Safety Assessment of Alkane Diols as Used in Cosmetics Status: Draft Tentative Report for Panel Review Release Date: March 17, 2017 Panel Meeting Date: April 10-11, 2017 The 2017 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 Lillian J. Gill, D.P.A. This safety assessment was prepared by Laura N. Scott, Scientific Writer/Analyst. © Cosmetic Ingredient Review 1620 L Street, NW, Suite 1200 ♢ Washington, DC 20036-4702 ♢ ph 202.331.0651 ♢ fax 202.331.0088 ♢ [email protected] Commitment & Credibility since 1976 Memorandum To: CIR Expert Panel Members and Liaisons From: Laura N. Scott Senior Scientific Writer Date: March 17, 2017 Subject: Draft Tentative Report of the Safety Assessment of Alkane Diols as Used in Cosmetics Enclosed is the Draft Tentative Report of the Safety Assessment of Alkane Diols as Used in Cosmetics (identified as ADIOLS042017rep in the pdf document). At the September 26-27th, 2016 meeting, the Panel issued an Insufficient Data Announcement for all of the alkane diols with requested data needs as follows: method of manufacturing (all ingredients), impurities (all ingredients), penetration enhancement (all ingredients), neurotoxicity (Isopentydiol), and concentration of use (1,4-Butanediol). The CIR report history (ADIOLS042017hist), Process Flow Chart (ADIOLS042017flow), Literature Search Strategy (ADIOLS042017strat), 2017 VCRP data (ADIOLS042017FDA), Ingredient Data Profile (ADIOLS042017prof), and Minutes from the Sept 2016 Meeting (ADIOLS042017min) are enclosed for the Panel’s review. Council comments on the Draft Report from the Sept 2016 Meeting (ADIOLS042017pcpc) were received and have been addressed. Industry data submitted to the Council were received by CIR and have been incorporated into the report as appropriate (ADIOLS042017data_1; ADIOLS042017data_2; ADIOLS042017data_3; ADIOLS042017data_4; ADIOLS042017data_5). The following have been added (highlighted in Tables and │bracketed│in text) to the safety assessment since the September 2016 Meeting: 1. Unpublished ADME and phototoxicity data for 1,5-Pentanediol, which was presented to the Panel in Wave 2 at Sept 2016 Meeting. 2. Penetration enhancement and clinical studies data for 1,5-Pentanediol (from 3 journal articles referenced in Wave 2 from Sept 2016 Meeting). 3. Unpublished toxicity studies for 1,10-Decanediol (ADIOLS042017data_1); hardcopies were made available at the Sept Panel Meeting because it was received after Wave 2. 4. Impurities data for Propanediol; 1,4-Butanediol; 1,5-Pentanediol; Hexanediol; Methylpropanediol; and Isopentyldiol. 5. Penetration enhancement data (journal article) for Propanediol, 1,4-Butanediol, and 1,5-Pentanediol and method of manufacture for Propanediol (unpublished data from industry). 6. Chronic Toxicity study for 1,4-Butanediol (OECD-SIDS report). 7. Human dermal irritation/sensitization and phototoxicity data (unpublished data from industry) and a case report (journal article) for 1,5-Pentanediol. 8. Human sensitization data at maximum concentration of use for Methylpropanediol (21.2%, unpublished from industry). __________________________________________________________________________________________ 1620 L Street, NW Suite 1200, Washington, DC 20036 (Main) 202-331-0651 (Fax) 202-331-0088 (Email) [email protected] (Website) www.cir-safety.org Please consider for discussion the following: A. Additional data in #’s 4-8 above. B. Should the Discussion section of the report include analysis of the differences in toxicity between the alkane diol ingredients based on their regiochemistry? C. Should the Discussion section mention the systemic toxicity observed following dermal, oral, and inhalation exposure to high doses/concentrations of alkane diols in acute, short-term, and subchronic animal studies? D. Does the in vivo genotoxicity study indicating that Propanediol is converted to malondialdehyde, subsequently causing damage to rat DNA (liver and testicular homogenates were tested), need to be addressed in the Discussion section? E. In ADIOLS042017data_4 (last paragraph on pdf page 3) there is an industry synopsis of the English abstract for a reference to a Chinese article (abstract only in English with limited details) evaluating the ability of Propanediol to increase the in vitro skin penetration of diphenhydramine hydrochloride. A Google search produced this link to the English version of the abstract http://en.cnki.com.cn/Article_en/CJFDTOTAL-ZGYA200831009.htm. The abstract indicates that Propanediol is a penetration enhancer for diphenhydramine hydrochloride. Does the Panel recommend including any of these abstract details in the report and if