10 Conclusion ...... 10 Tables ...... 11 Table 1. Definitions, functions, and structures of the alkyl glucosides in this safety assessment...... 11 Table 2. Chemical and physical properties ...... 14 Table 3a. Frequency and concentration of use according to duration and type of exposure ...... 16 Table 3b. Ingredients Not Reported to be Used ...... 17 Table 4. Skin irritation and sensitization studies ...... 18 Table 5. Ocular irritation studies ...... 22 Table 6. Summaries of information on fatty alcohols from previous CIR reports ...... 24 References ...... 27

ii

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ABSTRACT The CIR Expert Panel assessed the safety of 19 alkyl glucosides as used in cosmetics. Most of these ingredients are reported to function as surfactants, but some are reported to function as skin conditioning agents, hair conditioning agents, or emulsion stabilizers instead. The Panel reviewed the available animal and clinical data on these ingredients. Since glucoside hydrolases in human skin are likely to break down these ingredients to release their respective fatty acids and glucose, the Panel also reviewed appropriate CIR reports that were available, and were able to extrapolate data from these previous reports to support safety. The Panel concluded that these ingredients are safe in the present practices of use and concentration when formulated to be non-irritating. It was noted that reported concentrations of use are as active ingredient.

INTRODUCTION This assessment reviews data relevant to the safety of decyl glucoside and 18 other alkyl glucoside ingredients as used in cosmetic formulations. Most of these ingredients are reported to function in cosmetics as surfactants. Other reported functions of some of these ingredients are skin conditioning agent, hair conditioning agent, or emulsion stabilizer. Hexadecyl D-glucoside and octadecyl D-glucoside are not listed in the International Cosmetic Ingredient Dictionary and Handbook, but are being included because they are listed by the Food and Drug Administration (FDA) Voluntary Cosmetic Registration Program (VCRP) as being used in cosmetic formulations. The ingredients included in this review are obtained by the condensation of an alcohol with a cyclic form of glucose (D- glucopyranose). The group includes:

Decyl Glucoside Coco-Glucoside Arachidyl Glucoside Ethyl Glucoside Butyl Glucoside Hexadecyl D-Glucoside C10-16 Alkyl Glucoside Isostearyl Glucoside C12-18 Alkyl Glucoside Lauryl Glucoside C12-20 Alkyl Glucoside Myristyl Glucoside C20-22 Alkyl Glucoside Octadecyl D-Glucoside Caprylyl/Capryl Glucoside Octyldodecyl Glucoside Caprylyl Glucoside Undecyl Glucoside Cetearyl Glucoside

Although the names of these ingredients imply that they are mono-glucosides, these ingredients are not limited to mono- glucosides, but may involve products that are the result of a number of condensed glucose repeat units. Glucoside hydrolases in human skin are likely to break down these chemicals to release their respective fatty alcohols and glucose. Therefore, summary information on the appropriate fatty alcohols that have previously been reviewed by the Cosmetic Ingredient Review (CIR) is presented at the end of this report in the last table (Table 6).

CHEMISTRY Definition and Structure This group of ingredients consists of anomerically-alkyl-substituted D-glycopyranosides. Specifically, the alkyl substituents range from 2 to 22 carbons in length, and the D-glycopyranosides consist of glucose-type mono-, di-, tri-, oligo-, or poly-saccharides (e.g., mono = glucose (i.e. D-glucopyranoside) and di = maltose (i.e. D-maltopyranoside)). The degree of polymerization of these ingredients refers to the number of glucose monomers (n in Figure 1). For example, a degree of polymerization of 2 means the di-glucose (disaccharide), maltose. Regardless of the degree of polymerization these ingredients are simply named “glucosides.” Although these ingredients are most likely the ß-anomers, the names of these alkyl glucosides are not necessarily specific to either anomer. The general decyl glucoside structure shown in Figure 1 is the ten-carbon, alkyl-chain substituted glycopyranoside, wherein n can be 1 (for a mono-glucoside) or more (for di-, tri-, oligo-, and poly-glucosides):

1

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Figure 1. General Decyl Glucoside Structure

Therefore, decyl glucoside may be monomeric or polymeric, but the International Nomenclature Cosmetic Ingredient (INCI) name will still be decyl glucoside. “Poly” will be used generically used throughout the rest of this report to refer to di-, tri-, oligo-, poly-glucosides, and mixtures thereof. Decyl glucoside, for example, may consist of one or more of the following polyglucosides (in this case isomaltopyranosides) shown in Figure 2:

Figure 2. Examples of Decyl Glucoside Forms

A decyl glucoside with a degree of polymerization of 1.6, for example, would then be a mixture comprised of decyl glucopyranoside and one of the decyl maltopyranosides (with a slightly higher percentage of the maltose derivative) shown in Figure 2. Because many of these fatty alcohols are supplied from natural feed stocks, the designated length may be the average (e.g., median) length (e.g. decyl glucoside may actually be a mixture of C6, C8, C10, C12, C14, and C16 chain lengths, each anomerically attached to a glucopyranose).1 The definitions and structures of the ingredients included in this review are provided in Table 1. Impurities, Constituents, and Physical and Chemical Properties These compounds are typically solids, with solubility in both aqueous and organic solutions. The available impur- ity, constituent, and physical and chemical property information is presented in Table 2. Method of Manufacture The first report of the synthesis of alkyl glucosides in 1893 involved reacting glucose with anhydrous ethanol under acidic conditions to produce ethyl glucoside.2 Alcoholysis of glucose and polysaccharides under acidic conditions is still the method of choice. It is considered to be a “green” process that can involve the use of natural and renewable sources (e.g., the alcohols can be obtained from coconut oil or palm oil and the glucose or polysaccharide can be obtained from corn, potato, or wheat starch).3 Of note, the reaction conditions that produce an ether linkage between a fatty alcohol and the anomeric hydroxy group of glucose are known to cause condensation of one molecule of glucose with another molecule of glucose, thereby producing alkyl polyglucosides (APGs) even when an alkyl monoglucoside may be the intended product.

USE Cosmetic The alkyl glucosides named in this safety assessment are reported to function primarily as surfactants.4 A few do not function as surfactants, and are reported to function as skin conditioning agents, hair conditioning agents, or emulsion stabilizers.

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VCRP data obtained in 2011 for this ingredient group indicate that decyl glucoside has the highest frequency of uses reported, 492; the majority of these uses, 421, are in rinse-off formulations.5 Cetearyl glucoside, lauryl glucoside, and coco- glucoside have 477, 399, and 350 reported uses, respectively. Cetearyl glucoside is mostly reported to be used in leave-on products. The remaining ingredients that are reported to be used have ≤75 uses. Based on data from a survey conducted by the Personal Care Products Council (Council), lauryl glucoside has the highest leave-on concentration of use at 8%; this leave-on use is in a hair color spray; it also is reported to have the highest leave-on concentration of use that involves dermal contact, and that concentration is 5%. Decyl glucoside has the highest rinse-off concentration of use, at 33%.6 Frequency and concentration of use data are provided in Table 3a. In some cases, reports of uses were received in the VCRP, but no concentration of use is available. For example, decyl glucoside is reported to be used in 25 baby products, but no use concentration was available. In other cases, no reported uses were received in the VCRP, but a use concentration was provided in the industry survey. For example, caprylyl glucoside was not reported in the VCRP to be used in non-color- ing hair products, but the industry survey indicated that it was used in such products at 4%. It should be presumed that caprylyl glucoside is used in at least one hair care product. The ingredients not listed in the VCRP or by the Council as in use are listed in Table 3b. Products containing alkyl glucosides are reported to be used on baby skin or applied to the eye area, and mucous membranes may be exposed to these products. Coco-glucoside is reported to be used in a product that could be ingested. A few of the ingredients are reported to be used in product types that include spray or powder forms that could be inhaled. In practice, 95% to 99% of the aerosols released from cosmetic sprays have aerodynamic equivalent diameters in the 10 to 110 µm range.7,8 Therefore, most aerosols incidentally inhaled from these sprays are deposited in the nasopharyngeal region and are not respirable.9,10 There is some evidence indicating that deodorant spray products can release substantially larger fractions of particulates having aerodynamic diameters in the range considered to be respirable.10 However, the information is not sufficient to determine whether significantly greater lung exposures result from the use of deodorant sprays, compared to other cosmetic sprays. All of the glucosides named in the report, with the exception of C20-22 alkyl glucoside, hexadecyl D-glucoside, and octadecyl D-glucoside, are listed in the European Union inventory of cosmetic ingredients.11 Non-Cosmetic Caprylyl glucoside and similar alkyl glucosides are effective solubilizers of lipids and proteins below their critical micelle concentrations (CMC), and are used in various biochemical techniques and membrane research. These ingredients also can be used to reconstitute enzymes or other proteins from crude biological preparations.12 The use of decyl glucoside as a stabilizer in nanosuspensions for dermal delivery has been investigated; decyl glucoside was effective as a stabilizer with resveratrol13 and hesperetin ((S)-2,3-dihydro-5,7-dihydroxy-2-(3-hydroxy-4- methoxy-phenyl)-4H-1-benzopyran-4-one)14 nanosuspensions.

TOXICOKINETICS In an in vitro dermal absorption study using human skin samples, the mean absorbed dose of caprylyl/capryl gluco- side (10% solution) was 0.01%. In an oral study in which female mice were dosed by gavage with a 5% aq. solution of caprylyl [U-14C]glucoside, the highest levels of radioactivity at 2 h after dosing were found in the stomach, intestines, liver, and kidneys. The radioactivity in the stomach was primarily unchanged substrate, while only a trace amount found in the liver was unchanged. Labeled glucose was found in all of these organs. In a feeding study in rats in which dietary sucrose was replaced with 10 or 20% ethyl glucoside for 39 days, 60-90% of the ingested ethyl glucoside was recovered in the urine. Absorption, Distribution, Metabolism, and Excretion Dermal Glucoside hydrolases are known to be present in human skin. Therefore, the first step in the metabolism of these ingredients may be breaking down these chemicals to glucose and their respective fatty alcohols.15 In Vitro Caprylyl/Capryl Glucoside The dermal penetration of caprylyl/capryl glucoside, diluted to 10% in Hanks’ buffered salt solution, pH 6.5, was evaluated in vitro using human skin.16 Two skin samples from each of three donors were used in the study (n=6). The receptor fluid was Krebs ringer’s bicarbonate buffer without HEPES and glucose. After 24 h, the mean recovery was 0.52% of caprylyl/capryl glucoside from two tape strips and 0.30% of caprylyl/capryl glucoside in the further 18 tape strips. The mean amount of caprylyl/capryl glucoside removed from the skin (by washing) ranged from 109-145% of the dose applied.

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The mean absorbed dose of caprylyl/capryl glucoside, as the sum of the amounts found in the viable epidermis, dermis, and receptor medium, was 0.01%. Oral Non-Human Caprylyl Glucoside Three female NMRI mice were given a single oral dose, by gavage, of 37 MBq/mmol caprylyl [U-14C]glucoside in 0.05 ml of a 5% aq. solution of phophatidylcholine.17 The animals were killed 2 h after dosing. The highest levels of radio- activity were found in the stomach, intestines, liver, and kidneys, with most of the radioactivity (81-98%) distributed in the aqueous phase. High levels of radioactivity that were not extractable with chloroform were found in the urine, which, according to the researchers, indicated a high rate of degradation to water-soluble metabolites. In the stomach, 75% of the radioactivity was associated with unchanged substrate. In the kidneys and intestines, 50% of the total radioactivity was unchanged substrate, while only a trace amount found in the liver was associated with unchanged substrate. Labeled glucose was detected in all four of these organs. In the stomach, intestines, and kidneys, 13- 19% of the radioactivity was contained in the chloroform extract, and most of it was derived from caprylyl [U-14C]glucoside. In this extract in the stomach, approximately 2% acylated-labeled substrate was detected. Ethyl Glucoside Groups of 6 male Wistar ST rats were fed a diet for 39 days in which sucrose was replaced with 10 or 20% ethyl glucoside, and a control group was fed unaltered (i.e., sucrose-containing) feed.18 A 24-h urine volume was measured weekly. Approximately 60-90% of the ethyl glucoside ingested by treated animals was recovered in the urine. Absorption Enhancement Caprylyl glucoside has been shown to increase the absorption of poorly absorbed drugs (e.g., insulin), both in vitro across human carcinoma monolayers and in vivo through mucosal membranes. In the in vitro study, the enhancement of the permeability of insulin across T84 and Caco-2 cell monolayers by caprylyl glucoside was concentration-dependent; permea- bility of insulin was not significantly enhanced at concentrations of 0.2 and 0.3%, while it was enhanced with 0.4 and 0.5% caprylyl glucoside.19 In a transmucosal absorption study, the effect of caprylyl glucoside on the nasal, buccal, and rectal absorption of insulin was examined using male Lewis rats.12 A 5% solution of caprylyl glucoside had an enhancing effect on buccal absorption. The effect of other alkyl glycosides, including decyl and lauryl glucoside, on mucosal penetration was also eval- uated. A 5% solution of decyl glucoside also enhanced the buccal absorption of insulin, but 5% lauryl glucoside did not have a significant effect. The researchers stated that there was no consistent relationship between alkyl chain length and penetra- tion enhancement.

