Evaluation of the prenatal developmental toxicity of orally administered arsenic trioxide in rats

A thorough review of the literature revealed no published repeated-dose ora l developmental toxicity studies of inorganic arsenic in rats. Tn the prese nt study, which was conducted according to modern regulatory guidelines, ar senic trioxide was administered orally beginning 14 days prior to mating an d continuing through mating and gestation until gestational day 19. Exposur es began prior to mating in an attempt to achieve a steady state of arsenic in the bloodstream of dams prior to embryo-foetal development. Groups of 2 5 Crl:CD (SD)BR female rats received doses of 0, 1, 2.5, 5 or 10 mg/kg/day by gavage. The selection of these dose levels was based on a preliminary ra nge-finding study, in which excessive post-implantation loss and markedly d ecreased foetal weight occurred at doses of 15 mg/kg/day and maternal death s occurred at higher doses. Maternal toxicity in the 10 mg/kg/day group was evidenced by decreased food consumption and decreased net body weight gain during gestation, increased Liver and kidney weights, and stomach abnormal ities (adhesions and eroded areas). Transient decreases in food consumption in the 5 mg/ kg/day group caused the maternal no-observed-adverse-effect l evel (NOAEL) to be determined as 2.5 mg/ kg/day. Intrauterine parameters we re unaffected by arsenic trioxide, No treatment-related foetal malformation s were noted in any dose group. Increased skeletal variations at 10 mg/kg/d ay were attributed to reduced foetal weight at that dose level. The develop mental NOAEL was thus 5 mg/kg/day. Based on this study, orally administered arsenic trioxide cannot be considered to be a selective developmental toxi cant (i.e, it is not more toxic to the conceptus than to the maternal organ ism), nor does it exhibit any propensity to cause neural tube defects, even at maternally toxic dose levels. (C) 2000 Elsevier Science Ltd. All rights reserved.