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

• Published in: Reproductive toxicology (Elmsford, N.Y.) N.Y.), 2013-01, Vol.35, p.56-69
• Main Authors: Clewell, Rebecca A., Sochaski, Mark, Edwards, Kendra, Creasy, Dianne M., Willson, Gabrielle, Andersen, Melvin E.
• Format: Article
• Language: English
• Subjects: Amniotic Fluid - metabolism; Animals; Developmental effects; DiNP; Endocrine Disruptors - blood; Endocrine Disruptors - pharmacokinetics; Endocrine Disruptors - toxicity; Female; Fetus - drug effects; Fetus - physiology; Gestation; Liver - metabolism; Male; Metabolism; No-Observed-Adverse-Effect Level; Phthalate; Phthalic Acids - blood; Phthalic Acids - pharmacokinetics; Phthalic Acids - toxicity; Placenta - metabolism; Pregnancy; Rats; Rats, Sprague-Dawley; Sexual Development - drug effects; Testis - drug effects; Testis - metabolism; Testis - pathology; Testosterone; Testosterone - metabolism; Tissue Distribution
• ISSN: 0890-6238; 1873-1708
• DOI: 10.1016/j.reprotox.2012.07.001

► Metabolite kinetics and fetal effects were measured after diisononyl phthalate (DiNP) doses of 50, 250, or 750mg/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 2h post-dosing with 250 and 750mg DiNP/kg/day. ► Multinucleated gonocytes were increased with 250 and 750mg/kg/day DiNP. Pregnant Sprague-Dawley rats received 50, 250, and 500mg/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 750mg/kg/day. Testosterone concentration in the fetal testes was reduced at 250 and 750mg/kg/day. Multinucleated germ cells were increased in the testes of rats at 250 and 750mg/kg/day. The no observed effect level (NOEL) for this study was 50mg/kg/day based on increased MNGs and reduced testes testosterone concentration in the fetal rat.