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The value of the “threshold of toxicological concern” (TTC) concept is undeniable, but many experts were concerned, and remain concerned, that the maximum daily exposure of 1.5 μg was overly conservative (being based on the combination of several “worst case” assumptions in its derivation) and especially conservative if applied to short duration usage and acute‐use therapies. Importantly, the guideline as published did not provide clear guidance on what standards would be expected of investigational medicinal products during the clinical development phases, when controlled and often short duration clinical trials are conducted. It should be unnecessary to apply a control standard applicable to lifetime exposure in such short duration clinical studies, but the guideline gave no specific guidance on what standard would be expected, leaving the implementation of the guideline to be potentially inconsistent. Of primary concern was the lack of any indication as to whether or not the staged TTC concept, as outlined in the Mueller paper [5], was acceptable or not. This led to considerable confusion and uncertainty, which was ultimately resolved with the publication, some 18 months later, of the EMEA staged TTC limits through the SWP Q&A Document [10].