Cyclohexane-1,2-dicarboxylic acid diisononyl ester (DINCH) and its metabolites in body fluids of rats and humans after single oral doses of DINCH

Abstract

The European Food Safety Authority (EFSA) has established a tolerable daily intake (TDI) of 1 mg/kg bw/d for the plasticizer DINCH (Cyclohexane-1,2-dicarboxylic acid diisononyl ester). To characterize the maximum internal doses resulting from a single dosing and to assess species differences relevant for extrapolating rat toxicokinetics to humans, concentration-time profiles of DINCH and its metabolites (specific monoesters: MINCH, OH-MINCH, oxo-MINCH, cx-MINCH; non-specific metabolite: CHDA) were quantified in the blood of male Wistar rats and male human volunteers. Urinary excretion of metabolites was additionally evaluated for humans. Single oral doses of ring-deuterated DINCH were administered (rats: 1 or 40 mg/kg bw; humans: 1 mg/kg bw). In rats, gastrointestinal absorption exhibited saturation, as a 40-fold increase in administered dose resulted in only ∼25-fold increases in C_max and AUC. Across species, the hierarchy of C_max in blood was consistent: DINCH > CHDA > cx-MINCH > MINCH > OH-MINCH > oxo-MINCH. Notably, C_max values for DINCH and MINCH in blood after a 1 mg/kg bw (1.74 µM and 0.10 µM) dose in humans were like those observed in rats following a 40-fold higher dose (4.4 µM and 0.11 µM). Corresponding AUC∞ values showed the same pattern, indicating greater systemic availability of DINCH in humans, although this is partly counter balanced by plasma protein binding. In humans, approximately 50% of MINCH and 70–80% of the other monoester metabolites were glucuronidated, whereas these metabolites remained unconjugated in rats. CHDA was unconjugated in both species. Overall, the data highlight both shared and species-specific features of DINCH metabolism in rats and humans.