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Improvement of the Cramer classification for oral exposure using the database TTC RepDose - A strategy description
Citation:
TLUCZKIEWICZ, I. I., H. E. BUIST, M. T. MARTIN, I. MANGELSDORF, AND S. E. ESCHER. Improvement of the Cramer classification for oral exposure using the database TTC RepDose - A strategy description. REGULATORY TOXICOLOGY AND PHARMACOLOGY. Elsevier Science BV, Amsterdam, Netherlands, 61(3):340-350, (2011).
Impact/Purpose:
The wide spread of NOEL values observed for the halogenated compounds in the TTC RepDose DB indicates that the halogenated compounds do not represent a homogenous structural class of compounds with similar toxicological potency. A more detailed correlation of structural elements and toxicological potency in the subclass of halogenated but multifunctional compounds is needed to distinguish halogenated compounds of low, moderate and high toxicity reassignable to the Cramer scheme or alternatively applicable to category specific TTC values.
Description:
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.
