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Metabolism and urinary excretion kinetics of di(2-ethylhexyl) terephthalate (DEHTP) in three male volunteers after oral dosage

  • Toxicokinetics and Metabolism
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Abstract

Di(2-ethylhexyl) terephthalate (DEHTP) is used as a substitute for di(2-ethylhexyl) phthalate (DEHP), an ortho-phthalate-based plasticizer that is classified and labeled due to its toxicity to reproduction. In this study the metabolism and urinary excretion kinetics of DEHTP were investigated by single oral dosage of 50 mg DEHTP to three male volunteers (resulting in individual dosages between 0.55 and 0.59 mg/kg body weight). Separate urine samples were consecutively collected for 48 h. In analogy to DEHP, we quantified specific side-chain-oxidized monoester metabolites of DEHTP (5OH-MEHTP, 5oxo-MEHTP, 5cx-MEPTP and 2cx-MMHTP) by HPLC–MS/MS with online sample clean-up and isotope dilution. All postulated metabolites were detectable in all samples after dosage. The predominant, specific urinary metabolite was 5cx-MEPTP representing about 13.0 % of the applied dose as mean of the three volunteers (range 7.0–20.4 %) in urine, followed by 5OH-MEHTP (mean: 1.8 %; range 1.3–2.4 %) and 5oxo MEHTP (mean: 1.0 %; range 0.6–1.6 %). 2cx-MMHTP was a minor metabolite representing only 0.3 % (range 0.2–0.4 %). In total, about 16.1 % of the dose was recovered in urine as the above investigated specific metabolites within 48 h with the major share (95 %) being excreted within the first 24 h. Investigation of the glucuronidation patterns revealed that the carboxy-metabolites are excreted almost completely in their free form (>90 %), whereas for 5OH-MEHTP and 5oxo-MEHTP, glucuronidation is preferred (>70 %). With this study we provide reliable urinary excretion factors to calculate DEHTP intakes based on metabolite concentrations in environmental and occupational studies.

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Acknowledgments

The development of the analytical method and its first application in a human metabolism and population study are part of a large-scale 10-year project on the advancement of human biomonitoring in Germany. This project is a cooperation agreed in 2010 between the German Federal Ministry for the Environment, Nature Conservation, Building and Nuclear Safety (BMUB) and the Verband der Chemischen Industrie e.V. (German Chemical Industry Association—VCI) and is managed by the German Environment Agency (UBA). In this cooperation project the analytical method development and the human metabolism study are financed by the Chemie Wirtschaftsförderungsgesellschaft mbH while the first application of the novel methodology in a population study is financed by the German Environment Agency. Experts from governmental scientific authorities, industry and science closely accompany and advise the project in selecting substances and developing methods.

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Authors and Affiliations

  1. Institute for Prevention and Occupational Medicine of the German Social Accident Insurance, Institute of the Ruhr-Universität Bochum (IPA), Bürkle-de-la-Camp-Platz 1, 44789, Bochum, Germany

    Frederik Lessmann, André Schütze, Tobias Weiss, Thomas Brüning & Holger M. Koch

  2. BASF SE, Ludwigshafen, Germany

    Angelika Langsch & Rainer Otter

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  1. Frederik Lessmann
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  2. André Schütze
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  3. Tobias Weiss
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  4. Angelika Langsch
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  6. Thomas Brüning
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  7. Holger M. Koch
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Correspondence to Holger M. Koch.

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Ethical approval

The study design was in accordance with the ethical standards of the institutional and/or national research committee and with the 1964 Declaration of Helsinki and its later amendments or comparable ethical standards. Approval for the study protocol was obtained from the Ethics Commission of the Faculty of Medicine of the Ruhr-Universität Bochum, Germany (IRB Reg. No.: 4757-13). Written informed consent was obtained from all individual participants included in the study.

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Lessmann, F., Schütze, A., Weiss, T. et al. Metabolism and urinary excretion kinetics of di(2-ethylhexyl) terephthalate (DEHTP) in three male volunteers after oral dosage. Arch Toxicol 90, 1659–1667 (2016). https://doi.org/10.1007/s00204-016-1715-x

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  • DOI: https://doi.org/10.1007/s00204-016-1715-x

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