In January 2014, a chemical mixture used for cleaning coal was accidently released into the Elk River in West Virginia, resulting in contamination of the water supply for nearly 300,000 people. The mixture included 4-methylcyclohexanemethanol (MCHM), 1,4-cyclohexanedimethanol (CHDM), 4-methoxymethylcyclohexanemethanol (MMCHM), dimethyl 1,4-cyclohexanedicarboxylate (DMCHDC), and methyl 4-methylcyclohexanecarboxylate (MMCHC) a proprietary mixture of propylene glycol ethers containing propylene glycol phenyl ether (PPH) and dipropylene glycol phenyl ether (DiPPH). Limited toxicological data were available for these chemicals; therefore, a review of the available Tox21 high throughput screening (HTS) assay data was performed along with a structure activity relationship (SAR) analysis to predict potential toxicological effects. Four chemicals (MCHM, CHDM, DMCHDC, PPH) were evaluated in 27 stress response pathway and nuclear receptor assays. All four chemicals were inactive at concentrations up to ~100 mM. For SAR evaluations, 7 platforms were used (ADMET Predictor™, CASE Ultra, Leadscope®, MetaDrug™, SymmetrySM, Toxtree, VEGA). The results were organized based on the category of predicted endpoints and an integrated analysis was performed. Consistent with observed effects in West Virginia residents following the spill, the SAR analyses predicted that a number of the chemicals would be irritating to the skin, eyes, and lung. The chemicals also were predicted to produce effects in the liver and kidney, which is largely consistent with the limited, available toxicity data. A focused assessment of dose-response for effects on these and other target organs/systems will be performed as part of ongoing NTP toxicological studies.