Safety Assessment of Parabens as Used in Cosmetics Status: Draft Report for Panel Review Release Date: February 23, 2018 Panel Meeting Date: March 5-6, 2018 The 2018 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 Executive Director is Bart Heldreth, Ph.D. This report was prepared by Lillian C. Becker, Scientific Analyst/Writer and Bart Heldreth. © 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1200 ♢ Washington, DC 20036-4702 ♢ ph 202.331.0651 ♢ fax 202.331.0088 [email protected] Distributed for comment only -- do not cite or quote Commitment & Credibility since 1976 MEMORANDUM To: CIR Expert Panel and Liaisons From: Bart Heldreth, PhD, CIR Executive Director Date: February 23, 2018 Subject: Parabens Attached is the updated draft review of 20 parabens as used in cosmetics. These parabens are reported to function in cosmetics primarily as preservatives. In 2017, the Panel agreed to add Sodium Methylparaben to the Priority List due to the large number of reported uses in the FDA’s Voluntary Cosmetic Registration Program (VCRP) database. The Expert Panel agreed that it would be appropriate to group this ingredient with 7 parabens reviewed in the CIR safety assessment published in 2008: Methylparaben; Ethylparaben; Propylparaben; Butylparaben; Benzylparaben; Isopropylparaben; and Isobutylparaben. In addition, the Panel included 12 other paraben salts that had not yet been reviewed: Calcium Paraben; Potassium Butylparaben; Potassium Ethylparaben; Potassium Methylparaben; Potassium Paraben; Potassium Propylparaben; Sodium Butylparaben; Sodium Ethylparaben; Sodium Isobutylparaben; Sodium Isopropylparaben; Sodium Paraben; and Sodium Propylparaben. At the June 2017 meeting, the Panel also elected to add 4-Hydroxybenzoic Acid to the group. However, the Panel was concerned that new data from a developmental and reproductive toxicity (DART) study indicated reduced sperm counts and reduced expression of a specific enzyme, and a specific cell marker in the testes of offspring of female rats orally dosed with 10 mg/kg/day Butylparaben during the gestation and lactation periods. Reductions in anogenital distance and other effects were reported at 100 mg/kg/day in this study. In comparison, the previous CIR safety assessment of the parabens included the calculation of margin of safety (MOS) values for adults and infants, assuming a no observed adverse effect level (NOAEL) of 1000 mg/kg/day from an older DART study. The Panel agreed that a subject matter expert should be consulted to review the reproductive toxicity data available for the parabens, and identify additional relevant data that the Panel should consider, if any. [parabe032018Rep] This expert should provide professional opinions on the relevance of the animal-model toxicity endpoints reported in the DART studies available for assessing the safety of the parabens as used in cosmetics. This expert should evaluate the quality, and facilitate the interpretation of, the data on which NOAELs, lowest- observed adverse effect levels (LOAELs), and MOS values may be derived to assess the safety of these cosmetic ingredients. The Panel agreed to table the re-review of the parabens pending the input of such an expert. Just such an expert is scheduled to present on this topic at this CIR Expert Panel Meeting. Distributed for comment only -- do not cite or quote Furthermore, someadditional references have been submitted by stakeholders or discovered by CIR. These references are not yet incorporated into the report, and the Panel is asked to consider the merit and relevance of these documents to this safety assessment. [parabe032018Refs] Specifically, these are titled: Urinary concentrations of parabens and reproductive parameters in young men Effects on the reproductive system of young male rats of subcutaneous exposure to n-butylparaben Personal Care Product Use in Men and Urinary Concentrations of Select Phthalate Metabolites and Parabens: Results from the Environment and Reproductive Health (EARTH) Study Human Semen Quality, Sperm DNA Damage, and the Level of Reproductive Hormones in Relation to Urinary Concentrations of Parabens The Panel should review the information presented at this meeting and either affirm or change the conclusion from the 2008 report on the original seven paraben ingredients. The Panel should also determine if this conclusion can be applied to the newly added ingredients, or if a split conclusion is warranted. Whether