Abstract
The retention, distribution, metabolism, and excretion of [14C]octamethylcyclotetrasiloxane (D4) were studied in Fischer 344 rats after single and multiple exposures to 7, 70, or 700 ppm [14C]D4. Subset groups were established for body burden, distribution, and elimination. Retention of inhaled D4 was relatively low (5–6% of inhaled D4). Radioactivity derived from [14C]D4 inhalation was widely distributed to tissues of the rat. Maximum concentrations of radioactivity in plasma and tissues (except fat) occurred at the end of exposure and up to 3 h postexposure. Maximum concentrations of radioactivity in fat occurred as late as 24 h postexposure. Fat was a depot, elimination of radioactivity from this tissue was much slower than from plasma and other tissues. With minor exceptions, there were no consistent gender effects on the distribution of radioactivity and the concentrations of radioactivity were nearly proportional to exposure concentration over the exposure range. Excretion of radioactivity was via exhaled breath and urine, and, to a much lesser extent, feces. Urinary metabolites included dimethylsilanediol and methylsilanetriol plus five minor metabolites. Relative abundance of these metabolites was the same from every test group. Elimination was rapid during the first 24 h after exposure and was slower thereafter (measured up to 168 h postexposure). In singly-exposed female (but not male) rats, small dose-dependent shifts in elimination pathways were seen. After multiple exposures, the elimination pathways were dose- and gender-independent. These data define possible pathways for metabolism of D4 and allow estimation of the persistence of D4 and/or its metabolites in rats.
Footnotes
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Send reprint requests to: Dr. Kathleen P. Plotzke, Manager, Toxicology Research, Health and Environmental Sciences, Dow Corning Corporation, Mail no. CO3101, 2200 W. Salzburg Rd., Midland, MI 48686. E-mail: kathy.plotzke{at}dowcorning.com
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↵1 Present address: Lorus Therapeutics, Inc., 7100 Woodbine Ave., Suite 215, Markham, ON Canada L3R 5J2.
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↵2 Present address: Sierra Biomedical Inc., 587 Dunn Circle, Sparks, Nevada.
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Supported in part by the Silicones Environmental, Health and Safety Council of North America.
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↵4 Additional tissues were collected and processed for radioactivity in a pilot study as well as the two studies presented here. In the interest of space, only data from select tissues will be discussed. Copies of the full reports can be obtained from the Environmental Protection Agency (EPA). Please refer to the Document Control Number (DCN) for the respective report. A Pilot Study for the Determination of 14C-Octamethylcyclotetrasiloxane (D4) Pharmacokinetics in Fischer 344 Rats following a Single Nose-Only Vapor Inhalation Exposure to 700 ppm14C-D4, EPA DCN 86960000517. Pharmacokinetics of 14C-Octamethylycyclotetrasiloxane (D4) in the Rat following Single Nose-Only Vapor Inhalation Exposure, DCN 86960000024. Pharmacokinetics of14C-Octamethylcyclotetrasiloxane in the Rat following 14 Repeat Daily Nose-Only Vapor Inhalation Exposures to Unlabeled D4 and a Single (Day 15) Exposure to14C-D4 at Two Exposure Levels, EPA DCN 86970000875.
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↵5 The blood-to-plasma ratios were approximately 1 or somewhat lower over the time course of the study for all exposure regimens, indicating that radioactivity was readily taken up by the red blood cells and eliminated at approximately the same rate as from plasma. Therefore, only plasma data are reported here.
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↵6 Plasma samples were taken during exposure, but for logistical reasons samples of solid tissues were only available postexposure.
- Abbreviations used are::
- D4
- octamethylcyclotetrasiloxane
- AUC
- area under the concentration curve versus time
- t1/2
- apparent elimination half-life
- tmax
- time to maximum concentration
- Cmax
- maximum concentration
- PB
- phenobarbital
- GC/MS
- gas chromatography mass-spectrometry
- 2-EE
- 2-ethoxyethanol
- Received June 1, 1999.
- Accepted October 22, 1999.
- The American Society for Pharmacology and Experimental Therapeutics
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