Carbamates and ICH M7 classification: Making use of expert knowledge

Area of Science:

• Toxicology
• Computational Chemistry
• Regulatory Science

Background:

• Carbamates are prevalent in the chemical industry, necessitating toxicity understanding for safety.
• Structural alerts for mutagenicity aid in classifying genotoxic risks of pharmaceutical impurities under ICH M7 guidelines.
• Assessing carbamate mutagenicity is crucial for regulatory compliance and risk management.

Purpose of the Study:

• To evaluate the utility of a hypothetical bacterial mutagenicity alert for carbamates.
• To determine the impact of this alert on International Council for Harmonisation (ICH) M7 classifications.
• To assess the predictive performance of computational systems for carbamate mutagenicity.

Main Methods:

• Utilized (Quantitative) Structure-Activity Relationship ((Q)SAR) predictions from Derek Nexus and Sarah Nexus.
• Tested a carbamate-specific bacterial mutagenicity alert.
• Analyzed public and proprietary datasets for mutagenic carbamate prevalence.
• Conducted expert review of mutagenic carbamate findings.

Main Results:

• Public and proprietary datasets showed a low prevalence of mutagenic carbamates.
• Systems incorporating the carbamate alert exhibited poor performance in achieving correct ICH M7 classifications.
• Mutagenicity in carbamates was often observed under non-standard conditions.
• The Ames test may not reliably predict carcinogenicity risk for carbamates.

Conclusions:

• A structural alert for carbamate in vitro bacterial mutagenesis does not benefit ICH M7 classification workflows.
• The Ames test's utility in predicting carbamate carcinogenicity is questionable.
• Relying solely on bacterial mutagenicity alerts for carbamates may lead to inaccurate genotoxic risk assessments.