Recent results of the analysis of Cramer classes for inhalation studies indicate that local effects of the respiratory tract and eyes dominate the very low NOEC values in Cramer class 1 and also to some extent in class 3 and thus trigger inhalation thresholds (Escher S.E. et al., 2010 in section: details of ongoing work). This finding indicates that the lower inhalation thresholds compared to the oral application are specific for the inhalation route. It can be assumed that these local effects are associated with local reactivity e.g. irritative properties of the compound.
The aim of the project is the development of a strategy to derive new potency classes for inhalation toxicity. The added value of the project will be an improved evaluation of the existing inhalation studies regarding toxic potency, mode of action, structural alerts incl. descriptors of the irritant potency as well as physico chemical descriptors. These analyses are expected to reveal route specific criteria which will lead to inhalation potency classes or alternatively improved Cramer classes with the aim of deriving inhalation specific TTC values.
The general strategy is described in detail in section 2 and will consider the following aspects:
- Extension of the RepDose database
- Analysis of ”mode of action” to clearly define systemic and local toxicity
- Evaluation of irritative properties and their consequences for grouping
- Evaluation of physico chemical properties to refine grouping
- Identification of structural features that lead to very high or low NOEC values for systemic and local toxicity and evaluation of consequences for grouping
- Combination of grouping methods to derive robust thresholds values for inhalation exposure
The developed strategy of grouping and regrouping of substances shall lead to robust thresholds values for inhalation exposure for which distinct thresholds values will be derived. A final report will address the following issues:
- Which route specific parameters are needed to modify the TTC concept for inhalation exposure?
- Which strategy results in robust TTC values for inhalation exposure? Is this strategy also applicable to the refinement of TTCs for oral exposure?
- Is it possible to derive precisely distinguished potency classes for inhalation exposure?
- Which new potency classes and thresholds have been obtained? Where are the limitations of the developed approach?
Research project summary:
Inhalation threshold of toxicological concern (TTC) — Structural alerts discriminate high from low repeated-dose inhalation toxicity by Schüürmann G., Ebert R-U, Tluczkiewicz I., Escher S.E., Kühne R., Environment International 88 (2016) 123-132
The 296 in vivo studies of the RepDose TTC inhalation database, the structural descriptors of the compounds and the physico chemical properties are available online under www.fraunhofer-repdose.de
LRI-B8 Threshold of Toxicological Concern (TTC) for inhalation exposure by I. Tluczkiewicz, R. Kühne, R.U. Ebert, M. Batke, G. Schüürmann, I. Mangelsdorf and S.E. Escher
The Threshold of Toxicological Concern (TTC) concept for inhalation exposure: New TTC concept for inhalation exposure and derivation of thresholds with the database RepDose by Inga Tluczkiewicz , Ralph Kühne, Ralf-Uwe Ebert, Gerrrit Schüürmann, Inge Mangelsdorf and Sylvia E. Escher, presented at the 14th Cefic-LRI Annual Workshop 2012
Refinement of TTC values – Identification of outliers in Cramer class I – III by Inga Tluczkiewicz, Sylvia Escher, Annette Bitsch and Inge Mangelsdorf
Structural alerts to classify inhalation toxicity by Ralph Kühne, Ralf-Uwe Ebert, Inga Tluczkiewicz, Sylvia Escher and Gerrit Schüürmann
TTC: A new concept for inhalation exposure by Sylvia E. Escher, Inga Tluczkiewicz, Ralph Kühne, Ralf-Uwe Ebert, Gerrit Schüürmann, Inge Mangelsdorf