ASSESSMENT OF THE TERATOGENIC POTENTIAL OF TRIMETHADIONE IN THE CD-1 MOUSE

The oxazolidine-2,4-dione anticonvulsant trimethadione was shown to be highly embryotoxic and teratogenic in the CD-1 mouse, at doses well below those which caused overt maternal toxicity. Administration of the drug over the phase of early embryonic organogenesis (pregnancy Days 8-10) caused 80% embryomortality, with 100% malformations in live fetuses, at the highest dose tested (7.3 mmol/kg [1045 mg/kg], daily). The teratogenicity ED50 (tD50) over this period was computed to be 3.76 mmol/kg compared to the adult LD1 of 7.52 mmol/kg and LD50 of 8.91 mmol/kg. Fetal birth weight was reduced by daily doses of trimethadione as low as 0.24 mmol/kg (35 mg/kg). There were few differences between the effects of intraperitoneal and oral administrations. Malformations were induced in a wide range of visceral organs and in the skeletal system, the most common defects being of the vertebral column and the aortic arch. Embryos in the late phase of organogenesis (Days 11-13) were less sensitive to maternal trimethadione treatment. The tD50 was 5.97 mmol/kg and the maximum levels of embryomortality and congenital malformations were 21 and 74%, respectively, following daily doses of 7.3 mmol/kg. Cleft palate and defects in the great vessels of the heart were the most common abnormalities induced during this treatment period. Several of the types of malformations reported in this study, particularly the cardiovascular anomalies, have also been observed in the children of mothers receiving trimethadione therapy. © 1979.