Codeine: Developmental Toxicity in Hamsters and Mice

Codeine: Developmental Toxicity in Hamsters and Mice. Williams,J., PRICE, C. J., SLEET, R. B., GEORGE, J. D., MARR, M. C, KIMMEL,C. A., AND MORRISSEY, R. E. (1991). Fundam. Appl. Toxicol. 16,401–413. Timed-pregnant LVG Syrian hamsters and SwissCD-I mice were dosed orally twice daily (b.i.d.) with codeinein water on Gestational Days (gd) 5–13 (0, 10, 50, or150 mg/kg, b.i.d.—hamsters) or 6–15 (0, 37.5, 75,150, or 300 mg/kg, b.i.d.—mice). Dams were necropsiedon gd 14 (hamsters) or 17 (mice), and fetuses were weighed,sexed, and examined for external, visceral, and skeletal malformations.No maternal deaths were observed in hamsters, while 19% of thepregnant mice in the high-dose group died. Maternal weight gain(gestational and treatment periods) and gravid uterine weightswere significantly depressed in hamsters (150 mg/kg, b.i.d.)and in mice (300 mg/kg, b.i.d.). However, the corrected weightgain for both species, although decreased, was not significantlydifferent from that of the controls. In both species, maternalliver weights (relative) were significantly increased in thehigh-dose groups. There were increases in the percentage resorptionsper pregnant dam and in the proportion of litters with 100%resorptions in the high-dose groups of both species. Consideringonly live litters, the number of live fetuses per litter andthe sex ratio were unaffected in both species. Mean fetal bodyweights were also significantly decreased in the 50 and 150mg/kg, b.i.d. (hamsters), and the 150 and 300 mg/kg, b.i.d.(mice), groups. The no-observed-adverse-effect levels (NOAELs)for developmental toxicity were 10 (hamsters) and 75 (mice)mg/kg, b.i.d., whereas the NOAELs for maternal toxicity were50 (hamsters) and 150 (mice) mg/kg, b.i.d. The predominant structuralmalformation in hamsters was meningoencephalocele (high-dosegroup only), affecting 3% of fetuses and 19% of litters (neitherstatistically significant). Codeine did not induce any increasein structural malformations in mice. Thus, codeine produceddevelopmental toxicity (as indicated by decreased fetal bodyweight) at doses below those producing maternal toxicity inboth hamsters and mice. In the hamster, the more sensitive speciesto codeine developmental toxicity, effects were observed ata total daily dose of 100 mg/kg, which is only 11 times themaximum human therapeutic oral dose.