While toxicity information is available for selected PFAS, little or no information is available for most, thereby necessitating a resource-effective approach to screen and prioritize those needing further safety assessment. The threshold of toxicological concern (TTC) approach proposes a de minimis exposure value based on chemical structure and toxicology of similar substances. The applicability of the TTC approach to PFAS was tested by incorporating a data set of no-observed-adverse-effect level (NOAEL) values for 27 PFAS into the Munro TTC data set. All substances were assigned into Cramer Class III and the cumulative distribution of the NOAELs evaluated. The TTC value for the PFAS-enriched data set was not statistically different compared to the Munro data set. Derived human exposure level for the PFAS-enriched data set was 1.3 μg/kg/day. Structural chemical profiles showed the PFAS-enriched data set had distinct chemotypes with lack of similarity to substances in the Munro data set using Maximum Common Structures. The incorporation of these 27 PFAS did not significantly change TTC Cramer Class III distribution and expanded the chemical space, supporting the potential use of the TTC approach for PFAS chemicals.