A variety of flavor ingredients are used in potentially reduced-risk tobacco or nicotine products, including e-vapor products. For this work, the ingredients were initially evaluated for quality and purity, which included assessment of food grade and GRAS (Generally Recognized as Safe) status, followed by a comprehensive review of the available toxicological data. Considering the number of available flavors and the numerous potential flavor combinations, toxicity testing of each individual compound or formulation may not always be feasible. This presentation outlines a pragmatic approach to selecting representative compounds and flavor mixtures that reflect a range of more than 200 commonly used flavors (e.g., a flavor “toolbox”). To develop a representative mixture, each individual flavor in our toolbox was allocated to one of 34 structural groups defined in the European Commission (EC) Regulation No 1565/2000 (European Commission, 2000), and broader structural groups were further subdivided to better reflect the range of structural differences. Flavors within a given structural group are expected to exhibit similar metabolic and biological properties. Following this approach, 38 groups were defined, encompassing 27 of the original 34 EC groups. We then ranked each flavor within a group based on a toxicological evaluation (literature, in silico predictive analysis, and internal data). Lastly, using an objective computational procedure and scoring system, we selected representative flavors (i.e., predicted worst-case based on the toxicological profile) from each structural group, which were combined to create a full “toolbox” flavor mixture. The final flavor mixture created by this approach could be tested in preclinical (in vitro and in vivo) toxicity studies, in part, to support the range of flavors in a flavor toolbox.