Safety Assessment of Hydrofluorocarbon 152a as Used in Cosmetics Status: Tentative Report for Public Comment Release Date: October 7, 2016 Panel Meeting Date: April 10-11, 2017 All interested persons are provided 60 days from the above date to comment on this safety assessment and to identify additional published data that should be included or provide unpublished data which can be made public and included. Information may be submitted without identifying the source or the trade name of the cosmetic product containing the ingredient. All unpublished data submitted to CIR will be discussed in open meetings, will be available at the CIR office for review by any interested party and may be cited in a peer-reviewed scientific journal. Please submit data, comments, or requests to the CIR Director, Dr. Lillian J. Gill. The 2016 Cosmetic Ingredient Review Expert Panel members are: Chairman, 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 report was prepared by Christina Burnett, Senior Scientific Analyst/Writer. Cosmetic Ingredient Review 1620 L Street NW, Suite 1200 ♢ Washington, DC 20036-4702 ♢ ph 202.331.0651 ♢ fax 202.331.0088 ♢ [email protected] ABSTRACT The Cosmetic Ingredient Review (CIR) Expert Panel (the Panel) reviewed the safety of Hydrofluorocarbon 152a, which functions as a propellant in personal care products. The Panel reviewed relevant data provided in this safety assessment, and concluded that Hydrofluorocarbon 152a is safe in the present practices of use and concentration described in this safety assessment. INTRODUCTION Hydrofluorocarbon 152a is a gas that functions as a propellant in personal care products, according to the International Cosmetic Dictionary and Handbook.1 It is commonly known as 1,1-difluoroethane. CHEMISTRY Definition Hydrofluorocarbon 152a (CAS No. 75-37-6) is the halocarbon, 1,1-difluoroethane, that conforms to the 1 formula CH3CHF2. Figure 1. Hydrofluorocarbon 152a Chemical and Physical Properties Hydrofluorocarbon 152a is a colorless, odorless gas, with a vapor pressure of 4550 mmHg at 25 oC. This ingredient is distinct from chlorofluorocarbon propellants, such as Hydrochlorofluorocarbon 142b, because there are no chlorine atoms to react with stratospheric ozone. Additional physical and chemical properties of Hydrofluorocarbon 152a are provided in Table 1. Method of Manufacturing Hydrofluorocarbon 152a may be derived by reacting hydrogen fluoride with acetylene.2 The material may also be produced by a catalytic reaction of vinyl chloride with hydrofluoric acid, in a closed system.3 Impurities Hydrofluorocarbon 152a is reported to be greater than 99.9% pure.3 Impurities may include water, residual hydrochloric acid, and residual hydrofluoric acid. USE Cosmetic The safety of the cosmetic ingredient included in this assessment is evaluated based on data received from the U.S. Food and Drug Administration (FDA) and the cosmetics industry on the expected use of this ingredient in cosmetics. Use frequencies of individual ingredients in cosmetics are collected from manufacturers and reported by cosmetic product category in FDA’s Voluntary Cosmetic Registration Program (VCRP) database. Use concentration data are submitted by Industry in response to surveys, conducted by the Personal Care Products Council (Council), of maximum reported use concentrations by product category. According to 2016 VCRP data, Hydrofluorocarbon 152a is used in 372 formulations; the majority of uses are in leave-on hair care products (Table 2).4 The results of the concentration of use survey conducted in 2015 by the Council indicate the highest reported maximum concentration of use to be 80% in hair sprays.5 This product is believed to be solely used in spray products, like hair spray and spray deodorants. However, because this ingredient is a gas under all exposure conditions, inhalation is possible for all product types in which it is used. Hydrofluorocarbon 152a is not restricted from use as a cosmetic in any way under the rules governing cosmetic products in the European Union.6 Non-Cosmetic Hydrofluorocarbon 152a may be used as an aerosol propellant, a foam expansion agent, a refrigerant, and as a catalyst regenerator.3 TOXICOKINETICS Absorption, Distribution, Metabolism, and Excretion (ADME) Animal Inhalation Metabolites identified in urine collected for nuclear magnetic resonance (NMR) spectroscopy analysis from male CD rats exposed via inhalation to 3000 ppm Hydrofluorocarbon 152a (see Acute Toxicity for further study details) included fluoride ion and a trace of acetyl fluoride.7 No fluoroacetate was detected. The time at which the urine was collected after exposure was not identified in the study report. Human Inhalation The uptake, distribution, and elimination of Hydrofluorocarbon 152a were studied in male and female subjects.8,9 Six women and 4 men completed all exposure