Evaluation of the TTC concept with the database RepDose

The Thresholds of Toxicological Concern (TTC) are generic human exposure threshold values derived for oral uptake for groups of chemicals below which no appreciable risk to human health is assumed. To reduce animal tests under REACH, in ANNEX XI of the REACH Guidance exposure based waiving is described for complex endpoints like repeated dose- or repro-toxicity, where no/limited alternative testing methods are available. The thresholds of the TTC concept could be used to define a structure based safe level of exposure for chemicals below which no further testing is needed. So far, the TTC concept has already been applied for contaminants in food and pharmaceuticals and for flavouring substances. These applications are characterised by very low exposure levels of the substances. We evaluated, whether the TTC concept is applicable to existing chemicals relevant for REACH. The database RepDose (Bitsch et al., 2006), which focuses on repeated dose toxicity studies of existing chemicals, was compared to the Munro database, which was originally used for deriving the TTCs. The distributions of NOELs and LOELs in both databases are very similar, although only 100 of about 600 chemicals are common in both databases. The TTC concept therefore may be applied to existing chemicals. The analysis of both databases also showed that the Cramer Classes do not discriminate adequately toxic from non-toxic chemicals, indicating a need to improve the Cramer decision tree. The analysis further revealed that local effects trigger low NOELs and LOELs in inhalation studies. Thresholds for inhalation exposure are derived