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There are no in vivo data on the toxicokinetics of 1,1,3,3-tetramethyldisiloxane (H2-L2).

The following summary has therefore been prepared based on measured toxicokinetic data for a closely related substance hexamethyldisiloxane, and validated predictions of the physicochemical properties of 1,1,3,3-tetramethyldisiloxane itself and its hydrolysis products and using this data in algorithms that are the basis of manycomputer-based physiologically based pharmacokinetic or toxicokinetic (PBTK) prediction models. The main input variable for the majority of these algorithms is log Kowso by using this, and other where appropriate, known or predicted physicochemical properties of1,1,3,3-tetramethyldisiloxaneor its hydrolysis product, reasonable predictions or statements may be made about their potential absorption, distribution, metabolism and excretion (ADME) properties.

H2-L2 is a moisture-sensitive liquid that hydrolyses rapidly in contact with water, generating dimethylsilanol (half-life of approximately 11 minutes at pH 7 and 25oC). Further slower hydrolysis generates dimethylsilanediol (half-life of 2.5 days) Human exposure can occur via the inhalation or dermal routes. Due to the very rapid hydrolysis, relevant dermal and inhalation exposure would be to dimethylsilanol. As the hydrolysis to dimethylsilanediol is much slower, human exposure to this substance is only relevant via the environment so it only discussed in the oral absorption section.

Absorption

Oral

Significant oral exposure is not expected for H2-L2.

However, oral exposure to humans via the environment may be relevant for the hydrolysis products, dimethylsilanol and dimethylsilanediol.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 both dimethylsilanol anddimethylsilanediol, are highly water soluble and a have molecular weights of <100, they meet both of these criteria, so should oral exposure occur it is reasonable to assume systemic exposure will occur also.

Dermal

The fat solubility and therefore potential dermal penetration of a substance can be estimated by using the water solubility and log Kowvalues. Substances with log Kowvalues between 1 and 4 favour dermal absorption (values between 2 and 3 are optimal) particularly if water solubility is high. Due to the likely very rapid hydrolysis ofH2-L2on contact with skin, systemic exposure via this route is predicted to be minimal. However, although the predicted water solubility of dimethylsilanol is 19000 mg/l, the log Kowof 0.6 is less than optimal for dermal absorption so while there is potential for it to occur it is considered the rate would be slow. Furthermore, as the after or during deposition of a liquid on the skin, evaporation of the substance and dermal absorption occur simultaneously so the vapour pressure of a substance is also relevant. Dimethylsilanol is volatile so this would further reduce the potential for dermal absorption.A dermal irritation study for H2-L2did not show any signs of systemic toxicity. No other dermal toxicity data are available.

In an in vitro dermal absorption study with hexamathyldisiloxane only 0.023% of the applied dose was absorbed through human cadaver skin. The majority of the dose volatilised from the application site (97.5%).

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 coefficient and the octanol:air partition coefficient (Koct:air) as independent variables.

The high water solubility of the hydrolysis product, dimethylsilanol, results in a moderate blood:air partition coefficient so once hydrolysis of the parent has occurred, as it would be expected to in the lungs, then uptake of dimethylsilanol would be expected into the systemic circulation. However, the high water solubility of dimethylsilanol may lead to some of it being retained in the mucus of the lungs so once hydrolysis has occurred, absorption is likely to slow down.

In the acute inhalation study there was no sign of systemic availability.

After a 6-hour inhalation exposure of hexamethyldisiloxane to female rats to 5000 ppm approximately 3% of the achieved dose was retained.

Distribution

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 (Kow) is described. Using this value for the hydrolysis product, dimethylsilanol, predicts that distribution will be minimal into liver, muscle, brain and kidney and slightly more (about 3-fold) into fat.

Table 1: tissue:blood partition coefficients

 

Log Kow

Kow

Liver

Muscle

Fat

Brain

Kidney

Dimethylsilanol

0.6

3.98

0.8

0.8

3.1

0.9

0.9

The related substance, hexamathyldisiloxane,was measured in blood and tissues: brain, fat, kidney, liver, lung and ovaries, and the highest concentrations were found in fat and ovaries following inhaled exposure to rats.

Metabolism

H2-L2 is hydrolysed into dimethylsilanol before absorption. There are no data regarding the metabolism of dimethylsilanol. Genetic toxicity testsin vitroshowed no observable differences in effects with and without metabolic activation for H2-L2. 

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 Kowas 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 dimethylsilanol in blood is approximately 97% suggesting it is likely to be effectively eliminated via the kidneys in urine.

The majority of the systemically absorbed related substance, hexamethyldisiloxane, was eliminated in the urine