so, should the abstract in the above link or the industry submission (in ADIOLS042017data_4) be cited? If the data included in this report adequately address the safety of the alkane diols, the Panel should be prepared to formulate a tentative conclusion, provide the rationale to be described in the Discussion, and issue a Tentative Report for public comment. If the data are not sufficient for making a determination of safety, then an Insufficient Data Announcement should be issued with a listing of the additional data that are needed. __________________________________________________________________________________________ 1620 L Street, NW Suite 1200, Washington, DC 20036 (Main) 202-331-0651 (Fax) 202-331-0088 (Email) [email protected] (Website) www.cir-safety.org SAFETY ASSESSMENT FLOW CHART INGREDIENT/FAMILY ____Alkane Diols_________________________________________________ MEETING _____April 2017_____________________________________________________________ Public Comment CIR Expert Panel Report Status Priority List INGREDIENT PRIORITY LIST SLR July 20, 2016 DRAFT REPORT Sept 2016 Draft Report 60 day public comment period Table Table IDA TR IDA Notice IDA Sept 30, 2016 DRAFT TENTATIVE REPORT Apr 2017 Draft TR Table Table Issue TR Tentative Report Draft FR DRAFT FINAL REPORT 60 day Public comment period Table Table Different Conclusion Issue PUBLISH Final Report FR ___ Distributed for comment only -- do not cite or quote Report History-Alkane Diols July 20th, 2016-The Alkane Diols Scientific Literature Review was posted at www.cir-safety.org for public comment. September 26-27th, 2016-This was the first time the Expert Panel saw this safety assessment. The Panel issued an Insufficient Data Announcement for the Alkane Diols Draft Report presented at this meeting. December 5th-6th, 2016-This report was not reviewed at the December Panel Meeting. Distributed for comment only -- do not cite or quote Alkane Diols Data Profile for April 10-11, 2017. Writer – Laura Scott Penetration ADME Acute Toxicity Short- Sub- Chronic DART Carcin- Neuro Dermal Dermal Photo- Occular Enhancement Term chron. Tox. ogenicity -tox Irr. Sen. Irr/Sen Irr. Toxicity Tox. Geno-tox Cosmetics? Used in Available? Safety Data Penetration VitroIn VitroIn Animal Human VitroIn Animal Animal Animal Animal Human Animal Human Animal Human VitroIn Animal Human Human Animal Animal Animal Animal Animal Animal Animal Animal In VitroIn In Vivo Animal Animal VitroIn Animal - - - - - - - - - - - - - - - - Inhalation IV Oral Oral Dermal Other Inhalation Oral Oral Inhalation Oral Oral Oral Dermal Dermal Oral & IV Propanediol Y Y X X X X X X X X X X X X X X X X X X (1,3-Propanediol) 1,4-Butanediol Y Y X X X X X X X X X X X X X X * X X X X X X 2,3-Butanediol N Y X X X X X X X X X 1,5-Pentanediol N Y X X X X X X X X X X X X Hexanediol Y Y X X X X X X X X X X X (1,6-Hexanediol) Octanediol Y N (1,8-Octanediol) 1,10-Decanediol Y Y X X X X X X X X X Methylpropanediol Y Y X X X X X X X X X X X X X X (2-Methyl-1,3- Propanediol) Butyl Ethyl Y Y X X X X X X X X X X Propanediol Isopentyldiol Y Y X X X X X X X X indicates available, relevant studies included in this safety assessment in each applicable category. Blank boxes indicate no available, relevant data were found in the literature or submitted. *This study evaluated gamma-butyrolactone, which converts to gamma-hydroxybutyrate (GHB) in the body as does 1,4-Butanediol. Distributed for comment only -- do not cite or quote Alkane Diols Search Strategy Info Ingredient Cas No. Prev in NTIS FDA/ NTP TOXNET WHO ECHA EPA OECD/ EU NICNAS Web Rev Use CFR SIDS Propanediol (26264-14- 26264-14-2; 2); 1,3-Propanediol 504-63-2 No Yes X X - X - X X - - - X (504-63-2) 1,4-Butanediol 110-63-4 No Yes X X X X X X X X - X* X 1,5-Pentanediol 111-29-5 No No X X - X - X - - - - X Hexanediol (1,6- 26762-52-7; No Yes - X - X - X - X - X Hexanediol) 629-11-8 - Octanediol (1,8- 629-41-4 No No X - - - - - - - - - X Octanediol) 1,10-Decanediol 112-47-0 No Yes - - X X - - - - - - X Methylpropanediol (2- 2163-42-0 No Yes - - - X - X X - - X** X Methyl-1,3-Propanediol) 2,3-Butanediol 513-85-9 No No - - - X - X - - - - X Butyl Ethyl Propanediol 115-84-4 No Yes - - - X - X - - - - X Isopentyldiol 2568-33-4 No Yes - - - - - - - - - X** X X indicates data were available; - indicates no relevant data were available; * indicates ingredients are in the Australian Inventory of Chemical Substances (AICS) and secondary notification conditions do not apply; ** indicates ingredients are in the Australian Inventory of Chemical Substances (AICS) and secondary notification conditions do apply PubMed: 12-9-2015 Searched: