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March 01, 2021

Threshold of Toxicological Concern

Risk Assessment Formula

The Threshold of Toxicological Concern (TTC) is a pragmatic risk assessment tool and is considered to be an exposure level below which the risk of adverse effects to human health is expected to be negligible.  TTC values for a given compound can be derived using its molecular structure to determine the hazard ranking based on the Cramer classification.  TTC values have been assigned by Kroes et al to various classes of chemical compounds as determined by a QSAR analysis.  Based on this principle, it became a widely employed approach to screen out chemical compounds occurring below the TTC levels and avoid performing an in-depth toxicological evaluation to derive tolerable exposure levels based on a No Observed Adverse Effect Level (NOAEL) value.

However, a specific guidance on when and where to employ this approach in toxicological risk assessments was not available and regulatory agency (FDA) response to the acceptability of this approach in submissions over the years has been inconsistent.  In 2019. ISO released guidance on the use of TTCs in medical device toxicological risk assessment, namely ISO 21726 in which the conditions under which TTC levels can be used not to avoid or replace an in-depth chemical-specific toxicological evaluation but as an alternative when one cannot be performed are clearly stated.

ISO 21726 recommends the application of the TTC approach when no published toxicological data are available on the given compound, or when the identity of chemical compounds found among the extractables and leachables of a medical device cannot be established after performing analytical work at the highest level of resolution or most sensitive analytical method.

Furthermore, the guidance also prohibits the use of TTC for toxicological evaluation of chemical compounds belonging to “Cohorts of Concern” which includes: N-nitroso compounds, Azo compounds, Polyhalogenated –dibenzodioxins, -dibenzofurans, and -biphenyls, Strained heteronuclear rings, Heavy metals (e.g. elemental, ionic, or compounds), Alpha-nitro furyl compounds, Hydrazines/triazenes/azides/azoxy compounds, Polycyclic amines, Steroids, and Organophosphorous compounds.

Based on the new ISO guidance and our experience with FDA, it is strongly recommended that the TTC approach should be limited to the evaluation of unknown compounds and not be used as a screening method in toxicological risk assessment.

Author – Devaki Sadhu Ph.D. – Department Head, ToxSmart