Different xenobiotics were detected in both SRM 1958 and SRM 1950 and are summarized in Table . Concentrations were calculated based on the calibration curves built for MRM-HR + SWATH and SWATH-only methods (Tables and). Concentration values were not significantly different in almost all cases when considering raw p-values from a paired t-test (performed in Metaboanalyst using the individual concentrations for each replicate). Exception compounds were mono-benzyl phthalate and trans-3-hydroxy-cotinine for SRM 1958 and nonylphenol and PFOS for SRM 1950. Acetaminophen was found to be different between methods for both SRM 1950 and SRM 1958. The results showcase the higher capability for compound detection. From the total of 17 compounds detected in SRM 1958, roughly 41% (7) were detected in MRM-HR+SWATH mode only, covering different classes (bisphenols, PFAS, phthalates, and herbicides/pesticides such as metribuzin). Similarly, 44% of the compounds detected in SRM 1950 (7 out of 16) were found only with the use of the combined method. MRM-HR+SWATH and SWATH-only using MS-DIAL (two sets of triplicate non-spiked samples see Material and Methods, Data analysis and quality control section for detailed information). As an initial assessment, the number of features obtained using the same processing method was evaluated. As observed in Table , MRM-HR+SWATH data retrieved a larger number of features for all experiments. When comparing the total number of MS 2 matching retrieved from the libraries, SWATH-only data initially seemed to outperform the newly developed MRM-HR+SWATH method. After manual curation of the data and removal of false positives, it was observed that annotation of compounds was, in fact, of high similarity between both methods. More specifically, all compounds that could be reasonably annotated (minimum of 2 matching ions and mass error below 5 ppm for parent compound) in SWATH-only mode had the same suggested compound in MRM-HR+SWATH, with highly comparable matching scores (dot product, reverse dot product and total score ). Mirror plots of annotated compounds for SRM 1950 in both ESI+ and ESI-including matching scores is described in details in Tables and, along with all mirror plots for both methodologies (Figures ). Since a large overlap was observed for the compounds annotated between SRM 1958 and SRM 1950 in both ionization modes, we opted to not include mirror plots for the first as a way to avoid repetitive description of the data. Despite the clear similarity in MS 2 matching performance, it is important to highlight that SWATH-only method indeed outperformed MRM-HR+SWATH data in the quality of a few spectral matches, more prominently for low abundance compounds (peak height <1000 counts). Figure presents two illustrative cases of spectral matches. The first (phenylalanine, Figure ) showcases an optimal MS 2 match with the library for both SWATH-only and MRM-HR+SWATH, outlining the high MS 2 spectral similarity between both methods. Figure , on the other hand, intends to exemplify a case for which, despite the good matching score for both methods, spectra similarity is lower across both methods, with missing fragments for the deconvoluted MS 2 spectrum from MRM-HR+SWATH. This may be explained by the lower accumulation time for both MS 1 and MS 2 data, possibly hindering the deconvolution process (i.e., matching fragments with precursor ions). The same trend can be observed, for instance, for citric acid (Figure ) and tyrosine (Figure ) as highly similar spectral matches between both methods (with peak heights all above 1500) as well as for 4-nitrophenol (Figure ) and glycocholic acid (Figure ) as less reliable matches in MRM-HR+SWATH due to missing fragments in the deconvoluted spectra and with peak heights for both compounds at around 300 counts