Threshold of Toxicological Concern-An Update for Non-Genotoxic Carcinogens

Area of Science:

• Toxicology
• Chemical Risk Assessment

Background:

• The Threshold of Toxicological Concern (TTC) concept establishes exposure limits for organic compounds.
• TTC differentiates between genotoxic and non-genotoxic carcinogens, applying different thresholds.
• Non-genotoxic compounds are typically assigned TTC values based on Cramer classes.

Purpose of the Study:

• To investigate the adequacy of Cramer class TTC values for protecting against non-genotoxic carcinogens.
• To compare benchmark dose levels with no observed effect levels (NOELs) for non-genotoxic carcinogens.

Main Methods:

• Classified 137 non-genotoxic carcinogens using data from the CEFIC LRI project B18.
• Derived NOEL values from chronic oral exposure studies using RepDose, ToxRef, and COSMOS DB.
• Calculated effective tumor dose (ETD10) and benchmark dose levels (BMDL10) for comparison.

Main Results:

• Potentially bioaccumulative compounds and steroids, identified as exclusion categories, were predominantly in the lower percentile ranges.
• Excluding these 25 compounds resulted in higher, comparable fifth percentile chronic NOEL and BMDL10 values.
• The fifth percentile ETD10 value was slightly higher but not statistically significant after exclusions.

Conclusions:

• The distributions of NOELs align with existing Cramer classes and their derived TTC values.
• Supports the application of Cramer class TTC values for all non-genotoxic compounds, including non-genotoxic carcinogens.