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2009
Conference Paper
Titel
Applicability domain of TTC (Threshold of Toxicological Concern) schemes - a conceptual approach
Titel Supplements
Abstract
Abstract
The TTC concept is based on the assumption that for a wide range of chemical substances there can be defined a threshold level of exposure belowwhich there is no significant risk of adverse effects to human health. Originally proposed for the regulation of foodpacking materials, a TTC of 1.5 mg/day had been established in 1995 by the US FDA for food additives expected to be non-carcinogenic. Subsequently, statistical analysis of oral rodent and rabbit NOELs for 613 compounds (Munro database) lead to TTC values for three general structural classes with different inherent toxicity potentials (Cramer scheme) of 1800, 540 and 90 mg/day. Extension to organophosphate neurotoxicity and potential genotoxicity yielded respective additional TTCs of 18 and 0.15 mg/day. An ongoing study using the RepDose database investigates the possibility of deriving TTC values for the inhalation pathway. With regard to TTC applications for the risk evaluation of industrial substances under REACH, an important question is how the compound class coverage of the TTC database relates to the chemistry of REACH substances. In the present communication,we show how the ACF (atom-centered fragment) methodology can be used for identifying and characterizing the structural domain of chemical substances. Application to both the Munro and RepDose databases as well as to the EINECS list of ca. 70.000 organic compounds provides a first characterization of their overlaps with respect to the structural domain. Moreover, examples are taken to demonstrate the integration of the ACF-based applicability domain characterization into the TTC approach.