Developmental toxic effect after subcutaneous injections of methadone in Charles River CD-1 mice.
Four groups of Charles River CD-1 pregnant mouse dams were dosed subcutaneously daily with 5, 10, 20, and 28 mg/kg of methadone during day 6 to 15 of gestation. Prenatal and postnatal studies were conducted in the offspring and mouse dams. Caesarean sections were performed on some of the females from each group on day 19 of gestation and fetuses evaluated by routine teratologic methods. All females remaining were allowed to deliver, and several postnatal signs were recorded from the pups during the lactation period. Maternal mean body weight gains and food consumption were reduced. No apparent alteration in the food efficiency index was detected, thus maternal malnutrition may not have been a factor in producing adverse effects on offspring. The incidence of external and visceral malformations was neither dose-related nor significantly different from those of the controls. However, administration of methadone decreased ossification of the digits, sternum, and skull of the offspring. Adverse effects of methadone on reproduction were apparent at doses of 20 mg/kg/day and above, and characterized by an increase in resorptions and a decrease in the number of live fetuses per litter. Methadone was found not to be teratogenic to the CD-1 mice. However, adverse effects on intrauterine growth, fetal ossification, neonatal growth, development, and survival rate were seen among weaned pups.