TOXICOLOGICAL STUDIES In single dose dermal studies with caprylyl/capryl glucoside and C10-16 alkyl glucoside (both 50% active ingredient (a.i.), n:1.6) in rabbits, the LD50 was greater than the 2000 mg/kg dose administered. In oral studies, no mice dosed with 2000 mg/kg caprylyl glucoside and none of the rats dosed with 5000 mg/kg C10-16 alkyl glucoside died during the study. In 2-wk repeated dose dermal studies in rabbits with 60% active caprylyl/capryl glucoside, occlusive appli- cations produced testicular effects, while non-occlusive application did not. In the two occlusive studies, one with 0.09 and 1.8 g a.i./kg and the other with 0.14-1.25 g a.i./kg, a no-observed effect level (NOEL) for testicular effects could not be established; the NOEL for microscopic effects in the epididymides, prostate, and vesicular glands was 0.14 g a.i./kg. In the non-occlusive study, the NOEL for systemic toxicity was 0.18 g a.i./kg caprylyl/capryl glucoside. Severe dermal irritation was observed in both occlusive studies, while slight to moderate irritation was reported in the non-occlusive study. In oral repeated dose toxicity studies, moderately-dilated renal tubules were observed in 3 of 6 rats fed 20% ethyl glucoside for 39 days, but in none of the rats fed 10% ethyl glucoside. Kidney weights were statis- tically significantly increased in the test animals. In rats dosed orally with 250-1000 mg/kg C12/16 APG for 13 wks, reversible irritation and ulceration of the stomach mucosa was observed, but there was no systemic toxicity reported for any group.

Single Dose (Acute) Toxicity Dermal Caprylyl/Capryl Glucoside Groups of 5 male and 5 female New Zealand White (NZW) rabbits were given a single dermal dose of 2000 mg/kg bw caprylyl/capryl glucoside, 50% active ingredient (a.i.) (as C8/C10 APG); the degree of polymerization, n, was 1.6.20 (Whether occlusion was used was not stated.) Mild to moderate irritant effects, fecal staining, yellowing around the applica- 4

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tion site, emaciation, nasal discharge, and lacrimation were observed. One animal died of an unrelated infection, and at necropsy, 5 had spotty areas of hemorrhage on the lungs. C10-16 Alkyl Glucoside Groups of 5 male and 5 female NZW rabbits were given a single dermal dose of 2000 mg/kg bw C10-16 alkyl glucoside, 50% a.i. (as C10-16 APG; n:1.6).20 (Whether occlusion was used was not stated.) Slight depression, hunched posture, mild to marked erythema, and marked desquamation were observed. None of the animals died during the study. Oral Caprylyl Glucoside Female NMRI mice were given a single oral dose of 40 mg (2000 mg/kg bw) caprylyl glucoside as a suspension in 0.2 ml of a 5% aq. solution of phosphatidylcholine.17 No toxic effects were observed during a 2-wk post-dose observation period. Growth and behavior were not affected. Caprylyl/Capryl Glucoside Groups of 5 male and 5 female Sprague-Dawley rats were given a single oral dose of 5000 mg/kg bw caprylyl/cap- ryl glucoside (as C8/10 APG; n:1.6, 50% a.i.).20 None of the animals died during the study. C10-16 Alkyl Glucoside Groups of 5 male and 5 female Sprague-Dawley rats were given a single oral dose of 5000 mg/kg bw C10-16 alkyl glucoside (as C10/16 APG; n:1.6, 50% a.i.).20 None of the animals died during the study. Additionally, no mortality was ob- served upon dosing of 2 male and 2 female Wistar rats with a single oral dose of 2000 mg/kg bw C12/14 APG, n: 1.6 and 60% a.i. Repeated Dose Toxicity Dermal Caprylyl/Capryl Glucoside Groups of 6 male and 6 female NZW rabbits were dosed dermally with 0, 0.9, and 1.8 g a.i./kg (0, 22.5, and 45 w/v%, respectively) caprylyl/capryl glucoside (60% active) in distilled water (4 ml/kg).21,22 Ten 6-h occlusive applications were made over a 2-wk period. Treatment-related signs of toxicity, such as ataxia, lethargy, and emaciation, were observed in both test groups. One female of the 1.8 g a.i./kg group died after 10 doses, and the death was considered test article- related. Slight irritation was observed 1 day after the initial dose, and severe dermal irritation was observed in males and females of both test groups by days 5-6 of the study. Body weights of treated male and female rabbits were significantly less than those of controls, and mean body weight loss was observed for both groups. Significant changes were observed in some hematology and clinical chemistry values; a dose-response relationship was not observed for most of the hematology changes. Compared to controls, absolute testes weights were significantly lower in treated males of both dose groups. No other compound-related changes in organ weights were observed. Small testes were observed in 3 of the 6 treated males of each group; the researchers stated that occurrence of this lesion was rare, and while the occurrence was not statistically significantly different from controls, it was considered biologically significant. Microscopic examination of selected male tissues reported very slight to marked testicular degeneration in all rabbits in the 0.9 g a.i./kg group and slight to marked testicular degeneration in four rabbits of the 1.8 g a.i./kg group. Very slight to moderate atrophy of the prostate and “acces- sory sex glands” was observed in 3 rabbits of each group. The researchers stated that irritation, inflammation, and stress in these animals were major contributing factors to many, if not all, of the toxicologic effects; however, the researchers also stated that it is possible that caprylyl/capryl glucoside produced some of the effects. (Published findings have reported that degenerative changes occur commonly in the testes of normal rabbits, and these changes may be increased during stress.23) A NOEL was not obtained. In another 2-wk study, 10 occlusive applications of 0.14, 0.41, and 1.25 g a.i./kg (60% active) caprylyl/capryl gluco- side in distilled water (0, 3.5, 10.4, and 31.1% a.i., respectively) were made to intact skin on the backs of 6 male NZW rabbits per group in order to determine the NOEL for testicular toxicity.24,25 Two of the high dose animals died during the study, and the 4 surviving animals had signs of treatment-related toxicity. No treatment-related mortality occurred in the low or mid- dose groups. Dermal irritation, which progressed from slight to severe with time, was observed in all test groups, and slight to moderate irritation was observed in the controls. Changes in some hematology and clinical chemistry values were observed, but were attributed to stress of the occlusive procedure, irritation, and body weight loss. A decrease in the mean absolute testicular weights in animals of the mid- and high dose groups was considered treatment-related. A treatment-re- lated loss in body weight was observed in all test groups, and the mean terminal body weights of rabbits of all test groups were decreased compared to controls. Relatively small testes were observed in 1, 2, 4, and all 6 males of the control, low.

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mid and high dose groups, respectively. Treatment-related microscopic changes were observed in the testes, epididymides, prostate, and vesicular glands of the mid and high dose group animals; some of the lesions included an increased incidence and severity of diffuse bilateral testicular atrophy with necrotic spermatocytes and atrophy of the prostate and vesicular glands. The NOEL for the microscopic effects in the epididymides, prostate and vesicular gland was 0.14 g a.i./kg. One rabbit of the low dose group, which had the greatest body weight loss, had moderate testicular atrophy and a moderate amount of necrotic spermatocytes/spermatids. The researchers stated that the testes and accessory sex organs of the animals in the control and treatment groups were relatively immature due to age (12 wks) and low body weights, and the immature nature of these organs complicated the evaluation. Changes in the testes and accessory sex glands were attributed to the stress. An NOEL for the study was not established. In another 2-wk study, using non-occlusive applications, 2 ml of 0, 0.06, 0.18, or 0.54 g a.i./kg caprylyl/capryl glucoside (60% active) in distilled water (corresponding to concentrations of 0, 3, 9, and 27% a.i., respectively) were applied to the intact skin of the backs of 6 male rabbits/group.26 These doses were selected following a 2-wk pilot study, in which unoccluded exposure to 0.12, 0.23, and 0.45 a.i. g/kg caprylyl/capryl glucoside produced slight to moderate erythema and edema. In the main study, treatment-related signs of toxicity were not observed. Slight dermal irritation was observed in all groups after the initiation of dosing; the irritation became moderate in the high dose group after 3 days of dosing. Body weights of rabbits of the high dose group were slightly, but significantly, decreased compared to controls. Absolute testes weights were slightly, but not significantly, decreased in the high dose group. No treatment-related effects on hematology or clinical chemistry values or organ weights were reported. Microscopically, epithelial hyperplasia, hyperkeratosis, conges- tion, and eschar formation were observed in the skin of rabbits of the high dose group; these changes were not observed in rabbits of the other test groups. No test article-related microscopic changes were observed in the testes or accessory sex glands at any dose. The NOEL for systemic toxicity was 0.18 g a.i./kg caprylyl/capryl glucoside. Oral Ethyl Glucoside In a study described earlier under “Toxicokinetics,” in which groups of 6 male Wistar ST rats were fed for 39 days a diet in which sucrose was replaced with 10 or 20% ethyl glucoside, body weight gains, but not final body weights, were statistically significantly decreased in the 20% group when compared to control values.18 All animals survived until study termination. Total water intake was increased with increased ethyl glucoside consumption. In animals fed ethyl glucoside, kidney weights were statistically significantly increased and epididymal and abdominal fatty pad weights were statistically significantly decreased. The renal tubules of 2 and 4 control rats were “not-dilated” and “slightly dilated,” respectively, and the renal tubules of all the rats in 10% group were “slightly dilated.” In the group fed 20% ethyl glucoside, the renal tubules of 3 rats were “slightly dilated”, while the other 3 had “moderately-dilated” renal tubules. No microscopic damage to renal cells was observed. Alkyl Polyglucosides (APG) Groups of 10 male and 10 female Sprague-Dawley rats were dosed orally, by gavage, with 0, 250, 500 and 1000 mg/kg bw C12/16 APG for 13 wks.20 An additional 5 male and 5 female control and high dose rats were used as a recovery group. No treatment-related changes in body weights, organ weights, or biochemistry or hematology parameters were ob- served. Absolute gonad weights were decreased in all test groups, but the decrease was not considered treatment related by the researchers because of a lack of a dose-response. A dose-dependent, slowly reversible, irritation and ulceration of the forestomach mucosa was observed in animals of the 500 and 1000 mg/kg bw groups. Systemic toxicity was not observed in any group. The no-observed adverse effect level (NOAEL) for systemic toxicity was 1000 mg/kg bw. The no-observed effect concentration for “local compatibility” was deduced as 2.5% a.i.

REPRODUCTIVE AND DEVELOPMENTAL TOXICITY Dermal application of 60% active caprylyl/capryl glucoside, 0.9-1.8 g a.i./kg, under occlusive conditions may affect the testes and accessory sex glands of rabbits; however, it was not clear if the effects were test-article related or due to stress of the occlusive procedure and resulting irritation and weight loss. Lauryl glucoside, 100-1000 mg/kg by gavage, did not produce adverse reproductive or developmental effects when given to female Sprague-Dawley rats on days 6-15 of gestation or when administered from 2 wks prior to mating to 4 days after delivery. Lauryl glucoside, 0.1-10,000 nmol, did not have any effects in in vitro estrogenicity assays.

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Dermal Caprylyl/Capryl Glucoside Repeated dose dermal toxicity studies with caprylyl/capryl glucoside (60% active), cited earlier, reported decreased testes weighs, small testes, testicular degeneration, atrophy of the prostate, and microscopic changes in the testes, epididy- mides, prostate, and vesicular glands. 21,22,24,25 These effects were observed in studies using occlusive wraps, but not in non- occlusive testing. These effects were attributed to the stress of the study, and possible irritation or inflammation. Oral Lauryl Glucoside Groups of 24 gravid female Sprague-Dawley CD rats were dosed orally, by gavage, with 0, 100, 300, or 1000 mg/kg bw/day lauryl glucoside (as C10-14 or C10-16, n: 1.4) on days 6-15 of gestation.27 All animals were killed on day 20 of gestation. No maternal toxicity was observed, and no reproductive or developmental effects were indicated. There were also no differences in external, visceral or skeletal malformations between groups. The NOAELs for maternal toxicity, embryo- toxicity/fetotoxicity, and teratogenicity were all 1000 mg/kg bw/day. Lauryl glucoside (as APG C12-C14 fatty alcohol from renewable sources, n: 1.43) was given orally, by gavage, to groups of 10 male and 10 female Sprague-Dawley rats at doses of 0, 100, 300, or 1000 mg/kg/day, from 2 wks prior to mat- ing to 4 days after delivery.27 No signs of general toxicity were observed in the parental animals. The relative and absolute weights of the testes, epididymides, and seminal vesicles were similar for treated and control animals. There were no test article-related effects on reproductive parameters. The mean litter weights, mean pup weights, sex ratio, and gestation period was similar for all groups; a slight variation in pre-birth loss observed in the high-dose group was not statistically significant. There were no treatment-related effects observed for the neonates. In Vitro Estrogenicity Assays Lauryl Glucoside Lauryl glucoside (as APG C12-C14 fatty alcohol from renewable sources, n: 1.43) was evaluated in the E-Screen assay, in which the induction of cell proliferation in the estrogen-dependent human breast tumor MCF-7 cells is determined, at concentrations of 0.1-10,000 nmol/ml.27 17-β-Estradiol and bisphenol-A were reference substances, and the medium was the negative control. No effects were reported at concentrations up to 105 higher than the concurrent controls. The effects of 0.1-1000 nmol/ml lauryl glucoside (as APG C12-C14 fatty alcohol from renewable sources, n: 1.43) were determined in the MCF-7 reporter gene assay, in which the induction of luciferase activity in stable transfected MCF-7 cells is determined.27 No effects were seen with lauryl glucoside alone, and no anti-estrogenic or other synergistic effects were observed after incubation with 0.01-1000 nmol/ml estradiol:lauryl glucoside (1:1 molar ratio).

