The developmental toxicity of ethylene glycol diethyl ether in mice and rabbits

Timed-pregnant CD-1 outbred Albino Swiss mice and New Zealand White rabbits were dosed by gavage with ethylene glycol diethyl ether (EGdiEE) in distilled water during major organogenesis. Mice were dosed on Gestational Days (gd) 6 through 15 (0, 50, 150, 500, or 1000 mg/kg/day) and rabbits on gd 6 through 19 (0, 25, 50, or 100 mg/kg/day). Maternal clinical status was monitored daily during treatment. At termination (gd 17, mice; gd 30, rabbits), confirmed-pregnant females (22-24 per group, mice; 26-32 per group, rabbits) were evaluated for clinical status and gestational outcome; each live fetus was examined for external, visceral, and skeletal malformations. In mice, no maternal mortality was observed, but maternal body weight gain during gestation and treatment, and at termination was reduced at 1000 mg/kg/day. The reduction of maternal body weight gain during gestation was secondary to embryo/fetal toxicity, i.e., reduced gravid uterine weight as a consequence of decreased litter size and fetal weight. The no-observed adverse effect level (NOAEL) for developmental toxicity was 50 mg/kg/day. At greater than or equal to 150 mg/kg/day the number of litters of mice with malformed fetuses was increased. At greater than or equal to 500 mg/kg/day fetal body weight was reduced, and malformation incidence was significantly increased. Exencephaly and fused ribs were observed most often. In rabbits, maternal body weight was unaffected by treatment even though 6% maternal mortality was observed at 100 mg/kg/day. The developmental NOAEL was 25 mg/kg/day. Malformations were increased at greater than or equal to 50 mg/kg/day; short tail, small spleen, fused sternebrae, and fused rib cartilage were observed most often. In summary, oral administration of EGdiEE to mice and rabbits during organogenesis produced profound adverse developmental effects even in the absence of significant maternal toxicity. Developmental effects in rabbits were more varied.