Effects of di-n-butyl phthalate (DBP) on male reproductive development in the rat: Implications for human risk assessment

The National Toxicology Program (NTP) conducted a continuous breeding study in SD rats with di-n-butyl phthalate (DBP) given via the diet at dose leve ls of up to 650 mg/kg/day. In the parental generation effects on reproducti on were modest (small decreases in litter size and pup weight following tre atment). However, the FI male offspring had marked decreases in fertility ( at 650 mg/kg/day), with reduced sperm counts and reproductive tract malform ations on reaching adulthood. A no-observed-adverse-effect level (NOAEL) wa s not established for the study [lowest-observed-adverse-effect level (LOAE L) 66mg/kg/day]. In a study conducted at CIIT, the majority of these advers e changes could be reproduced over a similar dose range, but with a much sh orter dosing regimen covering a critical window of development (gestation d ays 12-20). A default risk assessment for DBP indicates a reference dose (R fD) of 66 mu g/kg/day, based on a LOAEL of 66 mg/kg/day and default factors of 10 for inter-species and inter-individual differences and the lack of a NOAEL. Human exposure data would indicate worst-case scenarios to infants (via formula) in the dose range of the RfD. A default risk assessment appea rs to be inappropriate since rodents, unlike primates, metabolize phthalate diesters (including DBP) to monoesters extensively in the gut following or al administration. It is believed that the monoester is the active principl e for induction of reproductive and developmental toxicity of specific phth alate esters. Thus, if humans produce very low levels of the monoester from an environmental exposure to the diester, the likelihood of any reproducti ve or developmental toxicity via the oral route appears extremely remote. ( C) 2000 Elsevier Science Ltd. All rights reserved.