GENOTOXICITY Alkyl Polyglucosides (APG) The mutagenic potential of APGs (chain length not specified) was determined in two Ames tests at concentrations of 8-500 µg/l and 11-900 µg/plate in distilled water, with and without metabolic activation.20 APGs were not mutagenic. Posi- tive and negative controls gave expected results. The genotoxic potential of C10/16 APG was evaluated in an assay for chromosomal aberrations using Chinese hamster V79 lung fibroblasts, at concentrations of ≤160 µg/ml with and ≤16 µg//ml without metabolic activation.20 C10-16 alkyl glucoside was not clastogenic in this assay. Positive and negative controls gave expected results.

CARCINOGENICITY Published carcinogenicity studies were not found.

IRRITATION AND SENSITIZATION Dermal Irritation and Sensitization In dermal repeated dose (2-wk) toxicity tests using rabbits, caprylyl/capryl glucoside (60% a.i.) tested at concentra- tions ranging from-3.5-45% a.i. in distilled water produced severe irritation over time at all concentrations tested; in a non-occlusive study, slight dermal irritation was seen in similar testing with 3 and 9% (a.i.) caprylyl/capryl gluco- side, and moderate irritation was reported with 27% a.i. after 3 days of testing. Caprylyl/capryl glucoside, 30% a.i., was slightly irritating to rabbit skin in studies for which the details were not provided. APGs of varying chain length (C8/10 to C12/16; 15-70% a.i.) demonstrated a structure-response relationship, with irritation potential decreasing with increasing chain length, and, independent of the degree of polymerization, the irritation was mostly con-

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centration-dependent. The primary dermal irritation indices (PDIIs) ranged from 0.0 to 4.6 in rabbits. (A PDII of 2 was considered a positive responder).

In clinical studies, the dermal irritation of decyl, lauryl, and coco-glucosides was evaluated in epicutaneous patch (2.0% a.i.) and soap chamber tests (1.0% a.i.), and decyl glucoside was evaluated in an SIOPT (0.5% a.i.). At most, these ingredients were slightly irritating.

Glucosides with alkyl chain lengths ranging from C8-C10 to >C18, as well as a C18 branched glucoside, were evaluated in both the guinea pig maximization test (GPMT), at concentrations of 1.25-10% for intradermal induction, 5-100% for epidermal induction, and 2.5-50% for challenge, and the local lymph node assay (LLNA) at concentra- tions of 1.25-50%. None of the glucosides tested were irritants or sensitizers in the GPMT, but the LLNA indicated that one C12-C18 glucoside, C14 glucoside, and C18 branched glucoside may cause skin sensitization at concentra- tions of 8.4%, 5.9%, and 0.43%, respectively. The sensitization potential of C12/16 APG was evaluated in studies in guinea pigs using the Buehler method (test concentrations of 20%) and the Magnusson-Kligman protocol (1, 60, and 10% used for intracutaneous induction, epidermal induction, and epidermal challenge respectively). C12/16 APG was not a sensitizer in the Buehler or Magnusson-Kligman studies.

In clinical testing, the sensitization potential of 0.5, 0.75, and 1.8% a.i. decyl glucoside (in formulation), 5% a.i. aq. decyl and lauryl glucoside and 1% a.i. aq. coco-glucoside was evaluated in a human repeated insult patch test (HRIPT). These ingredients were not irritating or sensitizing.

Dermal irritation and sensitization studies are summarized in Table 4. Case Studies Decyl Glucoside Case studies with reactions to antiseptic, hair, and sunscreen products that contain decyl glucoside are described in published literature.1,28-32 Subsequent patch testing with decyl glucoside at 0.5-10% had positive results in these cases. Patch testing with other glucosides also produced positive results in these patients. Ocular Irritation In alternative system studies for ocular irritation, the irritation potential of 0.6-3.0% a.i. decyl, lauryl, and coco- glucosides, and of C10-16 alkyl glucosides (pH 7, 11.5; concentration not stated), were non to slightly irritating. Caprylyl/capryl glucoside (concentration not stated) was highly irritating in a hen’s egg test-chorioallantoic membrane (HET-CAM) assay. In a HET-CAM study with APGs of varying proportions of alkyl chain length, the ocular irritation potential increased with the increased proportion of shorter-chain APGs. In studies using rabbits, neutralized lauryl glucoside produced slight ocular reactions. Caprylyl/capryl glucoside was severely irritating to rabbit eyes when tested undiluted; the irritation threshold value was 10% for 30% a.i. caprylyl/capryl glucoside and 5% for 60% a.i. caprylyl/capryl glucoside.

Ocular irritation studies are summarized in Table 5.

SUMMARY The 19 alkyl glucosides reviewed in this safety assessment are ingredients that consist of anomerically-alkyl- substituted D-glycopyranosides; alkyl substituents range from 2 to 22 carbons in length and the D-glycopyranosides consist of glucose-type mono-, di-, tri-, oligo-, or poly-saccharides. The alkyl glucosides are synthesized by the alcoholysis of glucose and polysaccharides under acidic conditions. Most of these glucosides are reported to function in cosmetics as surfactants; a few are reported to function as skin conditioning agents, hair conditioning agents, or emulsion stabilizers. In 2011, decyl glucoside was reported to be used in 492 cosmetic formulations, 421 of which are rinse-offs. The most frequently used glucoside in leave-on formulations is cetearyl glucoside, with 445 of 477 uses being in leave-on formulations. Lauryl glucoside has the highest leave-on concen- tration of use at 8%; this leave-on use is in a hair color spray. It also is reported to have the highest leave-on concentration of use that involves dermal contact, and that concentration is 5%. Decyl glucoside has the highest rinse-off concentration of use, at 33%. In an in vitro dermal absorption study using human skin samples, the mean absorbed dose of 10% caprylyl/capryl glucoside was 0.01%. In an oral study in which female mice were dosed by gavage with a 5% aq. solution of caprylyl [U- 14C]glucoside, the highest levels of radioactivity at 2 h after dosing were found in the stomach, intestines, liver, and kidneys. The radioactivity in the stomach was primarily unchanged substrate, while only a trace amount found in the liver was un-

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changed. Labeled glucose was found in all of these organs. In a feeding study in rats in which dietary sucrose was replaced with 10 or 20% ethyl glucoside for 39 days, 60-90% of the ingested ethyl glucoside was recovered in the urine. In single dose dermal studies with caprylyl/capryl glucoside and C10-16 alkyl glucoside (both 50% a.i., n:1.6) in

rabbits, the LD50 was greater than the 2000 mg/kg dose administered. In oral studies with the same test substances, none of the mice dosed with 2000 mg/kg caprylyl glucoside and none of the rats dosed with 5000 mg/kg C10-16 alkyl glucoside died during the study. In 2-wk repeated dose dermal studies in rabbits with 60% active caprylyl/capryl glucoside, occlusive applications produced testicular effects, while non-occlusive application did not. In the two occlusive studies, one with 0.09 and 1.8 g a.i./kg and the other with 0.14-1.25 g a.i./kg, an NOEL for testicular effects could not be established; the NOEL for micro- scopic effects in the epididymides, prostate, and vesicular glands was 0.14 g a.i./kg. In the non-occlusive study, the NOEL for systemic toxicity was 0.18 g a.i./kg caprylyl/capryl glucoside. It was not clear if the effects were test-article related, due to inflammation, or due to stress of the occlusive procedure and resulting irritation and weight loss. Severe dermal irritation was observed in both occlusive studies, while slight to moderate irritation was reported in the non-occlusive study. In oral repeated dose toxicity studies, moderately-dilated renal tubules were observed in 3 of 6 rats fed 20% ethyl glucoside for 39 days, but in none of the rats fed 10% ethyl glucoside. Kidney weights were statistically significantly in- creased in the test animals. In rats dosed orally with 250-1000 mg/kg C12/16 APG for 13 wks, reversible irritation and ulcer- ation of the stomach mucosa was observed, but there was no systemic toxicity reported for any group. Lauryl glucoside, 100-1000 mg/kg by gavage, did not produce adverse reproductive or developmental effects when given to female Sprague-Dawley rats on days 6-15 of gestation or when administered from 2 wks prior to mating to 4 days after delivery. Lauryl glucoside, 0.1-10,000 nmol, did not have any effects in in vitro estrogenicity assays. APGs (chain length not specified), tested at 8-500 µg/l and 11-900 µg/plate in distilled water, were not mutagenic in Ames tests with or without metabolic activation. C10-16 APG, tested at concentrations of ≤160 µg/ml with and ≤16 µg/ml without metabolic activation, was not clastogenic in Chinese hamster V79 lung fibroblasts. In dermal repeated dose (2-wk) toxicity tests using rabbits, caprylyl/capryl glucoside (60% a.i.) tested at concentra- tions ranging from-3.5-45% a.i. in distilled water produced severe irritation over time at all concentrations tested; in a non- occlusive study, slight dermal irritation was seen in similar testing with 3 and 9% (a.i.) caprylyl/capryl glucoside, and moder- ate irritation was reported with 27% a.i. after 3 days of testing. Caprylyl/capryl glucoside, 30% a.i., was slightly irritating to rabbit skin in studies for which the details were not provided. With APGs of varying chain length (C8/10 to C12/16; 15-70% a.i.), there was a structure-response relationship with irritation potential decreasing with increasing chain length, and, independent of the degree of polymerization, the irritation was concentration-dependent. The primary dermal irritation indices (PDIIs) ranged from 0.0 to 4.6 in rabbits. (A PDII of 2 was considered a positive responder). In clinical studies, the dermal irritation of decyl, lauryl, and coco-glucosides was evaluated in epicutaneous patch (2.0% a.i.) and soap chamber tests (1.0% a.i.), and decyl glucoside was evaluated in an SIOPT (0.5% a.i.). At most, these ingredients were slightly irritating. Glucosides with alkyl chain lengths ranging from C8-C10 to >C18, as well as a C18 branched glucoside, were evaluated in both the guinea pig maximization test (GPMT), at concentrations of 1.25-10% for intradermal induction, 5- 100% for epidermal induction, and 2.5-50% for challenge, and the local lymph node assay (LLNA) at concentrations of 1.25- 50%. None of the glucosides tested were irritants or sensitizers in the GPMT, but the LLNA indicated that one C12-C18 glucoside, C14 glucoside, and C18 branched glucoside may cause skin sensitization at concentrations of 8.4%, 5.9%, and 0.43%, respectively. The sensitization potential of C12/16 APG was evaluated in studies in guinea pigs using the Buehler method (test concentrations of 20%) and the Magnusson-Kligman protocol (1, 60, and 10% used for intracutaneous induc- tion, epidermal induction, and epidermal challenge respectively). C12/16 APG was not a sensitizer in the Buehler or Magnusson-Kligman studies. In clinical testing, the sensitization potential of 0.5, 0.75, and 1.8% a.i. decyl glucoside (in formulation), 5% a.i. aq. decyl and lauryl glucoside, and 1% a.i. aq. coco-glucoside was evaluated in HRIPTs. These ingredients were not irritating or sensitizing. In alternative system studies for ocular irritation, the irritation potential of 0.6-3.0% a.i. decyl lauryl, and coco- glucosides, and of C10-16 alkyl glucosides (pH 7, 11.5; concentration not stated), were non to slightly irritating. Cap- rylyl/capryl glucoside (concentration not stated) was highly irritating in a hen’s egg test-chorioallantoic membrane (HET- CAM) assay. In a HET-CAM study with APGs of varying proportions of alkyl chain length, the ocular irritation potential increased with the increased proportion of shorter-chain APGs. In studies using rabbits, neutralized lauryl glucoside produced slight ocular reactions. Caprylyl/capryl glucoside was severely irritating to rabbit eyes when tested undiluted; the irritation threshold value was 10% for 30% a.i. caprylyl/capryl glucoside and 5% for 60% a.i. caprylyl/capryl glucoside.

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DISCUSSION Alkyl glucosides, like many other cosmetic ingredients, are provided to formulators at less than 100% active substance. The Panel was interested in knowing whether or not the concentrations of use reported by industry were as active ingredient, and they were informed that those concentrations are reported as active ingredient. The Panel was satisfied that sensitization data are adequate. The highest leave-on concentration of use that involves dermal contact is 5% lauryl glucoside. Irritation and sensitization data on lauryl and decyl glucoside at 5% a.i., indicating no sensitization reactions were reported. In dermal repeated dose studies using an occlusive wrap, effects on the testes and accessory sex organs of rabbits were observed. These effects were not reported with a non-occlusive application. The researchers stated that these changes could be due to irritation, inflammation, or stress. It is known that changes in these organs can be observed during stress, and it was the opinion of the Panel that these effects were due to the stress of the study and were not a true toxic lesion. For issues other than sensitization, the Panel noted there were gaps in the available safety data for many of the alkyl glucosides included in this group. The Panel was able to extrapolate the existing data, including the data from previous CIR assessments on fatty alcohols, to address all the alkyl glucosides included in this safety assessment; those data could be read- across due to structure activity relationships and similarity of function. The Expert Panel recognized that the alkyl glucosides can enhance the penetration of other ingredients through the skin. The Panel cautioned that care should be taken in formulating cosmetic products that may contain these ingredients in combination with any ingredients whose safety was based on their lack of dermal absorption data, or when dermal absorption was a concern. The Expert Panel was also concerned that the potential exists for dermal irritation with the use of products formu- lated using decyl glucoside or other alkyl glucosides. Therefore, the Panel specified that products must be formulated to be non-irritating. Because these ingredients can be used in products that might be sprayed, the Panel discussed the issue of potential inhalation toxicity. In the absence of sufficient safety test data to evaluate this endpoint directly, the Panel considered other data that were available to characterize the potential for the alkyl glucosides to cause systemic toxicity, ocular or dermal irritation or sensitization, and other effects. The Panel noted that 95 – 99% of particles produced in cosmetic aerosols are not respirable. Coupled with the small actual exposure in the breathing zone and the concentrations at which the ingredients are used, this information suggested that inhalation would not be a significant route of exposure that might lead to local respiratory or systemic toxic effects.

