LAUSR

ABSTRACT Selective serotonin reuptake inhibitors (SSRIs) have developed as novel antidepressants and have been determined to possess higher efficacy and less adverse effects compared to other antidepressants. Our previous studies have showed that LPM570065, a new potent TRI, is relatively nontoxic in acute, subchronic toxicity and genotoxicity evaluations. In the current study, toxicity of LPM570065 was further evaluated on the fertility and early embryonic development in Sprague‐Dawley rats. A total of 264 rats were treated with various concentrations of LPM570065 (30mg/kg, 100mg/kg, and 300mg/kg) or used as control. Females rats were treated for two consecutive weeks, followed by mating via cohabitation up to the 7th gestation day (GD). The male rats were treated for four consecutive weeks, which were followed by first mating with treated female rats. Then, all males were treated up to the 9th week and followed by second mating with non‐treated female rats, and were sacrificed. All surviving pregnant females were euthanized on GD 15. We evaluated the following parameters, namely, mortality, toxicity symptoms, body weight, amount of food consumed, sexual cycle, mating behavior, pregnancy, sperm production, gross necropsy, and weight of organs. Excessive salivation was observed post treatment in nearly all females and males in the 100 and 300mg/kg LPM570065 treatment groups. Body weight gain was decreased in gravid rats treated with 300mg/kg LPM570065 during GD 0–6 (P<0.05). The application of 300mg/kg of LPM57006 to male rats induced a decrease in implantation sites and lower fertility rates (P<0.05). However, sperm concentration and count were higher in the LPM570065‐treated groups (30mg/kg, 100mg/kg, and 300mg/kg) compared to the controls. Moreover, duration of mating significantly decreased to 37.5% after nine weeks of LPM570065 treatment at a concentration of 300mg/kg (P<0.05). In conclusion, the no observable adverse effect level (NOAEL) was established at 100mg/kg and 300mg/kg for female and male rats, respectively. The NOAEL for fertility and early embryonic development was established at 300mg/kg and 100mg/kg for female and male rats, respectively. HIGHLIGHTSThe NOAEL of LPM570065 was 100mg/kg for female rats.The NOAEL of LPM570065 was 300mg/kg for male rats.The NOAEL of fertility and early embryonic development was 300mg/kg for female rats.The NOAEL of fertility and early embryonic development was 100mg/kg for male rats.