Evaluation of teratogenic potential codeine sulfate in CF-1 mice

The most prominent defect of codeine sulfate, 100 mg/kg sc, was delayed ossification of the supraoccipital bone, paws, xiphoid, and sternebrae as well as other sternebral defects such as checkerboard sternebrae and polysternebrae. Although these anomalies were similar to the minor defects seen in the fetuses of morphine sulfate-treated mice, the major anomalies such as exencephaly, cryptorchid testes, and rib and vertebral fusions produced by morphine were not present in the fetuses of mice challenged with codeine. Thus, codeine sulfate appears to be less teratogenic than morphine sulfate. A review of the incidences of the various defects in mice treated on a single day with codeine showed that there was a range of days on which the mouse fetus was susceptible to codeine's teratogenic effects, with the most critical days of gestation being Days 8-10. Furthermore, a comparison of the defects that occurred in those treated on both Days 8 and 9 with the defects that occurred in those treated on a single day of gestation reveals an additive or cumulative teratogenic response to codeine.