Ethylene glycol, a widely used industrial chemical, was administered by gavage to pregnant CD rats (F0 generation) on gestational days 6 through 20 at doses of 0, 250, 1250 or 2250 mg/kg/day (i.e., 0, 4. 20 or 36 mmol/kg/day, respectively). The offspring (F1 generation) were fostered to untreated mothers on postnatal day (gd) 1 and evaluated for postnatal growth and viability, developmental landmarks, sexual maturation, locomotor activity and performance of a complex learning task. Maternal body weight (gd 20) and weight gain during treatment and gestation were negatively influenced by 2250 mg EG/kg/day, but similar effects were not found at lower doses. The gestational period was significantly longer in dams exposed to 1250 or 2250 mg/kg/day EG. On pnd 1, absolute and relative maternal kidney weights and postpartum uterine weight were decreased in the high- dose group. No differences among groups were noted on pnd 1 for maternal body weight, maternal liver weight, or number of implantation sites per dam. Evidence of treatment-related renal pathology was noted in 27% (4/15) of females examined in the mid- dose group and in 33% (5/15) of females examined in the high-dose group, as compared to a 0% (0/18) incidence of similar lesions in the control group. Per the study protocol, no other maternal organs were examined microscopically.
Live litter size and neonatal pup body weight were decreased, and cumulative mortality of offspring through pnd 4 (expressed as a percent of implantation sites) was increased in the high-dose group. There was no effect of treatment on the age of incisor eruption or development of external genitalia (i.e., vaginal opening or testes descent). While there was an initial difference between groups in the percentage of pups per litter with wire grasping skills on pnd 9 (9%, 18%, 40% and 37% for control through high-dose groups, respectively), by pnd 10, the control group contained 70% pups per litter with wire grasping skills, and no differences among groups were noted on pnd 10-15. Thus, no adverse effects of prenatal ethylene glycol upon postnatal acquisition of wire grasping skills were observed. There were no statistically significant effects of treatment on exploratory behavior (preweaning) or performance on a visual discrimination task (~12-24 weeks of age). A significant increase in skeletal malformations was observed on pnd 22 for pups in the 2250 mg EG/kg/day group. Hydrocephalus was observed in the 250 and 2250 mg/kg/day groups, but not at 1250 mg/kg/day, suggesting that the incidence was related to treatment only at the high dose. Relative kidney weights tended to be lower than controls on pnd 63 at the mid- and high-dose levels. However, no treatment-related pathology was noted upon microscopic examination of the liver or kidneys collected from F1 pups at scheduled sacrifices on pnd 4, 22 or 63.
In summary, administration of ethylene glycol to timed-mated CD rats on gd 6 through 20 resulted in no observed toxicity at 250 mg/kg/day. At 1250 mg/kg/day, the gestational period was lengthened, and maternal renal pathology was noted, but no adverse developmental effects were observed. At 2250 mg/kg/day, reduction of maternal body weight, weight gain, kidney weight and postpartum uterine weight were observed. In addition, gestation was lengthened and maternal renal pathology was present. Developmental toxicity at 2250 mg/kg/day included reduced pup body weight, reduced viability and increased malformation incidence (primarily hydrocephaly and abnormalities of the axial skeleton), but adverse effects upon other indices of postnatal development were not observed.