Following publication of FDA’s Expanded Decision Tree (EDT), a question of whether applying the Kroes workflow to the EDT dataset would yield Threshold of Toxicological Concern (TTC) values comparable to those derived from the original Munro dataset was raised. Herein, the Kroes workflow was applied to the EDT dataset to identify all Cramer class applicable substances from which TTCs were derived by bootstrapping 5th percentile NOAELs. The resulting values (34, 13.7, and 1.54 µg/kg bw/day for Cramer classes I-III) closely matched the existing Munro-derived thresholds. Comparison of chemical structure using ToxPrint fingerprints found only minor differences, with most structural features appearing at similar frequencies in both datasets, supporting the validity of the Munro-based TTCs. When EDT and Cramer class assignments were compared against expert derived classifications from a reference dataset, agreement stood at 65%, with the EDT scheme proving more permissive in roughly a quarter of cases, partly due to limitations in how the original Cramer tree handled certain substance types. Within EDT class I, a carbohydrate-based subgroup emerged which could justify a new “class 0” designation, carrying a proposed TTC of 1387 µg/kg bw/day. Lastly, because Toxtree’s existing Cramer module currently lacks a programmatic interface to support computational workflows, a Python-based reimplementation of the Cramer scheme was developed, and validated against the Munro dataset to confirm it reproduced results from the original Toxtree module. Together, these findings support the continued validity of Munro-derived TTCs whilst identifying specific opportunities to refine both schemes for computational use.