Comparative Subchronic and Chronic Dietary Toxicity Studies on 2,4-Dichlorophenoxyacetic Acid, Amine, and Ester in the Dog

Abstract

Forms of 2,4-dichlorophenoxyacetic acid (2,4-D) are herbicides used in the control of a wide variety of broadleaf and woody plants. Subchronic toxicity studies in dogs were conducted on three forms of 2,4-D: the parent form, 2,4-D acid (ACID); 2,4-D dimethylamine salt (DMA); and 2,4-D 2-ethylhexyl ester (2-EHE). The three studies were designed to allow for comparison of the toxicity of the three forms. Doses in the subchronic studies, on an acid equivalent basis, were 0, 0.5 (ACID only), 1.0, 3.75, and 7.5 mg/kg/day. Treatment related findings in the three studies included reductions in body weight gain, and food consumption, and minor increases in blood urea nitrogen, creatinine, and alanine aminotransferase. The data from the three subchronic studies demonstrated the comparable toxicity of ACID, DMA, and 2-EHE and support a subchronic no observed adverse effect level (NOAEL) of 1.0 mg/kg/day for all three forms. Due to the similarity in toxicity of the three forms of 2,4-D, a 1-year chronic toxicity study was performed on the parent ACID to fully characterize the potential toxicity of 2,4-D in the dog. ACID was well tolerated at doses of 0, 1.0, 5.0, and 7.5 mg/kg/day. The clinical pathology alterations were similar to those seen in the subchronic studies and were not progressive. The histopathology alterations observed were not severe in nature and the no observed effect level in the chronic study was determined to be 1.0 mg/kg/day. There was no indication of any immunotoxic or oncogenic response in the studies. In conclusion, the findings of these studies indicate comparable toxicity among representative forms of 2,4-D and their generally low toxicity following subchronic and chronic dietary exposure in the dog.

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

“…Given this non-linear behavior, saturation of 2,4-D renal clearance at 50 mg/kg suggests that animal toxicity findings observed at this dose level and higher overestimate potential human risks. In the case of dogs, both subchronic and chronic studies indicate this species, with an overall NOAEL of 1 mg/kg/day (Charles et al 1996b), is more sensitive to 2,4-Dinduced toxicity than rodents, with an overall NOAEL of 5 mg/kg/ day (Charles et al 1996c). Since the dog is lacking an effective renal organic anion clearance mechanism, this differential species response has been attributed to an inability of the dog to effectively clear 2,4-D from the body, resulting in significantly higher 2,4-D blood concentrations in dog relative to rats and humans at an equivalent oral dose of 5 mg/kg (Van Ravenswaay et al 2003;Timchalk, 2004).…”

“…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.…”

“…OPP 82-1 guideline 13-week mouse subchronic toxicity (Schulze 1991b); OPP 83-2 guideline-equivalent mouse oncogenicity evaluations (Stott 1995a(Stott , 1995bCharles et al 1996c); OPP 82-1 non-guideline 13-week dog subchronic toxicity study (Schulze 1990) OPP 82-1 guideline 13-week dog subchronic toxicity (Dalgard 1993a;Charles et al 1996b); and OPP 83-1 guideline dog chronic toxicity study (Dalgard 1993b;Charles et al 1996b). …”

“…A third article by Charles et al (1996b) presents data from dog subchronic toxicity studies conducted with 2,4-D DMA, or 2,4-D 2-EHE. It also includes results from subchronic and chronic dog studies on 2,4-D acid (Dalgard 1993a(Dalgard , 1993b, which were reviewed based on the study reports.…”

“…A second article by Charles et al (1996b) presents data from dog subchronic toxicity studies conducted with 2,4-D DMA or 2,4-D 2-EHE (and also included one of the dog subchronic studies (Dalgard 1993a) and the dog chronic toxicity study (Dalgard 1993b) on 2,4-D acid discussed above). These studies were GLP guideline studies conducted to satisfy US EPA testing requirements.…”