Next Generation Risk Assessment (NGRA) is defined as an exposure-led, hypothesis-driven risk assessment approach that integrates New Approach Methodologies (NAMs) to assure safety without the use of animal testing. These principles were applied to a hypothetical safety assessment of 0.1% coumarin in face cream and body lotion. For the purpose of evaluating the use of NAMs, existing animal and human data on coumarin were excluded. Internal concentrations (plasma Cmax) were estimated using a physiologically-based kinetic (PBK) model for dermally applied coumarin. Systemic toxicity was assessed using a battery of in vitro NAMs to identify points of departure (PoDs) for a variety of biological effects such as receptor-mediated and immunomodulatory effects (Eurofins Safety44™ screen and BioMap® Diversity 8 Panel, respectively), and general bioactivity (ToxCast data, an in vitro cell stress panel and high-throughput transcriptomics (HTTr)). In addition, in silico alerts for genotoxicity were followed up with the ToxTracker® tool. The PoDs from the in vitro assays were plotted against the calculated in vivo exposure in order to calculate a margin of safety (MoS) with associated uncertainty. The predicted Cmax values for face cream and body lotion were lower than all PoDs with MoS higher than 100. Furthermore, coumarin was not genotoxic, did not bind to any of the 44 receptors tested and did not show any immunomodulatory effects at consumer relevant exposures. In conclusion, this case study demonstrated the value of integrating exposure science, computational modelling and in vitro bioactivity data, in order to reach a safety decision without animal data.