NTP Developmental and Reproductive Toxicity Technical Report on the Modified One-Generation Study of 2-Ethylhexyl p-Methoxycinnamate (CASRN 5466-77-3) Administered in Feed to Sprague Dawley (Hsd:Sprague Dawley® SD®) Rats with Prenatal, Reproductive Performance, and Subchronic Assessments in F1 Offspring

Abstract

2-Ethylhexyl p-methoxycinnamate (EHMC), also known as octinoxate and octyl methoxycinnamate, is a common component of sunscreens, cosmetics, and personal care products. Mechanistic screening studies have purported that EHMC, and its metabolites, are capable of activating the estrogen receptor to varying degrees. The objective of this study was to characterize the potential for EHMC to adversely affect any phase of rat development, maturation, and ability to reproduce. The potential for EHMC to induce subchronic toxicity in the F1 generation, to adversely affect the ability of the F1 generation to reproduce viable F2 offspring, and to adversely affect the F2 embryo-fetal development was assessed in Sprague Dawley (Hsd:Sprague Dawley® SD®) rats administered EHMC in 5K96 feed, a diet low in phytoestrogens, using the National Toxicology Program modified one-generation (MOG) study design. The dietary route of administration was selected to approximate continual exposure in group-housed animals. EHMC exposure via the diet, rather than topical application, was selected for this study to sustain internal exposure; if applied topically, the internal dose would have been influenced by intra- and interanimal grooming behavior. Exposure concentration selection for the MOG study was based on a dose range-finding study in which time-mated rats were exposed to 0, 2,250, 5,000, 10,000, or 20,000 ppm EHMC in the diet from gestation day (GD) 6 through lactation day (LD) 28. Dams exposed to 20,000 ppm displayed significantly decreased mean body weights on GD 21 and body weight gain from GD 6 through GD 21. Dams exposed to 20,000 ppm displayed lower live litter size, and pups in this group displayed significantly decreased PND 1 weights and lower postnatal viability resulting in the group being removed from study on postnatal day (PND) 14. Pup body weights of the 10,000 ppm group were also lower than those in the control group. Therefore, exposure concentrations of 0, 1,000, 3,000, and 6,000 ppm were selected for the subsequent MOG study. Test article consumption was exposure concentration-proportional. EHMC intake for F0 females in the 2,250, 5,000, 10,000, and 20,000 ppm groups, based on feed consumption and dietary concentrations for GD 6 through GD 21, was approximately 161, 365, 714, and 1,841 mg EHMC/kg body weight/day (mg/kg/day), respectively; from LD 1 through LD 14, EHMC intake was approximately 410, 925, and 1,615 mg/kg/day for the 2,250, 5,000, and 10,000 ppm groups, respectively.