Abstract
Cumene is a high-production volume chemical that has been shown to be a central nervous system depressant and has been implicated as a long-term exposure carcinogen in experimental animals. The absorption, distribution, metabolism, and excretion of [14C]cumene (isopropylbenzene) was studied in male rats and mice of both sexes after oral or intravenous administration. In both species and sexes, urine accounted for the majority of the excretion (typically ≥70%) by oral and intravenous administration. Enterohepatic circulation of cumene and/or its metabolites was indicated because 37% of the total dose was excreted in bile in bile duct-cannulated rats with little excreted in normal rats. The highest tissue 14C levels in rats were observed in adipose tissue, liver, and kidney with no accumulation observed after repeat dosing up to 7 days. In contrast, mice contained the highest concentrations of 14C at 24 h after dosing in the liver, kidney, and lung, with repeat dosing accumulation of 14C observed in these tissues as well as in the blood, brain, heart, muscle, and spleen. The metabolites in the expired air, urine, bile, and microsomes were characterized with 16 metabolites identified. The volatile organics in the expired air comprised mainly cumene and up to 4% α-methylstyrene. The major urinary and biliary metabolite was 2-phenyl-2-propanol glucuronide, which corresponded with the main microsomal metabolite being 2-phenyl-2-propanol.
Footnotes
This project was conducted for the National Toxicology Program, National Institutes of Health National Institute of Environmental Health Sciences [Contract N01-ES-75562, HHSN291200775562C].
This article may be the work product of an employee or group of employees of the National Institutes of Health (NIH) National Institute of Environmental Health Sciences (NIEHS); however, the statements, opinions, or conclusions contained therein do not necessarily represent the statements, opinions or conclusions of NIH, NIEHS, or the U.S. government.
Article, publication date, and citation information can be found at http://dmd.aspetjournals.org.
doi:10.1124/dmd.110.034769.
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The online version of this article (available at http://dmd.aspetjournals.org) contains supplemental material.
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ABBREVIATIONS:
- AMS
- α-methylstyrene
- HPLC
- high-performance liquid chromatography
- ESI
- electrospray ionization
- MS
- mass spectrometry
- MS/MS
- tandem mass spectrometry
- BDC
- bile duct-cannulated
- LSC
- liquid scintillation counter
- VOC
- volatile organic compound.
- Received June 17, 2010.
- Accepted November 22, 2010.
- U.S. Government work not protected by U.S. copyright
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