The toxicity of aerosol from the mentholated Tobacco Heating System (THS2.2M), a candidate modified risk tobacco product (cMRTP), was characterized in Sprague-Dawley rats in a subchronic inhalation study following the OECD Test Guideline 413, and compared to the one inherent to cigarette smoke (CS) from mentholated reference cigarettes (MRC). Rats were nose-only exposed for 6 hours per day, 5 days per week for 90 days to either filtered air, CS from MRC to a target nicotine concentration of 23 μg/L (with 2 menthol concentrations in CS) or to aerosol from THS2.2M to 3 different target nicotine concentrations (15, 23 and 50 μg/L). The analysis of the test atmosphere showed a reduction of up to 90% and 98% in aldehydes and CO, respectively when compared to CS from MRC. Aerosols were reproducibly taken up by the rats as indicated by determination of carboxyhemoglobin and selected aerosol constituents and their metabolites in blood. Exposure to CS resulted in typical smoke related toxicological effects consistent with findings reported in previous studies. Histopathological findings in the respiratory tract and pulmonary inflammation in THS2.2M exposed groups were significantly lower in severity or absent when compared to MRCexposed groups. This was consistent with reduced inflammatory cells infiltration and cytokine expression in bronchioalveolar lung fluid suggesting reduced inflammatory processes as compared to the response to CS exposure. Overall, the data demonstrate that aerosol generated by THS2.2M causes much lower systemic and respiratory tract toxicity than CS from mentholated combustible cigarettes. Furthermore, no menthol related effects were detected after THS2.2M aerosol or MRC CS-exposure.