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Toxicokinetics of di-isodecyl phthalate and its major metabolites in rats through the application of a developed and validated UHPLC-ESI-MS/MS method

  • Toxicokinetics and Metabolism
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Abstract

Di-isodecyl phthalate (DiDP) is a high-molecular-weight phthalate that is mainly used as a plasticizer for plastics. Therefore, exposure to DiDP in the environment has become common with the increasing use of plastics around the world. Environmental regulations and scientific risk management for DiDP, which can be associated with endocrine disruption and various metabolic diseases, are urgently needed. The purpose of this study was to provide useful reference material for future human DiDP risk assessments by conducting toxicokinetic studies on DiDP. Rats were given 100 mg/kg of DiDP orally or intravenously, and plasma, urine, feces, and various tissues were sampled at preset times. DiDP and its major metabolites mono-isodecyl-phthalate (MiDP), mono-hydroxy-isodecyl-phthalate (MHiDP), mono-carboxy-isononyl-phthalate (MCiNP), and mono-oxo-isodecyl-phthalate (MOiDP) were simultaneously quantified from collected biological samples through the application of a newly developed and verified ultrahigh-performance liquid chromatography–electrospray ionization-tandem mass spectrometer (UHPLC–ESI-MS/MS) method. Based on the quantitative results for each analyte, toxicokinetic analyses were performed. DiDP was rapidly and extensively metabolized to MiDP, MHiDP, MCiNP, and MOiDP. The major metabolite excreted in the urine was MCiNP, suggesting that it could be a useful biomarker. The conjugated forms of DiDP and its metabolites have been significantly quantified in the plasma, urine, and feces. DiDP and its major metabolites were also distributed in various tissues in significant quantities. The toxicokinetic properties of DiDP, which have not been clearly reported previously, were identified through this study. This report will serve as a useful reference for future DiDP environmental regulation and scientific human risk assessment studies.

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Abbreviations

DiDP:

Di-isodecyl phthalate

MiDP:

Mono-isodecyl phthalate

MHiDP:

Mono-hydroxy-isodecyl phthalate

MCiNP:

Mono-carboxy-isononyl phthalate

MOiDP:

Mono-oxo-isodecyl phthalate

CV:

Coefficient of variation

GI:

Gastrointestinal

ESI:

Electrospray ionization

SPE:

Solid-phase extraction

LLE:

Liquid–liquid extraction

PP:

Protein precipitation

LLOQ:

Lower limit of quantitation

BQL:

Below of quantification level

MRM:

Multiple reaction monitoring

PBPK:

Physiologically based pharmacokinetic

ADHD:

Attention deficit-hyperactivity disorder

PEG:

Polyethylene glycol

PBS:

Phosphate-buffered saline

QC:

Quality control

UHPLC–ESI-MS/MS:

Ultrahigh-performance liquid chromatography–electrospray ionization-tandem mass spectrometer

HPLC:

High-performance liquid chromatography

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Acknowledgements

This work was supported by a grant from the Ministry of Food and Drug Safety, Republic of Korea in 2021 (No. 21162MFDS077). This research was also supported by the Basic Science Research Program through the National Research Foundation of Korea (NRF) funded by the Ministry of Education (No. 2020R1A6A3A13074075).

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Author notes

  1. Seung-Hyun Jeong and Ji-Hun Jang have contributed equally to this work.

Authors and Affiliations

  1. College of Pharmacy, Chonnam National University, 77 Yongbong-ro, Buk-gu, Gwangju, 61186, Republic of Korea

    Seung-Hyun Jeong, Ji-Hun Jang & Yong-Bok Lee

  2. College of Pharmacy, CHA University, 335 Pangyo-ro, Bundang-gu, Seongnam-si, Gyeonggi-do, 13488, Republic of Korea

    Hea-Young Cho

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  1. Seung-Hyun Jeong
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Contributions

S-HJ: conceptualization, investigation, methodology, writing—original draft, writing—review and editing, software, data analysis, and visualization; J-HJ: conceptualization, investigation, writing—review and editing, software, and data analysis; H-YC: writing—review, project administration, and conceptualization; Y-BL: conceptualization, methodology, writing—review and editing, funding acquisition, and supervision.

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Correspondence to Yong-Bok Lee.

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Jeong, SH., Jang, JH., Cho, HY. et al. Toxicokinetics of di-isodecyl phthalate and its major metabolites in rats through the application of a developed and validated UHPLC-ESI-MS/MS method. Arch Toxicol 95, 3515–3537 (2021). https://doi.org/10.1007/s00204-021-03153-6

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