Hydroxytrimethylsilane

Endpoint summary

Additional information

There are no in vivo data on the toxicokinetics of trimethylsilanol.

The following summary has therefore been prepared based on validated predictions of the physicochemical properties of the substanceand using this data in algorithms that are the basis of many computer-based physiologically based pharmacokinetic or toxicokinetic (PBTK) prediction models.The main input variable for the majority of these algorithms is log K_owso by using this, and, where appropriate, other known or predicted physicochemical properties of trimethylsilanol (TMS) predictions or statements may be made about its potential absorption, distribution, metabolism and excretion (ADME) properties.

TMS in the aqueous phase can react with itself in a condensation reaction to form hexamethyldisiloxane (HMDS, CAS 107-46-0) and water. In aqueous solution, an equilibrium is established between TMS (monomer) and HMDS (dimer). The condensation reactions of TMS are reversible unless the concentration of HMDS exceeds its solubility; in this case, HMDS forms a separate phase, driving the equilibrium towards HMDS. At a loading of 100 mg/l, >99.9% TMS is expected. At loadings above about 500-1000 mg/l the concentration of HMDS is predicted to exceed its solubility, resulting in formation of a separate phase. It is anticipated that condensation is possible in contact with moist skin and in the aqueous environment of the lungs, therefore the toxicokinetics of the condensation product hexamethyldisiloxane (HMDS) is also discussed.

 

Absorption

Oral

When oral exposure takes place it is necessary to assume that except for the most extreme of insoluble substances, that uptake through intestinal walls into the blood takes place. Uptake from intestines can be assumed to be possible for all substances that have appreciable solubility in water or lipid. Other mechanisms by which substances can be absorbed in the gastrointestinal tract include the passage of small water-soluble molecules (molecular weight up to around 200) through aqueous pores or carriage of such molecules across membranes with the bulk passage of water (Renwick, 1993).

As trimethylsilanol is very water soluble (1E+06 mg/l) and has a molecular weight of approximately 90.20 it meets both of these criteria, so should oral exposure occur it is reasonable to assume systemic exposure will occur also.  The condensation product hexamethyldisiloxane is moderately soluble (0.93 mg/L) and has a molecular weight of 162.4, therefore systemic exposure to the condensation product is also possible should oral exposure occur. Although no quantitative information can be deduced, evidence of oral absorption of HMDS is available from an oral metabolism study (Dow Corning Corporation, 2001), and oral repeated dose studies (Dow Corning Corporation, 1990; Shin-Etsu Chemical Co., 1994) in rats. Similarly, adverse effects were observed in oral acute (Bayer AG, 1985) and repeated dose (Bayer AG, 1996) studies in rats on trimethylsilanol, providing evidence of absorption of the parent and/or condensation products.

 

 Dermal

A well conducted guideline in vitro skin absorption study conducted to OECD 428 and GLP (reliability score 1) is available for the substance. The total percentage of the dose of the radiolabelled substance (14C-TMS) absorbed was estimated to be <0.08% of the applied dose. Almost all (99.9%) of the recovered 14C-TMS volatilised from the skin surface and was captured in the charcoal baskets placed above the exposure sites. The majority of the absorbed dose penetrated through the skin to the receptor fluid. Therefore, dermal absorption of trimethylsilanol is poor (Dow Corning Corporation, 2008).

Condensation of trimethylsilanol to form hexamethyldisiloxane (HMDS) is possible on contact with skin. In an in vitro dermal absorption study (Dow Corning Corporation, 2000) using a Bronaugh Flow Through method, human cadaver skin was exposed to HMDS for 24 hours. A statistical analysis of the data indicated that only 0.023% of the applied dose of HMDS was absorbed through the human cadaver skin. The majority of the dose volatilised from the application site (97.5%). Therefore, absorption of HMDS is also poor.

 

Inhalation

The moderate partition coefficient of 1.19 and low molecular weight of trimethylsilanol are favourable for absorption directly across the respiratory tract epithelium by passive diffusion.

There is a QSPR to estimate the blood:air partition coefficient for human subjects as published by Meulenberg and Vijverberg (2000). The resulting algorithm uses the dimensionless Henry’s Law coefficient and the octanol:air partition coefficient (K_oct:air) as independent variables.

Using these values for trimethylsilanol results in a high blood:air partition coefficient (approximately 89:1) so uptake into the systemic circulation would be expected. However, the high water solubility of trimethylsilanol might lead to some of it being retained in the mucus of the lungs so absorption is then likely to slow down.

Condensation of trimethylsilanol to HMDS is also possible in the aqueous environment of the lungs. In a toxicokinetic study (Dow Corning Corporation, 2006) rats were exposed (6-hour nose-only) to HMDS for either 14 consecutive days followed by a single exposure (6-hour) to 14C-HMDS, or to a single exposure (6-hour) of 14C-HMDS. All concentrations of HMDS were 5000ppm. In both experiments approximately 4% of the dose was retained. Parent HMDS was measured in blood and tissues; brain, fat, kidney, liver, lung and testes and the highest concentrations were found in fat and kidney. Elimination of radioactivity from blood and tissues (excluding fat) was multiphasic, with the majority of the radioactivity eliminated within 24 hours post-exposure. The majority of systemically absorbed HMDS was eliminated in the urine or expired volatiles. Urinary elimination was as polar metabolites only. Considering the effective removal of HMDS through metabolism and exhalation, the authors of the study considered accumulation in the body after repeated exposures to be unlikely.

