Maternal and developmental toxicity evaluation of melatonin administered orally to pregnant Sprague-Dawley rats

Melatonin (MEL) is a widely used, over-the-counter sleep aid, and it has pu tative contraceptive, antioxidant, antiaging, and anticancer effects. The d evelopmental toxicity potential for repeated oral doses of MEL had not prev iously been evaluated. In the present studies, time-mated, Sprague-Dawley-d erived (CD(R)) rats were administered MEL or vehicle by gavage on gestation days (gd) 6-19. MEL-treated groups received 1-, 10-, 100-, 150-, or 200-mg /kg body weight/day in the screening study (15 rats/group), and 50, 100, or 200 mg/kg/day in the definitive study (25 rats/group). In both studies, ma ternal food/water consumption, body weight, and clinical signs were monitor ed at regular intervals throughout gestation. At termination (gd 20, both s tudies:), maternal liver and gravid uterine weights, number of ovarian corp ora lutea, conceptus survival, fetal sex, and fetal body weight were evalua ted. Fetal morphological examination included external structures (both stu dies) as well as visceral and skeletal structures (definitive study). In th e screening study, maternal serum levels of 17 beta-estradiol, progesterone , prolactin, and luteinizing hormone were determined by radioimmunoassay, a nd mammary tissue was fixed, stained, and evaluated for percent glandular a rea within the fat pad. No maternal morbidity/mortality was found In either study. In the screening study, aversion to treatment (greater than or equa l to 100 mg/kg/day) and reduced maternal weight gain (greater than or equal to 150 mg/kg/day) were noted, but reproductive/endocrine parameters and fe tal development were not affected. In the definitive study, aversion to tre atment was noted at greater than or equal to 50 mg/kg/day, and mild sedatio n, reduced maternal food intake, and reduced body weight gain were found du ring initial treatment with 200 mg/kg/day. MEL had no effect on prenatal su rvival, fetal body weight, or incidences of fetal malformations/variations. Thus, in the definitive study, the maternal toxicity NOAEL and LOAEL were 100 and 200 mg/kg/day, respectively, and the developmental toxicity NOAEL w as greater than or equal to 200 mg/kg/day.