1,1,5,5,5-hexamethyl-3,3-bis[(trimethylsilyl)oxy]trisiloxane

Endpoint summary

Additional information

There are no in vivo data on the toxicokinetics of 1,1,1,5,5,5-hexamethyl-3,3-bis[(trimethylsilyl)oxy]trisiloxane. The following summary has therefore been prepared based on validated predictions of the physicochemical properties of the substance itself and 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 other where appropriate, known or predicted physicochemical properties of 1,1,1,5,5,5 -Hexamethyl-3,3-bis[(trimethylsilyl)oxy]trisiloxane reasonable predictions or statements may be made about its potential ADME properties.

1,1,1,5,5,5-hexamethyl-3,3-bis[(trimethylsilyl)oxy]trisiloxane is an insoluble substance that is therefore stable in water. Human exposure can occur via the inhalation or dermal routes.

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 must 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).

Although significant oral exposure for 1,1,1,5,5,5-hexamethyl-3,3-bis[(trimethylsilyl)oxy]trisiloxane is not expected to occur, its insolubility and molecular weight of 384.85, mean that even if oral exposure did occur then uptake into the systemic circulation would be very unlikely.

Dermal

The fat solubility and therefore potential dermal penetration of a substance can be estimated by using the water solubility and log K_owvalues. Substances with log K_owvalues between 1 and 4 favour dermal absorption (values between 2 and 3 are optimal) particularly if water solubility is high. Therefore as 1,1,1,5,5,5-hexamethyl-3,3-bis[(trimethylsilyl)oxy]trisiloxane fulfils neither of these criteria, absorption across the skin is unlikely. There are no dermal toxicity data that can be checked for signs of systemic availability.

 

Inhalation

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 (Koct:air) as independent variables.

Using these values for 1,1,1,5,5,5-hexamethyl-3,3-bis[(trimethylsilyl)oxy]trisiloxane results in an extremely low blood:air partition coefficient (<3.3E-05) so systemic exposure via the inhalation route would almost certainly not occur. There are no reliable inhalation data that could be reviewed for signs of systemic toxicity, and therefore absorption.

 

Distribution

For blood:tissue partitioning a QSPR algorithm has been developed by DeJonghet 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 a log K_owvalue 9 for 1,1,1,5,5,5-hexamethyl-3,3-bis[(trimethylsilyl)oxy]trisiloxane predicts that should systemic exposure occur it will distribute into the main body compartments as follows: fat >> brain > liver ≈ kidney > muscle with tissue:blood partition coefficients of 113.9 for fat and 5.5 to 20.5 for the remaining tissues.

Table5.1.1Tissue:blood partition coefficients

	Log Kow	Kow	Liver	Muscle	Fat	Brain	Kidney
1,1,1,5,5,5 -Hexamethyl-3,3-bis[(trimethylsilyl)oxy]trisiloxane	9	1.0E09	8.9	5.5	113.9	20.5	8.4

 

Metabolism

There are no data regarding the metabolism of 1,1,1,5,5,5-hexamethyl-3,3-bis[(trimethylsilyl)oxy]trisiloxane. However, it is likely that this substance would be metabolised to more water-soluble metabolites. Genetic toxicity testswith a read-across substance showed no observable differences in effects with and without metabolic activation for 1,1,1,5,5,5-hexamethyl-3,3-bis[(trimethylsilyl)oxy]trisiloxane.

Excretion

A determinant of the extent of urinary excretion is the soluble fraction in blood. QPSRs as developed by DeJonghet 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 1,1,1,5,5,5-hexamethyl-3,3-bis[(trimethylsilyl)oxy]trisiloxane in blood is <2E-06%. Therefore, should systemic exposure occur, 1,1,1,5,5,5-hexamethyl-3,3-bis[(trimethylsilyl)oxy]trisiloxane would not be eliminated via the urine, however, it is possible that it may be partly excreted in urine as water soluble metabolites.