CONCLUSION The CIR Expert Panel concluded that the 19 alkyl glucosides listed below are safe in the present practices of use and concentration when formulated to be non-irritating. The ingredients included in this safety assessment are:

Decyl Glucoside Coco-Glucoside Arachidyl Glucoside Ethyl Glucoside Butyl Glucoside* Hexadecyl D-Glucoside C10-16 Alkyl Glucoside* Isostearyl Glucoside* C12-18 Alkyl Glucoside* Lauryl Glucoside C12-20 Alkyl Glucoside Myristyl Glucoside C20-22 Alkyl Glucoside* Octadecyl D-Glucoside Caprylyl/Capryl Glucoside Octyldodecyl Glucoside* Caprylyl Glucoside Undecyl Glucoside* Cetearyl Glucoside

*Were ingredients in this group not in current use (as indicated by *) to be used in the future, the expectation is that they would be used at concentrations comparable to others in this group and be formulated to be non-irritating.

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TABLES

Table 1. Definitions, functions, and structures of the alkyl glucosides in this safety assessment. Ingredient Reported CAS No. Definition Function(s)4 Formula/structure Ethyl Ethyl Glucoside is the Skin- Glucoside product obtained from the Conditioning 30285-48-4 condensation of ethyl Agents - alcohol and glucose. Humectant

Butyl Butyl Glucoside is the Surfactants - Glucoside product obtained by the Cleansing Agents 5391-18-4 condensation of butyl 41444-57-9 alcohol with glucose.

Caprylyl Caprylyl Glucoside is the Surfactants - Glucoside product obtained by the Cleansing Agents 29836-26-8 condensation of caprylic alcohol with glucose.

Decyl Decyl Glucoside is the Surfactants - Glucoside product obtained from the Cleansing Agents 58846-77-8 condensation of decyl 68515-73-1 alcohol with glucose. 141464-42-8

Undecyl Undecyl Glucoside is the Surfactants - Glucoside product obtained by the Cleansing Agents 98283-67-1 condensation of undecyl alcohol with glucose.

Lauryl Lauryl Glucoside is the Surfactants - Glucoside product obtained by the Cleansing Agents 27836-64-2 condensation of lauryl 110615-47-9 alcohol with glucose.

Myristyl Myristyl Glucoside is the Surfactants - Glucoside product obtained by the Cleansing Agents 54549-26-7 condensation of myristyl alcohol with glucose.

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Table 1. Definitions, functions, and structures of the alkyl glucosides in this safety assessment. Ingredient Reported CAS No. Definition Function(s)4 Formula/structure Hexadecyl Hexadecyl D-Glucoside this ingredient is D-Glucoside (Cetyl Glucoside) is the not listed in the (VCRP name) product obtained by the Dictionary condensation of cetyl alcohol with glucose.

O O CH3 H O

H O OH OH n Octadecyl Octadecyl D-Glucoside this ingredient is D-Glucoside (Stearyl Glucoside) is the not listed in the (VCRP name) product obtained by the Dictionary condensation of stearyl alcohol with glucose.

O O CH3 H O

H O OH OH n Arachidyl Arachidyl Glucoside is the Surfactants - Glucoside product obtained by the Cleansing Agents 144982-05-8 condensation of Arachidyl Alcohol with glucose.

Mixtures Caprylyl/ Caprylyl/Capryl Glucoside Surfactants - Capryl is the product obtained by Cleansing Agents Glucoside the condensation of a mix- 68515-73-1 ture of caprylic and decyl alcohols with glucose.

wherein R = an alkyl chain 8 or 10 carbons long C10-16 Alkyl C10-16 Alkyl Glucoside is Surfactants - Glucoside the product obtained by the Emulsifying 110615-47-9 condensation of C10-16 Agents alcohols with glucose.

wherein R = an alkyl chain 10 to 16 carbons long C12-18 Alkyl C12-18 Alkyl Glucoside is Emulsion Glucoside the product obtained by the Stabilizers condensation of C12-18 alcohols with glucose.

wherein R = an alkyl chain 12 to 18 carbons long C12-20 Alkyl C12-20 Alkyl Glucoside is Surfactants - Glucoside the product obtained by the Emulsifying condensation of C12-20 Agents alcohols with glucose.

wherein R = an alkyl chain 12 to 20 carbons long

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Table 1. Definitions, functions, and structures of the alkyl glucosides in this safety assessment. Ingredient Reported CAS No. Definition Function(s)4 Formula/structure Cetearyl Cetearyl Glucoside is the Surfactants - Glucoside product obtained by the Emulsifying condensation of cetearyl Agents alcohol with glucose.

wherein R = an alkyl chain 16 or 18 carbons long C20-22 Alkyl C20-22 Alkyl Glucoside is Glucoside the product obtained by the condensation of C20-22 alcohols with glucose.

wherein R = an alkyl chain 20 to 22 carbons long Coco- Coco-Glucoside is the Surfactants - Glucoside product obtained by the Cleansing Agents condensation of coconut alcohol with glucose.

wherein R = alkyl chain residue of fatty alcohols derived from Coconut Acid Branched Isostearyl Isostearyl Glucoside is the Surfactants - one example of an “iso” Glucoside product obtained by the Emulsifying 200413-69-0 condensation of isostearyl Agents alcohol with glucose.

Octyldodecyl Octyldodecyl Glucoside is Surfactants - Glucoside the product obtained by the Emulsifying reaction of octyldodecanol Agents with glucose.

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Table 2. Chemical and physical properties Property Description Reference Decyl Glucoside appearance cloudy, viscous aq. solution (as Plantacare 2000 UP) (of poly) 33 light yellow aq. solution (as APG 0810) (of poly) 34 molecular weight 340.2 (of mono) 35 390 g/mol (as Plantacare 2000) (of poly) 33 active substance 51-55% (as Plantacare 2000 UP) (of poly) 33 ≥50% (as APG 0810) (of poly) 34 boiling point 467.5°C (of mono) 35 melting point 135.6°C (of mono) 36 critical micelle concentration 2-3 mM (of poly, specifically the maltopyranoside) 12 viscosity 1000-6000 mPas (20°C) aq. solution (as Plantacare 2000 UP) (of poly) 33 ≤500 mPas (20°C) aq. solution (as APG 0810, a polyglucoside) (of poly) 34 density 1.14 g/cm3 (at 20°C) (of mono) 35 log P 2.092 (at 25°C) (of mono) 35 may contain (as Plantacare 2000 UP): 37 magnesium oxide max. 500 ppm (of poly) free fatty alcohol max. 1.0% (of poly) sulfate ash max. 3.0% (of poly) (as APG 0810): 34 free fatty acid ash ≤1% (of poly) ≤2% (of poly) Ethyl Glucoside (mono) molecular weight 208.21 35 boiling point 395.1°C 35 melting point 176-179°C 38 density 1.40 g/cm3 (at 20°C) 35 log P -2.159 (at 25°C) 35 Butyl Glucoside (mono) molecular weight 236.26 35 boiling point 412.0°C 35 melting point 86-87°C 39 density 1.30 g/cm3 (at 20°C) 35 log P -1.151 (at 25°C) 35 Caprylyl Glucoside appearance white solid 40 yellowish, slightly cloudy and viscous aq. solution (as Plantacare 810 UP) (of 41 poly) molecular weight 292.37 40 active substance 62-65% (as Plantacare 810 UP) (of poly) boiling point 454.1°C 35 melting point 65-99° (sic) 40 critical micelle concentration 20-25 mM 12 density 1.18 g/cm3 (at 20°C) 35 log P 0.887 (at 25°C) 35 may contain (as Plantacare 810 UP): 41 fatty alcohol ≤0.7% (of poly)

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Table 2. Chemical and physical properties Property Description Reference Undecyl Glucoside (mono) molecular weight 334.45 35 boiling point 487.8°C 35 density 1.13 g/cm3 (at 20°C) 35 log P 2.642 (at 25°C) 35 Lauryl Glucoside appearance viscous pale yellow aq. solution (as APG 1214,) (of poly) 34 molecular weight 343.2 16 348.47 (of mono) 35 420 (as Plantacare 1200 UP) (of poly) 42 active substance 50-53% (as APG 1214 and as Plantacare 1200 UP) (of poly) 34,42 boiling point 499.1°C (of mono) 35 critical micelle concentration 0.13 mM (of poly, specifically the maltopyranoside) 12 viscosity ≥2000 mPas (20°C) aq. solution (as APG 1214) (of poly) 34 density 1.12 g/cm3 (at 20°C) (of mono) 35 log P 2.925 (at 25°C) (of mono) 35 may contain (as Plantacare 12900 UP) 42 fatty alcohol ≤0.8% (of poly) ash ≤2%(of poly) (as APG 1214): 34 free fatty acid ≤1% (of poly) ash ≤2%(of poly) Myristyl Glucoside (mono) molecular weight 376.53 35 boiling point 521.5°C 35 density 1.09 g/cm3 (at 20°C) 35 log P 4.218 (at 25°C) 35 Arachidyl Glucoside (mono) molecular weight 460.69 35 boiling point 586.8°C 35 density 1.04 g/cm3 (at 20°C) 35 log P 7.406 (at 25°C) 35 Coco-Glucoside (poly) appearance cloudy, viscous aq. solution (as Plantacare 818 UP) 43 cloudy, viscous pale yellow aq. solution (as APG 0814, a polyglucoside) 34 % active 51-53% (as Plantacare 818 UP) 43 ≥50% (as APG 0814, a polyglucoside) 34 viscosity 2500-6000 mPas (20°C) aq. solution (as Plantacare 818 UP) 43 ≤2000 aq. solution (as APG 0814, a polyglucoside) 34 may contain (as Plantacare 818 UP) 43 magnesium oxide max. 500 ppm magnesium free fatty alcohol max. 1.0% sulfate ash max. 3.0% may contain (as APG 0814): 34 free fatty acid ≤1% ash ≤2%

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Table 3a. Frequency and concentration of use according to duration and type of exposure Decyl Glucoside Arachidyl Glucoside C12-20 Alkyl Glucoside # of Uses5 Max Concs of Use (%)6 # of Uses5 Max. Concs of Use (%)6 # of Uses5 Max. Concs. of Use (%)6 Totals* 492 0.002-33# 75 0.08-0.6 54 0.1-1 Duration of Use Leave-On 62 0.002-2 73 0.08-0.6 42 0.2-1 Rinse Off 421 0.3-33 2 0.5 12 0.1 Diluted for (Bath) Use 9 0.5-1 NR NR NR NR Exposure Type Eye Area 12 0.02-6 3 0.08 2 0.2-0.8 Incidental Ingestion NR NR NR NR NR NR Incidental Inhalation-Sprays 5a 0.2-0.8a 13a 0.2-0.5a 2a 0.2-0.5a Incidental Inhalation-Powders 1 NR NR NR NR NR Dermal Contact 379 0.002-33 75 0.08-0.6 48 0.1-1 Deodorant (underarm) NR NR NR NR NR 0.6b Hair - Non-Coloring 94 0.2-7 NR 0.5 6 1 Hair-Coloring 9 2-8 NR NR NR NR Nail NR NR NR NR NR NR Mucous Membrane 208 0.3-11 NR NR NR NR Baby Products 25 NR NR NR NR NR

Caprylyl/Capryl Glucoside Caprylyl Glucoside Cetearyl Glucoside 5 44 5 44 5 44 # of Uses Max. Concs of Use (%) # of Uses Max. Concs of Use (%) # of Uses Max Conc of Use (%) Totals* 58 0.06-3 NR 4 477 0.03-3 Duration of Use Leave-On 27 0.06-0.8 NR 4 445 0.2-2 Rinse Off 31 0.3-3 NR NR 31 0.03-3 Diluted for (Bath) Use NR NR NR NR 1 NR Exposure Type Eye Area 6 0.2-0.3 NR NR 61 0.6-2 Incidental Ingestion NR NR NR NR NR NR Incidental Inhalation-Sprays 1a 0.3a NR NR 29a 0.2-0.6a Incidental Inhalation-Powders NR NR NR NR 2 NR Dermal Contact 51 0.06-0.9 NR NR 466 0.03-3 Deodorant (underarm) NR NR NR NR NR NR Hair - Non-Coloring 7 0.3-3 NR 4 4 0.3-0.6 Hair-Coloring NR 3 NR NR NR 0.2 Nail NR NR NR NR 2 NR Mucous Membrane 6 NR NR NR 6 0.03 Baby Products NR 0.06 NR NR 3 NR

