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The objective was to challenge cross-species extrapolation factors with which to scale animal doses to human by any route for non-carcinogenic endpoints. The conventional hypothesis of the toxicokinetics (TK)-toxicodynamics (TD) relationship was equal toxicity at equal plasma level of the total drug moiety in each species, but this should also follow the free drug assumption, which states that only the unbound drug moiety in plasma may elicit a TD effect in tissue. Therefore, a protein binding factor (PBF) was combined with the Chemical-Specific Adjustment Factor (CSAF) (i.e., CSAF x PBF). The value of PBF of each drug was set equal to the ratio between human and animals of the unbound fraction in plasma (fup). Recent drug datasets were investigated. Our results indicate that any CSAF value would be increased or decreased while PBF deviates to the unity, and this required more attention. Accordingly, further testing indicated that the CSAF values set equal to basic allometric uncertainty factors according to the conventional hypothesis (dog˜2, monkey˜3.1, rat˜7, mouse˜12) would increase by including PBF for 30% of the drugs tested that showed a superior fup value in human compared to animals. However, default uncertainty factors in the range of 10–100 were less frequently exceeded. Overall, PBF could be combined with any other uncertainty factor to get reliable estimate of CSAF for each bound drug in deriving health-based exposure limits.The estimation of additional uncertainties in interspecies extrapolation is studied.The impact of species differences in plasma protein binding is challenged.The Chemical-Specific Adjustment Factor (CSAF) is adjusted for binding.Species differences in plasma protein binding would significantly affect CSAF.