Stakeholder input towards further refinement and consolidation of the alternative safety profiling algorithm (ASPA) for next generation risk assessment (NGRA)

Next-generation risk assessment (NGRA) aims to enable transparent, reproducible chemical safety assessments based on human-relevant, animal-free new approach methodologies (NAMs). The Alternative Safety Profiling Algorithm (ASPA) was developed within the ASPIS cluster to provide an algorithmic workflow that structures problem formulation, evidence integration, and decision-making across three main pillars-hazard, ADME (toxicokinetics), and exposure. To refine ASPA, a stakeholder workshop was organized. Four breakout groups systematically reviewed corresponding workflow sections, identifying strengths, conceptual gaps, and opportunities for harmonization. Across groups, participants endorsed ASPA's modular, technology-neutral nature and its focus on standardizing processes rather than prescribing specific test batteries. The hazard pillar discussions emphasized a sensitive, hypothesis-generating Tier 1, complemented by a specific, mechanistic Tier 2, capable of deriving points of departure (PoDs). ADME experts supported a physiology-based kinetic (PBK) modelling strategy, advancing from generic towards more complex models, using mechanistic information and experimental data. The exposure group proposed refinements for transparent, tiered exposure modelling, with emphasis on realistic worst-case scenarios and explicit uncertainty communication. Cross-pillar discussions highlighted the importance of feedback loops between all pillars, and the documentation of decision points to achieve consistency and defensibility. The workshop outcomes informed three parallel developments: (i) algorithmic refinement and re-design toward the next ASPA version, (ii) the creation of detailed guidance for each building block, and (iii) the establishment of practical case studies to demonstrate workflow implementation. This report already contains a first case study (developmental neurotoxicity assessment of desnitro-imidacloprid). These advances increase the operability, transparency, and regulatory readiness of ASPA.