The TTC concept assigns thresholds to structural classes of compounds below which no risk for human health is assumed given a life-time exposure. Currently, these thresholds were developed by analyzing datasets of oral repeated-dose studies. Inhalation is, however, an important route in human risk assessment, e.g. at workplace and for consumer exposure. The application of the TTC concept/Cramer classification scheme to datasets of repeated-dose studies with inhalation exposure resulted in very low thresholds compared to the oral TTC values. Reasons might be route specific differences which are reflected e.g. in the high sensitivity of the respiratory tract to local effects.

We present an integrative approach to derive threshold values for inhalation exposure (Cefic_project: LRI-B8). 296 chemicals with repeated-dose toxicity studies in rodents from the FhG RepDose database were analysed. A special focus was set on the observed of mode of action (MoA), systemic versus local activity. About 20 structural features (SF) triggering low and high toxicity values were identified. Only few structural features related only to local or systemic activity indicating that this MoA is not the predominant driving force of toxicity. The identified SF were further evaluated taking into account structural homogeneity, differences in absorption, metabolism and the analysis of the target and effects observed in the corresponding in vivo studies. This approach is depicted with an example. The structural features as well as calculated properties were obtained by the UFZ software system ChemProp. Initial inhalation specific TTC values are proposed.