Coco-Glucoside Ethyl Glucoside Lauryl Glucoside 5 44 5 44 5 44 # of Uses Max. Conc of Use (%) # of Uses Max. Conc of Use (%) # of Uses Max. Conc of Use (%) Totals* 350 0.006-15 24 0.02-0.3 399 0.03-10 Duration of Use Leave-On 42 0.006-2 14 0.02-0.3 22 0.03-8 Rinse Off 294 0.2-15 10 0.02-0.05 347 0.3-10 Diluted for (Bath) Use 14 NR NR NR 30 0.3-4 Exposure Type Eye Area 6 2-3 2 0.02 NR 5 Incidental Ingestion NR 0.5 NR NR NR NR Incidental Inhalation-Sprays 1 0.4-1a NR NR NR 8 Incidental Inhalation-Powders NR NR NR NR NR NR Dermal Contact 275 0.006-15 24 0.02-0.3 308 0.03-10 Deodorant (underarm) NR NR NR NR NR NR Hair - Non-Coloring 59 0.2-8 NR NR 70 0.4-5 Hair-Coloring 16 0.3-5 NR NR 15 0.3-8 Nail NR NR NR NR NR NR Mucous Membrane 177 0.4-15 1 NR 218 0.3-8 Baby Products 11 NR NR NR 5 NR

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Table 3a. Frequency and concentration of use according to duration and type of exposure Myristyl Glucoside Hexadecyl D-Glucoside** Octadecyl D-Glucoside** # of Uses5 Max. Conc of Use (%)6 # of Uses5 Max Conc of Use (%)45 # of Uses5 Max. Conc of Use (%)45 Totals* 5 0.4-0.6 1 3% 1 NR Duration of Use Leave-On 4 0.4-0.6 1 3 1 NR Rinse Off 1 NR NR NR NR NR Diluted for (Bath) Use NR NR NR NR NR NR Exposure Type Eye Area 2 0.4 NR NR NR NR Incidental Ingestion NR NR NR NR NR NR Incidental Inhalation-Sprays NR NR NR NR NR NR Incidental Inhalation-Powders NR NR NR NR NR NR Dermal Contact 5 0.4-0.6 1 3 1 NR Deodorant (underarm) NR NR NR NR NR NR Hair - Non-Coloring NR NR NR NR NR NR Hair-Coloring NR NR NR NR NR NR Nail NR NR NR NR NR NR Mucous Membrane NR NR NR NR NR NR Baby Products NR NR NR NR NR NR * Because each ingredient may be used in cosmetics with multiple exposure types, the sum of all exposure types my not equal the sum of total uses. ** These ingredients are included in the VCRP, but are not listed in the International Cosmetic Ingredient Dictionary and Handbook #Concentration of use is provided as active ingredient a Includes suntan products, in that it is not known whether or not the reported product is a spray. b It is not known whether or not the product is a spray. NR – none reported

Table 3b. Ingredients Not Reported to be Used Butyl Glucoside C10-16 Alkyl Glucoside C12-18 Alkyl Glucoside C20-22 Alkyl Glucoside Isostearyl Glucoside Octyldodecyl Glucoside Undecyl Glucoside

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CIR Panel Book Page 42

Table 4. Skin irritation and sensitization studies Ingredient/Chain Length % a.i.; n; conc. tested Test Population Method Results Reference IRRITATION STUDIES NON-HUMAN Caprylyl/Capryl Glucoside 60% a.i.; 0.9 and 1.8 g 6 male and female NZW 10 occlusive 6-h applications made over a slight irritation was observed on day 1 after 21 a.i./kg applied (22.5 and rabbits/group 2-wk period; 4 ml/kg applied the initial dose; severe dermal irritation was 45 w/v%, respectively) in observed in males and females of both test distilled water groups by days 5-6 Caprylyl/Capryl Glucoside 60% a.i.; 0.06, 0.18 and 6 male rabbits/group 10 non-occlusive 6-h applications made slight dermal irritation in all groups after 26 0.54 g a.i./kg applied (3, 9, over a 2-wk period;; 2 ml applied to intact initiation of dosing; moderate irritation in and 27 % a.i., respective- skin the high-dose group after 3 days ly) in distilled water Caprylyl/Capryl Glucoside 60% a.i.; 0.14, 0.41 and 6 male NZW rabbits/ 10 occlusive applications made over a 2-wk dermal irritation progressed from slight to 24 1.25 g a.i./kg applied (3.5 group period severe with time in all test groups; slight to Distributed 10.4, and 31.1 % a.i., re- moderate irritation was observed in controls spectively) in distilled water Caprylyl/Capryl Glucoside 30% a.i. rabbits; no. not specified not provided slightly irritating,; PII 0-2 46-48 for CIR Comment Panel C8/10 APG 15% a.i 5 rabbits 4 h application; semi-occlusive patch PDII=0.0 20 Only Book C8/10 APG 35% a.i.; n:1.6 3 rabbits 4 h application; semi-occlusive patch PDII = 1.3; no signs of systemic toxicity; 20 edema was reported in 2/3 rabbits -- Page 20

C8/10 APG 70% a.i.; n:1.6 3 rabbits 4 h application; semi-occlusive patch PDII = 0.8; no signs of systemic toxicity Do Not 43 C10/16 APG 20% a.i.; n:1.4 4 rabbits 4 h application; occlusive patch PDII=0.4; no signs of systemic toxicity 20 C10/16 APG 60% a.i.; n:1.4 4 rabbits 4 h application; occlusive patch PDII=4.6; erythema and edema in all 20 Cite

animals; 24/48/72 h mean erythema score- or

2.9, mean edema score-2.1 Quote C12/16 APG 50% a.i.; n:1.4 3 rabbits 4 h application; semi-occlusive patch PDII=3.7; no signs of systemic toxicity; 20 erythema and edema in all animals; 24/48/72 h mean erythema score-2.2, mean edema score-1.6 C12/16 APG 50% a.i.; n:1.4 3 rabbits 4 h application; semi-occlusive patch PDII=3.0; no signs of systemic toxicity; 20 erythema in all animals and edema in 1 animal; 24/48/72 h mean erythema score- 2.1, mean edema score-0.9 C12/16 APG 50% a.i.; n:1.4 3 rabbits 4 h application; semi-occlusive patch PDII=3.0; no signs of systemic toxicity; 20 erythema in all animals and edema in 1 animal; 24/48/72 h mean erythema score- 1.9, mean edema score-1.1 C8/10 + C12/16 APG C8/10, 21% a.i. 3 rabbits 4 h application; semi-occlusive patch PDII=2.7; erythema and edema in all 20 C12/16, 35% a.i. animals; 24/48/72 h mean erythema score- 1.8, mean edema score-0.8

18

Table 4. Skin irritation and sensitization studies Ingredient/Chain Length % a.i.; n; conc. tested Test Population Method Results Reference HUMAN Decyl Glucoside 2.0% a.i., pH 6.5 20 subjects epicutaneous patch test; 75 μl, 24 h very slightly irritating 49 occlusive application Decyl Glucoside 1.0% a.i., pH 6.5 22 subjects soap chamber test; 100 μl applied occlu- slightly irritating 49 sively to the ventral for 24 h on day 1 and 6 h on days 2-5 Decyl Glucoside a.i. not stated; tested at 105 subjects; 14.3% were SIOPT; 40 μl was applied for 48 h using AII=0.046; non-irritating 50 0.5% aq. atopic patients Haye’s test chambers

Lauryl Glucoside 2.0% a.i., pH 6.5 20 subjects epicutaneous patch test; 75 μl, 24 h slightly irritating 49 occlusive application

Lauryl Glucoside 1.0% a.i., pH 6.5 22 subjects soap chamber test; 100 μl applied occlu- slightly irritating 49 Distributed sively to the ventral for 24 h on day 1 and 6 h on days 2-5 Lauryl Glucoside a.i. not stated; tested at 105 subjects; 14.3% were SIOPT; 40 μl was applied for 48 h using AII=0.046; non-irritating 50 0.5% aq. atopic patients Haye’s test chambers for CIR Comment Coco-Glucoside 2.0% a.i., pH 6.5 20 subjects epicutaneous patch test; 75 μl, 24 h slightly irritating 49 Panel occlusive application Coco-Glucoside 1.0% a.i., pH 6.5 22 subjects soap chamber test; 100 μl applied occlu- slightly irritating 49 Only Book sively to the ventral forearm for 24 h on day

1 and 6 h on days 2-5 -- Page

SENSITIZATION Do Not

44 NON-HUMAN 51

C8-C10 glucoside a.i. not stated; tested at 4-5 CBA/j mice LLNA; 25 µl/ear not an irritant or a sensitzer Cite 1.25-25% in acetone/olive oil (4:1) or Quote C8-C10 glucoside a.i. not stated; tested at guinea pigs; 10 treated, GPMT with FCA and SLS; 0.5 ml applied not an irritant or sensitizer 51 5% - intraderm induction 5 controls to an 8 cm2 area under an occlusive 5% - epiderm induction induction patch; at challenge, 0.2 ml was 2.5 and 5% - challenge applied to a 4 cm2 area C10-C14 glucoside a.i. not stated; tested at 4-5 CBA/j mice LLNA; 25 µl/ear not an irritant or sensitizer 51 1.25-5% in DMF C10-C14 glucoside a.i. not stated; tested at guinea pigs; 10 treated, GPMT with FCA and SLS; 0.5 ml applied not an irritant or sensitizer 51 5% - intraderm induction 5 controls to an 8 cm2 area under an occlusive 5% - epiderm induction induction patch; at challenge, 0.2 ml was 2.5 and 5% - challenge applied to a 4 cm2 area C12/16 APG (may be a.i. not provided 20 guinea pigs Buehler method; 20% tested at induction not a sensitizer; one very weak reaction 52 similar to C12-18 alkyl and challenge during induction and challenge for one glucoside) guinea pig C12/16 APG (may be a.i. not provided 20 guinea pigs Magnusson-Kligman study; 1% used for not a sensitizer; no positive reactions 52 similar to C12-18 alkyl intracutaneous and 60% for epidermal glucoside) induction; 10% for epidermal challenge

19

Table 4. Skin irritation and sensitization studies Ingredient/Chain Length % a.i.; n; conc. tested Test Population Method Results Reference C12-C18 glucoside a.i. not stated; tested at 2.5- 4-5 CBA/j mice LLNA; 25 µl/ear not an irritant or sensitizer 51 (granules) 10% in DMF C12-C18 glucoside a.i. not stated; tested at guinea pigs; 10 treated, GPMT with FCA and SLS; 0.5 ml applied not an irritant or sensitizer 51 (granules) 10% - intraderm induction 5 controls to an 8 cm2 area under an occlusive 50% - epiderm induction induction patch; at challenge, 0.2 ml was 5 and 10% - challenge applied to a 4 cm2 area C12-C18 glucoside (flakes) a.i. not stated; tested at 4-5 CBA/j mice LLNA; 25 µl/ear EC3=8.4%, may cause skin sensitization 51 1.25-10% in DMF C12-C18 glucoside (flakes) a.i. not stated; tested at guinea pigs; 10 treated, GPMT with FCA and SLS; 0.5 ml applied not an irritant or sensitizer 51 10% - intraderm induction 5 controls to an 8 cm2 area under an occlusive 50% - epiderm induction induction patch; at challenge, 0.2 ml was 5 and 10% - challenge applied to a 4 cm2 area Distributed C14 glucoside a.i. not stated; tested at 4-5 CBA/j mice LLNA; 25 µl/ear all concentrations were irritants (based on 51 1.25-10% in DMF ear thickness); EC3=5.9%, may cause skin sensitization for 51 CIR

C14 glucoside a.i. not stated; tested at guinea pigs; 10 treated, GPMT with FCA and SLS; 0.5 ml applied not an irritant or sensitizer Comment 1.25%-intraderm induction 5 controls to an 8 cm2 area under an occlusive Panel 50% - epiderm induction induction patch; at challenge, 0.2 ml was 25 and 50% - challenge applied to a 4 cm2 area Only Book C16-C18 glucoside a.i. not stated; tested at 2.5- 4-5 CBA/j mice LLNA; 25 µl/ear not an irritant or sensitizer 51 10% in DMF -- Page 51 C16-C18 glucoside a.i. not stated; tested at guinea pigs; 10 treated, GPMT with FCA and SLS; 0.5 ml applied not an irritant or sensitizer Do 2

10% - intraderm induction 5 controls to an 8 cm area under an occlusive Not 45 10% - epiderm induction induction patch; at challenge, 0.2 ml was 5 and 10% - challenge applied to a 4 cm2 area Cite 51 >C18 glucoside a.i. not stated; tested at 2.5- 4-5 CBA/j mice LLNA; 25 µl/ear not an irritant or sensitizer or

10% in DMF Quote >C18 glucoside a.i. not stated; tested at guinea pigs; 10 treated, GPMT with FCA and SLS; 0.5 ml applied not an irritant or sensitizer 51 5% - intraderm induction 5 controls to an 8 cm2 area under an occlusive 10% - epiderm induction induction patch; at challenge, 0.2 ml was 2.5 and 5% - challenge applied to a 4 cm2 area C18 branched glucoside a.i. not stated; tested at 2.5- 4-5 CBA/j mice LLNA; 25 µl/ear all concentrations were irritants (based on 51 50% in DMF ear thickness); there was not a clear dose response of stimulation index vs. concentra- tion; EC3=0.43%, may cause skin sensitization C18 branched glucoside a.i. not stated; tested at guinea pigs; 10 treated, GPMT with FCA and SLS; 0.5 ml applied not an irritant or sensitizer 51 2.5% - intraderm induction 5 controls to an 8 cm2 area under an occlusive 100% - epiderm induction induction patch; at challenge, 0.2 ml was 6.25 and 12.5% - challenge applied to a 4 cm2 area

