ABSTRACT The FDA PMTA guidance suggests that ENDS be analyzed for HPHCs as part of the application. The ENDS device is complex and needs to be analyzed from the perspective of the materials that are used to generate the aerosol and also come in contact with the E-Liquid. The components of the E-Liquid need to be evaluated to determine if they are appropriate for their intended use and, when aerosolized, if they are likely to lead to the production of hazardous constituents (HPHCs) as well as generate potential new unknown toxic chemicals. We have developed a wholistic approach tying extractables and leachables, HPHC analysis of liquid and vapor, toxicity testing (Ames, cytotox, in vitro and in vivo micronucleus, and sensitization (in silico, in vitro, and human) and ingredient safety evaluation. Inhalation thresholds of concern are used to identify potential chemicals of concern. The results are normalized to normal daily usage and compared to conventional cigarettes to demonstrate that the products are appropriate for the protection of public health. Market comparator data is used to show that the products are not different from currently marketed products. Total ion chromatograms are used to demonstrate that no new chemicals of toxicological concern are created in the vaporization process of newly manufactured materials as well as at the end of storage stability and end of life of the pod. The approach will be described in the presentation.