Developmental toxicity studies in rats and rabbits on 2,4-dichlorophenoxyacetic acid and its forms

Abstract

The potential for 2,4-D and its salts and esters to induce developmental toxicity was investigated in rats (8 studies) and rabbits (7 studies). Maternal toxicity associated with exposure was dependent on the dose level expressed as 2,4-D acid equivalents. The severity of the maternal effect was correlated to the 2,4-D acid-equivalent dose, with increasing dose levels that exceeded renal clearance causing increasingly more severe maternal effects. In both species, maternal body weight effects began to be manifested at dose levels of 30 mg 2,4-D acid equivalent/kg/day. At higher dose levels (50-75 mg/kg/day in rats and 75-90 mg/kg/day in rabbits), body weights and feed consumption were more severely affected. At dose levels > or =90 mg/kg/day in rats, clinical signs of toxicity (ataxia, muscular stiffness, and decreased motor activity) and mortality were noted. The no-observed-adverse-effect level (NOAEL) for maternal toxicity in both species across the family of 2,4-D salts and esters was approximately 10 mg/kg/day. Significantly decreased fetal body weights and increased fetal variations were seen in rats only at maternally toxic dose levels in excess of 90 mg/kg/day acid equivalent. At maternally toxic doses in rabbits, embryonal and fetal development were essentially unaffected. There were no effect on maternal reproductive measures such as litter size, resorption rates, or fetal body weights, and there was no evidence of teratogenic activity. In summary, equivalent toxicity of the salts and esters is consistent with rapid and complete metabolic conversion to 2,4-D acid. No adverse fetal effects were noted at dose levels that did not also produce evidence of maternal toxicity or exceed renal clearance of 2,4-D indicating that the developing rat and rabbit fetus were not uniquely sensitive to 2,4-D and its forms.