Acute, pharmacokinetic, and subchronic toxicological studies of 2,4-dichlorophenoxyacetic acid

Abstract

The single-dose oral LD 50 values in Fischer 344 rats for technical-grade 2,4-dichlorophenoxyacetic acid (2,4-D), esters, and salts ranged from 553 mg/kg (isobutyl ester in females) to 1090 mg/kg (dimethylamine salt in males). The LD 50 values for the acid, esters, or salts, when expressed as acid equivalents, were consistent which suggests that the acute toxicity was due to 2,4-D per se. Acute dermal LD 50 values in rabbits for the acid, esters, and salts were greater than 2000 mg/kg. Overall, these results indicate that the acute oral and dermal toxicity of 2,4-D are low. Pharmacokinetics were evaluated in male Fischer 344 rats given single oral doses of 10, 25, 50, 100, or 150 mg 2,4-[ 14C ]D/kg. The amount of 2,4-D in the plasma, kidney, and urine 6 hr postdosing indicated that the urinary elimination of 2,4-D was saturated in male rats given oral doses in excess of 50 mg/kg. Subchronic dietary studies in male and female Fischer 344 rats used dose levels of 0, 15, 60, 100, or 150 mg/kg/day of purified or technical-grade 2,4-D acid for 13 weeks. Body weight gains were decreased for both sexes at the higher dose levels of purified and technical-grade 2,4-D acid. Kidney weights were increased in all treated male rats and in females given the higher three dose levels of purified 2,4-D. Treatment-related cytoplasmic alterations were present in the renal proximal tubules of most rats given 60 mg/kg/day and higher of purified or technical-grade 2,4-D; a few females given 15 mg/kg/day also had slight alterations in the cytoplasm of the proximal tubules. A dose-related degenerative change was identified in the descending proximal renal tubules of all male rats given the highest three dose levels of either test material and some given 15 mg/kg/day. Dose levels of 100 or 150 mg/kg/day of either compound for both sexes produced minimal swelling and increased staining homogeneity in the liver cells and were associated with a slight elevation of liver weight and serum glutamic pyruvic transaminase activity. Higher dose levels of technical-grade and purified 2,4-D decreased total serum tetraiodothyronine levels in female rats, however, the morphology of the thyroid gland was normal. The no-observed-effect level (NOEL) was less than 15 mg/kg/day for both purified and technical-grade 2,4-D acid.