1,4-Butanediol was evaluated for developmental toxicity due to its widespread use in chemical manufacturing, its structural similarity to ethylene glycol (a developmental toxicant in rodents) and its potential pharmaceutical uses. 1,4-Butanediol (0, 100, 300 or 600 mg/kg/day ) in aqueous solution was administered by gavage on gestational days 6 through 15 to timed-pregnant Swiss albino (CD-1 ) mice (28-32 per group). Maternal body weights, food and water consumption, and clinical signs were monitored at regular intervals throughout gestation. At termination (gd 17), the number of resorptions, and dead or live fetuses were recorded. Live or dead fetuses were weighed. Live fetuses were sexed and examined for external, visceral and skeletal malformations.
No maternal deaths occurred in this study. The low dose (100 mg/kg/day ) produced no significant maternal effects. In contrast, acute symptoms of intoxication (hypoactivity, immobility, loss of righting reflex, and/or prone posture) were observed after daily administration of 300 or 600 mg/kg/day 1,4-butanediol. Symptoms of intoxication resolved within 4 hours after each treatment. and tolerance did not appear to develop across ten days of treatment. Other expressions of maternal toxicity included significant reductions of body weight on gd 12 and 17 (mid dose) or gd 9-17 (high dose). Maternal body weight gains were significantly reduced in the mid- and high-dose groups as follows: weight gain during treatment (gd 6 to 15), weight gain during gestation (gd 0 to 17), and gestational weight gain corrected for gravid uterine weight. Mid and high-dose dams also showed significantly reduced food intake (g/kg/day) throughout both the treatment period (gd 6 to 15) and the post-treatment period (gd 15 to 17). Maternal water intake was not affected. Absolute maternal liver weight was decreased at the mid- and high-doses and absolute maternal kidney weight was decreased at the high dose. Relative maternal liver and kidney weights (% body weight on gd 17) were unaffected by 1,4-butanediol exposure.
Developmental toxicity was expressed primarily as a significant reduction in live fetal body weight per litter (92% and 83% of controls in the mid and high-dose groups, respectively). While the incidence of resorptions was comparable across groups, a decreasing trend was observed for the percent late fetal deaths per litter, and the percentage of litters with one or more late fetal deaths was actually lower at 300 and 600 mg/kg/day . The incidence of fetuses with external (gross) or visceral malformations was comparable across groups, but an increasing trend was observed for the percent fetuses with skeletal malformations per litter and for the percentage of litters with one or more skeletally malformed fetuses. The most frequently observed skeletal defects observed in the high dose group were fused, missing or branched ribs and fused thoracic vertebrae (fused centra or arches).
In summary, 100 mg/kg/day 1,4-butanediol was a no-observed-adverse-effect-level for maternal and developmental toxicity. Dams exposed to 300 or 600 mg/kg/day exhibited sedation, decreased food intake during and after treatment and decreased body weight gain. A trend toward decreased late fetal death was observed, but the cumulative incidence of post-implantation mortality (resorptions plus late fetal deaths) was not altered by exposure to 1,4-butanediol. Developmental toxicity was expressed primarily as decreased fetal body weight at 300 and 600 mg/kg/day, with a trend toward increased skeletal defects at 600 mg/kg/day.