Challenges in working towards an internal threshold of toxicological concern (iTTC) for use in the safety assessment of cosmetics: Discussions from the Cosmetics Europe iTTC Working Group workshop

Abstract

The Threshold of Toxicological Concern (TTC) is an important risk assessment tool which establishes acceptable low-level exposure values to be applied to chemicals with limited toxicological data. One of the logical next steps in the continued evolution of TTC is to develop this concept further so that it is representative of internal exposures (TTC based on plasma concentration). An internal TTC (iTTC) would provide threshold values that could be utilized in exposure-based safety assessments. As part of a Cosmetics Europe (CosEu) research program, CosEu has initiated a project that is working towards the development of iTTCs that can be used for the human safety assessment. Knowing that the development of an iTTC is an ambitious and broad-spanning topic, CosEu organized a Working Group comprised a balance of multiple stakeholders (cosmetics and chemical industries, the EPA and JRC and academia) with relevant experience and expertise and workshop to critically evaluate the requirements to establish an iTTC. Outcomes from the workshop included an evaluation on the current state of the science for iTTC, the overall iTTC strategy, selection of chemical databases, capture and curation of chemical information, ADME and repeat dose data, expected challenges, as well as next steps and ongoing work.

Keywords: Cosmetics; Cosmetics europe; PBPK; Physiologically based pharmacokinetic model; Risk assessment; TTC; Thresholds of toxicological concern.

Figure 1

Proposed approach for deriving iTTC values

Figure 2

Principal component analysis (PCA) for the 1251 chemicals in the iTTC project when including molecular and ADME descriptors and Toxprint fingerprints. PCA when considering continuous descriptors and plotting PC1 vs PC2 vs PC3 (A). Discrete descriptors for k-means clustering (B), Cramer Classification (C) or expected clearance pathway (D) were integrated into the PCA to further classify the chemicals. The color code for Cramer classification is class I (green), class II (red) and class III (blue). The color code for clearance pathways is metabolism (green), renal (cyan), hepatic uptake (blue) and hepatic uptake or renal (red).

Figure 3

Principal component analysis (PCA) for the iTTC chemicals filtered so that it only displays chemicals from one cluster (cluster 21), from the k-means clustering assessment (A). Discrete descriptors for Cramer classification (B) and clearance pathway (C), as well as chemical structure (D) were integrated into the PCA to further classify the chemicals. The color code for Cramer classification is class I (green) and class III (blue). Only one clearance pathway (hepatic uptake or renal) was represented in the selected cluster.