Feasibility study: refinement of the TTC concept by additional rules based on in silico and experimental data

Area of Science:

• Toxicology
• Computational Chemistry
• Risk Assessment

Background:

• The threshold of toxicological concern (TTC) concept has evolved, with refined versions like Munro et al. commonly used.
• Current TTC approaches utilize differentiated structural classes based on Cramer et al. rules.

Purpose of the Study:

• To explore refining the TTC concept by incorporating additional structure-activity relationships and toxicity data.
• To investigate the potential for higher TTC values through new subgroup criteria.

Main Methods:

• Computer modeling using the OECD Toolbox.
• Collection of no observed (adverse) effect level (NO(A)EL) data for 176 substances.
• Creation of new subgroups based on extended Cramer rules, bioavailability, acute toxicity, protein binding, and predicted liver metabolism.

Main Results:

• A subgroup combining 'no protein binding affinity' and 'predicted liver metabolism' yielded the highest TTC value of 236 µg/kg/day.
• This determined TTC value is approximately eight times higher than the original Cramer class 1 limit value.
• The study demonstrated the feasibility of improving TTC values with the proposed criteria.

Conclusions:

• Inclusion of novel criteria like protein binding and liver metabolism can enhance TTC values.
• Refined TTC values can broaden the applicability of the TTC concept in risk assessment.
• This approach may reduce the necessity for animal testing in toxicological evaluations.