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94–96% oral bioavailability in rats following the administration of 14C-labeled dimethylamine salt of 2,4-D is reported (Pelletier et al., 1989). In mice, the absorption t1/2 was approximately 0.01 h and the area-under the plasma concentration curve (AUC) was nearly the same following oral and intravenous (i.v.) administration of 2,4-D at doses ranging from 5 to 90 mg/kg of body weight, indicating rapid and nearly complete absorption (Eiseman, 1984).

The dermal absorption of the free acid is ~ 2 % (based on human data submitted under Directive 91/414/EEC). This value is also assumed for the test substance. Because of the greater polarity of the sodium salt compared to the protonated acid, it is safe to assume that the sodium salt will have an even lower tendency for skin penetration.

Once absorbed the overall tissue distribution of 2,4-D is similar across species (Erne, 1966). Van Ravenzwaay et al. (2003) reported that in rats 2,4-D was highly bound (93–97%) to plasma proteins over a broad range of concentrations.

It is known that 2,4-D and its esters and salts share the same metabolic fate. Esters undergo rapid acid and/or enzymatic hydrolysis to form 2,4-D acid, whereas the salts undergo a physiological dissociation.Erne (1966) reported only trace amounts of 2,4-D butyl ester (2,4-D BE) in blood, following oral exposure in pigs and rats, and Schulzeet al.(1985) found no parent 2,4-D BE in the urine of rats. Likewise, only 2,4-D was found in the blood or urine of rats given 130 mg 2,4-D EHE/kg (Frantz and Kropscott, 1993). Knopp and Schiller reported that the concentrations of urinary 2,4-D were much lower after dermal exposure with the sodium or the ammonium salt than after oral administration. Peak concentrations were measured 20 h after application. The percentage of 2,4-D excreted in urine increased almost steadily over the first 70 hours and more slowly from 70 to 116 h, cumulating to about 10-15%. Generally, the parent 2,4-D is excreted by the kidneys via the organic acid active transport process (Berndt and Koschier, 1973; Gehring and Betso, 1978). Urinary excretion of 2,4-D in rats has been shown to be saturated at dose levels of 50 mg/kg and above (Gorzinski et al., 1987; Khanna and Fang, 1866; Smith et al., 1980). Sandberg et al. (1996) studied the distribution of 2,4-D in maternal and fetal rabbits following intravenous administration. The results of these studies showed the saturation of renal organic acid active transport in rabbits. Furthermore, it was shown that maternal toxicity observed in studies following repeated gavage doses of ≥30 mg/kg/day are likely to occur under conditions of saturated renal clearance of 2,4-D.

Griffin et al. (1997) compared the metabolism of 2,4-D in the rat, hamster and mouse. They reported that in all three species 2,4-D was the major urinary metabolite, the same is true for humans. In dogs administered 0.1 mg/kg, it was noted that80% of the total urinary excretion was 2,4-D with the remaining 20% being conjugates (Timchalk, 1994). After administration of 5 mg/kg, at least nine metabolites of 2,4-D were noted in dog urine which included taurine, serine, glycine, glucuronide, glutamic acid, sulfate and cysteine conjugates with unchanged 2,4-D accounting for1% of the total metabolites present (Van Ravenzwaay et al., 2003). This difference in the amount of “free” 2,4-D eliminated in the dog urine may be a reflection of the dose-dependent nature of 2,4-D clearance.

These data presented support the hypothesis that the dog’s particularly sensitivity to the effects of phenoxyacetic acid herbicides like 2,4-D and its derivates is due to the unique limited capacity of this species to excrete organic acids via the kidneys. Likely mechanisms responsible for this decreased clearance include saturation of renal secretion and increased renal tubule re-absorption. Therefore, based on scientific evidence it would seem reasonable to use the toxicity data generated in rodents for risk evaluation.

 

 

Knopp, D. and Schiller, F. (1992). Oral and dermal application of 2,4-dichlorophenoxyacetic acid sodium and dimethylamine salts to male rats: investigations on absorption and excretion as well as induction of hepatic mixed-function oxidase activities. Arch Toxicol, 1992, 66, 170-174.

 

Erne, K. (1966). Distribution and elimination of chlorinated phenoxyacetic acids in animals. Acta Vet. Scand. 7:264–256.

 

Schulze, G. E., Blake, J. W., and Dougherty, J. A. (1985). The metabolic fate of 2,4-dichlorophenoxyacetic acid-n-butyl ester in Wistar rats. Arch. Toxicol. 57:231–236.

 

Frantz, S. W., and Kropscott, B. E. (1993). Pharmacokinetic evaluation of a single oral administration of the 2-ethylhexyl (isooctyl) ester of 2,4-D to Fischer 344 rats. J. Occup. Med. Toxicol. 2:75–85.

 

Berndt, W. O., and Koschier, F. (1973). In vitro uptake of 2,4-dichlorophenoxyacetic acid (2,4-D) and 2,4,5-trichlorophenoxyacetic acid (2,4,5-T) by renal cortical tissue of rabbits and rats. Toxicol. Appl. Pharmacol. 26:559–570.

 

Gehring, P. J., and Betso, J. E. (1978). Phenoxy acids: Effects and fate in mammals. Ecol. Bull. 27:122–133.

 

Gorzinski, S. J., Kociba, R. J., Campbell, R. A., Smith, F. A., Nolan, R. J., and Eisenbrandt, D. E. (1987). Acute, pharmacokinetic, and subchronic toxicological studies of 2,4D. Fundam. Appl. Toxicol. 9:423–435.

 

Khanna, S., and Fang, S. C. (1966). Metabolism of C14-labeled 2,4-dichlorophenoxyacetic acid in rats. J. Agr. Fd. Chem. 14:500–503.

 

Smith, F. A., Nolan, R. J., Hermann, E. A., and Ramsey, J. C. (1980). Pharmacokinetics of 2,4-dichlorophenoxyacetic acid (2,4-D) in Fischer 344 rats. Nineteenth Annual Meeting of the Society of Toxicology, Abstract No. 180.,.

 

Sandberg, J. A., Durhart, H. M., Lipe, G., Binienda, Z., Slikker, W., Jr., and Kim, C. S. (1996). Distribution of 2,4-dichlorophenoxyacetic acid (2,4-D) in maternal and fetal rabbits. J. Toxicol. Environ. Health 49:P497–509.

 

Pelletier, O., Ritter, L.; Caron, J.; Somers, D., (1989). Disposition of 2,4-dichlorophenoxyacetic acid dimethylamine salt by Fischer 344 rats dosed orally and dermally. J. Toxicol. Environ. Health. 28:221–234.

 

Eiseman, J. (1984). The Pharmacokinetic Evaluation of [Carbon 14]-2,4-Dichlorophenoxyacetic Acid (2,4-D) in the Mouse: Final Report: Project No. 2184-104. Hazleton Laboratories America, Inc. Unpublished.

 

Van Ravenzwaay, B., Hardwick, T.D.,, D., Pethen, S., Lappin, G.J., (2003). Comparative metabolism of 2,4-dichlorophenoxyacetic acid (2,4-D) in rat and dog. Xenobiotica 33:805–821.

European Commission, Directorate E1 - Plant Health (2001). Commission working document - Review report for the active substance 2,4 -D, 7599/VI/97 -final