Diethylene glycol dimethyl ether a widely used organic solvent, was evaluated for potential developmental toxicity. DYME (0, 62.5, 125, 250 or 500 mg/kg/day) was administered to CD-1 mice by gavage (by mouth) on gestational days 6-15. Mice were monitored daily during treatment for evidence of maternal toxicity and were sacrificed on gd 17 (20-24 confirmed pregnancies per group). Resorptions were noted and live fetuses were examined for body weight, external malformations, visceral malformations, and sex. One-half of the fetal carcasses were decapitated; heads were fixed in Bouin's solution and internal structures examined using a free hand section technique. All fetal carcasses were stained for evaluation of skeletal development.
DYME-treated dams failed to exhibit treatment-related clinical signs, death, or differences from control in corrected maternal body weight gain (i.e., gestational weight gain minus gravid uterine weight) or relative maternal liver weight. However, intact maternal body weight (i.e., including gravid uterine weight) was reduced at 250 and 500 mg DYME/kg/day on gd 15 and 17, as were maternal weight gain during treatment and gestation. Gravid uterine weight in DYME-treated groups was significantly reduced at all doses in a dose-related manner. There were dose-related and significant increases at 250 and 500 mg/kg/day in the percentage of nonlive implants per litter (4.88%, 8.41%, 7.05%, 12.02% and 50.41% in the vehicle control through high-dose groups, respectively), as well as the percentage of adversely affected implants per litter (5.25%, 8.41%, 9.35%, 32.29% and 96.93% nonlive or malformed in the vehicle control through high-dose groups, respectively).
The mean live litter size was significantly less than control at 500 mg/kg/day and was marginally reduced at all lower dose levels. The average fetal body weight per litter was significantly reduced at and above 125 mg DYME/kg/day. Examination of fetuses for anatomical malformations revealed a dose-dependent trend toward an increased percentage of malformed live fetuses per litter, and the difference from control was statistically significant in the 250 and 500 mg DYME/kg/day groups. The mean percent malformed live fetuses per litter was 0.37%, 0.00%, 2.47%, 23.86% and 95.82% in the vehicle through high-dose groups, respectively. The proportion of litters with gross, visceral or skeletal malformations was increased at the high dose, and the proportion of litters with gross or skeletal malformations was increased in the 250 mg/kg/day group. The types of malformations observed in the present study were quite diverse. Major malformations affected primarily the development of the neural tube, limbs and digits, craniofacial structures, abdominal wall, cardiovascular system, urogenital organs, and both the axial and appendicular skeleton. The two most frequently observed malformations were fused ribs in 74% of high dose fetuses and exencephaly in 54% of high dose fetuses.
In summary, exposure of timed-pregnant CD-1 mice to diethylene glycol dimethyl ether throughout major organogenesis produced no notable evidence of maternal toxicity. The lowest dose level, 62.5 mg/kg/day, appeared to be a no observed effect level for indices of fetal development. At higher doses, DYME produced profound adverse effects upon fetal growth ( greater than or equal to 125 mg/kg/day), fetal viability (greater than or equal to 250 mg/kg/day), and fetal morphological development (greater than or equal to 250 mg/kg/day). At the highest dose, all 23 litters contained at least one malformed fetus compared to 1 of 21 control litters, and 94% of the high-dose fetuses were malformed compared to 0.35% of the fetuses in the control group. Thus, diethylene glycol dimethyl ether posed an extreme degree of risk to the embryo or fetus at dose levels which did not cause observable toxicity to the maternal organism.