Improvement of the Cramer classification for oral exposure using the database TTC RepDose--a strategy description

Area of Science:

• Toxicology
• Chemical Safety
• Risk Assessment

Background:

• The Cramer classification system categorizes chemicals based on structural alerts for toxicity.
• Existing Cramer classes (1-3) exhibit overlap, necessitating improved discrimination of toxicological potency.
• A comprehensive database, TTC RepDose, was utilized to address these limitations.

Purpose of the Study:

• To refine the Cramer classification system for Threshold of Toxicological Concern (TTC) compounds.
• To improve the separation of structural classes based on their likelihood of being toxic, moderately toxic, or of low toxicity.
• To establish more precise TTC values for improved chemical risk assessment.

Main Methods:

• Utilized the TTC RepDose database containing a broad range of chemical structures.
• Identified and reassigned structurally similar compounds based on their observed toxicological potency from in vivo studies.
• Analyzed toxicological potency to refine class boundaries and derive new TTC values.

Main Results:

• Refined Cramer classes show better discrimination, particularly between classes 1 (high toxicity) and 3 (low toxicity).
• Class 2 (moderate toxicity) saw an increase in assigned substances.
• Derived TTC values per person per day are 8.7 μmol (class 1), 6.72 μmol (class 2), and 0.28 μmol (class 3).
• Corresponding TTC values (μg/person/day) are 1930 (class 1), 1478 (class 2), and 63 (class 3), closely aligning with Munro's initial proposals.

Conclusions:

• The refined Cramer classification enhances the separation of chemical toxicity classes.
• The updated TTC values provide a more accurate basis for risk assessment of chemicals.
• Further refinement of the Cramer classification scheme is suggested through the consideration of additional structural classes.