AN ASSESSMENT OF IN VIVO ESTROGENIC ACTIVITY OF BUTYL BENZYL PHTHALATE AND ITS PRINCIPAL MAMMALIAN METABOLITES

Abstract

Butyl benzyl phthalate (BBP) has been reported to exhibit weak estrogenic activity in a number of in vitro assays. The monoester metabolites of BBP have been shown to lack estrogenic activity in vitro. This work has evaluated the estrogenic activity of BBP in vivo by examining the ability of BBP and its primary monoester metabolites to stimulate uterine growth in sexually immature female rats. BBP has been administered by both oral and subcutaneous (sc) routes to address the possible differences in systemic exposure patterns and to analyze the pharmacokinetics. Groups of 6 immature female rats were administered BBP or its monoester metabolites daily for 3 days at a range of dose levels up to a maximum tolerated dose (MTD). Twenty-four hours after the last dose, the uteri were excised and weighed. Estradiol benzoate (EB, 0.5 1g/animal/day) was administered sc as a positive control. In all experiments, EB administration increased absolute and relative uterine weights by 3.4to 4.0-fold. BBP dosed orally at 56– 2240 mg/kg/day had no effects on absolute or relative uterine weight. Monobutyl phthalate (1–1000 mg/kg/day) or monobenzyl phthalate (50–1000 mg/kg/day) dosed orally did not increase absolute or relative uterine weight, although the latter produced a small decrease at highest dose levels. BBP dosed sc at 0.5– 5000 mg/kg/day had no effects on uterine weight. In a pharmacokinetic study, the levels of BBP and its monoester metabolites were measured in blood, plasma, and urine over a 24-h period following administration of BBP to immature female