The carcinogenicity of safrole following transplacental exposure of the mouse fetus and exposure of the neonatal mouse via the mother's milk was investigated in C57BL/6J × C3HeB/FeJ F1 (hereafter called B6C3F1) mice by intragastric administration of the agent to pregnant and lactating C57BL/6J females. Safrole (120 µg/g body weight per treatment) was administered to (a) pregnant mice (4 times on Days 12, 14, 16, and 18 of gestation); (b) lactating mothers (12 times every second day following parturition); or (c) 4-week-old offspring (180 times twice weekly for 90 weeks). Two additional groups of offspring received a, b, and a, b, and c combination treatments. All survivors were killed at 94 weeks of age. Renal epithelial tumors were observed in 7% of female offspring exposed to safrole in utero; none of the other experimental and control animals developed these tumors. Only male offspring nursed during the preweaning period by mothers treated with safrole developed hepatocellular tumors (34%). In contrast, direct administration of safrole, beginning at the time of weaning and continuing for the duration of experiment, led to a significantly high incidence of hepatocellular tumors in females (48%), but not in males (8%). Eighty-six % of the liver tumors observed in females were hepatocellular carcinomas with a high rate of pulmonary metastases (42%). The data suggest that safrole or its metabolites came into contact with fetuses by crossing the placenta and with infants through its excretion in milk to exert the perinatal carcinogenicity.

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This investigation was supported in part by NIH Contract N01-CP-43317 from the National Cancer Institute. Preliminary information on the content of this paper has been presented in part at the Conference on Perinatal Carcinogenesis held in Tampa, Fla., January 19 to 21, 1976 (13).

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