•A method is described that compares elution directly from RBC and elution indirectly from teeth with restored cavities.•Direct comparison of eluates from bulk fill restoratives was achieved.•Critical substances including TINUVIN® 328 were found in the eluates.•Elution from restored carious lesions gives new insights into amounts of elutable substances.•Due to synergistic effects between teeth and restoratives, multiple models are important for toxicological assessments. To compare elutable substances directly released from bulk-fill (BF) resin-based composites (RBCs) with indirect elution from teeth restored with a BF composite. In addition to (co)monomers, the analytical focus was on other potentially toxic ingredients or impurities. Furthermore, the barrier function of the residual dentin/adhesive layer was studied. Six BF-RBC materials were studied. For each material subgroup, ten human third molar teeth with standard Class-I occlusal cavities were prepared and provided with a three-step adhesive system and the respective composite restoration (tooth groups). Same sized control specimens of the restorative material were prepared (‘direct BF-RBC’ groups). Each specimen was placed in an elution chamber such that the elution media (ethanol/water, 3:1) only contacted the tooth root or ¾ height of each specimen. They were incubated at 37 °C for up to 7 d. Samples of eluate were taken after 1, 2, 4 and 7 d and were analysed by high-temperature gas chromatography/mass spectrometry. (Co)monomers such as Bisphenol A ethoxylate dimethacrylate (bisEMA) or tetraethylene glycol dimethacrylate (TEEGDMA) were mostly found in the eluates of the ‘direct BF-RBC’ groups in statistically significantly greater amounts than in the eluates of the ‘tooth groups’. The residual dentin and/or adhesive layers acted as a diffusion barrier for most of the substances except for triethylene glycol dimethacrylate (TEGDMA) or diethylene glycol dimethacrylate (DEGDMA). For TEGDMA up to 3 orders of magnitude more were found in the ‘tooth groups’ compared to the ‘direct BF-RBC’ groups, evidently released by the adhesive system. Substances of Very High Concern (SVHC) including TINUVIN® 328 and BPA were found mainly in the eluates of ‘direct BF-RBC’ groups. For estimation of biocompatibility, a total system, specifically BF-RBC + adhesive, should always be investigated since individual considerations, such as only elution from a BF-RBC, do not correctly reflect the total clinical situation. The focus of elution tests should not only be on the co(monomers), but also on other ingredients or impurities that may be released.