Structure-activity relationships for percutaneous absorption of herbicides derived from 2,4-dichlorophenoxy acid

Ethyl to octyl esters of 2,4-dichlorophenoxy-acetic acids (2,4DAA), 2,4-dichlorophenoxy-propionic acids (2,4DPA) or 2,4-dichlorophenoxy-butyric acids (2,4DBA) are present in the most commonly used herbicides. Their use involves a significant risk of skin exposure, but little is known about the percutaneous flux of these substances. Studies have shown that percutaneous transition of esters may be dependent on their hydrolysis by esterases present in the skin. In this study, we describe ex vivo percutaneous absorption of seven pure esters (methyl to decyl) with a 2,4DA structure for rats (n=6) and humans (n=7). Esters were applied at 50 L.cm-2 to dermatomed skin (approximately 0.5 mm thick) for 24 hours. The enzymatic constants for hydrolysis of each ester by skin esterases were determined in vitro using skin homogenates from both species. Structure-activity relationships linking the evolution of the ex vivo percutaneous flux of esters and the 2,4D structure with enzymatic (Vmax; Km) and/or physical parameters (molecular weight, molecular volume, size of the ester, log(kow)) were examined to develop a good flux estimation model. The most relevant model was determined by comparing the flux estimated by each model with the flux measured ex vivo for human (n=3) and rat skin (n=4) for three esters with a 2,4DP and 2,4DB structure (ethyl, pentyl, octyl). For the two species, total inhibition of skin esterase activity reduced the ex vivo percutaneous flux of the three types of esters by 76 to 97%. Although the percutaneous flux of 2,4D-family esters is esterase-dependent, the best parameter for flux estimation is its log(kow). A linear regression is observed in rats (r2 = 0.943; n=42) and humans (r2 = 0.937; n=49) between the log(percutaneous flux) and the log(kow) for 2,4DA esters. This structure-activity relationship allows a good estimation of the ex vivo percutaneous flux of herbicides in both rats and humans (133%; cv = 35%; n=42) for all pure esters of this family.