Codeine, a widely used narcotic analgesic, was evaluated for potential developmental toxicity in timed-pregnant LVG hamsters. COD was dissolved in distilled water to provide doses of 0, 10, 50, or 150 mg/kg and administered by gavage twice daily (bid) on gestational days 5 through 13. A positive control study was performed concurrently with the teratology study. Diethylene glycol dimethyl ether, the positive control compound, was administered by gavage at a dose of 400 mg/kg, twice daily.
Maternal viability was not affected by codeine through the dosing period (gd 5 through 13) to sacrifice on gd 14. The predominant clinical sign of toxicity occurring during treatment was weight loss ( greater than or equal to 2.5 g/day) which was mainly exhibited by dams administered 50 and 150 mg/kg, twice daily. Maternal body weight showed a decreasing trend with treatment on gd 8, 11 and 14, and at the high dose was significantly below the control level on gd 11 and 14. Maternal weight gain (gestation, treatment and corrected) and gravid uterine weight exhibited downward trends with treatment. With the exception of corrected weight gain, the values determined for the high dose group were significantly below control values. Relative liver weight (% body weight) exhibited an increasing trend with treatment and was significantly greater than control at 150 mg/kg, twice daily.
Embryo/fetal toxicity occurred In a dose dependent manner. At 10 mg codeine/kg, twice daily, there were no effects on any of the parameters that indicate changes in embryo/fetal viability or growth. The incidence of resorption per litter showed an increasing trend with treatment and at the high dose (37.9%) was significantly greater than the control level (10.5%). Late fetal death occurred only in the 150 mg/kg, twice daily, dose group at a rate of 1.0% per litter which was significantly greater than the control level (0.0%). The number of live fetuses per litter and their sex ratio were not affected by the codeine treatment. The body weights of fetuses from dams exposed to 50 and 150 mg/kg, twice daily, were significantly lower than control weights.
The incidence of malformations per litter showed an increasing trend with treatment which ranged from 0.9% for control to 4.6% for the high dose group. When analyzed by malformation type per litter, i.e. external, visceral or skeletal, no obvious dose-related trends were identified. There was a nonstatistically significant increase in % malformations at the 150 mg/kg, twice daily, dose with meningoencephalocele the predominant observation. Gestational exposure of dams to DYME (400 mg/kg, twice daily, by mouth) produced a wide range of defects at an overall malformation incidence of 33% per litter (1% for control) (DYME results, see Appendix VII).
In conclusion, embryo/fetal development of the LVG hamster was sensitive to codeine administered at a maternally nontoxic dose of 50 mg/kg, twice daily. At that dose, fetal body weight was significantly reduced while all parameters of maternal toxicity indicated no effect. The no observed effect level for codeine-induced developmental toxicity was 10 mg/kg, twice daily. Maternal toxicity was demonstrated in the 150 mg/kg, twice daily, group by significant changes in body and organ weights. The NOEL for codeine-induced maternal toxicity was 50 mg/kg, twice daily.