Percutaneous absorption of industrial esters: structure-activity relationship between absorption flux and substitution of the aromatic-type acid group

Determining the intensity of the absorption flux of industrial toxic substances is necessary to define the risk related to exposure via the skin. Structure-activity relationships make it possible to estimate the absorption flux of numerous molecules on the basis of their molecular mass and of their relative affinities for aqueous and lipid environments. However such models suffer from limitations. In particular, they do not take into account the metabolic activity of the skin that can play a predominant role in percutaneous absorption of industrial toxic substances, such as esters.
The esters used in a large number of sectors of activities, including the chemical industry, with solvents (i.e. acetate), plasticisers (i.e. phthalates), phytosanitary products (i.e. 2,4-dichlorophenoxy acid), and the pharmaceutical and cosmetic industry (i.e. paraben). The toxicity of these compounds varies. They are irritants, cutaneous and respiratory sensitizers, reprotoxic compounds or endocrine disruptors.
In prior studies, we have shown that percutaneous absorption of certain esters, including phthalates or esters of 2,4-dichlorophenoxyacetic acid (2,4-D) required them to be previously hydrolysed under the action of the esterases contained in the skin. For derivatives of 2,4-D, by causing the number of carbon atoms in the carbon chain of alcohol to vary (from methanol to decanol), it has been possible to establish a simple structure-activity relationship between the absorption fluxes of these herbicides and their octanol-water partition coefficients.
Similarly, this new study will aim to seek to determine whether a structure-activity relationship can be established between the percutaneous absorption flux and the chemical structure of the acid group. For about ten esters, for which the acid group presents an aromatic nucleus that is substituted to a greater or lesser extent and a constant alcohol group (ethyl or methyl), their percutaneous absorption fluxes and their speeds of hydrolysis by two isozymes of esterases of human type will be measured. About ten esters have been selected, based on the presence of a common structure derived from benzoic acid, from phenoxy acid, or from phthalic acid. Esters are preservatives (i.e. ethyl benzoate, ethylparaben) or phthalates (ethyl phthalate), or herbicides (ethyl 2,4-dichlorophenoxy acetate).
The results should enable the percutaneous absorption flux of industrial toxic substances to be estimated better by basing the estimation on a semi-quantitative structure-activity relationship.
Planned dissemination: Publication in a peer-reviewed international scientific journal.