Nanomaterials (NMs), such as titanium dioxide (TiO2), are already widely used, and many innovative types, such as nanocelluloses (CNMs), are under development for applications in food and feed industry, requiring a thorough safety assessment regarding ingestion. This chapter describes the protocol for an integrated approach that uses a static in vitro digestion protocol to mimic human digestion prior to a battery of genotoxicity tests adapted to NMs, covering mammalian gene mutations, numerical, and structural chromosome aberrations. The inclusion of the digestion simulation in the design of the safety testing strategy can be seen as a new approach methodology (NAM) contributing to bridge the in vitro to in vivo physiology, providing important data for hazard assessment without the use of animal models.