In vitro and in vivo percutaneous absorption of 14C-octamethylcyclotetrasiloxane (14C-D4) and 14C-decamethylcyclopentasiloxane (14C-D5).

Octamethylcyclotetrasiloxane (D4) and decamethylcyclopentasiloxane (D5) are cyclic siloxanes used as chemical intermediates with some applications in consumer products. The in vitro percutaneous absorption of 14C-D4 and 14C-D5 was studied in flow-through diffusion cells. Single doses were applied neat and in antiperspirant formulations to dermatomed human skin for 24h. The majority of applied D4 and D5 ( approximately 90%) volatilized before being absorbed. Only 0.5% of applied D4 was absorbed while the absorption of D5 (0.04%) was one order of magnitude lower. The largest percentage (>90%) of the absorbed D4 and D5 was found in the skin. The fate of D4 and D5 absorbed in the skin was studied in rat in vivo. A single dose of 14C-D4 (10, 4.8 and 2mg/cm2) and 14C-D5 (10mg/cm2) was topically applied inside a dosing chamber attached to the dorsal area. Rats were housed in metabolism cages up to 24h to enable collection of urine, feces, expired/escaped volatiles. The majority of applied D4 or D5 had volatilized from the skin surface. Less than 1.0% of the applied D4 and only 0.2% of applied D5 was absorbed with approximately 60% of absorbed D4 and 30% of absorbed D5 reaching systemic compartments. The amount absorbed into the skin decreased with time showing that residual D4 and D5 diffused back to the skin surface and continued to evaporate. Overall, a low tendency to pass through the skin into systemic compartments was demonstrated for both D4 (< or = 0.5% of applied dose) and D5 (<0.1% of applied dose).

In vitro and in vivo evaluation of the estrogenic, androgenic, and progestagenic potential of two cyclic siloxanes.

The purpose of these experiments was to determine the potential estrogenic, androgenic, and progestagenic activity of two cyclic siloxanes, octamethylcyclotetrasiloxane (D4) and decamethylcyclopentasiloxane (D5). Receptor-binding experiments and a luciferase reporter gene assay were used to determine if the materials were able to bind and activate either the estrogen receptors (ERs) or progesterone receptors (PRs)-alpha or beta. The rat uterotrophic assay (RUA) for estrogenic activity and the Hershberger assay for androgenic activity were utilized as the in vivo assays. For the ER-binding studies, D4 was shown to bind to ERalpha but not to ERbeta. D5 did not bind to either of the two receptors. D4 activated the reporter gene at 10 microM, while D5 was considered negative in the estrogen reporter gene assay. Neither material was a ligand for the PRs. Both the RUA and Hershberger assays were conducted using whole-body inhalation of the two materials for 16 h/day. D4 resulted in a small but significant increase in both wet and blotted uterine weight as well as increases in both luminal and glandular epithelial cell height in both Sprague Dawley and Fischer 344 rats. D5 was negative in both rat strains, indicating that D5 does not possess estrogenic activity. Neither material possessed any significant antiestrogenic activity. Both materials were negative in the Hershberger assay indicating that neither material possesses any significant androgenic activity. Our studies have shown that D4 exhibits a low affinity for ERalpha in vitro and a weakly estrogenic response in vivo.

Metabolites of hexamethyldisiloxane and decamethylcyclopentasiloxane in Fischer 344 rat urine--a comparison of a linear and a cyclic siloxane.

Hexamethyldisiloxane (MM or HMDS) and decamethylcylclopentasiloxane (D(5)) are examples of a linear and a cyclic siloxane, respectively. These volatile low molecular weight siloxanes are of significant commercial importance. To aid in the pharmacokinetic investigations, major metabolites of MM and D(5) were identified in urine collected from Fischer (F-344) rats administered [(14)C]MM and [(14)C]D(5) orally and via intravenous injection. The metabolite profiles were obtained using a high-pressure liquid chromatography (HPLC) system equipped with a radioisotope detector. The metabolite elution was carried out on a C(18) column using an acetonitrile/water mobile phase. The structural assignments were based on GC-MS analysis of the tetrahydrofuran extract of urine containing the metabolites. Some of the metabolites in the extracts were first protected with trimethylsilyl groups prior to GC-MS analysis using bis(trimethylsiloxy)trifluoroacetamide or highly purified hexamethyldisiloxane. The structures were also confirmed by comparisons with synthetic (14)C-labeled metabolite standards. The following are among the major metabolites identified in the case of MM: Me(2)Si(OH)(2), HOMe(2)SiCH(2)OH, HOCH(2)Me(2)SiOSiMe(2)CH(2)OH, HOMe(2)SiOSiMe(2)CH(2)-OH, HOCH(2)Me(2)SiOSiMe(3), and Me(3)SiOH. The metabolites of D(5) are as follows: Me(2)Si(OH)(2), MeSi(OH)(3), MeSi(OH)(2)OSi(OH)(3), MeSi(OH)(2)OSi(OH)(2)Me, MeSi(OH)(2)OSi(OH)Me(2), Me(2)Si(OH)OSi(OH)Me(2), Me(2)Si(OH)OSiMe(2)OSi(OH)Me(2), nonamethylcyclopentasiloxanol, and hydroxymethylnonamethylcyclopentasiloxane. No parent MM or D(5) was present in urine The presence of certain metabolites such as HOMe(2)SiCH(2)OH and Me(2)Si(OH)(2) in MM and D(5), respectively, clearly established the occurrence of demethylation at the silicon-methyl bonds. Metabolites of the linear siloxane are structurally different from that obtained for cyclic siloxane except for the commonly present Me(2)Si(OH)(2). Mechanistic pathways for the formation of the metabolites were proposed.