Evaluation of the dermal subchronic toxicity of phenoxyethyl isobutyrate in the rat

Abstract

Phenoxyethyl isobutyrate (PEIB) is a fragrance and food ingredient that has been granted GRAS status and approved by the FDA for food use. The present studies investigated the dermal absorption parameters and subchronic toxicity of PEIB. For the absorption, distribution and elimination study, Sprague–Dawley rats received a dermal application of 2-[ring U 14C]-PEIB under occlusion for 6 h. PEIB was diluted in diethyl phthalate (DEP) to administer, a total application volume of 2 ml/kg, concentrations of 0.5, 5 and 50% (≅10, 100 and 1000 mg PEIB/kgBW). Approximately 61–69% of the applied dose was recovered from the dressing and skin surface washing procedure performed after 6-h exposure. By 72 h post dose, systemic elimination of radioactivity was ≅18 to 19% of the absorbed dose via the urine with small amounts also found in the feces (<1.0%). Terminal (72 h) tissue analysis showed that 0.35–0.72% of the applied dose of radioactivity was retained in the carcass with low levels (⩽0.03%) measured also in the liver, kidney and gastrointestinal tract. Plasma levels increased in a dose-related manner, with concentrations equal to 0.02, 0.2 and 2.0 μg equiv/ml from low to high dose, respectively. The total recovery for these studies ranged from 92.2 to 96.2% of the dermally applied radioisotope. In a 13-week subchronic rat toxicity study, daily dermal applications of PEIB were made under occlusion for 6 h. All groups were dosed at a constant 2 ml/kgBW volume of PEIB in the DEP vehicle at concentrations calculated to administer 0, 100, 300 or 1000 mg PEIB/kgBW/day. Clinical observations, assessments of skin irritation, hematology, and blood chemistry, necropsy, and gross and histopathologic evaluation of tissues demonstrated no treatment-related effects. The local skin irritation and systemic toxicity no-observed-effect-levels (NOELs) for PEIB in this study were determined to be >1000 mg/kgBW/day.