Abstract
Octamethylcyclotetrasiloxane (D4) is an industrial chemical of significant commercial importance. In this study, its major urinary metabolites were identified. The urine samples described here were collected from male and female Fischer rats (F-344) administered [14C]D4 i.v. The metabolite profile was obtained using an HPLC system equipped with a radioisotope detector. HPLC analysis was performed on a C18 column, using an acetonitrile/water mobile phase. The HPLC radiochromatogram revealed two major and at least five minor metabolites. The two major metabolites, constituting 75 to 85% of the total radioactivity, were identified as dimethylsilanediol [Me2Si(OH)2] and methylsilanetriol [MeSi(OH)3]. Formation of MeSi(OH)3 clearly established demethylation at the silicon-methyl bonds of D4. No parent D4 was present in urine. The minor metabolites identified were tetramethyldisiloxane-1,3-diol [Me2Si(OH)-O-Si(OH)Me2], hexamethyltrisiloxane-1,5-diol [Me2Si(OH)-OSiMe2-OSi(OH)Me2], trimethyldisiloxane-1,3,3-triol [MeSi(OH)2-O-Si(OH)Me2], dimethyldisiloxane-1,1,3,3-tetrol [MeSi(OH)2-O-Si(OH)2Me], and dimethyldisiloxane-1,1,1,3,3-pentol [Si(OH)3-O-Si(OH)2Me]. The structural assignments were based on gas chromatography-mass spectrometry analysis of the tetrahydrofuran metabolite extracts, which were derivatized using bis(trimethylsiloxy)triflouroacetamide, a trimethylsilylating agent. The structures were confirmed by synthesizing 14C-labeled standards and comparing their HPLC radiochromatograms with the corresponding components in the rat urine. GC-MS spectral comparisons of the trimethylsilylated derivatized standards and urinary components also were made to further confirm their identities. Finally, several of the urinary metabolites were fractionated using HPLC, and GC-MS comparisons were again made for positive structural identification. The pathways for metabolite formation are not yet understood, but a mechanistic hypothesis has been proposed to account for the various metabolites observed thus far.
Footnotes
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Send reprint requests to: Sudarsanan Varaprath, Ph.D., Senior Research Chemist, Dow Corning Corporation, 2200 W. Salzburg Road, Auburn, MI 48686-0994. E-mail:sudarsanan.varaprath{at}dowcorning.com
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↵1 Present address: SmithKline Beecham, King of Prussia, PA.
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This work was supported in part by the Silicones Environmental, Health and Safety Council of North America.
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↵3 HPLC and GC-MS of standards were not included in this manuscript. They will be available on request.
- Abbreviations used are::
- MM
- hexamethyldisiloxane
- MDM
- octamethyltrisiloxane
- MD2M
- decamethyltetrasiloxane
- M3T
- methyltris(trimethylsiloxy)silane
- M4Q
- tetrakis(trimethylsiloxy)silane
- D4
- octamethylcyclotetrasiloxane
- GC-MS
- gas chromatography-mass spectrometry
- THF
- tetrahydrofuran
- BSTFA
- bis(trimethylsilyl)trifluoroacetamide
- ASFT
- Aqueous Silanol Functionality Test
- The abbreviations are based on the General Electric’s siloxane notation [Hurd CB (1946) Studies on siloxanes. 1. The specific volume and viscosity in relation to temperature and constitution. J Am Chem Soc 68:364] which is as follows
- M, Me3SiO1/2
- D
- -Me2SiO2/2
- T
- MeSiO3/2
- Q
- SiO4/2
- Received November 6, 1998.
- Accepted May 27, 1999.
- The American Society for Pharmacology and Experimental Therapeutics
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