Dermal absorption study OECD TG 428 mass balance recommendations based on the EFSA database.

Area of Science:

• Toxicology
• Risk Assessment
• Analytical Chemistry

Background:

• The European Food Safety Authority (EFSA) guidance mandates stringent mass balance (MB) limits (95-105%) for dermal absorption (DA) studies.
• EFSA's 'addition rule' requires unrecovered material to be added to the absorbed dose if MB is below 95%, disproportionately affecting low absorption pesticides.
• Existing data indicate that achieving EFSA's MB criteria is challenging, even with standardized protocols, with a significant portion of studies falling outside the recommended range.

Purpose of the Study:

• To investigate the impact of study protocols on mass balance (MB) in dermal absorption (DA) studies.
• To evaluate the validity of EFSA's stringent MB criteria using the EFSA DA database.
• To propose a revised, data-driven MB criterion aligned with OECD recommendations.

Main Methods:

• Analysis of the EFSA Dermal Absorption (DA) database to assess mass balance (MB) variability.
• Evaluation of how different protocol procedures influence MB outcomes.
• Statistical assessment of MB data to demonstrate its inherent random variation.

Main Results:

• A significant proportion of MB values in the EFSA DA database fall outside the 95-105% range.
• Data suggest that MB is subject to random variation, not solely attributable to material loss after penetration.
• The application of EFSA's 'addition rule' can artificially inflate DA estimates, leading to potential risk assessment failures.

Conclusions:

• EFSA's strict 95-105% MB criterion is not consistently achievable and can lead to inaccurate DA estimations.
• "Missing material" in DA studies represents random negative deviations rather than solely post-penetration loss.
• A revised, data-driven MB criterion of 90-110% is proposed, offering a more scientifically sound approach consistent with OECD guidelines.