Natural, plant-derived botanical ingredients are increasingly being used in cosmetic and personal care products. Safety evaluation of these complex mixtures is a challenge due to factors such as a high degree of variability in composition. Where direct evidence of safety does not exist, it may be necessary to use Threshold of Toxicological Concern (TTC) and a weight-of-evidence (WoE) approach to evaluate safety. The first step in the safety evaluation of natural ingredients is to obtain a complete as possible characterization of chemical constituents. For each component, its maximum known concentration, its molecular weight, and LogP are use to estimated skin penetration potential and to estimate a maximal daily systemic exposure. Nominal exposure values are then compared with their respective TTC class, known NOAEL’s and/or food intake values of “no safety concern.” In cases where systemic exposure exceeds these values, additional in silico evaluation may be done. Read across using procedures such as the JECFA congeneric model and/or computer modeling to identify similar structures with known toxicity data may be used. In addition, potential structural alerts of individual components can be evaluated using commercially available databases – DEREK, OECD toolbox, Lead Scope, etc.). Therefore, a weight-of-evidence approach based on available toxicology data, extrapolated NOELs, and/or predictive in silico data can be used to evaluate the safe cosmetic use of complex plant-derived materials cosmetics.