Teratologic evaluation of the magnesium sulfate adduct of [2,2'-dithio-bis-(pyridine-1-oxide)] in swine and rats

Abstract

The magnesium sulfate adduct of [2,2'-dithio-bis-(pyridine-1-oxide)](MDS) was applied dermally (Study I, 30, 100, and 300 mg/kg; Study II, 10 and 30 mg/kg) to Yorkshire swine (Days 8–32 of gestation, 8-hr contact time per day) and given orally (3, 10, 30, and 100 mg/kg) to Charles River CD rats (Days 6–15 of gestation). Piglets obtained by Caesarian section on gestation Day 100 were examined for external, soft tissue, and skeletal abnormalities; rats, when taken by Caesarian section on Day 20 of gestation, were examined for external, soft tissue, and skeletal abnormalities. Control animals were evaluated concurrently. In Study I, the mean number of viable pig fetuses was significantly reduced in the 30 and 100 mg/kg groups, but was normal in the high (300 mg/kg) dose group. In Study II, the number of resorption sites was increased in swine at both dose levels but was largest at the lower dose (10 mg/kg). Skeletal examination revealed 9/10 fetuses from one litter in Study I (30 mg/kg) with multiple malformations. Fetuses with “crooked” tails were obtained from some sows in each MDS treatment group in Study I. Only one fetus from a sow given 10 mg/kg of MDS in Study II had a crooked tail. The crooked tails appeared to be drug induced and the incidence dose related when the results from both studies were considered together. In the rat, maternal weight gain among animals given 30 and 100 mg/kg of MDS was significantly reduced. The mean number of resorption sites was increased and the mean number of viable fetuses was decreased in the group given 100 mg/kg. An increased incidence of skeletal anomalies (bifurcated and fused ribs, asymmetrical sternum) was noted in fetuses from dams given 30 and 100 mg/kg, but was not observed in fetuses from dams given either 3 or 10 mg/kg of MDS. In summary, there was evidence of a teratogenic effect in both species. This finding is of questionable significance because the tail anomaly in swine may not have a counterpart in man and the sternal and rib alterations in rats occurred only at doses which were toxic to the dams.