1,1,1,3,5,5,5-heptamethyltrisiloxane

Endpoint summary

Additional information

There are no in vivo data on the toxicokinetics of 1,1,1,3,5,5,5-heptamethyltrisiloxane (H-L3).

The following summary has therefore been prepared based on in vitro data for a structurally related substance decamethyltetrasiloxane (L4, CAS 141 -62 -8), and the physicochemical properties of H-L3 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_ow so by using this, and other where appropriate, known or predicted physicochemical properties of H-L3 reasonable predictions or statements may be made about its potential absorption, distribution, metabolism and excretion (ADME) properties.

In contact with water, the substance reacts moderately to form methylsilanetriolandtrimethylsilanol (half-life of 2.15 days at pH 7 and 25°C).

Relevant human exposure to H-L3 can occur via the oral, inhalation or dermal routes.

Absorption

Oral

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 molecular weight of H-L3 (approximately 223) is close to the favourable range for absorption but due to its highly lipophilic nature and low water solubility the only means by which absorption from the gastrointestinal tract is likely to occur is via micellar solubilisation.

Oral exposure to the hydrolysis products methylsilanetriol and trimethylsilanol is potentially possible via the environment. As they are both highly water soluble and have molecular weights below 200 they therefore possess favourable characteristics for absorption so should oral exposure occur then systemic exposure is likely.

There was evidence of oral absorption in the repeated dose toxicity study in rats for H-L3.

Dermal

The fat solubility and therefore potential dermal penetration of a substance can be estimated by using the water solubility and log K_ow values. Substances with log K_ow values between 1 and 4 favour dermal absorption (values between 2 and 3 are optimal) particularly if water solubility is high. Therefore, with a log K_ow of 6.2 and water solubility of 0.02 mg/l, dermal absorption is unlikely to occur as H-L3 is not sufficiently soluble in water to partition from the stratum corneum into the epidermis. Furthermore, 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. H-L3 is volatile so this would further reduce the potential for dermal absorption.

There are no dermal toxicity studies available on H-L3 to check for signs of dermal absorption.

However, there is a dermal absorption study for the structurally related substance, L4, which has similar physicochemical properties to H-L3. In this in vitro dermal penetration study (Dow Corning Corporation, 2006) using human skin, conducted using a protocol comparable to OECD Test Guideline 428 and in compliance with GLP, almost all (99.9%) of the recovered ¹⁴C-L4 volatilised from the skin surface and was captured in the charcoal baskets placed above the exposure site. Only a small amount of applied dose (0.06%) was found on the skin surface after 24 hours exposure or remained in the skin after washing and tape stripping (0.03%). Little, if any (0.001%), of the applied dose penetrated through the skin into the receptor fluid. The total amount of dose absorbed was estimated to be 0.03% of applied dose with virtually all of the absorbed test substance retained in the skin.

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 (K_oct:air) as independent variables.

Using these values for H-L3 results in an extremely low blood:air partition coefficient (approximately 2.0E-04:1) so absorption across the respiratory tract epithelium is likely to be restricted to micellar solubilisation. There are no inhalation toxicity studies to check for signs of absorption.

 

Distribution

For blood:tissue partitioning a QSPR algorithm has been developed by DeJongh 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 (K_ow) is described.

Using this for H-L3 predicts that should systemic exposure occur, it will distribute into the main body compartments as follows: fat >> brain > liver ≈ kidney > muscle

Table 1: Tissue:blood partition coefficients

 

	Log Kow	Kow	Liver	Muscle	Fat	Brain	Kidney
H-L3	6.2	1.58E+06	8.9	5.5	113.9	18.0	8.1

 

The repeated dose toxicity study showed effects in the liver and kidney, indicating that H-L3-related material must have distributed to these organs.  However, there were no reported effects in the brain.

Metabolism

There are no data regarding the metabolism of H-L3. Genetic toxicity tests in vitro showed no observable differences in effects with and without metabolic activation for H-L3. There was no observable biodegradation in a ready biodegradation test. This suggests that the substance and its hydrolysis product are not recognised by biological systems containing all the mammalian enzymes and metabolic systems.

Excretion

A determinant of the extent of urinary excretion is the soluble fraction in blood. QPSR’s as developed by DeJongh et al. (1997) using log K_ow 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 this algorithm, the soluble fraction of H-L3 in blood is <1E-04%. Therefore, H-L3 would not be eliminated via the urine.

References:

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.

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

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