ECETOC Guidance on Dose Selection - Technical Report No. 138

The National Cancer Institutes (NCI) defined the MTD as “the highest dose of the test agent during the chronic study that can be predicted not to alter the animals’ longevity from effects other than carcinogenicity” (Sontag et al., 1976), and further suggested that the choice of the MTD should be based on the results of a 90-day study where the highest dose caused “no more than a 10% weight decrem. [...] Effects detected at doses around or above the limit dose (1000 mg/kgbw/d) contributed only a very minor number of classification outcomes (0% for the NOAELs and 4% at the LOAEL), further challenging the assumption that the higher the dose the greater the number of classifiable outcomes. [...] In the more recent version, the authors point out that “Defining the MTD in the studies of shortest duration informs dose setting in subsequent studies and is crucially important in application of the 3Rs since this reduces the chances of larger numbers of animals that are used in regulatory studies being exposed to unanticipated suffering”. [...] The kinetic objectives of the regulatory and non-regulatory studies with integrated TK remains the same as those for the early repeated dose studies i.e., characterising the dose vs exposure relationship and the range of dose proportionality in parallel to toxicity assessment. [...] Time Effects and Accumulation Ratio (Rac) To assess whether the TK of the compound changes with time and repeated dose administration, it is important to characterise the TK profile after the first dose (Section 3.4.4.1); sampling should follow the first dose (which acts as the reference point) and the last dose, or on a day close to the end of the study, where steady-state has been achieved.