Regulatory integration of new approach methodologies for human-relevant developmental and reproductive toxicity...

Developmental and reproductive toxicity (DART) assessment is a critical component of regulatory safety evaluation across pharmaceutical, chemical, environmental, and consumer product sectors. Traditionally, DART testing has relied on animal-based studies designed to detect adverse effects on fertility, embryonic development, and postnatal growth. However, these conventional approaches present increasing scientific and ethical challenges, including high costs, extended study durations, limited mechanistic insight, and interspecies differences that may reduce their predictive value for human health outcomes. Concurrently, regulatory frameworks increasingly emphasize the principles of Replacement, Reduction, and Refinement (3Rs), driving the development of alternative testing strategies. This systematic review examines the evolving regulatory landscape for DART assessment and evaluates the scientific and regulatory progress associated with emerging New Approach Methodologies (NAMs). A structured literature search was conducted across major scientific databases following PRISMA 2020 guidelines, identifying relevant scientific and regulatory publications from January 2005 to February 2026. The review analyzes key international regulatory frameworks, including OECD Test Guidelines, ICH S5(R3), the European Union REACH regulation, and guidance from U.S. and European regulatory authorities. Particular emphasis is placed on mechanistic frameworks such as Adverse Outcome Pathways (AOPs) and Integrated Approaches to Testing and Assessment (IATA), which facilitate the integration of diverse data streams within weight-of-evidence-based regulatory decision-making. Overall, NAMs offer significant potential to enhance the efficiency, mechanistic understanding, and human relevance of DART assessment. Nevertheless, challenges related to method validation, regulatory harmonization, and integration into existing safety assessment frameworks remain, highlighting the need for continued scientific innovation and international regulatory collaboration.