Evolving Regulatory Positions and Legacy Data Challenges: A Case Study of Fludioxonil's Unknown Metabolite Fraction MF2 in European Active Ingredient Renewal

Changing interpretation of legacy study data can have significant implications for existing data packages and risk assessments during regulatory Active Ingredient Renewal (AIR) programs of an active substance under European Regulation (EC) 1107/2009 [1]. This paper outlines one example relating to the aerobic soil metabolism data package for the fungicide fludioxonil. An historic aerobic soil metabolism study generated an unknown metabolite fraction (MF2) that exceeded 5% of the applied active substance in two sequential measurements and more than 5% at the end of the study. This finding was discussed at an European Food Safety Authority (EFSA) Expert Meeting [2] following European submission in 2003 with the conclusion that MF2 consisted of at least two single compounds which did not meet the criteria for soil and groundwater assessment. However, at the time of fludioxonil renewal under the AIR progam, further characterization of MF2 was requested. With no original study samples remaining, a new aerobic soil study was conducted to regenerate MF2 and allow further investigation. The soil from the original study and a surrogate soil were incubated under the original study test conditions. MF2 was generated at >5% active substance applied at consecutive timepoints in both soils. Enhanced high performance liquid chromatography (HPLC) demonstrated MF2 consisted of at least two individual components each <5%. This finding supports the original conclusion that MF2 does not meet the criteria for identification and soil/groundwater assessment. This study provides a methodological framework for addressing similar challenges with legacy studies.