20

Table 4. Skin irritation and sensitization studies Ingredient/Chain Length % a.i.; n; conc. tested Test Population Method Results Reference HUMAN Decyl Glucoside 0.5% a.i. in an indoor 103 subjects HRIPT; 0.2 ml applied to a 20 mm2 Webril not a primary irritant or sensitizer 53 tanning preparation pad, 24-h occlusive, 3x/wk for 3 wks; 9 applications; challenge performed after 10- 14 day non-treatment period Decyl Glucoside 0.75% a.i. in a self- 107 subjects HRIPT; 24-h semi-occlusive, 3x/wk for 3 not an irritant or sensitizer 54 tanning formulation wks; 9 applications; challenge performed after 2-wk non-treatment period Decyl Glucoside 1.8% a.i. in a liquid 103 subjects HRIPT; 150 µl applied to a 2 cm2 patch; 24- not an irritant or sensitizer 55 foundation h semi-occlusive, 3x/wk for 3 wks; 9 appli- cations; challenge performed after 2-wk Distributed non-treatment period Decyl Glucoside; tested 5% a.i. 49 subjects HRIPT; 0.2 ml, 24-h semi-occlusive; 3x/wk not an irritant or a sensitizer 56 under 4 tradenames for 3 wks; 10 applications; challenge per-

formed after 2-wk non-treatment period for CIR Lauryl Glucoside; tested 5% a.i. 49 subjects HRIPT, as above not an irritant or a sensitizer 56 Comment

Panel under 5 tradenames Coco-Glucoside 52% a.i. diluted to 2% aq. 213 subjects HRIPT; 0.2 ml, 24 h occlusive; 3x/wk for 3 not an irritant or a sensitizer 57 Only Book (1% a.i. tested) wks; 9 applications; challenge performed after 2-wk non-treatment period -- Page 51 C8-C10 glucoside a.i. not stated; tested at 5% 50 subjects HRIPT; 20 µl, 9 occlusive applications, 20 irritation index during induction=0.04; no Do 2

aq. µl applied to a 50 mm area positive reactions at challenge Not 46 51

C10-C14 glucoside a.i. not stated; tested at 5% 50 subjects HRIPT; 20 µl, 9 occlusive applications, 20 irritation index during induction = 0; no Cite aq. µl applied to a 50 mm2 area positive reactions at challenge C12-C18 glucoside a.i. not stated; tested at 5% 50 subjects HRIPT; 20 µl, 9 occlusive applications, 20 irritation index during induction = 0.10; no 51 or (granules) aq. µl applied to a 50 mm2 area positive reactions at challenge Quote C12-C18 glucoside (flakes) a.i. not stated; tested at 1% 50 subjects HRIPT; 20 µl, 9 occlusive applications, 20 irritation index during induction = 0.15; no 51 aq. µl applied to a 50 mm2 area positive reactions at challenge C14 glucoside a.i. not stated; tested at 5% 50 subjects HRIPT; 20 µl, 9 occlusive applications, 20 irritation index during induction = 0.62; no 51 aq. µl applied to a 50 mm2 area positive reactions at challenge C16-C18 glucoside a.i. not stated; tested at 5% 50 subjects HRIPT; 20 µl, 9 occlusive applications, 20 irritation index during induction = 0.03; no 51 aq. µl applied to a 50 mm2 area positive reactions at challenge >C18 glucoside a.i. not stated; tested at 5% 50 subjects HRIPT; 20 µl, 9 occlusive applications, 20 irritation index during induction = 0.21; no 51 aq. µl applied to a 50 mm2 area positive reactions at challenge C18 branched glucoside a.i. not stated; tested at 6% 50 subjects HRIPT; 20 µl, 9 occlusive applications, 20 irritation index during induction = 0.04; no 51 µl applied to a 50 mm2 area positive reactions at challenge Abbreviations: a.i. – active ingredient; AII – average index of skin irritation; APG – alkyl polyglucoside; DMF – dimethyl formamide; FCA – Freund’s complete adjuvant; HRIPT – human repeat insult patch test; LLNA – local lymph node assay; n – degree of polymerization; PDII – primary dermal irritation index; SIOPT – single insult occlusive patch test; SLS – sodium lauryl sulfate positive responder: irritation score = 2

21

Table 5. Ocular irritation studies Ingredient/Chain Length % a.i.; pH; conc. tested Animals Method Results Reference ALTERNATIVE STUDIES Decyl Glucoside 1.0% a.i. in PBS; pH 7 RBC not irritating 49 Decyl Glucoside 3.0% a.i.; pH 6.5 , aq. soln HET-CAM assay slightly irritating 49 Decyl Glucoside 0.6% a.i.; pH 7.0 , aq. soln ocular tissue model not irritating 49

Lauryl Glucoside 1.0% a.i. in PBS; pH 7 RBC slightly irritating 49 Lauryl Glucoside 3.0% a.i.; pH 6 , aq. soln HET-CAM assay slightly irritating 49 Lauryl Glucoside 0.6% a.i.; pH 7.0, aq. soln ocular tissue model not irritating 49 Caprylyl/Capryl Glucoside, not specified HET-CAM assay highly irritating 20 as C8/C10 APG Distributed C10-16 Alkyl Glucoside, as pH 7 HET-CAM assay produced slight reactions 20 C10/16 APG C10-16 Alkyl Glucoside, as pH 11.5 HET-Cam assay produced slight reactions 20 C10/16 APG for CIR Comment Coco-Glucoside 1.0% a.i. in PBS; pH 7.4, RBC not irritating 49 Panel aq. Soln Coco-Glucoside 3.0% a.i.; pH 6.5, aq. soln HET-CAM assay slightly irritating 49 Only Book Coco-Glucoside 0.6% a.i.; pH 7.0, aq. soln ocular tissue model not irritating 49

NON-HUMAN STUDIES -- Page Lauryl Glucoside, 12.5% a.i. 6 NZW rabbits 0.1 ml instilled into the conjunctival sac;eyes very slight reactions, in one animal (subsided in 20 Do Not

47 neutralized were not rinsed 48 h); medium to mild conjunctival irritation was

observed in all rabbits; effects were reversible Cite within 7 days in all but one of the rabbits

47 or

Caprylyl/Capryl Glucoside 30% a.i. 9 rabbits 0.1 ml instilled into the conjunctival sac; eyes severely irritating; rinsing reduced the intensity Quote of 3 rabbit rinsed 20-30 sec after dosing and duration Caprylyl/Capryl Glucoside 30% a.i. 9 rabbits 0.1 ml instilled into the conjunctival sac; eyes severely irritating; rinsing reduced the intensity 46 of 3 rabbit rinsed 20-30 sec after dosing and duration Caprylyl/Capryl Glucoside 30% a.i. 9 rabbits 0.1 ml instilled into the conjunctival sac; eyes severely irritating 48 of 3 rabbit rinsed 20-30 sec after dosing Caprylyl/Capryl Glucoside 30% a.i. 9 rabbits 0.1 ml instilled into the conjunctival sac; eyes severely irritating 58 of 3 rabbit rinsed 20-30 sec after dosing Caprylyl/Capryl Glucoside 30% a.i. 9 rabbits 0.1 ml instilled into the conjunctival sac; eyes severely irritating 59 of 3 rabbit rinsed 20-30 sec after dosing Caprylyl/Capryl Glucoside 30% a.i.; 0.1-50% tested 2 rabbits/group; 0.1 ml instilled into the conjunctival sac 0.1, 0.5, 1.0, 5.0%: non or inconsequential irritant 60 4 additional rab- 10%: conjunctival irritation in 6/6 at 4 h; bits dosed w/5 subsided in 4/6 by 72 h; moderate irritant and 10% 20%: moderate irritant 50% substantial to severe irritant Irritation threshold determined to be 10% (v/v); equivalent to 3% solids

22

Table 5. Ocular irritation studies Ingredient/Chain Length % a.i.; pH; conc. tested Animals Method Results Reference Caprylyl/Capryl Glucoside 60% a.i. rabbits details not provided severely irritating 61 Caprylyl/Capryl Glucoside 60% a.i.; conc. of 0.5, 1.0, 6 rabbits/group 0.1 ml instilled into the conjunctival sac 0.5 and1.0%: no irritation 62 5.0, and 10.0% tested 5%: conjunctival irritation at 4 h, cleared by 72 h 10%: moderate irritation in 6/6, cleared by 72 h 60% a.i.; conc. of 20 and 2 rabbits/group 0.1 ml instilled into the conjunctival sac 20 and 50%: severely irritating 50.0% tested Irritation threshold determined to be 5.0% Caprylyl/Capryl Glucoside 70% a.i.; 40% solution 6 rabbits/study 0.1 ml instilled into the conjunctival sac; two moderately to highly irritating (both studies) 63 studies performed Caprylyl/Capryl Glucoside 70% a.i. not provided not provided; two studies performed moderately to highly irritating (both studies) 64 Caprylyl/Capryl Glucoside 70% a.i.; 40% solution 6 rabbits 0.1 ml instilled into the conjunctival sac; two moderately to highly irritating (both studies) 65

studies performed Distributed C12/16 APG (may be 50% a.i, aq. Solution 4 albino rabbits OECD Guideline 405 24/48/72 h mean scores for the cornea, conjuncti- 20 similar to C12-18 alkyl val erythema, and iris: 0.5/4, 2.08/3, and 0.25/2, glucoside) respectively; moderate to strong reactions in the

conjunctivae did not completely subside within 21 for CIR days in 2 of the animals, persistent corneal effects Comment did not subside in 1 of these rabbits Panel Abbreviations: a.i. – active ingredient; HET-CAM – hen’s egg test-chorioallantoic membrane; PBS – phosphate buffered saline; RBC – red blood cell test Only Book -- Page Do Not 48 Cite or Quote

23 Distributed for Comment Only -- Do Not Cite or Quote

Table 6. Summaries of information on fatty alcohols from previous CIR reports Ingredient Parameter Evaluated Outcome Reference n-Butyl Alcohol ADME can be absorbed through the lungs, gastrointestinal tract, the cornea, and the skin; mainly metabolized by alcohol dehydrogenase and eliminated rapidly from the 66 blood; dogs given i.v. n-butyl alcohol eliminated 15% of the does in CO2(none unchanged) and 2.7% in the urine animal toxicology dermal LD50 (rabbits), 4.2 g/kg; oral LD50 (rats), 0.79-4.36 g/kg short-term oral: 6.9% n-butyl alcohol and 25% sucrose given in drinking water for 3 wks produced some changes in hepatic mitochondria inhalation: results in irritation of the mucous membranes, intoxication, restlessness, ataxia, prostration, and narcosis; high concentrations can be fatal dermal irritation/sensitization no data mucosal irritation 15% n-butyl alcohol produced an ocular irritation score of <5/20 and a 40% solution produced a score of >5/20 in rabbit eyes repro/developmental toxicity fetotoxicity has been demonstrated at maternally toxic levels (1000 mg/kg); no significant behavioral or neurochemical effects were seen in offspring following either maternal or paternal exposure to 3000 or 600 ppm Genotoxicity negative in an Ames test, did not induce sister chromatid exchange 0.1 or (15% aq.) or micronuclei formation, and did not impair chromosome distribution in mitosis Carcinogenicity no data clinical assessment of safety a nail color containing 3% n-butyl alcohol was not a significant irritant or sensitizer in HRIPTs, and this product was not a phototoxin or photoallergen; negative for non-immunological urticaria occupational exposure: n-butyl alcohol (alone or with other solvents) produced complaints of ocular irritation, headache and vertigo, slight irritation of the nose and throat, and dermatitis of the hands and fingers at air concentrations of >50 ppm important Discussion items uses in products other than nail products are at very low concentrations, so there were no toxicity concerns Conclusion safe as used Cetearyl Alcohol animal toxicology no data 67 dermal irritation/sensitization formulation w/3%, mildly irritating (rabbits) mucosal irritation formulation w/3%, not irritating repro/developmental toxicity no data Genotoxicity no data Carcinogenicity no data clinical assessment of safety formulation w/3%: not a sensitizer important Discussion items no relevant items identified Conclusion safe as used Cetyl Alcohol ADME in general, long-chain aliphatic alcohols, such as cetyl alcohol, are oxidized to their 67 corresponding fatty acids in mammalian tissues; in rats administered radioactive cetyl alcohol by either stomach tube or thoracic duct fistulas, most of the radioactivity was found in the thoracic duct lymph, indicating good absorption; some of the cetyl alcohol was eliminated unchanged in waste products, but most of the cetyl alcohol was oxidized to palmitic acid and incorporated into triglycerides and phospholipids animal toxicology oral LD50(rats): >8.2 g/kg; formulations w/≤4%, no toxic effects; dermal LD50: >2.6 g/kg; formulation w/5%, 2 g/kg; inhalation: 6-h exposure, 26 ppm (rats, mice, guinea pigs), slight irritation of mucous membranes, but no signs of systemic toxicity or mortality; 6 h exposure, 2220 mg/m3, 100% mortality short-term dermal: 20 day, 11.5%, 5x/day, exfoliative dermatitis, parakeratosis, hyperkeratosis (rabbits); 30 day, 30% in methyl alcohol and propylene glycol, dermal infiltrates of histocytes 3 mos dermal study: formulations w/20%, well-defined erythema, mild edema, no systemic toxicity (rabbits) dermal irritation/sensitization undiluted, minimally to slightly irritating; formulations w/2-4%, no to well-defined erythema and edema mucosal irritation formulations w/≤6.36%, mostly non-irritating mucosal irritation 2%: not irritating to genital mucosa of rabbits repro/developmental toxicity no data Genotoxicity negative, Ames test Carcinogenicity no data clinical assessment of safety 100%: not irritating; formulations w/2-11.5%,:at most, mild irritants formulations w/1-8.4%, not sensitizers 30%: 11.2% of eczema patients (pop. 330) had allergic reactions formulations w/1-4%, not photosensitizers important Discussion items no relevant items identified Conclusion safe as used 24

