Disposition of diiosononyl phthalate and its effects on sexual development of the male fetus following repeated dosing in pregnant rats

Pregnant Sprague-Dawley rats received 50, 250, and 500 mg/kg/day diisononyl phthalate (DiNP) from GD 12 to 19 via corn oil gavage to study the dose response for effects on fetal male rat sexual development as well as metabolite disposition in the dam and fetus. Monoisononyl phthalate (MiNP), mono(carboxy-isooctyl) phthalate (MCiOP), mono(hydroxyl-isononyl) phthalate (MHiNP), mono(oxo-isononyl) phthalate (MOiNP), and monoisononyl phthalate glucuronide (MiNP-G) were found in all measured tissues. MCiOP was the major metabolite, followed in decreasing order by MiNP, MHiNP, MOiNP, and MiNP-G. Percentage of dose absorbed decreased at 750 mg/kg/day. Testosterone concentration in the fetal testes was reduced at 250 and 750 mg/kg/day. Multinucleated germ cells were increased in the testes of rats at 250 and 750 mg/kg/day. The no observed effect level (NOEL) for this study was 50 mg/kg/day based on increased MNGs and reduced testes testosterone concentration in the fetal rat.

► Metabolite kinetics and fetal effects were measured after diisononyl phthalate (DiNP) doses of 50, 250, or 750 mg/kg/day in pregnant rats.
► All five measured metabolites were present in maternal and fetal tissues and serum.
► Monocarboxy-isooctyl phthalate was the major metabolite in maternal serum, urine and fetal serum.
► Testes testosterone was reduced in male fetuses at 2 h post-dosing with 250 and 750 mg DiNP/kg/day.
► Multinucleated gonocytes were increased with 250 and 750 mg/kg/day DiNP.