Grouping approaches of nanomaterials have the potential to facilitate high throughput and cost effective nanomaterial screening. However, an effective grouping of nanomaterials hinges on the application of suitable physicochemical descriptors to identify similarities. To address the problem, we developed an integrated testing approach coupling acellular and cellular phases, to study the full life cycle of ingested silver nanoparticles (NPs) and silver salts in the oro-gastrointestinal (OGI) tract including their impact on cellular uptake and integrity. This approach enables the derivation of exposure-dependent physical descriptors (EDPDs) upon biotransformation of undigested nanoparticles, digested nanoparticles and digested silver salts. These descriptors are identified in: size, crystallinity, chemistry of the core material, dissolution, high and low molecular weight Ag-biomolecule soluble complexes, and are compared in terms of similarities in a grouping hypothesis. Experimental results indicate that digested silver nanoparticles are neither similar to pristine nanoparticles nor completely similar to digested silver salts, due to the presence of different chemical nanoforms (silver and silver chloride nanocrystals), which were characterized in terms of their interactions with the digestive matrices. Interestingly, the cellular responses observed in the cellular phase of the integrated assay (uptake and inflammation) are also similar for the digested samples, clearly indicating a possible role of the soluble fraction of silver complexes. This study highlights the importance of quantifying exposure-related physical descriptors to advance grouping of NPs based on structural similarities.