THE EVALUATION OF THE DEVELOPMENTAL TOXICITY OF HYDROCHLOROTHIAZIDE IN MICE AND RATS

Timed-pregnant CD-1 outbred albino Swiss mice and CD Sprague-Dawley ra ts were administered hydrochlorothiazide (HCTZ, USP) in corn oil by ga vage during major organogenesis, Gestational Days (GD) 6 through 15. T he doses administered were 0, 300, 1000, or 3000 mg/kg/day for mice an d 0, 100, 300, or 1000 mg/kg/day for rats. Maternal clinical status wa s monitored daily during treatment. At termination (GD 17, mice; GD 20 , rats), confirmed pregnant females (20-27 per group, mice; 36-39 per group, rats) were evaluated for clinical status and gestational outcom e; each live fetus was examined for external, visceral, and skeletal m alformations. In mice, no maternal mortality was observed. However, cl inical signs including dehydration, piloerection, lethargy, and single -day weight loss appeared to be dose-related. HCTZ had no effect on ma ternal weight gain or water consumption, gravid uterine weight, relati ve maternal liver weight, or relative maternal kidney weight. There wa s no definitive evidence of embryotoxicity or fetal toxicity for mice on GD 17. Thus, the no observed adverse effect level (NOAEL) for both maternal and developmental toxicity was 3000 mg/kg/day. In rats, HCTZ had no effect on maternal survival, clinical signs, or water consumpti on. Clinical signs were not dose-related. Maternal weight gain during treatment was depressed at 1000 mg/kg/day. Gravid uterine weight and r elative maternal liver weight were unaffected. Relative maternal kidne y weight was slightly (7-8%) increased at all dose levels, but there w as no evidence of a dose response. Thus, the maternal NOAEL for rats w as 300 mg/kg/day, based on decreased maternal weight gain during treat ment at 1000 mg/kg/day. HCTZ had no effect on prenatal mortality, feta l growth, or morphological development in rats. The developmental NOAE L was greater than or equal to 1000 mg/kg/day. In summary, oral admini stration of HCTZ to mice at doses up to 3000 mg/kg/day and rats at dos es up to 1000 mg/kg/day during organogenesis produced no evidence of d evelopmental toxicity in either species, in spite of mild maternal tox icity in rats at 1000 mg/kg/day. (C) 1995 Society of Toxicology.