Quantitative investigation of the urinary excretion of three specific monoester metabolites of the plasticizer diisononyl adipate (DINA)

Human Metabolism and Urinary Excretion Kinetics of Nonylphenol in Three Volunteers after a Single Oral Dose

“…Proposed chemical structures of these metabolites are shown in Figure , illustrated on the example of the single NP isomer 4-NP 9 [nomenclature according to Guenther et al (2006)] . We could not identify any terminal carboxylic acid metabolites of NP (NP-CA) or β-oxidation breakdown products thereof such as heptylphenol carboxylic acid, which might have been expected in analogy to other substances with branched nonyl side chains, such as diisononyl phthalate (DINP) , or diisononyl cyclohexane-1,2-dicarboxylate (DINCH), or with other branched and linear alkyl side chains. − , Qualitatively, we could thus confirm similar metabolic structures [alkyl-chain oxidized metabolites, ring-hydroxylated metabolites (catechols), and mixtures of both] previously reported by Doerge et al (2002) in rat tissues or Ye et al (2007) in rat and human liver microsomes. , However, contrary to Doerge et al (2002) and Ye et al (2007) who found the catechols to be dominant metabolites in their tissues, in our setting (oral dose to volunteers, urinary excretion) the alkyl chain metabolites OH-NP and oxo-NP exhibited highest signal intensities (see Figure S2 for qualitative excretion kinetics). These two NP metabolites had already been chosen as target analytes in our recently published analytical method [Ringbeck et al (2021)] .…”

“…While the F UE of non-oxidized NP (6.60%) is in good agreement with the 10% reported by Müller et al (1998), the high share of OH-NP in urine has been rather surprising even though we expected it to be a relevant metabolite based on our experience with similar substances with iso-nonyl-moieties. In fact, OH-NP (43.7 or 62.2%) is much more prominent than other urinary OH-metabolites, for example, OH-MINP of DINP (12.3–20.2%), , OH-MINCH of 1,2-cyclohexane dicarboxylic acid diisononyl ester, DINCH (10.7–16.2%), , or OH-MINA of diisononyl adipate, DINA (0.022%) . It should be considered, however, that in contrast to these examples, NP has no ester moiety prone to metabolic hydrolysiswhich is especially relevant in the case of DINA.…”

“…(2006)] with human and rat liver microsomes . In rainbow trout, several side chain and ring-hydroxylated metabolites were reported, and GC–MS analyses suggested hydroxylation in the terminal C8 and C9 ( n and n – 1) positions of the alkyl chain. − Based on our experience in human metabolism of chemicals with long, branched alkyl-chains such as plasticizers − and UV filters, , we also hypothesized metabolites oxidized (OH and oxo) in the n – 1 position as potentially relevant in humans. α,α-Dimethyl alkyl isomers contribute the largest share of NP-isomers (around 50%). , Of those, we chose the simplest isomer (α,α-dimethyl without additional branching) as the core structure for standard synthesis.…”

“…However, the agreement between the three volunteers was high and the F UE -difference was well below a factor of 2 and thus comparable to variabilities typically observed in human metabolism studies of structurally similar, challenging isomeric substances with isononylchains. 43,46,49,84 Overall, with the three metabolites included in this study, we capture the major share of the oral NP dose with a sum of 56.3 or 78.1%, depending on the MRM transitions used for quantification. The lower value includes 13 C 6 -NP, 13 C 6 -OH-NP (m/z 241 → 139), and 13 C 6 -oxo-NP (m/z 239 → 139), while the higher value includes 13 C 6 -NP, 13 C 6 -OH-NP (m/z 241 → 123), and 13 C 6 -oxo-NP (m/z 239 → 123) (see Table 2).…”

Human metabolism and urinary excretion of seven neonicotinoids and neonicotinoid-like compounds after controlled oral dosages

“…Having at least three or more volunteers of both sexes would have most likely substantiated our findings. Interestingly, significant intraspecies differences in experimental studies with controlled exposures in small sets of volunteers could not be observed for other xenobiotics (Modick et al 2016 ; Koch et al 2014 ; Gotthardt et al 2021 ; Moos et al 2016 ). The lack of such differences is most likely due to the generally limited number of studied volunteers in such studies although small but significant intraspecies differences, if present, may become evident when analyzing larger populations.…”