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Table 6. Summaries of information on fatty alcohols from previous CIR reports Ingredient Parameter Evaluated Outcome Reference Coconut Alcohol animal toxicology no data 68 dermal irritation/sensitization no data mucosal irritation no data repro/developmental toxicity no data Genotoxicity no data Carcinogenicity no data clinical assessment of safety no data important Discussion items toxicity and use profiles expected to be similar to coconut oil, coconut acid, hydrogenated coconut oil, hydrogenated coconut acid; addressed use in inhalation products; possible issues with botanicals Conclusion safe as used

67 Isostearyl Alcohol animal toxicology oral LD50: >20 g/kg (rats); formulations w/25-27%, >15 g/kg dermal irritation/sensitization formulation w/5%: mild irritant (rabbits); formulation w/25-27%: barely perceptible erythema 0.2-5%: not a sensitizer mucosal irritation formulations w/5 and 10%, transient irritation; formulations w/25-27%, minimal to mild irritation repro/developmental toxicity no data Genotoxicity no data Carcinogenicity no data clinical assessment of safety 100%: not irritating; formulations w/25-28%, not irritating; deodorant formulation w/ 5%, severe irritation in a 21-day cumulative study 25% in 95% isopropyl alcohol: not a sensitizer; formulations w/5%: sensitization reactions occurred important Discussion items no relevant items identified Conclusion safe as used

Myristyl Alcohol animal toxicology oral LD50 (rats): >8 g/kg; formulation w/0.8%, >5 g/kg; dermal LD50: formulation 67 w/0.8%, >2 g/kg inhalation: 3%, 1 h, ataxia and moderate nasal irritation in all animals 10 min after exposure, no mortality dermal irritation/sensitization formulation w/0.8%, non-irritating (rabbits) mucosal irritation formulation w/0.8%: not irritating; formulation w/3%: mildly irritating (rinsed eyes), moderately irritating (unrinsed eyes) repro/developmental toxicity no data Genotoxicity no data Carcinogenicity no data clinical assessment of safety formulations w/0.1-0.25%, not irritants; formulations w/0.25-0.8%, not irritating in a 4-wk clinical study formulations w/0.1-0.25%, not sensitizers formulation w/0.1%, not a photosensitizer important Discussion items no relevant items identified Conclusion safe as used

Octyl Dodecanol animal toxicology oral LD50 (rats): >5 g/kg, undiluted; formulation w/10.2%, >25 g/kg; dermal LD50: 69 >3 g/kg dermal irritation/sensitization 100%: irritation score of 0-1.13/4 (rabbits); 30%: irritation score 0/4 (rabbits); formulations w/4 and 10.2%, mild irritation, at most; technical grade: moderate to severe irritation (rabbits, guinea pigs, rats), no irritation (swine, humans) mucosal irritation 100%: irritation score of 1 or 4/110 (24 h) repro/developmental toxicity no data Genotoxicity no data Carcinogenicity no data clinical assessment of safety 100%: mild irritation in 1/40 subjects; undiluted technical grade: no irritation; formulations w/3-10.2%: essentially non-irritating screening patch tests for contact sensitization in large populations: incidence rate of 0.36% (6/1664) formulation w/10.2%: not phototoxic or photoallergenic important Discussion items no Discussion Conclusion safe as used

25

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Table 6. Summaries of information on fatty alcohols from previous CIR reports Ingredient Parameter Evaluated Outcome Reference Stearyl Alcohol ADME found naturally in various mammalian tissues; readily converted to stearic acid, another common constituent of mammalian tissues; results from several studies 69 indicate that stearyl alcohol is poorly absorbed from the GI tract animal toxicology oral LD50: >8 g/kg; 3 mos dermal study: formulations w/8%,some dermal effects, , no systemic toxicity (rabbits) dermal irritation/sensitization 100%: minimal to mild primary skin irritant (rabbits) formulation w/24%: not a sensitizer mucosal irritation 100%: mildly irritating repro/developmental toxicity no data Genotoxicity negative: Ames test Carcinogenicity did not promote tumor formation in mice when tested with dimethylbenz[a]anthracene clinical assessment of safety 100%: produced mild irritation in 1/80 subjects; formulations w/14-24% were non- to slightly irritating formulations w/14-2%, not sensitizers screening patch tests for contact sensitization in large population: incidence rate of 0.51% (19/3740) important Discussion items Discussion not included in report Conclusion safe as used

26

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52. Ecology and toxicology of alkyl polyglycosides. 2004. Chapter: 18. Handbook of Detergents, Part B. Environmental Impact. New York, NY: Marcel Dekker.

53. AMA Laboratories. 2002. 100 Human subject repeat insult patch test skin irritation/sensitization evaluation (occlusive patch) of an indoor tanning preparation containing 0.5% Decyl Glucoside. AMA Ref No.: MSO2.R1PTC38440. 100.DERM.TRLI. Unpublished data submitted by Personal Care Products Council.

54. Clinical Research Laboratories, Inc. Repeated insult pathc test of a body self tan mousse containing 0.75% decyl glucoside. CRLstudy number: CRL120705-9. 2006.

55. Product Investigations Inc and Product. 2005. Determination of the irritating and sensitizing propensities of a liquid foundation (containing 1.8%) Decyl Glucoside on human skin. Unpublished data submitted by Personal Care Products Council. 13 pages.

56. Consumer Product Testing Company. Repeat insult patch test on decyl glucoside (5% active) and lauryl glucoside (5% active) under numerous trade names. Experiment Refn. No. C-005-93. 3-2-1993. Unpublished data submitted by the Council on Dec. 14, 2010. (34 pp) Available from CIR.

57. Consumer Product Testing Company. Repeated insult patch test of coco-glucoside. Experiment Ref. No. C05- 0247.01. 2005. Unpublished data submitted by the Council on Dec 14, 2010 (21 pp) Available from CIR.

58. Rohm and Haas Company. Ocular irritation study on Triton CG-110, 30% surfactant. Report No. 81R 0046. 5-6- 1981. NTIS No. OTS0538042.

59. Rohm and Haas Company. Ocular irritation study on Triton CG-110, 30% surfactant. Report No. 81R 0047. 5-6- 1981. NTIS No. OTS0538042.

29

CIR Panel Book Page 54 Distributed for Comment Only -- Do Not Cite or Quote

60. Rohm and Haas Company. Triton CG-110: Rabbit eye irritation tirtration studies. Report No. 81R-131. Protocol No. 80P-439. 4-28-1982. NTIS No. 0538042.

61. Rohm and Haas Company. Ocular irritation study on Triton CG-110, 60% surfactant. Report No. 82R 0177. 4-19- 1983. NTIS No. OTS0538042.

62. Rohm and Haas Company. Triton CG-110 (60%): Rabbit eye irritation titration studies. Report No. 82P-289. Protocol No. 82R-178. 4-19-1983. NTIS No. OTS0538042.

63. Rohm and Haas Company. Ocular irritation study on Triton CG-110, 70% a.i. Report No. 74-66. 10-8-1974. NTIS No. OTS0538042.

64. Rohm and Haas Company. Ocular irritation study on Triton CG-110, 70% a.i. Report No. 74-67. 10-8-1974. NTIS No. OTS0538042.

65. Rohm and Haas Company. Ocular irritation study on Triton CG-110, 70% a.i. Report No. 74-68. 10-8-1974. OTS0538042.

66. Andersen, FA (ed). Final report of the addendum to the safety assessment of n-Butyl Alcohol as used in cosmetics. Int J Toxicol. 2008;27:(Suppl 2):53-69.

67. Elder, RL (ed). Final report o the safety assessment of Cetearyl Alcohol, Cetyl Alcohol, Isostearyl Alcohol, Myristyl Alcohol, and Behenyl Alcohol. J Am Coll Toxicol. 1988;7:(3):359-413.

68. Diamante, CD, Andersen, FA, and Cosmetic Ingredient Review Expert Panel. 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. 2008.

69. Elder, RL (ed). Final report on the safety assessment of Stearyl Alcohol, Oleyl Alcohol, and Octyl Dodecanol. J Am Coll Toxicol. 1985;4:(5):1-29.

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CIR Panel Book Page 55 Data

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Persona Care ‘ProductsCounci Committedto Safety, Quality& Innovation Memorandum

TO: F. Alan Andersen, Ph.D. Director - COSMETIC INGREDiENT REVIEW (Cifi)

FROM: Halyna Breslawec, Ph.D. Industry Liaison to the CIR Expert Panel

DATE: September 23, 2011

SUBJECT: Comments on the Draft Report on the Glucoside Ingredients Prepared for the September 26-27, 2011 Cifi Expert Panel Meeting

p.6 - In the first paragraph under Caprylyl/Capryl Glucoside, please correct “occurrence of this lesion was rate”. p.7, 10 - In the summary of the Reproductive and Developmental Toxicity section and in the Summary, please provide the species and gestation days of exposure used in the Lauryl Glucoside gavage study. p.9, 11 - In the summary of the Ocular Irritation section and in the Summary, please provide the concentrations that were considered irritating in in vitro studies. Some text needs to be added to this section to indicate that the ocular irritation studies are summarized in Table 5. 1p. 1 - Please note, the issue with the 11% product was not whether or not the percentage reflected the active concentration of the ingredient. The company confirmed that 11% was the active concentration, but the product was mistakenly placed in a leave-on product category when it is a rinse-off product. p.13, Table 1 - Please provide the reference(s) for this table (the reader should at least be told where the functions are coming from).

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

CIR Panel Book Page 56 Distributed for Comment Only -- Do Not Cite or Quote

PersonalCare ProductsCouncil Committedto Safety, Quality& Innovation Memorandum

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

FROM: Halyna Breslawec, Ph.D. Industry Liaison to the CIR Expert Panel

DATE: November 1,2011

SUBJECT: Comments on the Tentative Safety Assessment on Decyl Glucoside and Other Alkyl Glucosides as Used in Cosmetics

Key Issue

Are hexadecyl D-glucoside and octadecyl D-glucoside included in this report? These two ingredients are in Table 3a, but not mentioned elsewhere in the report. If hexadecyl D-glucoside and octadecyl D-glucoside are not a part of this review, they need to be deleted from this table. If these ingredients are left in this table, they should be added to Table 1, discussed in the report, and it should be made clear whether or not the conclusion applies to these ingredients.

Additional Comments

p.3 - Although the use information in the use tables are no longer presented by FDA product category, the concentration of use information from Council surveys is still provided by FDA product category. It would be helpful if the use concentrations provided in the text were associated with the specific FDA product category, rather than the general categories. p.4-- Although reference 13 may state that FDA has approved a pharmaceutical excipient, FDA approves drugs. There is no specific FDA process for approving drug excipients. FDA maintains a data base titled “Inactive Ingredients In FDA Approved Drugs” (found at

http ://www . accessdata.fda. gov/scripts/cder/iig/index .cfm), searching the term glucoside did not identify any approved drugs that contain a glucoside ingredient. p.5 - Please revise the following phrase: “In the in vitro study, the enhancement of the permeability of insulin across T84 and Caco-2 cell monolayers by was caprylyl glucoside concentration- dependent;...” p.5 - If available, please indicate whether or not the dermal exposures in the studies described in reference 21 were completed under occlusive or non-occlusive conditions. p.7 - The following needs to be revised: “Treatment-related microscopic changes, consisting of an increased incidence and severity of diffuse bilateral testicular atrophy with necrotic spermatocytes, and atrophy of the prostate and vesicular glands, were observed in the testes,

1101 17th Street, N.W., Suite 3O0 Washington, D.C. 20036-4702 202.331.1770 202.331.1969 (fax) www.personalcarecouncil.org

CIR Panel Book Page 57 Distributed for Comment Only -- Do Not Cite or Quote

epididymides, prostate and vesicular glands of the mid and high dose group animals;” This appears to be saying that atrophy of the prostate was observed in the testes. p.8, Reproductive and Developmental Toxicity Section - If Dr. Snyder provided a reference regarding stress and reproductive/testicular effects in rabbits it should be added to this section. The section (in addition to the summary of the section) should also include a brief description of the dermal studies in which testicular effects were observed. p.10 - In the Summary, please also note that the study authors also suggested an inflammatory response may have contributed to the reproductive effects observed in rabbits treated dermally with Caprylyl/Capryl Glucoside. p.10 - In the Summary, please include the system (Chinese hamster V79 fibroblasts) that was used to test the clastogenic activity of C10-16 APG. p.11 - In the Discussion, in addition to stress, it would also be helpful to note that the study authors attributed the testicular effects in rabbits to dermal irritation and inflammation. p.11 - Please identify previous Cifi assessments (fatty alcohols) that are being used to support the safety of the alkyl glucosides. p.12 - In the last paragraph of the Discussion, it would be helpful to add that the short duration of exposure also contributes to the low inhalation exposure expected following use of cosmetic spray products. p.21, Table 4 - The Method for reference 49, soap chamber test, indicates that the subjects were exposed “to the ventral”. The word “ventral” is an adjective. The part of the body to which the chamber was applied is not clear. p.21-23, Table 4 - In the Method column in the Sensitization section, it is not clear what the 2g/cm doses represent. As most studies tested more than one concentration, it is likely that this dose represents the dose of the test solution rather than the dose of the glucoside that was tested. Please make this clear. p.22, Table 4 - For the LLNA in which the results state “may cause skin sensitization” (reference 51), please provide the stimulation indices (especially for the highest concentrations, or for those concentrations for which the SI was 3) or the 3EC value. One strength of the LLNA is that it can provide a quantitative estimate of sensitization that can be compared to other substances, not just a yes or no answer. p.24.,Table 5 - What volume of material was instilled into the eyes of rabbits in the study described in reference 21?

