This study outlines the use of a recently developed fragment-based thiol reactivity profiler for Michael acceptors to predict toxicity toward Tetrahymena pyriformis and skin sensitization potency as determined in the Local Lymph Node Assay (LLNA). The results showed that the calculated reactivity parameter from the profiler, -log RC50(calc), was capable of predicting toxicity for both end points with excellent statistics. However, the study highlighted the importance of a well-defined applicability domain for each end point. In terms of Tetrahymena pyriformis, this domain was defined in terms of how fast or slowly a given Michael acceptor reacts with thiol leading to two separate quantitative structure-activity models. The first, for fast reacting chemicals required only -log RC50(calc) as a descriptor, while the second required the addition of a descriptor for hydrophobicity. Modeling of the LLNA required only a single descriptor, -log RC50(calc), enabling potency to be predicted. The applicability domain excluded chemicals capable of undergoing polymerization and those that were predicted to be volatile. The modeling results for both end points, using the -log RC50(calc) value from the profiler, were in keeping with previously published studies that have utilized experimentally determined measurements of reactivity. These results demonstrate that the output from the fragment-based thiol reactivity profiler can be used to develop quantitative structure-activity relationship models where reactivity toward thiol is a driver of toxicity.