Comprehensive review of ensulizole toxicology data and human exposure assessment for personal care products.

A comprehensive review of existing toxicity and human exposure data for the ultraviolet filter ensulizole (2-phenylbenzimidazole-5-sulfonic acid) as currently used in over-the-counter sunscreen formulations was conducted. Authorized maximum ensulizole usage levels in consumer end-use products worldwide range from 3% to 8%, with the maximum usage level limited to 4% in the United States, Canada, and Australia. Postmarketing clinical safety studies of ensulizole have reported only occasional local skin effects, none of which were associated with systemic toxicity. Ensulizole has been investigated in vitro, in animal toxicity studies, and in human studies for its pharmacokinetics, pharmacodynamics, and potential toxicological properties. Experimentally determined values of 4% for oral absorption in rats and of 0.26% for dermal absorption in humans were used for risk calculation purposes. There was no evidence of ensulizole bioaccumulation from rat in vivo studies, consistent with its high water solubility and low octanol/water partition coefficient. Ensulizole is not classifiable as an irritant, although local skin irritation with no systemic effects was noted in a 3-month repeated-dose dermal toxicity study in rabbits. Ensulizole is non-(photo)sensitizing, non-phototoxic, and has demonstrated low toxicity in acute (oral, dermal, and intraperitoneal) and subchronic repeated-dose studies in mammalian species. Subchronic 3-month no-observed-adverse-effect levels (NOAELs) were identified at 100 mg/kg/day (dermal rabbit) and 1000 mg/kg/day (oral rat OECD 408 study), the highest doses tested, respectively. Ensulizole is considered non-genotoxic, based on negative in vitro studies. No in vivo genotoxicity or long-term carcinogenicity studies were identified. Carcinogenicity risk is not expected based on the negative genotoxicity data, empirical evidence from repeated-dose toxicity and developmental toxicity studies, and the absence of effects on the androgen, estrogen, thyroid, immune, developmental, or reproductive systems. Based on the selected rat subchronic NOAEL of 1000 mg/kg/day and conservative assumptions for estimating the systemic exposure dose (SED) from the application of sunscreen products, margins of safety (defined as NOAEL/SED) >100 were obtained for ensulizole. Therefore, the available data show that ensulizole does not pose risks to human health when used in sunscreen products at concentrations up to 4%, the permitted maximum usage level in the United States, Canada, and Australia.