Developmental toxicity evaluation of Bendectin in CD rats.
Bendectin, composed of doxylamine succinate and pyridoxine HCl (1:1), is an antinauseant previously prescribed for nausea and vomiting during pregnancy. The present study examined the maternal and developmental effects of Bendectin (0, 200, 500, or 800 mg/kg/day, po) administered to timed-pregnant CD rats (36-41/group) during organogenesis (gestational days [gd] 6-15). At death (gd 20), all live fetuses were examined for external, visceral, and skeletal abnormalities. At 500 and 800 mg/kg/day, maternal toxicity included reduced food consumption during treatment and for the gestation period, increased water consumption in the posttreatment period, reduced weight gain during treatment, and sedation; water consumption was reduced during treatment and for the gestation period, and maternal mortality (17.1%) was observed only at the high dose. Developmental toxicity included reduced prenatal viability (800 mg/kg/day) and reduced fetal body weight/litter (500 and 800 mg/kg/day). In addition, reduced ossification of metacarpals (800 mg/kg/day), phalanges of the forelimbs (500 and 800 mg/kg/day), and of caudal vertebral centra (all doses) was observed. No increase in percent malformed live fetuses/litter was observed. The proportion of litters with one or more malformed fetuses was higher than vehicle controls only at 800 mg/kg/day, with short 13th rib (to which the test species is predisposed) as the predominant observation. By contrast, a positive control agent (nitrofen, 50 mg/kg/day, po, 14 dams) produced 85% malformed fetuses/litter with the predominant malformation being diaphragmatic hernia. In conclusion, the incidence of litters with one or more malformed fetuses was increased only at a dose of Bendectin which produced maternal mortality (17.1%) and other indices of maternal and developmental toxicity (see Discussion).
Tyl
R W
RW
Research Triangle Institute, Research Triangle Park, North Carolina 27709.
Price
C J
CJ
Marr
M C
MC
Kimmel
C A
CA
D000014:Abnormalities, Drug-Induced; D000818:Animals; D000932:Antiemetics / Q000633:toxicity*; D003509:Cyclohexanecarboxylic Acids / Q000633:toxicity*; D004025:Dicyclomine / Q000633:toxicity*; D004319:Doxylamine / Q000633:toxicity*; D004327:Drinking Behavior / Q000187:drug effects; D004338:Drug Combinations / Q000633:toxicity; D005247:Feeding Behavior / Q000187:drug effects; D005260:Female; D008098:Litter Size; D008297:Male; D011247:Pregnancy; D011270:Pregnancy, Animal / Q000187:drug effects*; D011725:Pyridines / Q000633:toxicity*; D011736:Pyridoxine / Q000633:toxicity*; D051381:Rats; D011919:Rats, Inbred Strains; D012016:Reference Values; D013723:Teratogens
D000932:Antiemetics; D003509:Cyclohexanecarboxylic Acids; D004338:Drug Combinations; D011725:Pyridines; D013723:Teratogens; C004454:dicyclomine, doxylamine, pyridoxine drug combination; D004025:Dicyclomine; D004319:Doxylamine; D011736:Pyridoxine