Considerations regarding a permitted daily exposure calculation for ethyl methanesulfonate

Area of Science:

• Toxicology
• Pharmacology
• Risk Assessment

Background:

• Human exposure limits for toxic compounds typically use acceptable daily intake (ADI) or permitted daily exposure (PDE) calculations with safety factors.
• Previous ethyl methanesulfonate (EMS) exposure limits relied on generic toxicological thresholds or as-low-as-reasonably-achievable criteria, often using conservative linear extrapolation.
• These older methods were based on a 1 in 100,000 excess cancer risk, which may not fully account for compound-specific dose-response data.

Purpose of the Study:

• To propose an EMS-specific PDE using a threshold-based approach.
• To establish a safe exposure limit grounded in reliable experimental evidence of EMS genotoxicity.
• To implement the methodology outlined in the ICH Q3C guideline for setting PDE limits.

Main Methods:

• Utilized experimental evidence demonstrating a threshold dose-response for EMS genotoxicity.
• Identified a no-observed-effect level (NOEL) for in vivo mutation induction at 25 mg/kg/day.
• Applied the safety factor approach described in ICH Q3C appendix 3 for residual solvents.

Main Results:

• A reliable NOEL for EMS-induced mutations in vivo was demonstrated at 25 mg/kg/day.
• Using conservative safety factors from ICH Q3C, an EMS-specific PDE was derived.
• The calculated PDE is approximately 100 microg/person/day, incorporating product safety factors of 12,000.

Conclusions:

• The proposed EMS-specific PDE provides a more scientifically robust exposure limit compared to generic TTC-derived limits.
• This threshold-based approach accounts for the specific genotoxic mode of action of EMS.
• The derived PDE offers a safer and more refined guideline for managing human exposure to EMS.