Perinatal toxicity of maneb, ethylene thiourea, and ethylenebisisothiocyanate sulfide in rodents

The potential of the fungicide maneb and two of its metabolites, ethylenebisisothiocyanate sulfide (EBIS) and ethylene thiourea (ETU), to induce perinatal toxicity in four species of rodents was investigated. The compounds were admininistered to rats and mice during the period of organogenesis, and ETU was also administered to rats and mice during the period of organogenesis, and ETU was also administered by oral gavage for a similar period to hamsters and guinea pigs. Treatment also continued through the lactational period in groups of rats that were allowed to give birth. Fetuses were examined for signs of toxicity, including terata, and neonates for reflex developement and open-field behavior. Maneb produced hydrocephalus in fetuses in litters of rats receiving 480 mg/kg . d. No fetotoxic effects were noted in litters of rats receiving EBIS at doses at high as 30 mg/kg . d. ETU proved to be a potent teratogen in the rat. Among the effects seen at doses of 40 mg/kg . d or greater were hydrocephalus, encephalocele, kyphosis, and various defects of the digits. Neither maneb (up to 1500 mg/kg . d), ETU (up to 200 mg/kg . d), nor EBIS (up to 200 mg/kg . d) elicited signs of fetal toxicity in the mouse. ETU also failed to result in fetal toxicity when administered to the hamster (100 mg/kg . d) or the guinea pig (100 mg/kg . d). Neither maneb nor EBIS produced significant dose-related alterations in the behavioral development of perinatally exposed rat neonates. At doses that also produced neonatal hydrocephalus, ETU produced significant increases in the open-field activity of the neonates. In addition to the perinatal effects noted above, both maneb and EBIS caused maternal limb paralysis in the rat, an effect not noted in the mouse at much higher doses.