After a 6 hour inhalation exposure of female rats to 5000 ppm HMDS, approximately 3% of the achieved dose was retained (Dow Corning Corporation, 2008). Parent HMDS was measured in blood and tissues: brain, fat, kidney, liver, lung and ovaries, and the highest concentrations were found in fat and ovaries. Elimination of radioactivity from blood and tissues (excluding fat) was multi-phasic, with the majority of the radioactivity eliminated within 24 hours post-exposure. The majority of the systemically absorbed HMDS was eliminated in the urine or expired volatiles. Urinary excretion consisted of entirely polar metabolites. The primary route of elimination was in expired volatiles and 71% of this radioactivity was attributed to parent HMDS with the remainder as metabolites. Considering the effective removal of HMDS through metabolism and exhalation, accumulation in the body after repeated exposures is unlikely despite its high lipophilicity.

 

Distribution

Trimethylsilanol is a small molecule, and is likely to be widely distributed. The log K_ow of this hydrolysis product means that it is likely to distribute widely into cells, and intracellular concentrations might be higher than the extracellular concentration, particularly in fatty tissues.

For blood:tissue partitioning a QSPR algorithm has been developed by De Jonghet al. (1997) in which the distribution of compounds between blood and human body tissues as a function of water and lipid content of tissues and the n-octanol:water partition coefficient (K_ow) is described. Using this value for trimethylsilanol predicts that it will distribute approximately equally to liver, muscle, brain and kidney and about 10-fold higher to fat. The predicted distribution profile is very similar for the condensation product, hexamethyldisiloxane.

	Log Kow	Kow	Liver	Muscle	Fat	Brain	Kidney
Trimethylsilanol	1.19	15.5	1.1	1.0	11.9	1.2	1.0
Hexamethyldisiloxane	5.06	126000	8.8	5.4	113.8	13.9	7.2

 

Metabolism

There are no data regarding the metabolism of trimethylsilanol. Genetic toxicity tests in vitro showed no observable differences in effects with and without metabolic activation.

Urinalysis conducted in the inhalation toxicokinetics study (Dow Corning Corporation, 2008) on HMDS demonstrated that several peaks were present, but none corresponded to the retention time of the parent. Primary metabolites detected were 1,3-bis(hydroxymethyl)tetramethyldisiloxane combined with an unknown metabolite with retention time of 26.6 minutes (61%; 6-12 h sample). Other metabolites that were detected at greater than 5% were hydroxymethyldimethylsilanol (14%), dimethylsilanediol (14%) and trimethylsilanol (6%).

Also, following oral exposure to HMDS the following are among the major metabolites identified in urine (Dow Corning Corporation, 2001): Me₂Si(OH)₂; HOMe₂SiCH₂OH; HOCH₂Me₂SiOSiMe₂CH₂OH (predominant); HOCH₂Me₂SiOSiMe₃; HOMe₂SiOSiMe₃; Me₃SiOH. Besides these there were also three other metabolites: HOMe₂SiOSiMe₂CH2OH; 2,2,5,5-tetramethyl-2,5-disila-1,3-dioxalene and 2,2,5,5-tetramethyl-1,4-dioxa-2,5-disilacyclohexane inferred from GC-MS analyses. Their presence in the HPLC metabolite profile was not established. No parent HMDS was present in urine.

 

Excretion

A determinant of the extent of urinary excretion is the soluble fraction in blood. QPSR’s as developed by De Jonghet al. (1997) using log K_owas an input parameter, calculate the solubility in blood based on lipid fractions in the blood assuming that human blood contains 0.7% lipids.

Using this algorithm, the soluble fraction of trimethylsilanol in blood is approximately 90% suggesting it is likely to be effectively eliminated via the kidneys in urine. In contrast, the soluble fraction of the hexamethyldisiloxane in blood is <1% meaning that once absorbed the hydrolysis product is likely to be eliminated via the kidneys in urine and accumulation is unlikely.

References

Renwick A. G. (1993) Data-derived safety factors for the evaluation of food additives and environmental contaminants.Fd. Addit. Contam.10: 275-305.

Meulenberg, C.J. and H.P. Vijverberg, Empirical relations predicting human and rat tissue:air partition coefficients of volatile organic compounds. Toxicol Appl Pharmacol, 2000. 165(3): p. 206-16.

DeJongh, J., H.J. Verhaar, and J.L. Hermens, A quantitative property-property relationship (QPPR) approach to estimate in vitro tissue-blood partition coefficients of organic chemicals in rats and humans. Arch Toxicol, 1997.72(1): p. 17-25.