Maltol and ethyl maltol are common flavor ingredients in ENDS e-liquids. Both ingredients have published data suggestive of potential genotoxicity, but they are not classified as carcinogenic by any authoritative bodies (IARC, Cal-OEHHA, EPA and NTP). Because of the isolated positive genotoxicity results, the FDA has raised concerns about the genotoxicity hazard of the ingredients. Following ICH guidelines, an in vitro mouse lymphoma assay (MLA) and an in vivo Pig-A assay were conducted on both maltol and ethyl maltol under GLP conditions. The results of the studies demonstrated that ethyl maltol was negative in both the in vitro MLA assay and in vivo Pig-A mutant frequency assay. Maltol was positive in the in vitro MLA but negative in the in vivo Pig-A assay. In light of the negative MLA and Pig-A results, ethyl maltol is considered to not be genotoxic. The positive MLA response to maltol and negative result in the in vivo Pig-A assay indicates that maltol should not be considered genotoxic. Following ICH and FDA guidance, a negative result in an in vivo Pig-A carries more weight than a positive result in an in vitro MLA. Both maltol and ethyl maltol have also been found negative in published carcinogenicity assays. Using a weight of evidence approach considering these results and the results of other published mutagenicity studies on the two ingredients, as well as the results of carcinogenicity studies, both maltol and ethyl maltol should be placed in Tier 5: Unlikely to contribute to carcinogenic risk of ENDS. Tier 5 designation indicates that these ingredients should not be included in ENDS product Excess Lifetime Carcinogen (ELCR) risk calculations.