Diethylhexyl phthalate. a widely used plasticizer, was administered to timed-mated Swiss CD-1 mice (F0 generation) on gestational days 0-17. Dietary concentrations of 0%, 0.01%, 0.025%, or 0.05% DEHP resulted in average doses of 0, 19, 48, and 95 mg/kg/day, respectively. DEHP was not added to the diet of P0 animals after gd 17, or to the diet of F1 animals. P0 dams were evaluated for DEHP toxicity (Task 1), and their offspring were evaluated for viability, growth and development (Task 2). At 52-57 days of age, F1 males and females were mated within treatment groups, and the F2a offspring were evaluated for viability and growth through postnatal day 4 (Task 3). Suggestive evidence of an adverse reproductive effect was observed during Task 3 in the first replicate of this investigation. Therefore, F1 animals were rebred across the high-dose and control groups in order to distinguish between potential effects upon each sex (Task 4). The resultant F2b litters were evaluated for viability and growth through pnd 4.
F0 maternal food consumption (g/kg/day) and weight gain during treatment were not influenced by DEHP. Maternal body weight exhibited a dose-related decreasing trend on pnd 4 and 7, but pairwise comparisons of DEHP-exposed groups to the control group were not significant. No other evidence of DEHP toxicity was noted in F0 dams through scheduled sacrifice. DEHP treatment did not affect the number of implantation sites per dam, the % fertile matings, the % pregnancies with live litters on pnd 1, or the % viable litters through pnd 4.
For F1 litters, the % prenatal mortality was significantly increased at the high dose (9.0, 6.0,1.4 and 26.4% per litter for the control through high-dose groups, respectively), and a concomitant decrease in live litter size on pnd 1 was also observed (10.9, 11.5, 10.8 and 8.5 live pups per litter, respectively). During the neonatal period (pnd 1-4), the percentage of viable pups was significantly decreased at 0.05% DEHP. During the postnatal period (pnd 4-169), minor reductions in F1 female body weight were observed during Task 3. No other effects of DEHP were observed upon growth, viability, age at acquisition of developmental landmarks (i.e., incisor eruption, wire grasping, eye opening, testes descent or vaginal opening), or spontaneous locomotor activity on pnd 14, 21 or 50.
No adverse effects were observed upon the reproductive performance of the F1 generation, except for a reduction of F2a live litter size at 0.05% DEHP in the first study replicate. The growth and viability of the F2a and F2b litters through pnd 4 were unaffected by treatment. Reproductive organs of F1 males and females did not differ in weight between the high-dose and control groups, nor were any treatment-related histopathologic findings revealed.
In summary, F0 females were exposed to DEHP (0%, 0.01%, 0.025% and 0.050%) in the diet on gd 0-17. No adverse effects were observed at 0.01% DEHP (19 mg/kg/day) or at 0.025S DEHP (48 mg/kg/day) except for minor, transient decreases in F1 female weight during Task 3. At 0.05% (95 mg/kg/day), indications of F0 maternal toxicity were minimal. Pre- and early postnatal (pnd 1-4) mortality of the F1 offspring were significantly increased at the high dose, and a transient reduction of F1 female body weight was observed during Task 3. Despite the presence of this developmental toxicity at 0.05X, no further residual or delayed effects were observed upon the growth, viability, development or reproductive performance of the F1 generation between pnd 4-169.