the conclusion remains the same (and extends to all of the new ingredients) or is to be changed and/or split, the Panel should issue a Tentative Amended Report, and develop the basis for the Discussion. However, if information (and/or added ingredients) raise new questions for the Panel that are not answered by the available data, then an Insufficient Data Announcement, with a list of data needs, should be issued. Safety Assessment of Parabens as Used in Cosmetics Status: Draft Report for Panel Review Release Date: February 23, 2018 Panel Meeting Date: March 5-6, 2018 The 2018 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 Executive Director is Bart Heldreth, Ph.D. This report was prepared by Lillian C. Becker, Scientific Analyst/Writer and Bart Heldreth. © 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 INTRODUCTION This is a re-review of the available scientific literature and unpublished data relevant to assessing the safety of parabens as used in cosmetics. According to the web-based Cosmetic Ingredient Dictionary and Handbook (Dictionary; wINCI), The ingredients in this paraben group are reported to function as preservatives, and two are reported to function as fragrances (Table 1).1 In 2017, the Expert Panel (Panel) agreed to add Sodium Methylparaben to the Priority List due to the large number of reported uses in the FDA’s Voluntary Cosmetic Registration Program (VCRP) database. The Expert Panel agreed that it would be appropriate to group this ingredient with the 7 parabens reviewed by the Cosmetic Ingredient Review (CIR) in the safety assessment published in 2008: Methylparaben; Ethylparaben; Propylparaben; Butylparaben; Benzylparaben; Isopropylparaben; and Isobutylparaben. In addition, the Panel included 12 other paraben salts that had not yet been reviewed: Calcium Paraben; Potassium Butylparaben; Potassium Ethylparaben; Potassium Methylparaben; Potassium Paraben; Potassium Propylparaben; Sodium Butylparaben; Sodium Ethylparaben; Sodium Isobutylparaben; Sodium Isopropylparaben; Sodium Paraben; and Sodium Propylparaben. At the June 2017 meeting, the Panel also elected to add 4-Hydroxybenzoic Acid to the group. However, the Panel was concerned that new data from a developmental and reproductive toxicity (DART) study indicated reduced sperm counts and reduced expression of a specific enzyme, and a specific cell marker in the testes of offspring of female rats orally dosed with 10 mg/kg/day Butylparaben during the gestation and lactation periods. Reductions in anogenital distance and other effects were reported at 100 mg/kg/day in this study. In comparison, the previous CIR safety assessment of the parabens included the calculation of margin of safety (MOS) values for adults and infants, assuming a no observed adverse effect level (NOAEL) of 1000 mg/kg/day from an older DART study. The Panel agreed that a subject matter expert should be consulted to review the reproductive toxicity data available for the parabens, and identify additional relevant data that the Panel should consider, if any. This expert should provide professional opinions on the relevance of the animal-model toxicity endpoints reported in the DART studies available for assessing the safety of the parabens as used in cosmetics. This expert should evaluate the quality, and facilitate the interpretation of, the data on which NOAELs, lowest- observed adverse effect levels (LOAELs), and MOS values may be derived to assess the safety of these cosmetic ingredients. The Panel agreed to table the re-review of the parabens pending the input of such an expert. Pertinent data were discovered in the European Chemicals Agency (ECHA) database.2-8 Data were also discovered in reports by the Joint FAO/WHO Expert Committee on Food Additives (JECFA) and the European Union’s (EU) Scientific Committee on Consumer Products (SCCP).9-17 An exhaustive search was conducted for new data on the safety of parabens in preparation of the previous iteration of this report. A few short-term, but no new acute, subchronic or chronic toxicity studies, were discovered. New epidemiology studies explored the possibility of associations between markers of paraben exposure and adverse health outcomes, including prospective and retrospective studies. Exposures to Methylparaben, Propylparaben and Butylparaben were evaluated in all of these studies. In addition, aggregate exposures to Ethylparaben and Benzylparaben were considered. Taken