Two-generation reproduction and developmental neurotoxicity study with sodium chlorite in the rat.
The potential for sodium chlorite to produce reproductive toxicity, developmental neurotoxicity and alterations in hematology and thyroid hormones was evaluated in Sprague-Dawley rats administered sodium chlorite in the drinking water continuously for two generations. The F(0) generation animals (30 of each gender per group) and F(1) generation animals (25 of each gender per group) selected to rear the F(2) generation were allowed free access to drinking water containing 0, 35, 70 or 300 ppm sodium chlorite for a 10-week prebreed period, through mating for males and through mating, gestation and lactation for females. These drinking water concentrations corresponded to sodium chlorite doses of approximately 4, 8 and 30 mg kg(-1) day(-1) for males and 5, 10 and 39 mg kg(-1) day(-1) for females, respectively. Evaluations included standard reproductive and postnatal indices, sperm morphology and motility, estrous cyclicity, a functional observational battery, motor activity, auditory startle, swim maze, hematology, serum thyroid hormone analyses and histopathology of reproductive and nervous system tissues. Sodium chlorite resulted in a decrease in water consumption in all groups and a decrease in food consumption and body weights in the 70 and 300 ppm groups. There was no evidence of reproductive toxicity. Pup body weight was decreased in the 300 ppm group and small delays were observed in the time to preputial separation and vaginal opening. Mild anemia and mild methemoglobinemia were observed for animals in the 300 ppm group. Thyroid hormone levels were not affected by treatment. Changes to the nervous system were limited to small decreases in amplitude of auditory startle response for postnatal day (PND) 25 pups in the 70 and 300 ppm groups and a small decrease in absolute brain weight for PND 11 pups in the 300 ppm group. These effects were considered to be of questionable neurotoxicological significance. Based on the results of this study, the no-observed-effect level (NOEL) for effects on reproduction and thyroid hormones is 300 ppm. The no-observed-adverse-effect levels (NOAEL) for hematological toxicity and neurotoxicity are considered to be 70 and 300 ppm, respectively.
Gill
M W
MW
Toxicology/Regulatory Services, Inc., 2345 Hunters Way #3, Charlottesville, VA 22911, USA. michael.gill@bms.com
Swanson
M S
MS
Murphy
S R
SR
Bailey
G P
GP
D000704:Analysis of Variance; D000818:Animals; D002712:Chlorides / Q000633:toxicity*; D004906:Erythrocyte Count / Q000187:drug effects; D005260:Female; D006128:Growth / Q000187:drug effects; D006454:Hemoglobins / Q000187:drug effects / Q000378:metabolism; D008297:Male; D009043:Motor Activity / Q000187:drug effects; D020258:Neurotoxicity Syndromes / Q000209:etiology*; D051381:Rats; D017207:Rats, Sprague-Dawley; D012098:Reproduction / Q000187:drug effects*; D013961:Thyroid Gland / Q000187:drug effects* / Q000378:metabolism; D013963:Thyroid Hormones / Q000378:metabolism
D002712:Chlorides; D006454:Hemoglobins; D013963:Thyroid Hormones; C001599:chlorite