Quantitative structure-Activity relationships for skin irritation and corrosivity of neutral and electrophilic...

Quantitative structure-activity relationships (QSARs) have been derived by relating skin irritation and corrosivity data of neutral and electrophilic organic chemicals to their log(octanol/water partition coefficient) (logP), molecular volume, dipole moment and 1/molecular weight. Datasets were analysed using stepwise regression, discriminant and principal components analysis. Discriminant analysis between irritant and non-irritant neutral and electrophilic organic chemicals using the above parameters, which broadly model skin permeability (logP and molecular volume), 'reactivity' (dipole moment) and l/molecular weight to compensate for the fact that skin irritation/corrosivity testing is carried out using a fixed mass or volume of chemical, was found to discriminate well for only 73.1% of the dataset (67.3% cross-validated). The poor discrimination at the irritant/non-irritant classification boundary is attributed largely to biological variability. Stepwise regression analysis of the Primary Irritation Index (PII) for the same dataset showed a poor correlation (r(2) = 0.422; cross-validated r(2) = 0.201) with a positive dependence on logP and dipole moment and a negative dependence on molecular volume; l/molecular weight was not a significant variable. While this QSAR for PII has little value as a predictive model, mainly because of the large biological variability evident in PII values, it is useful in confirming the putative model for skin irritation. Discriminant analysis using logP, molecular volume and dipole moment, was able to discriminate reasonably well (92.9% well-classified; 92.9% cross-validated) between corrosive and non-corrosive electrophiles. A plot of the first two principal components of the same parameters showed a clear demarcation between corrosive and non-corrosive electrophiles. In contrast to the QSARs for skin irritation, increasing skin corrosivity was found to correlate with decreasing molecular volume, with increasing dipole moment, and with decreasing logP. The predominant parameter in determining the skin corrosivity of electrophilic organic chemicals appears to be the molar dose at which they are tested; this arises because skin corrosivity testing is conducted using a fixed mass or volume of chemical. A stepwise approach to the skin corrosivity/irritation classification of neutral and electrophilic organic chemicals is outlined. The derived QSARs should be useful for the prediction of the skin corrosivity potential of new or untested electrophiles. (Non-electrophilic neutral organic chemicals, as a category, do not generally appear to be corrosive.) Discrimination between some non-irritant and irritant neutral and electrophilic organic chemicals using these techniques is also possible. For a large number of chemicals whose irritation potentials lie in a fairly broad band around the irritant/non-irritant classification boundary, no firm prediction of classification is possible.