2

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DECYL GLUCOSIDE 6 01A - Baby Shampoos DECYL GLUCOSIDE 1 01B - Baby Lotions, Oils, Powders, and Creams DECYL GLUCOSIDE 18 01C - Other Baby Products DECYL GLUCOSIDE 6 02B - Bubble Baths DECYL GLUCOSIDE 3 02D - Other Bath Preparations DECYL GLUCOSIDE 1 03B - Eyeliner DECYL GLUCOSIDE 1 03D - Eye Lotion DECYL GLUCOSIDE 4 03E - Eye Makeup Remover DECYL GLUCOSIDE 4 03F - Mascara DECYL GLUCOSIDE 2 03G - Other Eye Makeup Preparations DECYL GLUCOSIDE 86 05F - Shampoos (non-coloring) DECYL GLUCOSIDE 4 05G - Tonics, Dressings, and Other Hair Grooming Aids DECYL GLUCOSIDE 4 05I - Other Hair Preparations DECYL GLUCOSIDE 9 06D - Hair Shampoos (coloring) DECYL GLUCOSIDE 2 07C - Foundations DECYL GLUCOSIDE 1 07H - Makeup Fixatives DECYL GLUCOSIDE 1 07I - Other Makeup Preparations DECYL GLUCOSIDE 141 10A - Bath Soaps and Detergents DECYL GLUCOSIDE 58 10E - Other Personal Cleanliness Products DECYL GLUCOSIDE 3 11E - Shaving Cream DECYL GLUCOSIDE 1 11G - Other Shaving Preparation Products DECYL GLUCOSIDE 106 12A - Cleansing DECYL GLUCOSIDE 15 12C - Face and Neck (exc shave) DECYL GLUCOSIDE 2 12D - Body and Hand (exc shave) DECYL GLUCOSIDE 1 12F - Moisturizing DECYL GLUCOSIDE 7 12H - Paste Masks (mud packs) DECYL GLUCOSIDE 4 12J - Other Skin Care Preps DECYL GLUCOSIDE 1 13C - Other Suntan Preparations

ARACHIDYL GLUCOSIDE 2 03D - Eye Lotion ARACHIDYL GLUCOSIDE 1 03G - Other Eye Makeup Preparations ARACHIDYL GLUCOSIDE 1 11A - Aftershave Lotion ARACHIDYL GLUCOSIDE 2 12A - Cleansing ARACHIDYL GLUCOSIDE 18 12C - Face and Neck (exc shave) ARACHIDYL GLUCOSIDE 10 12D - Body and Hand (exc shave) ARACHIDYL GLUCOSIDE 1 12E - Foot Powders and Sprays ARACHIDYL GLUCOSIDE 15 12F - Moisturizing ARACHIDYL GLUCOSIDE 8 12G - Night ARACHIDYL GLUCOSIDE 4 12J - Other Skin Care Preps ARACHIDYL GLUCOSIDE 6 13A - Suntan Gels, Creams, and Liquids ARACHIDYL GLUCOSIDE 6 13B - Indoor Tanning Preparations ARACHIDYL GLUCOSIDE 1 13C - Other Suntan Preparations

C12-20 ALKYL GLUCOSIDE 1 03D - Eye Lotion C12-20 ALKYL GLUCOSIDE 1 03G - Other Eye Makeup Preparations C12-20 ALKYL GLUCOSIDE 3 05A - Hair Conditioner C12-20 ALKYL GLUCOSIDE 1 05F - Shampoos (non-coloring) C12-20 ALKYL GLUCOSIDE 2 05G - Tonics, Dressings, and Other Hair Grooming Aids C12-20 ALKYL GLUCOSIDE 7 12A - Cleansing C12-20 ALKYL GLUCOSIDE 20 12C - Face and Neck (exc shave) C12-20 ALKYL GLUCOSIDE 6 12D - Body and Hand (exc shave) C12-20 ALKYL GLUCOSIDE 5 12F - Moisturizing C12-20 ALKYL GLUCOSIDE 1 12H - Paste Masks (mud packs) C12-20 ALKYL GLUCOSIDE 1 12I - Skin Fresheners C12-20 ALKYL GLUCOSIDE 4 12J - Other Skin Care Preps C12-20 ALKYL GLUCOSIDE 2 13B - Indoor Tanning Preparations

CAPRYLYL/CAPRYL GLUCOS 1 03D - Eye Lotion CAPRYLYL/CAPRYL GLUCOS 3 03E - Eye Makeup Remover CAPRYLYL/CAPRYL GLUCOS 2 03G - Other Eye Makeup Preparations CAPRYLYL/CAPRYL GLUCOS 2 05A - Hair Conditioner CAPRYLYL/CAPRYL GLUCOS 5 05F - Shampoos (non-coloring)

CIR Panel Book Page 59 Distributed for Comment Only -- Do Not Cite or Quote

CAPRYLYL/CAPRYL GLUCOS 1 07I - Other Makeup Preparations CAPRYLYL/CAPRYL GLUCOS 3 10A - Bath Soaps and Detergents CAPRYLYL/CAPRYL GLUCOS 3 10E - Other Personal Cleanliness Products CAPRYLYL/CAPRYL GLUCOS 15 12A - Cleansing CAPRYLYL/CAPRYL GLUCOS 8 12C - Face and Neck (exc shave) CAPRYLYL/CAPRYL GLUCOS 2 12D - Body and Hand (exc shave) CAPRYLYL/CAPRYL GLUCOS 3 12F - Moisturizing CAPRYLYL/CAPRYL GLUCOS 2 12G - Night CAPRYLYL/CAPRYL GLUCOS 7 12J - Other Skin Care Preps CAPRYLYL/CAPRYL GLUCOS 1 13A - Suntan Gels, Creams, and Liquids

CETEARYL GLUCOSIDE 2 01B - Baby Lotions, Oils, Powders, and Creams CETEARYL GLUCOSIDE 1 01C - Other Baby Products CETEARYL GLUCOSIDE 1 02D - Other Bath Preparations CETEARYL GLUCOSIDE 1 03C - Eye Shadow CETEARYL GLUCOSIDE 33 03D - Eye Lotion CETEARYL GLUCOSIDE 5 03F - Mascara CETEARYL GLUCOSIDE 22 03G - Other Eye Makeup Preparations CETEARYL GLUCOSIDE 3 04E - Other Fragrance Preparation CETEARYL GLUCOSIDE 1 05F - Shampoos (non-coloring) CETEARYL GLUCOSIDE 2 05G - Tonics, Dressings, and Other Hair Grooming Aids CETEARYL GLUCOSIDE 1 05I - Other Hair Preparations CETEARYL GLUCOSIDE 2 07C - Foundations CETEARYL GLUCOSIDE 1 07F - Makeup Bases CETEARYL GLUCOSIDE 1 07I - Other Makeup Preparations CETEARYL GLUCOSIDE 1 08B - Cuticle Softeners CETEARYL GLUCOSIDE 1 08C - Nail Creams and Lotions CETEARYL GLUCOSIDE 3 10A - Bath Soaps and Detergents CETEARYL GLUCOSIDE 2 10E - Other Personal Cleanliness Products CETEARYL GLUCOSIDE 1 11A - Aftershave Lotion CETEARYL GLUCOSIDE 11 12A - Cleansing CETEARYL GLUCOSIDE 64 12C - Face and Neck (exc shave) CETEARYL GLUCOSIDE 60 12D - Body and Hand (exc shave) CETEARYL GLUCOSIDE 164 12F - Moisturizing CETEARYL GLUCOSIDE 37 12G - Night CETEARYL GLUCOSIDE 14 12H - Paste Masks (mud packs) CETEARYL GLUCOSIDE 17 12J - Other Skin Care Preps CETEARYL GLUCOSIDE 3 13A - Suntan Gels, Creams, and Liquids CETEARYL GLUCOSIDE 22 13B - Indoor Tanning Preparations CETEARYL GLUCOSIDE 1 13C - Other Suntan Preparations

COCO-GLUCOSIDE 3 01A - Baby Shampoos COCO-GLUCOSIDE 8 01C - Other Baby Products COCO-GLUCOSIDE 2 02A - Bath Oils, Tablets, and Salts COCO-GLUCOSIDE 10 02B - Bubble Baths COCO-GLUCOSIDE 2 02D - Other Bath Preparations COCO-GLUCOSIDE 1 03D - Eye Lotion COCO-GLUCOSIDE 3 03E - Eye Makeup Remover COCO-GLUCOSIDE 2 03G - Other Eye Makeup Preparations COCO-GLUCOSIDE 4 05A - Hair Conditioner COCO-GLUCOSIDE 52 05F - Shampoos (non-coloring) COCO-GLUCOSIDE 3 05I - Other Hair Preparations COCO-GLUCOSIDE 15 06A - Hair Dyes and Colors (all types requiring caution statements and patch tests) COCO-GLUCOSIDE 1 06D - Hair Shampoos (coloring) COCO-GLUCOSIDE 113 10A - Bath Soaps and Detergents COCO-GLUCOSIDE 3 10C - Douches COCO-GLUCOSIDE 47 10E - Other Personal Cleanliness Products COCO-GLUCOSIDE 1 11D - Preshave Lotions (all types) COCO-GLUCOSIDE 3 11E - Shaving Cream COCO-GLUCOSIDE 1 11G - Other Shaving Preparation Products COCO-GLUCOSIDE 48 12A - Cleansing COCO-GLUCOSIDE 7 12C - Face and Neck (exc shave) COCO-GLUCOSIDE 12 12D - Body and Hand (exc shave)

CIR Panel Book Page 60 Distributed for Comment Only -- Do Not Cite or Quote

COCO-GLUCOSIDE 1 12E - Foot Powders and Sprays COCO-GLUCOSIDE 5 12F - Moisturizing COCO-GLUCOSIDE 3 12J - Other Skin Care Preps

ETHYL GLUCOSIDE 2 03D - Eye Lotion ETHYL GLUCOSIDE 1 10A - Bath Soaps and Detergents ETHYL GLUCOSIDE 8 12A - Cleansing ETHYL GLUCOSIDE 4 12C - Face and Neck (exc shave) ETHYL GLUCOSIDE 3 12F - Moisturizing ETHYL GLUCOSIDE 1 12G - Night ETHYL GLUCOSIDE 1 12H - Paste Masks (mud packs) ETHYL GLUCOSIDE 1 12I - Skin Fresheners ETHYL GLUCOSIDE 3 12J - Other Skin Care Preps

HEXADECYL D-GLUCOSIDE 1 12F - Moisturizing

LAURYL GLUCOSIDE 4 01A - Baby Shampoos LAURYL GLUCOSIDE 1 01C - Other Baby Products LAURYL GLUCOSIDE 1 02A - Bath Oils, Tablets, and Salts LAURYL GLUCOSIDE 15 02B - Bubble Baths LAURYL GLUCOSIDE 14 02D - Other Bath Preparations LAURYL GLUCOSIDE 1 05A - Hair Conditioner LAURYL GLUCOSIDE 1 05E - Rinses (non-coloring) LAURYL GLUCOSIDE 65 05F - Shampoos (non-coloring) LAURYL GLUCOSIDE 1 05G - Tonics, Dressings, and Other Hair Grooming Aids LAURYL GLUCOSIDE 2 05I - Other Hair Preparations LAURYL GLUCOSIDE 13 06A - Hair Dyes and Colors (all types requiring caution statements and patch tests) LAURYL GLUCOSIDE 1 06B - Hair Tints LAURYL GLUCOSIDE 1 06D - Hair Shampoos (coloring) LAURYL GLUCOSIDE 131 10A - Bath Soaps and Detergents LAURYL GLUCOSIDE 2 10C - Douches LAURYL GLUCOSIDE 55 10E - Other Personal Cleanliness Products LAURYL GLUCOSIDE 2 11A - Aftershave Lotion LAURYL GLUCOSIDE 72 12A - Cleansing LAURYL GLUCOSIDE 3 12C - Face and Neck (exc shave) LAURYL GLUCOSIDE 3 12D - Body and Hand (exc shave) LAURYL GLUCOSIDE 4 12F - Moisturizing LAURYL GLUCOSIDE 1 12G - Night LAURYL GLUCOSIDE 1 12H - Paste Masks (mud packs) LAURYL GLUCOSIDE 5 12J - Other Skin Care Preps

MYRISTYL GLUCOSIDE 2 03D - Eye Lotion MYRISTYL GLUCOSIDE 1 12A - Cleansing MYRISTYL GLUCOSIDE 1 12D - Body and Hand (exc shave) MYRISTYL GLUCOSIDE 1 12F - Moisturizing

OCTADECYL D-GLUCOSIDE 1 12F - Moisturizing

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