Triethylene glycol dimethyl ether, a widely distributed industrial chemical, was evaluated for toxic and teratogenic effects in inseminated New Zealand white rabbits. Based on the results of preliminary dose range-finding studies, TGDM was administered by gavage on gestational days 6 through 19 at doses 0, 75, 125, 175, or 250 mg/kg/day. The study was conducted using a three-replicate design.
During TGDM treatment, does exhibited clinical signs of toxicity consisting primarily of lacrimation, alopecia, weight loss, and absence of feces. Exposure to TGDM did not increase maternal mortality. Maternal body weight and gravid uterine weight were significantly reduced at 250 mg/kg/day, whereas maternal weight gain during treatment was significantly depressed at doses of 175 mg/kg/day and above. Relative maternal liver weight was elevated at 250 mg/kg/day.
Prenatal mortality was significantly increased compared to the control group at 250 mg TGDM/kg/day and was primarily due to an increased incidence of resorption of implanted embryos. When all adverse outcomes were considered (resorptions, dead fetuses, and malformed live fetuses), the percent adversely affected implants per litter and percent litters with adversely affected implants was significantly increased compared to the control group at both the 175 and 250 mg/kg/day dose levels. Live litter size tended to be reduced but was not significantly different from controls at any dose level of TGDM. Average fetal body weight was unaffected by treatment. TGDM at doses of 175 and 250 mg/kg/day caused a significant increase in the incidence of malformed fetuses per litter, and in the incidence of litters with malformed fetuses. Male and female fetuses were similarly affected by TGDM treatment.
A significant increase in the number of litters with one or more fetuses with external (gross) and visceral malformations was detected at the 175 and 250 mg/kg/day dose levels. The incidence of skeletal malformations was not significantly elevated by treatment. Malformations noted most frequently in fetuses of normal size included missing toenails with no digital abnormalities, abnormally small spleen, and hydronephrosis. Variations of development that were noteworthy included an abnormal number of papillary muscles (more than 3 or less than 2 attached to the side of a valve), clubbed limbs without skeletal change, and cysts on the reproductive organs of both sexes.
In conclusion, exposure of inseminated NZW rabbits to TGDM (0, 75, 125, or 250 mg/kg/day) by gavage on gestational days 6-19 produced the following results:
- A no effect level for maternal toxicity at 125 mg/kg/day based on body weight and weight gain, and minimal evidence of maternal toxicity at 175 and 250 mg/kg/day as evidenced by relatively small decreases in maternal body weight and weight gain that appeared to be secondary to embryofetal toxicity.
- A no effect level for embryo toxicity at 75 mg/kg/day, an indication of an increase in embryo toxicity at 125 and 175 mg/kg/day, and significant embryo toxicity at 250 mg/kg/day, as reflected in the percent resorptions per litter.
- No clear cut evidence of late fetal toxicity at any dose level, as reflected by fetal body weight.
- A clear cut teratogenic effect at doses of 175 mg/kg/day and above.
Thus, under the conditions of this study, TGDM presented a risk to the conceptus, as evidenced by an increase in prenatal mortality and the incidence of fetal malformations at doses that caused minimal maternal and no fetal toxicity.