A series of regulatory studies were carried out to investigate the effects of the FAAH inhibitor BIA 10-2474 on fertility, embryo-fetal toxicity and pre- and post-natal development in rats and rabbits. Despite some reductions in sperm count in rats from 50 mg/kg, there were no major changes in male fertility up to 100 mg/kg. In female rats administered up to GD6, there were increases in pre-implantation loss at 50 and 100 mg/kg but neither post-implantation loss nor early embryonic development was affected. In contrast, when administered to female rats during pregnancy (GD6-GD17), BIA 10-2474 at 75 mg/kg/day reduced food consumption resulting in weight loss, increased post-implantation loss and reduced mean fetal body weight. In rabbits, the same maternal toxicity was seen but there were no effects in this species on post-implantation loss or fetal body weights. There were no teratological effects clearly due to BIA 10-2474 and developmental milestones and behavior of offspring were not affected. When administered during pregnancy and lactation (GD6-PND20), some post-implantation loss was seen from 20 mg/kg/day, but developmental milestones and behavior of the offspring were not affected, although males tended to have lower body weight. Based on these data the NOAEL for parental fertility was established as 50 mg/kg/day, the maternal NOAEL during pregnancy was 25 mg/kg/day in rats and developmental NOAEL was 25 and 75 mg/kg/day in rats and rabbits, respectively. When administered during post-natal development to rats the maternal NOAEL was 6 mg/kg/day. The parental reproductive NOAEL, the NOAEL for viability and growth of the F1 offspring, the F1 parental NOAEL and the F1 reproductive NOAEL were all considered to be 20 mg/kg/day.

中文翻译：

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BIA 10-2474的发育和生殖毒性研究。

进行了一系列调控研究，以研究FAAH抑制剂BIA 10-2474对大鼠和兔子的生育力，胚胎-胎儿毒性以及产前和产后发育的影响。尽管大鼠的精子数量从50 mg / kg减少了一些，但直到100 mg / kg的雄性育性并没有重大变化。在给予高达GD6的雌性大鼠中，植入前的损失在50和100 mg / kg时有所增加，但是植入后的损失和早期胚胎发育都没有受到影响。相反，当在怀孕期间对雌性大鼠给药（GD6-GD17）时，BIA 10-2474的剂量为75 mg / kg / day减少了食物消耗，从而减轻了体重，增加了植入后的损失并降低了平均胎儿体重。在兔子里 观察到相同的母体毒性，但该种对植入后的损失或胎儿体重没有影响。由于BIA 10-2474，没有明显的致畸作用，并且发育里程碑和后代的行为均未受到影响。当在妊娠和哺乳期（GD6-PND20）给药时，从20 mg / kg /天开始观察到一些植入后损失，但尽管雄性倾向于体重较轻，但其发育里程碑和后代的行为并未受到影响。根据这些数据，将父母生育力的NOAEL确定为50 mg / kg /天，妊娠期大鼠的母体NOAEL为25 mg / kg /天，大鼠和兔子的发育NOAEL分别为25和75 mg / kg / day，分别。当在产后发育期对大鼠给药时，母体NOAEL为6 mg / kg /天。