A key concern in mixtures studies is whether administered doses are sufficient to elicit genotoxic responses from individual constituents.  In vitro to in vivo extrapolation (IVIVE) can increase confidence in determining whether administered in vivo doses for mixture constituents are sufficient to elicit genotoxic responses and whether the target tissue (i.e., bone marrow) is adequately exposed to cause a response.  IVIVE, through reverse dosimetry, was used to determine estimated external in vivo doses assuming equivalence of the in vitro assay concentrations to predicted plasma concentrations to increase confidence of systemic exposure of mixture constituents. Plasma data for 2,6-dimethoxyphenol (2,6-DMP) from an in vivo rat micronucleus (MN) study were used to ensure that a generic physiologically-based toxicokinetic (PBTK) model in TKPlate could sufficiently predict kinetics for oral exposure to 2,6-DMP.  Reverse dosimetry was performed to estimate the external dose assuming the equivalence of the 2,6-DMP in vitro MN assay concentration to a predicted internal plasma concentration. Reverse dosimetry was then conducted for catechol and 2,5H-furanone. Estimated external doses for 2,6-DMP, catechol and 2,5H-furanone were lower than the negative in vivo rat MN study doses, demonstrating that the in vivo doses were sufficient to elicit a genotoxic response, but none was observed.  Reverse dosimetry provided justification that the negative in vivo rat MN study doses were sufficiently high to elicit a genotoxic response despite no genotoxic response occurring in the in vivo study. Systemic exposure assessments and reliability of in vivo mixture data can be strengthened by application of IVIVE methods.