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Description of key information

Key value for chemical safety assessment

Bioaccumulation potential:
no bioaccumulation potential

Additional information

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

The following summary has therefore been prepared based on validated predictions of the physicochemical properties of the substance itself and its hydrolysis products and using this data in algorithms that are the basis of many computer-based physiologically based pharmacokinetic or toxicokinetic (PBTK) prediction models. Although these algorithms provide a numerical value, for the purposes of this summary only qualitative statements or comparisons will be made.

The main input variable for the majority of these algorithms is log Kow so by using this, and other where appropriate, known or predicted physicochemical properties of hexamethyldisilazane or its hydrolysis products, reasonable predictions or statements can be made about their potential absorption, distribution, metabolism and excretion (ADME) properties.

Hexamethyldisilazane hydrolyses very rapidly in contact with water (≤0.04 min, ≤0.5 min, and ≤0.1 at pH 4, 7 and 9 and 1.5°C), generating trimethylsilanol and ammonia. Human exposure can occur via the inhalation or dermal routes. Due to the very rapid hydrolysis relevant inhalation and dermal exposure would be to the hydrolysis products.

The ADME properties of ammonia have been reviewed in other major reviews (OECD SIDS, 2007) and are not considered further here.

Absorption

Oral

Significant oral exposure is not expected for this substance.

When oral exposure takes place it can be assumed, except for the most extreme of insoluble substances, that uptake through intestinal walls into the blood occurs. 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).

The water solubility of the silanol hydrolysis product, trimethylsilanol has been measured as 20 000 mg/l, but at concentration around 1000 mg/l condensation reactions may take place over time, limiting the concentration dissolved in water.The solubility of 20 00 mg/l is considered valid for use in toxicokinetic modelling because it is adequate to describe the hydrophilicity of the substance and hence the partitioning behaviour. Therefore, if oral exposure did occur the favourable molecular weight (90.2) and water solubility (20000 mg/l) of the hydrolysis product trimethylsilanol means systemic exposure is very likely.

Clinical signs (sedation and paralysis) and death were recorded in the key (Bayer, 1988) and supporting acute oral toxicity studies with hexamethyldisilazane indicating systemic exposure to substance-related material had occurred.

Dermal

Dermal exposure would be to the hydrolysis products.

The fat solubility and therefore potential dermal penetration of a substance can be estimated by using the water solubility and log Kow values. Substances with log Kow values between 1 and 4 favour dermal absorption (values between 2 and 3 are optimal) particularly if water solubility is high.

With a water solubility of 20000 mg/L and log Kow of 1.19, trimethylsilanol is in the favourable range for dermal absorption and is therefore expected to be absorbed and result in systemic exposure. After or during deposition on the skin, evaporation of the substance and dermal absorption occur simultaneously so the vapour pressure of a substance is also relevant. With a vapour pressure of 1300 Pa, evaporation of trimethylsilanol is relevant and is likely to be a factor reducing potential dermal absorption. The parent substance, hexamethyldisilazane is corrosive to the skin so damage to the skin may increase potential for dermal penetration of the hydrolysis products.

Clinical signs (including sluggishness, prostration and lethargy) were recorded in the key (BRRC, 1981) and supporting acute dermal toxicity studies with hexamethyldisilazane indicating systemic exposure to substance-related material had occurred.

Inhalation

There is a Quantitative Structure-Property Relationship (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.

Using these values for trimethylsilanol predicts a blood:air partition coefficient of approximately 200:1 meaning that, if lung exposure occurred there would be uptake into the systemic circulation. The water solubility of trimethylsilanol also suggests that it could be dissolved in the mucous of the respiratory tract lining, so it may also be passively absorbed from the mucous, further increasing the potential for absorption.

Clinical signs and other indications of systemic exposure were noted in the key acute (Dow Corning Corporation, 2007) and repeat dose (Harlan, 2014) inhalation studies indicating systemic exposure to substance-related material had occurred.

Distribution

For blood:tissue partitioning a QSPR algorithm has been developed by De Jongh et 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 trimethylsilanol predicts that, should systemic exposure occur, potential distribution into the main body compartments would primarily be into fatty tissues with minimal distribution into the other tissues.

Table 5.1: Tissue:blood partition coefficients

 

Log Kow

Kow

Liver

Muscle

Fat

Brain

Kidney

trimethylsilanol

1.19

15.49

1.1

1.0

11.9

1.2

1.0

Metabolism

There are no data on the metabolism of hexamethyldisilazane. However, it will hydrolyse to form trimethylsilanol and ammonia once absorbed into the body. Genetic toxicity tests in vitro showed no observable differences in effects with and without metabolic activation.

Excretion

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

Using the algorithm, the soluble fraction of the hydrolysis product trimethylsilanol in blood is approximately 90% meaning it 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.

OECD SIDS (2007). SIDS Initial Assessment Report for SIAM 24, Paris, France, 17-20 April 2007, Ammonia Category.