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Abstract The transition towards Safe and Sustainable by Design (SSbD) chemicals and materials necessitates a fundamental shift from reactive hazard assessment to predictive, mechanism-based innovation governance. Traditional animal-based toxicology and late-stage risk assessment approaches are increasingly inadequate to address the pace, complexity, and sustainability expectations of modern product development. This article examines how New Approach Methodologies (NAMs), including in silico modeling, in vitro systems, and quantitative in vitro to in vivo extrapolation (QIVIVE), can serve as an integrated knowledge engine supporting the SSbD framework. We discuss how these methodologies provide a pathway to integrate human-relevant mechanistic evidence into Next Generation Risk Assessment (NGRA) supporting SSbD decisions through tiered, hypothesis-driven workflows. Emphasis is placed on mechanistic anchoring via Adverse Outcome Pathways (AOPs) and digital workflow integration aligned with FAIR data principles. By aligning mechanistic toxicology with exposure science and digital decision-support systems, integrated NAM workflows provide a scientifically robust strategy for advancing transparent and sustainable chemical innovation. The convergence of SSbD and NGRA represents a transformative opportunity to enhance human and environmental protection while fostering responsible technological progress.