Bendectin, an anti-nausea drug used for women in the first trimester of pregnancy, was tested for teratogenicity following maternal exposure. Timed-pregnant Sprague-Dawley dams, 33-37 per group, were dosed by gavage on gestational days (gd) 6-15 with 0, 200, 500, 800 mg/kg/day BEN in distilled water. Nitrofen (50.0 mg/kg/day) in corn oil was used as a positive control. The suggestion of limb defects in women taking this drug focused special attention on skeletal development. All fetal carcasses were cleared with KOH and stained with Alizarin Red S (a stain for ossified bone). The entire skeleton was examined, with special attention to limb and vertebral development.
There were seven maternal deaths at 800 mg/kg/day (17.5% mortality); all other dams survived until scheduled sacrifice on gd 20. A significant dose-response trend for reduction in maternal body weight was observed on gd 11, 15, and 20, but not on gd 0 or 6, with values from the 500 and 800 dose groups significantly lower than in controls. There was also a significant downward trend for maternal weight gain and gravid uterine weight in the 500 and 800mg/kg/day dose groups; whereas, relative liver weight exhibited a significant upward trend. Both food and water consumption were decreased at 800 mg/kg/day while only food intake was reduced at 500 mg/kg/day. There were no significant differences among the dose groups for the number of corpora lutea per dam. The number of implantation sites per litter was significantly reduced in the 500 mg/kg/day group.
The percent resorptions, nonlive (dead plus resorbed), and affected (nonlive plus malformed) fetuses per litter were significantly higher than control values in the 800 mg/kg/day dose group. The number of live fetuses per litter was reduced in the 500 and 800 mg/kg/day treatment groups. Average fetal body weight per litter (separated by sex) exhibited a significant downward trend with significant values at 500 and 800 mg/kg/day. Since the possibility of an association between Bendectin usage and limb reduction deformities has been suggested, ossification in fetal limbs was examined in this study. Reduced numbers of ossification centers per fetus per litter, but with no associated changes in gross limb morphology, were seen in fetal metacarpals at the high dose and phalanges (cranial limbs) at 500 and 800 mg/kg/day doses. The degree of ossification in the caudal fetal limbs was unaffected by treatment. The mean number of ossified caudal vertebrae per fetus also exhibited a significant downward trend across dose groups with values from all BEN exposed groups significantly lower than controls. The number of litters with skeletal malformations (predominantly short rib) in the high dose group was significantly greater than control values. There were no treatment-related increases in the incidence of external or visceral malformations. Nitrofen produced malformations in 148 out of 176 fetuses; 85% of the fetuses per litter were malformed. The predominant malformation was diaphragmatic hernia (73.3%).
In conclusion, administration of 800 mg/kg/day of Bendectin in distilled water by gavage to pregnant rats during organogenesis produced clear indications of maternal and fetal toxicity and a significant increase in the number of litters with one or more malformed fetuses. Maternal and fetal toxicity, but no increase in the incidence of malformations, were seen at the 500 mg/kg/day dose. Evidence of fetal toxicity (delayed ossification of caudal vertebrae), but no increase in the incidence of malformations or maternal toxicity was observed at the 200 mg/kg/day dose.