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PUBERTAL DEVELOPMENT IN FEMALE WISTAR RATS FOLLOWING EXPOSURE TO PROPAZINE AND ATRAZINE BIOTRANSFORMATION BY-PRODUCTS, DIAMINO-S-CHLOROTRIAZINE AND HYDROXYATRAZINE
Citation:
Laws, S C., J M. Ferrell, T E. Stoker, AND R L. Cooper. PUBERTAL DEVELOPMENT IN FEMALE WISTAR RATS FOLLOWING EXPOSURE TO PROPAZINE AND ATRAZINE BIOTRANSFORMATION BY-PRODUCTS, DIAMINO-S-CHLOROTRIAZINE AND HYDROXYATRAZINE. TOXICOLOGICAL SCIENCES 76(1):190-200, (2003).
Description:
We have shown previously that the chlorotriazine herbicide, atrazine (ATR), delays the onset of pubertal development in female rats. ATR and its by-products of microbial degradation are present in soil and groundwater. Since current maximum contaminant levels are set only for ATR, it is important to determine whether or not these metabolites can also alter pubertal development and possibly pose a cumulative exposure hazard. We evaluated the effects of two atrazine metabolites, diamino-s-chlorotriazine (DACT) and hydroxyatrazine (OH-ATR), and a structurally similar chlorotriazine, propazine (PRO), on female pubertal development. Rats were gavaged from postnatal day (PND) 22 through PND 41 with DACT (16.9, 33.8, 67.5, 135 mg/kg), OH-ATR (22.8, 45.7, 91.5, 183 mg/kg), or PRO (13.3, 26.7, 53, 106.7, 213 mg/kg). The dose range for each chemical was selected as the molar equivalent of ATR (12.5, 25, 50, 100, 200 mg/kg). Females were monitored daily for vaginal opening (VO) and killed on PND 41. DACT, the primary chlorinated metabolite of ATR, delayed VO by 3.2, 4.8, and 7.6 days compared to controls (33.1 ? 0.4 (SE) days of age) following exposure to 33.8, 67.5 and 135 mg/kg, respectively. The NOAEL for DACT (16.7 mg/kg) was identical to the equimolar NOAEL for ATR (25 mg/kg). Although body weight (BW) on PND41 was reduced by the high dose of DACT (8.4% reduction), this reduction did not exceed the criteria for selecting the maximum tolerated dose (e.g., a dose that causes >10% decrease in body weight). None of the lower doses of DACT caused a significant difference in body weight gain. Additionally, BW on the day of VO was significantly increased by 33.7, 67.5 and 135 mg/kg DACT. PRO (107 or 213 mg/kg) delayed VO by 4 days, but did not alter BW on PND41. In contrast, the de-chlorinated metabolite, OH-ATR, did not significantly delay the age at VO, suggesting that the presence of the chlorine group may be necessary for the delay in pubertal development. Together, these data demonstrate that PRO and DACT can delay the onset of puberty in the female rat at doses equimolar to that of ATR, and suggest that potential environmental exposure to multiple chlorotriazines and metabolites may pose a cumulative hazard.