sessions (0, 200, and 1000 ppm test material), with one additional male exposed to 0 and 200 ppm, another male exposed to only 200 ppm, and another male exposed only to 0 ppm (n for 0 ppm = 12, n for 200 ppm = 12, and n for 1000 ppm = 10). Subjects were exposed for 2 h on three separate occasions to Hydrofluorocarbon 152a, and exposures were performed during light exercise on computer- controlled ergometer bicycles in an exposure chamber (20 m3) with a controlled climate. The concentration of the test material in the chamber was checked by gas chromatography (GC) at 5 minute intervals throughout the exposure sessions. Mixed exhaled air was collected once before the exposure, five times during the exposure, and seven times after the exposure. Pulmonary ventilation was recorded with an electric spirometer during every breath sampling period. Venous blood was collected from the brachial vein prior to exposure and at 3 h and 22 h after exposure for analysis of inflammatory markers, while arterialized capillary blood was collected from the subjects’ finger tips before, during, and after exposure. Urine was sampled once before exposure and at 2, 4, and 6 h after onset of exposure, as well as twice in the evening and once the following morning. The presence of Hydrofluorocarbon 152a in the blood and urine was analyzed by head-space GC. The urine was analyzed for fluoride with an ion selective electrode and for potential metabolites with NMR. In the blood, initial increases in Hydrofluorocarbon 152a were fast and average concentrations of 7.4 μM (for 200 ppm) and 34.3 μM (for 1000 ppm) were achieved within a few minutes of exposure. Within 4 h post- exposure, the concentration was less than 1% of the steady state level. Blood concentrations were below detection limits 22 h post-exposure. The area under the curve (AUC) of the test material in blood was 1042 μM min at 200 ppm and 4572 μM min at 1000 ppm, which indicated dose-proportional kinetics. No exposure-related effects were observed in inflammatory markers in the blood plasma. Total inhaled Hydrofluorocarbon 152a was approximately 20.6 and 99.6 mmol for the 200 and 1000 ppm exposures, respectively. Post-exposure decreases of the test material in exhaled air and urine were similar to that in blood. The AUCs of the test material in urine were 190 μM min for 200 ppm and 1271 μM min for 1000 ppm. After exposure to 200 ppm and 1000 ppm Hydrofluorocarbon 152a, about 0.004% and 0.009%, respectively, of the total amount inhaled was excreted in the urine within 23 h. About 20 μmol excess fluoride (0.013% of inhaled) was excreted in urine following the exposure to 1000 ppm test material when compared to the control. This was statistically significantly greater than the amount excreted in the urine of both the control and the 200 ppm exposed subjects (p=0.008) and remained significant elevated in the post hoc test (p<0.05). Fluoride excretion rate varied; however, it was statistically significantly higher in the first 2 urine samples after exposure to 1000 ppm test material when compared to the control subjects and subjects exposed to 200 ppm (p=0.0004). No fluorine-containing metabolites could be detected in the urine, indicating biotransformation of the test material in humans was very low.8,9 TOXICOLOGICAL STUDIES Acute Toxicity Studies 3,7,9 Acute oral and inhalation studies are summarized in Table 3. In rats, the lowest lethal oral dose (LDLO) reported for Hydrofluorocarbon 152a was greater than 1500 mg/kg, which was the highest dosage tested.3 However, this study was considered invalid by the Organization for Economic Co-operation and Development (OECD) because an unsuitable test system was used. The LC50 reported in a mouse inhalation study was 977,200 ppm. Cardiac arrhythmia was observed in dogs exposed for 5 min to 150,000 ppm Hydrofluorocarbon 152a in an inhalation study. Short-Term Toxicity Studies Inhalation In a short-term inhalation study of Hydrofluorocarbon 152a, 10 male ChR-CD rats were exposed to 100,000 ppm of the test material in air 6 h/day for 5 days/week for 2 weeks.3,9 Following the final exposure, 5 rats were killed for gross and histopathologic examination while the remaining rats were killed after a 14-day recovery period. Hematological, urine analytical, and biochemical indices were measured in all rats prior to being killed. During exposure to the test material, the rats appeared to be anesthetized, which was indicated by sleep and unresponsiveness to sound. No other adverse effects were observed. A slight increase in urinary fluoride was observed following the final exposure. In another short-term study, 8 albino rats (sex not provided) were exposed to 100,000 ppm Hydrofluoro- carbon 152a in air 16 h/day for 2 months.3,9 At the end of the exposure period, the animals were killed and examined for gross pathological changes.