Mechanistic applicability domains fro non-animal based toxicological endpoints. QSAR analysis of the Schiff base applicability domain for skin sensitization

Several recent (1999 onwards) publications on skin sensitisation to aldehydes and ketones which can sensitise by covalent binding to skin protein via Schiff base formation present QSARs based on the Taft sigma* parameter to model reactivity and log P to model hydrophobicity. Here all of the data are re-analysed together in a stepwise self-consistent way using the parameters log P and sum sigma*, the latter being the sum of sigma* values for the two groups R and R’ in RCOR’. A QSAR is derived: pEC3 = 1.12(±0.07)sum of sigma* + 0.42(±0.04) log P - 0.62(±0.13); n = 16 R2 = 0.952 R2adj = 0.945 s = 0.12 F = 129.6, based on mouse local lymph node assay (LLNA) data for 11 aliphatic aldehydes, one alpha-ketoester and four alpha,beta-diketones. In developing this QSAR, an initial regression equation for a training set of ten aldehydes was found to be well predictive predict a test set consisting of the other six compounds. The QSAR is found to be well predictive for LLNA data on a series of alpha,gamma-diketones and also correctly predicts the non-sensitising properties of simple dialkylketones. It is shown to meet all the criteria of the OECD principles for applicability within regulatory practice. In view of the structural diversity within the sets of compounds considered here, the present findings confirm the view that within the mechanistic applicability domain the differences in sensitisation potential are dependent solely on differences in chemical reactivity and partitioning.

ROBERTS Dw;  APTULA Ao;  TIER Grace; 

2006-12-18

AMER CHEMICAL SOC

JRC33772

https://publications.jrc.ec.europa.eu/repository/handle/JRC33772,   

10.1021/tx060102o,