Diflufenican (DFF) is a herbicide registered globally since the mid-1980s and submitted for renewal in the European Union (EU) in 2016. The submission included extensive data from repeat-dose studies, reproductive and developmental toxicity studies and ToxCast/Tox21 high-throughput in vitro screening data to allow an assessment of endocrine adversity and activity. Despite no evidence of estrogen, androgen, thyroid, or steroidogenic (EATS) mediated patterns of adversity, regulatory reviewers deemed the investigations insufficient due to outdated guidelines lacking EATS parameters. Such a shortfall is common for many plant protection products (PPPs) undergoing renewal due to advances in scientific methodology. The EU's stepwise testing strategy addresses this by requiring OECD Level 2 and Level 3 studies to assess activity. If negative, further testing is unnecessary. However, DFF's positive result in the in vitro steroidogenesis assay (Level 2) triggered an OECD Level 5 extended one-generation reproductive toxicity (EOGRT) study. The EOGRT data confirmed previous findings that DFF does not cause endocrine disruption (ED) related adversity. A comprehensive weight of evidence (WoE) assessment of existing data could have sufficed to conclude DFF's lack of ED properties, preventing unnecessary animal testing. This underscores the need to enhance WoE methodologies to better utilize existing data in regulatory evaluations. • Review of 16 in vivo toxicology studies showed DFF lacks EATS-mediated adversity • A recent DFF EOGRT study showed no effects on any reproductive parameters • Highlights ethical concerns regarding redundant and unecessary animal testing • Advocates for flexible regulatory practices using comprehensive datasets • EU’s Stop-the-Clock period poses challenges for timely ED assessments
McCoole et al. (Sun,) studied this question.