Evaluation of the Threshold of Toxicological Concern (TTC) – Challenges and approaches

Thresholds of Toxicological Concern for cosmetics-related substances: New database, thresholds, and enrichment of chemical space

“…There has also been discussion of whether it would be preferable, from a scientific perspective, to use molar quantities of chemical entities and convert NOAELs from mg/kg-bw into mmol/ kg-bw (Escher et al, 2010;Dewhurst and Renwick, 2013). This was not pursued in the present work for the COSMOS TTC dataset since the scientific community utilising the TTC approach is mostly working on a mg/kg-bw basis, and using that basis allows easier comparisons with other published TTC values.…”

“…It has been deemed still fit for purpose by European advisory bodies (EFSA, 2012;SCCS, SCHER and SCENIHR, 2012). However, the fact that it was developed on the basis of toxicological knowledge of several decades ago and because users of the Toxtree software for assignment of Cramer Classes have raised questions about inconsistencies and problems with some of the steps in the Cramer decision tree, the need to revise some aspects of the decision tree has been discussed and certain changes have been proposed Dewhurst and Renwick, 2013;EFSA/WHO, 2016;Lapenna and Worth, 2011;Patlewicz et al, 2008;Roberts et al, 2015). Some of the proposed changes have been implemented in the Toxtree software.…”

“…Although the intent was to cover a broad chemical domain, the dataset is now over 20 years old, and questions have been raised as to whether it is adequately representative of chemicals and structures used in contexts other than its original application in food (Dewhurst and Renwick, 2013). This issue was first raised in relation to cosmetics by Blackburn et al (2005) and was an important consideration for the use of TTC for chemicals in cosmetics and consumer products in the opinion of the European Commission's non-food Scientific Committees (SCCS, SCHER and SCENIHR, 2012).…”

Thresholds of Toxicological Concern – Setting a threshold for testing below which there is little concern

“…More modern identifications of toxic chemophores and aggregate similarity measures have yet to be explored. In Europe, the EU Scientific Committee on Food (SCF, 1996) first considered TTC use, raising questions on whether the initial TTC value of 1.5 µg/day, derived from the cancer database, 2011 (Dewhurst and Renwick, 2013), however, considered the current TTC value to be adequate and fit for purpose for cancer because it is derived by linear extrapolation from the owest toxicological dose 50% (TD 50 ) for each compound in the largest available rodent carcinogenicity database.…”

“…A large ILSI-Europe workshop (Dewhurst and Renwick, 2013) and subsequent ILSI-Europe Threshold of Toxicological Concern Task Force 2 , as well as several opinions by the European Agencies 3 , and the scientific committees of Directorate General for Health and Food Safety (SCHER, SCCP, SCENIHR, 2008;EFSA, 2012) addressed the topic. In 2012, three independent non-food Scientific Committees of the European Commission were jointly tasked with evaluating potential applications of the TTC approach for human health risk assessment of chemical substances (EC, 2012(EC, , 2013.…”