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.
Highlights
Animal welfare concerns and regulatory restrictions on animal testing, along with the aspiration to develop methods more predictive of human biology than historical animal toxicology tests, have stimulated global interest in the development of alternative test methods
The work by Partosch et al, (2015) provided an initial view for what an internal TTC (iTTC) could look like and was in the 9th and 10th Revisions of the SCCS Notes of Guidance for the testing of cosmetics ingredient (SCCS, 2016), where it was proposed that an iTTC would be an improvement on the external dose Threshold of Toxicological Concern (TTC) for the assessment of dermal exposures based on oral data (SCCS, 2016; SCCS, 2018)
As noted above, there are a number of further considerations that need to go into the development of an iTTC before it is ready to use in a safety assessment
Summary
Animal welfare concerns and regulatory restrictions on animal testing, along with the aspiration to develop methods more predictive of human biology than historical animal toxicology tests, have stimulated global interest in the development of alternative test methods. A paper by Kroes et al, (2007), was the first explicit discussion on how to apply the decision tree to topically and intermittently applied cosmetic ingredients with respect to the chemical domain and the route-to-route extrapolation (oral-dermal) They concluded that TTC is a useful tool with applicability to cosmetic ingredients and impurities and proposed 3 default adjustment factors for the percent of dose that would be absorbed across the skin based on estimates of Jmax (maximum flux). The work by Partosch et al, (2015) provided an initial view for what an iTTC could look like and was in the 9th and 10th Revisions of the SCCS Notes of Guidance for the testing of cosmetics ingredient (SCCS, 2016), where it was proposed that an iTTC would be an improvement on the external dose TTC for the assessment of dermal exposures based on oral data (SCCS, 2016; SCCS, 2018). As noted above (and discussed throughout this report), there are a number of further considerations that need to go into the development of an iTTC before it is ready to use in a safety assessment
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