In this study, we present a dissolution test system that allows for the testing of dissolution of nano- and micrometer size materials under highly controlled atmospheric composition (O2 and CO2), temperature, and pH. The system enables dissolution testing in physiological simulant fluids (here low-calcium Gamble’s solution and phagolysosomal simulant fluid) and derivation of the temporal dissolution rates and reactivity of test materials. The system was validated considering the initial dissolution rates and dissolution profiles using eight different materials (γ-Al2O3, TiO2 (NM-104 coated with Al2O3 and glycerin), ZnO (NM-110 and NM-113, uncoated, and NM-111 coated with triethoxycaprylsilane), SiO2 (NM-200—synthetic amorphous silica), CeO2 (NM-212), and bentonite (NM-600) showing high intra-laboratory repeatability and robustness across repeated testing (I, II, and III) in triplicate (replicate 1, 2, and 3) in low-calcium Gamble’s solution. A two-way repeated-measures ANOVA was used to determine the intra-laboratory repeatability in low-calcium Gamble’s solution, where Al2O3 (p = 0.5277), ZnO (NM-110, p = 0.6578), ZnO (NM-111, p = 0.0627), and ZnO (NM-113, p = 0.4210) showed statistical identical repeatability across repeated testing (I, II, and III). The dissolution of the materials was also tested in phagolysosomal simulant fluid to demonstrate the applicability of the ATempH SBR system in other physiological fluids. We further show the uncertainty levels at which dissolution can be determined using the ATempH SBR system.