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To clarify species differences in the developmental toxicity of procymidone (Sumilex ® , a fungicide for agricultural use), placental transfer studies were conducted using 14 C-labeled procymidone in pregnant rats, rabbits, and monkeys. These studies demonstrated that maternal-to-fetal transfer of the parent compound and its hydroxylated metabolite, which are both weak anti-androgenic agents, occurred more easily than that of other metabolites, with much higher absolute concentrations achieved in the fetal circulation of rats than of rabbits or monkeys. Notably, in rats, the fetal plasma concentration of the hydroxylated metabolite was higher than that of procymidone, especially after repeated oral administration of procymidone. These results suggest that the hydroxylated metabolite is the most relevant metabolite involved in teratogenic activity in rats.

) is a fungicide with a weak anti-androgenic activity. The anti-androgenic activity and androgen receptor (AR)-binding activity of procymidone and its six metabolites were evaluated. Anti-androgenic activity was determined in HeLa cells transiently transfected with an AREx3-luciferase reporter and full-length human or rat AR expression vectors (antiandrogen assay). AR-binding activity was determined by a competitive ligand-binding assay based on a fluorescence polarization method (AR-binding assay). It was clear that procymidone, its hydroxylated metabolite (PCM-CH 2 OH), and their imide linkage-cleaved compounds (PCM-NH-COOH and PA-CH 2 OH) have anti-androgenic activity and AR-binding activity, and procymidone has the highest activity among these compounds. There were no differences between rats and humans regarding the activities of procymidone and the metabolites. The activity of procymidone was 20-70 times lower than that of hydroxyflutamide, which is a potent anti-androgen. The results indicate that the anti-androgenic activities of procymidone and its metabolites are very weak.

A metabolite of procymidone, hydroxylated-PCM, causes rat-specific developmental toxicity due to higher exposure to it in rats than in rabbits or monkeys. When procymidone was administered to chimeric mice with rat or human hepatocytes, the plasma level of hydroxylated-PCM was higher than that of procymidone in rat chimeric mice, and the metabolic profile of procymidone in intact rats was well reproduced in rat chimeric mice. In human chimeric mice, the plasma level of hydroxylated-PCM was less, resulting in a much lower exposure. The main excretion route of hydroxylated-PCM-glucuronide was bile (the point that hydroxylated-PCM enters the enterohepatic circulation) in rat chimeric mice, and urine in human chimeric mice. These data suggest that humans, in contrast to rats, extensively form the glucuronide and excrete it in urine, as do rabbits and monkeys. Overall, procymidone's potential for causing teratogenicity in humans must be low compared to that in rats.

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