Toxicity of ebrotidine on reproduction. Toxicity on fertility and general reproductive performance, embryo-fetal toxicity and peri- and postnatal toxicity.

Reproduction toxicity studies of ebrotidine (N-[(E)-[[2-[[[2-[(diaminomethylene)amino]-4-thiazolyl]methyl] thio]ethyl]amino]methylene]-4-bromo-benzenesulfonamide, CAS 100981-43-9, FI-3542) are presented in this paper. Rats dosed with 50, 200 and 500 mg/kg p.o. of ebrotidine were used for the fertility and peri- and postnatal toxicity studies, and rabbits dosed with 25, 100 and 250 mg/kg and rats dosed with 50, 200 and 500 mg/kg of ebrotidine were used for the embryotoxicity study. The fertility study was designed in accordance with a 2-generation study protocol. The results showed that ebrotidine did not interfere with male and female gametogenesis, fertility, organogenesis, postnatal development and lactation in F0 or F1 animals. Only general or non-specific effects were attributed to treatment, such as a lower weight gain in parents or fetuses in rats, or a somewhat slower bone calcification in rats, which was shown to be recoverable and had no peri- or postnatal repercussions. Neither did the fertility study reveal a possible longer duration of gestation nor did the peri- and postnatal study show a lower weight of the F1 offspring. There was only an increase in rabbit embryonic mortality, probably related to some cases of abortion at the high dose. No potential antiandrogenic effect on the reproductive function has been found. Among the different doses used in both animal species, the maximum toxic effect-free dose was that of 25 mg/kg.