Vol. 27, Issue 11, 1267-1273, November 1999

Identification of Metabolites of Octamethylcyclotetrasiloxane (D₄) in Rat Urine

Sudarsanan Varaprath, Kevin L. Salyers,¹ Kathleen P. Plotzke, and Shrenik Nanavati

Dow Corning Corporation (S.V., K.P.P., S.N.), Midland, Michigan; and SmithKline Beecham (K.L.S.), King of Prussia, Pennsylvania

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.