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.

Weight-of-the-evidence evaluation of 2,4-D potential for interactions with the estrogen, androgen and thyroid pathways and steroidogenesis

“…Regulatory developmental toxicity studies in rats and rabbits on various esters, amines and salts of 2,4-D summarized by Charles et al (2001) do not predict any androgenic activity. None of the rat or rabbit developmental toxicity studies showed any urogenital malformations of the type that may signify endocrine modulating activity.…”

“…Regulatory developmental toxicity studies in rats and rabbits on various esters, amines and salts of 2,4-D summarized by Charles et al (2001) do not predict any estrogenic activity. This publication is considered Klimisch criteria 2 based on relative absence of detail in reporting because of the large number of studies covered.…”

“…Published mammalian toxicological studies of 2,4-D salts and esters (Charles et al 1996a(Charles et al , 1996b(Charles et al , 2001 were the primary source of information regarding activity of the salts and esters and were reviewed to determine only whether any of these forms presented a unique hazard of endocrine-related toxicity compared to the acid form; therefore, the original study reports were not reviewed in depth.…”

“…US EPA Office of Pesticide Program (OPP) 83-4 guideline two-generation reproductive toxicity study (Rodwell & Brown 1985); OPP 83-3 guideline developmental toxicity study in rats (Rodwell 1983;Charles et al 2001); OPP 83-3 guideline developmental toxicity study in rabbits (Hoberman 1990;Charles et al 2001); OPP 82-1 guideline 13-week rat subchronic toxicity study (Schulze 1991a;Charles et al 1996a) non-guideline 13-week rat subchronic toxicity studies (Gorzinski et al 1981a(Gorzinski et al , 1981b; OPP 83-5 guideline two-year rat chronic toxicity/oncogenicity study (Jeffries et al 1995;Charles et al 1996c);…”

Toxic effects of 2,4-dichlorophenoxyacetic acid on human sperm function <i>in vitro </i>

“…It can be absorbed by the human body after long periods of contact, but it is cleared quickly via urine without being metabolized or accumulating in tissues (Sauerhoff et al, 1977). Despite this, 2,4-D has been linked to human genotoxicity (Charles et al, 2001), carcinogenesis (Glickman et al, 2004), neurotoxicity (Bongiovanni et al, 2007), and reproductive toxicity (Arbuckle et al, 1999a). In addition, 2,4-D can cause abnormal embryogenesis (Weselak et al, 2007).…”