Improvement of the Cramer classification for oral exposure using the database TTC RepDose--a strategy description

Abstract

The present report describes a strategy to refine the current Cramer classification of the TTC concept using a broad database (DB) termed TTC RepDose. Cramer classes 1-3 overlap to some extent, indicating a need for a better separation of structural classes likely to be toxic, moderately toxic or of low toxicity. Groups of structurally similar compounds of high toxicity in Cramer class 1 and of moderate to low toxicity in Cramer class 3 were identified and reassigned to the appropriate Cramer class according to their observed toxicological potency in in vivo studies. This refinement results in a better discrimination of Cramer classes 1 and 3 and an increased number of substances in Cramer class 2. The TTC values are 8.7 μmol/person/d (class 1), 6.72 μmol/person/d (class 2) and 0.28 μmol/person/d (class 3). Assuming a median molecular weight of 220 g/mol for the compounds of the TTC RepDose DB, the corresponding TTC values are 1930, 1478 and 63 μg/person/d for classes 1, 2 and 3 respectively. The derived thresholds are close to the TTC values initially proposed by Munro with 1800, 540 and 90 μg/person/d for classes 1, 2 and 3 respectively. Additional structural classes are discussed with a view to further refinement of the current Cramer classification scheme.