Reproduction and teratology studies on hexamethylmelamine in the rat and rabbit

Abstract

The antineoplastic drug hexamethylmelamine (HMM) was evaluated for effects on reproduction and postnatal development in the rat and on embryonal and fetal development in the rat and rabbit. Daily po treatment of male rats for 62 days with doses of 0, 10, 20, or 40 mg/kg/day resulted in testicular atrophy, reduced fertility, and a possible dominant lethal mutagenic effect at the higher two dose levels. Alterations in morphology and function of the beta cells of the pancreatic islets were observed after treatment of males for more than 28 days with 20 or 40 mg/kg/day. The same dose levels administered to female rats for 14 days prior to breeding and through Day 13 or 20 of gestation had no adverse effects on fertility, but the highest dose was embryocidal and postnatal survival was decreased at both the 20- and 40-mg/kg/day dose levels. Similar effects on postnatal survival were observed when the drug was administered by gavage to rats during the last week of gestation and throughout the lactation period. Treatment of pregnant rats throughout organogenesis (Days 6 to 15) or for 4-day intervals during organogenesis (Days 6 to 9, 9 to 12, or 12 to 15) with po doses ranging from 20 to 80 mg/kg/day resulted in decreased body weight gain and food consumption, an increased resorption rate in dams receiving 80 mg/kg/day on Days 6 to 9, and decreased fetal weights at all dose levels and most treatment intervals. The incidence of minor skeletal defects was increased among litters of HMM-treated groups. Major fetal malformations were limited in number but were considered treatment related. Treatment of pregnant rabbits po on Days 6 to 18 of gestation with doses of 0, 20, 40, or 60 mg/kg/day did not result in an embryocidal or teratogenic effect. Treatment with 60 mg/kg/day did, however, result in decreased kit weights, indicating a mild embryo-fetotoxic effect.