Codeine: developmental toxicity in hamsters and mice.
Timed-pregnant LVG Syrian hamsters and Swiss CD-1 mice were dosed orally twice daily (b.i.d.) with codeine in water on Gestational Days (gd) 5-13 (0, 10, 50, or 150 mg/kg, b.i.d.--hamsters) or 6-15 (0, 37.5, 75, 150, or 300 mg/kg, b.i.d.--mice). Dams were necropsied on 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 the pregnant mice in the high-dose group died. Maternal weight gain (gestational and treatment periods) and gravid uterine weights were significantly depressed in hamsters (150 mg/kg, b.i.d.) and in mice (300 mg/kg, b.i.d.). However, the corrected weight gain for both species, although decreased, was not significantly different from that of the controls. In both species, maternal liver weights (relative) were significantly increased in the high-dose groups. There were increases in the percentage resorptions per pregnant dam and in the proportion of litters with 100% resorptions in the high-dose groups of both species. Considering only live litters, the number of live fetuses per litter and the sex ratio were unaffected in both species. Mean fetal body weights were also significantly decreased in the 50 and 150 mg/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 were 50 (hamsters) and 150 (mice) mg/kg, b.i.d. The predominant structural malformation in hamsters was meningoencephalocele (high-dose group only), affecting 3% of fetuses and 19% of litters (neither statistically significant). Codeine did not induce any increase in structural malformations in mice. Thus, codeine produced developmental toxicity (as indicated by decreased fetal body weight) at doses below those producing maternal toxicity in both hamsters and mice. In the hamster, the more sensitive species to codeine developmental toxicity, effects were observed at a total daily dose of 100 mg/kg, which is only 11 times the maximum human therapeutic oral dose.
Williams
J
J
Developmental and Reproductive Toxicology Group, National Institute of Environmental Health Sciences, Research Triangle Park, North Carolina 27709.
Price
C J
CJ
Sleet
R B
RB
George
J D
JD
Marr
M C
MC
Kimmel
C A
CA
Morrissey
R E
RE
D000014:Abnormalities, Drug-Induced / Q000473:pathology; D000284:Administration, Oral; D000818:Animals; D001835:Body Weight / Q000187:drug effects; D003061:Codeine / Q000633:toxicity*; D006224:Cricetinae; D005260:Female; D005333:Fetus / Q000187:drug effects; D005865:Gestational Age; D008297:Male; D008647:Mesocricetus; D051379:Mice; D008813:Mice, Inbred ICR; D009929:Organ Size / Q000187:drug effects; D011247:Pregnancy; D011897:Random Allocation; D013723:Teratogens
D013723:Teratogens; D003061:Codeine