Safety Assessment of Levulinic Acid and Sodium Levulinate as Used in Cosmetics Status: Draft Report for Panel Review Release Date: August 21, 2020 Panel Meeting Date: September 14-15, 2020 The Expert Panel for Cosmetic Ingredient Safety members are: Chair, Wilma F. Bergfeld, M.D., F.A.C.P.; Donald V. Belsito, M.D.; Curtis D. Klaassen, Ph.D.; Daniel C. Liebler, Ph.D.; James G. Marks, Jr., M.D.; Lisa A. Peterson, Ph.D.; Ronald C. Shank, Ph.D.; Thomas J. Slaga, Ph.D.; and Paul W. Snyder, D.V.M., Ph.D. The Cosmetic Ingredient Review (CIR) Executive Director is Bart Heldreth, Ph.D. This safety assessment was prepared by Preethi S. Raj, M.Sc., Senior Scientific Analyst/Writer, CIR. © Cosmetic Ingredient Review 1620 L Street, NW, Suite 1200 ♢ Washington, DC 20036-4702 ♢ ph 202.331.0651 ♢ fax 202.331.0088 ♢ [email protected] Distributed for Comment Only -- Do Not Cite or Quote Commitment & Credibility since 1976 Memorandum To: Expert Panel for Cosmetic Ingredient Safety Members and Liaisons From: Preethi S. Raj, M.Sc. Senior Scientific Analyst, CIR Date: August 21, 2020 Subject: Safety Assessment of Levulinic Acid and Sodium Levulinate as Used in Cosmetics Enclosed is the draft report of the Safety Assessment of Levulinic Acid and Sodium Levulinate as Used in Cosmetics (identified as levaci092020rep in the pdf). This is the first time the Panel is seeing a safety assessment of these cosmetic ingredients. A Scientific Literature Review (SLR) was announced on February 21, 2020. Following the announcement of the SLR, two human repeat insult patch tests for Sodium Levulinate were received, and have been included in this report (levaci092020data2): • Essex Testing Clinic, Inc. (2016) Clinical safety evaluation repeated insult patch test of a product containing 0.4011% Sodium Levulinate • Essex Testing Clinic, Inc. (2016) Clinical safety evaluation repeated insult patch test of a product containing 0.57% Sodium Levulinate Comments on the SLR (levaci092020pcpc) that were received from the Council have been addressed. Also included in this package, for your review, are a flow chart (levaci092020flow), literature search strategy (levaci092020strat), ingredient data profile (levaci092020prof), ingredient history (levaci092020hist), 2020 FDA VCRP data (levaci092020FDA), and 2019 concentration of use data (levaci092020data1). After reviewing these documents, if the available data are deemed sufficient to make a determination of safety, the Panel should issue a Tentative Report with a safe as used, safe with qualifications, or unsafe conclusion, and Discussion items should be identified. If the available data are insufficient, the Panel should issue an Insufficient Data Announcement (IDA), specifying the data needs therein. __________________________________________________________________________________________ 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 Distributed for Comment Only -- Do Not Cite or Quote SAFETY ASSESSMENT FLOW CHART INGREDIENT/FAMILY ___Levulinic Acid & Sodium Levulinate ______________________ MEETING ___September 2020 ___________________________________________________ Public Comment CIR Expert Panel Report Status Priority List INGREDIENT PRIORITY LIST SLR February 21, 2020 DRAFT REPORT Sept 2020 Draft Report 60-day public comment period Table Table IDA TR IDA Notice IDA DRAFT TENTATIVE REPORT Draft TR Table Table Tentative Report Issue TR 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 CIR History of: Levulinic Acid and Sodium Levulinate January 2019 -Concentration of use data submitted by Council January 2020 -FDA frequency of use data obtained February 2020 -Levulinic Acid and Sodium Levulinate SLR posted on the CIR website Data received: March 2, 2020: Two HRIPTs for 0.4011% and 0.57% Sodium Levulinate September 2020 -A Draft Report is being presented to the Panel. Distributed for Comment Only -- Do Not Cite or Quote Levulinic Acid and Sodium Levulinate Data Profile* – September 14-15th, 2020 – Writer, Preethi Raj Repeated Dermal Dermal Ocular Clinical Toxicokinetics Acute Tox DART Genotox Carci Dose Tox Irritation Sensitization Irritation Studies ow Mfg Mfg ro /log K n Vit Reported Use Method of Impurities log P Dermal Penetration ADME Dermal Oral Inhalation Dermal Oral Inhalation Dermal Oral I VivoIn Dermal Oral VitroIn Animal Human VitroIn Animal Human Phototoxicity VitroIn Animal Retrospective/ Multicenter Case Reports Levulinic Acid X X X X X X X X X X X X X X X Sodium Levulinate X X X X X * “X” indicates that data were available in a category for the ingredient 1 Distributed for Comment Only -- Do Not Cite or Quote [Levulinic Acid and Sodium Levulinate] Ingredient CAS # InfoB PubMed TOXNET FDA EU ECHA IUCLID SIDS ECETOC HPVIS NICNAS NTIS NTP WHO FAO NIOSH FEMA Web Levulinic Acid; 123-76-2 * * * NR NR NR * * NR NR NR 4-oxovaleric acid Sodium 19856-23-6 * * NR NR NR NR NR NR NR NR NR NR NR NR NR Levulinate; Sodium 4- oxovalerate NR – not reported or available - data is available *- in database, but data is not available or relevant total # useful/total # of hits Search Strategy [document search strategy used for SciFinder, PubMed, and Toxnet - total # useful/ total number of hits ] Sodium Levulinate – 2/6 Levulinic Acid – 3/926 "123-76-2" AND toxicity – 1/7 "19856-23-6" - 4/346 (((levulinic acid) OR "123-76-2") AND oral toxicity) - 0/1 (((levulinic acid) OR "123-76-2") AND chemical structure) – 3/432 (((levulinic acid) OR "123-76-2") AND manufacturing) – 0/4 (((levulinic acid) OR "123-76-2") AND impurities) – 1/6 ((((levulinic acid) OR "123-76-2") AND toxicokinetics)) - 3/25 ((((levulinic acid) OR "123-76-2") AND dermal penetration)) - 0/0 ((((levulinic acid) OR "123-76-2") AND inhalation)) -0/2 ((((levulinic acid) OR "123-76-2") AND acute toxicity)) – 0/2 ((((levulinic acid) OR "123-76-2") AND short term toxicity)) - 0/0 ((((levulinic acid) OR "123-76-2") AND subchronic toxicity)) – 0/0 ((((levulinic acid) OR "123-76-2") AND chronic toxicity)) – 0/2 ((((levulinic acid) OR "123-76-2") AND developmental toxicity)) – 0/2 ((((levulinic acid) OR "123-76-2") AND reproductive toxicity)) – 0/1 ((((levulinic acid) OR "123-76-2") AND cancer)) -0/87 ((((levulinic acid) OR "123-76-2") AND mutagenicity)) – 1/1 ((((levulinic acid) OR "123-76-2") AND genotoxicity)) – 0/0 ((((levulinic acid) OR "123-76-2") AND cytotoxicity)) – 0/8 ((((levulinic acid) OR "123-76-2") AND dermal irritation)) – 0/0 ((((levulinic acid) OR "123-76-2") AND dermal sensitization)) – 0/0 ((((levulinic acid) OR "123-76-2") AND phototoxicity)) – 1/2 ((((levulinic acid) OR "123-76-2") AND ocular irritation)) – 0/0 ((((levulinic acid) OR "123-76-2") AND mucous membrane irritation)) – 0/0 ((((levulinic acid) OR "123-76-2") AND case reports)) -0/22 Distributed for Comment Only -- Do Not Cite or Quote ((((levulinic acid) OR "123-76-2") AND adverse events)) – 1/1 ((((levulinic acid) OR "123-76-2") AND epidemiology)) – 0/4 General Search Levulinic acid cosmetic use Sodium Levulinate cosmetic use Typical Search Terms . INCI names . CAS numbers . chemical/technical names: o Levulinic Acid: . 3-Acetylpropionic Acid – 0/2,952,706 . 4-Ketovaleric Acid-0/2 . 4-Oxopentanoic Acid [AND toxicity] – 0/6 . 4-Oxovaleric Acid -1/2 . Pentanoic Acid, 4-Oxo-2/30 o Sodium Levulinate: . Pentanoic Acid, 4-oxo-, Sodium Salt – 0/0 . additional terms will be used as appropriate LINKS Search Engines . Pubmed (- http://www.ncbi.nlm.nih.gov/pubmed) . Toxnet (https://toxnet.nlm.nih.gov/); (includes Toxline; HSDB; ChemIDPlus; DART; IRIS; CCRIS; CPDB; GENE-TOX) appropriate qualifiers are used as necessary search results are reviewed to identify relevant documents Pertinent Websites . wINCI - http://webdictionary.personalcarecouncil.org . FDA databases http://www.ecfr.gov/cgi-bin/ECFR?page=browse . FDA search databases: http://www.fda.gov/ForIndustry/FDABasicsforIndustry/ucm234631.htm;, . EAFUS: http://www.accessdata.fda.gov/scripts/fcn/fcnnavigation.cfm?rpt=eafuslisting&displayall=true . GRAS listing: http://www.fda.gov/food/ingredientspackaginglabeling/gras/default.htm . SCOGS database: http://www.fda.gov/food/ingredientspackaginglabeling/gras/scogs/ucm2006852.htm . Indirect Food Additives: http://www.accessdata.fda.gov/scripts/fdcc/?set=IndirectAdditives . Drug Approvals and Database: http://www.fda.gov/Drugs/InformationOnDrugs/default.htm Distributed for Comment Only -- Do Not Cite or Quote . http://www.fda.gov/downloads/AboutFDA/CentersOffices/CDER/UCM135688.pdf . FDA Orange Book: https://www.fda.gov/Drugs/InformationOnDrugs/ucm129662.htm . OTC ingredient list: https://www.fda.gov/downloads/aboutfda/centersoffices/officeofmedicalproductsandtobacco/cder/ucm135688.pdf . (inactive ingredients approved for drugs: http://www.accessdata.fda.gov/scripts/cder/iig/ . HPVIS (EPA High-Production Volume Info Systems) - https://ofmext.epa.gov/hpvis/HPVISlogon . NIOSH (National Institute for Occupational Safety and Health) - http://www.cdc.gov/niosh/ . NTIS (National Technical Information Service) - http://www.ntis.gov/ . NTP (National Toxicology Program ) - http://ntp.niehs.nih.gov/ . Office of Dietary Supplements https://ods.od.nih.gov/ . FEMA (Flavor & Extract Manufacturers Association) - http://www.femaflavor.org/search/apachesolr_search/ . EU CosIng database: http://ec.europa.eu/growth/tools-databases/cosing/ . ECHA (European Chemicals Agency – REACH