Abstract
AbstractTruncates of cyclophosphamide including proposed in vivo metabolic products were administered to pregnant mice on day 11 of gestation. Minimal teratogenic dosages were determined: cytoxyl alcohol, 290 mg/kg; cytoxyl amine, 270 mg/kg; phosphoramide mustard, 154 mg/kg; nornitrogen mustard, 1.6 mg/kg; and 3‐amino‐l‐propanol, 5.7 mg/kg. Maternal toxicity was evident in each case. Malformations varied from agent to agent but no agent paralleled cyclophosphamide (20 mg/kg) teratogenicity. Cyclophosphamide produced more frequent and more severe soft tissue and skeletal malformations without maternal toxicity than did any of the cyclophosphamide truncates tested. Common teratogenic effects of cyclophosphamide, cytoxyl alcohol, and nitrogen mustard were polydactyly, oligodactyly, syndactyly, cleft palate, and some skeletal defects. Cytoxyl amine, phosphoramide mustard, nornitrogen mustard, and 3‐amino‐l‐propanol were less teratogenic. Alkylating activities of these agents were determined by nitrobenzyl pyridine reaction in plasma of mice 2, 4, 8, 16, 32, and 64 minutes after intraperitoneal dosages equimolar to cyclophosphamide (100 mg/ kg). No relation between teratogenicity and alkylating potencies of the various agents was demonstrated.
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