QUANTITATIVE STRUCTURE-ACTIVITY-RELATIONSHIPS FOR SKIN IRRITATION ANDCORROSIVITY OF NEUTRAL AND ELECTROPHILIC ORGANIC-CHEMICALS

Quantitative structure-activity relationships (QSARs) have been derive d by relating skin irritation and corrosivity data of neutral and elec trophilic organic chemicals to their log(octanol/water partition coeff icient) (logP), molecular volume, dipole moment and 1/molecular weight . Datasets were analysed using stepwise regression, discriminant and p rincipal components analysis. Discriminant analysis between irritant a nd non-irritant neutral and electrophilic organic chemicals using the above parameters, which broadly model skin permeability (logP and mole cular volume), 'reactivity' (dipole moment) and 1/molecular weight to compensate for the fact that skin irritation/corrosivity testing is ca rried out using a fixed mass or volume of chemical, was found to discr iminate well for only 73.1% of the dataset (67.3% cross-validated). Th e poor discrimination at the irritant/non-irritant classification boun dary is attributed largely to biological variability. Stepwise regress ion analysis of the Primary Irritation Index (PII) for the same datase t showed a poor correlation (r(2) = 0.422: cross-validated r(2) = 0.20 1) with a positive dependence on logP and dipole moment and a negative dependence on molecular volume; 1/molecular weight was not a signific ant 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 irr itation. Discriminant analysis using logP, molecular volume and dipole moment, was able to discriminate reasonably well (92.9% well-classifi ed; 92.9% cross-validated) between corrosive and non-corrosive electro philes. A plot of the first two principal components of the same param eters showed a clear demarcation between corrosive and non-corrosive e lectrophiles. In contrast to the QSARs for skin irritation, increasing skin corrosivity was found to correlate with decreasing molecular vol ume, with increasing dipole moment, and with decreasing logP. The pred ominant parameter in determining the skin corrosivity of electrophilic organic chemicals appears to be the molar dose at which they are test ed; this arises because skin corrosivity testing is conducted using a fixed mass or volume of chemical. A stepwise approach to the skin corr osivity/irritation classification of neutral and electrophilic organic chemicals is outlined. The derived QSARs should be useful for the pre diction of the skin corrosivity potential of new or untested electroph iles. (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 usi ng these techniques is also possible. For a large number of chemicals whose irritation potentials lie in a fairly broad band around the irri tant/non-irritant classification boundary, no firm prediction of class ification is possible. Copyright (C) 1996 Elsevier Science Ltd