Triethoxy(2,4,4-trimethylpentyl)silane

Endpoint summary

Additional information

There are no in vivo or in vitro data on the toxicokinetics of triethoxy(2,4,4-trimethylpentyl)silane.

The following summary has therefore been prepared based on 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. The main input variable for the majority of these algorithms is log K_ow so by using this and, where appropriate, other known or predicted physicochemical properties of triethoxy(2,4,4-trimethylpentyl)silane or its hydrolysis products, reasonable predictions or statements may be made about their potential absorption, distribution, metabolism and excretion (ADME) properties.

Triethoxy(2,4,4-trimethylpentyl)silane is a moisture-sensitive liquid that hydrolyses in contact with water (half-life 43 hours at pH 7 and 20-25°C), generating ethanol and (2,4,4-trimethylpentyl)silanetriol.

Human exposure can occur via the inhalation or dermal routes. Relevant inhalation exposure would be predominantly to the parent substance, but dermal exposure to the parent and hydrolysis product could occur. The toxicokinetics of ethanol is discussed elsewhere and is not included in this summary.

Absorption

Oral

Significant oral exposure is not expected for this substance.

However, oral exposure to humans via the environment may be relevant for the hydrolysis product, (2,4,4-trimethylpentyl)silanetriol. 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 (2,4,4-trimethylpentyl)silanetriol is water soluble (the concentration dissolved in water is limited to about 200 mg/L by condensation reactions, calculated solubility is 2.4E+05 mg/L at 20°C (QSAR)) and has a molecular weight of approximately 192.33 it meets both of these criteria, so should oral exposure occur it is reasonable to assume systemic exposure will also occur.

In an acute oral toxicity study, there was no evidence of systemic toxicity, and therefore no evidence of absorption.

Dermal

The molecular weight (276.5 g/mol) of triethoxy(2,4,4-trimethylpentyl)silane is not ideal for dermal absorption, but it would not preclude it. 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 K_ow values between 1 and 4 favour dermal absorption (values between 2 and 3 are optimal) particularly if water solubility is high.

At 37.5°C and pH 5.5 (relevant for dermal exposure), the hydrolysis half-life will be between half-lives at pH 4 and pH 7 (0.2 - 16 hours). Due to the likelihood that hydrolysis of triethoxy(2,4,4-trimethylpentyl)silane might occur during contact with skin, exposure via this route is predicted to be to the parent and hydrolysis products. After or during deposition of a liquid on the skin, evaporation of the substance and dermal absorption occur simultaneously so the vapour pressure of the substance is also relevant.  However, as triethoxy(2,4,4-trimethylpentyl)silane has a low vapour pressure (0.14 Pa at 20°C and 0.22 Pa at 25°C (OECD 104)), it is considered that volitilisation would be minimal therefore it would not limit the dermal absorption potential.

The predicted water solubility (<0.1 mg/l) and log Kow (>6.5) of triethoxy(2,4,4-trimethylpentyl)silane suggest that the rate of penetration might be limited by the rate of transfer between the stratum corneum and the epidermis, but uptake into the stratum corneum will be high. Therefore the amount of test substance that is absorbed into the blood is likely to be low.

The very high predicted water solubility (2.4E+05 mg/L at 20°C (QSAR)) and low predicted log K_ow (0.9 (QSAR)) of the hydrolysis product, (2,4,4-trimethylpentyl)silanetriol, suggest that it is too hydrophilic to cross the lipid rich stratum corneum. Therefore, dermal uptake is likely to be low.

Therefore, absorption of the test substance or silanol hydrolysis product through the skin is expected to be low.

Dermal toxicity studies did not show signs of systemic toxicity, therefore it is not possible to judge whether any absorption occurred.

Inhalation

The hydrolysis half-life of triethoxy(2,4,4-trimethylpentyl)silane at 37.5°C and pH 7 (relevant for lungs and blood) is approximately 16 hours. Therefore, relevant inhalation exposure would be predominantly to the parent substance.

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. Using these values for the parent substance, triethoxy(2,4,4-trimethylpentyl)silane results in low blood:air partition coefficient (approximately 2.4:1) and uptake into the systemic circulation is expected to be low. However, the water solubility and log Kow of triethoxy(2,4,4-trimethylpentyl)silane suggest that it could be taken up by micellar solubilisation.

There are no inhalation studies on triethoxy(2,4,4-trimethylpentyl)silane to check for signs of absorption.

Distribution

The absorbed material is likely to be in the form of the parent and hydrolysis products. The log K_ow of the parent substance and the hydrolysis product means that both substances are lipophilic and they are likely to distribute into cells and the intracellular concentration might be higher than the extracellular concentration particularly in fatty tissues.

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 value for the parent substance and the silanol hydrolysis product predicts that distribution of the parent substance is likely to occur while distribution of the hydrolysis product would be minimal.

Toxicity studies provide evidence for distribution to the bladder and kidneys.

Table 1 Tissue:blood partition coefficients

	Log Kow	Kow	Liver	Muscle	Fat	Brain	Kidney
Triethoxy(2,4,4-trimethylpentyl)silane	6.5	3.2E+06	8.9	5.5	113.9	18.7	8.2
(2,4,4-Trimethylpentyl)silanetriol	0.9	7.9E+01	0.9	0.9	6.2	1.0	0.9

 

 

Metabolism

Triethoxy(2,4,4-trimethylpentyl)silane will hydrolyse to form ethanol and (2,4,4-trimethylpentyl)silanetriol once absorbed into the body. In vitro mammalian mutagenicity and cytogenicity tests gave negative results with metabolic and without metabolic activation.

There are no data regarding the metabolism of triethoxy(2,4,4-trimethylpentyl)silane except by abiotic hydrolysis. The predicted hydrolysis half-life at pH 7 (20-25°C) is 43 hours. At physiological temperature (37°C), this half-life will be substantially shortened. Likewise, under gastric conditions (pH 2), the hydrolysis is predicted to be quantitative within a few minutes. Gastric transit half-life in the rat is about 2 hours, so that there is little likelihood that appreciable amounts of parent enter the duodenum (Enck, P. et al., 1989).

The hydrolysis product could theoretically be subject to further metabolism, e.g., via monooxygenases. However, after the initial hydrolysis step has occurred, the reaction product, 2,4,4-trimethylpentylsilanetriol, already possesses an appreciable water solubility of 240 g/L which qualifies the molecule for immediate urinary excretion. Thus, further enzymatic oxidation of 2,4,4-trimethylpentylsilanetriol is rather unlikely to occur. It is therefore assumed that abiotic hydrolysis is the only significant route of metabolism. Phase-II metabolism by conjugation with glucuronic acid or sulphate is often seen in molecules bearing hydroxyl groups. However, these conjugates are either not formed at all or very short-lived, because such conjugates could not be detected in ADME studies with the siloxanes D4, D5, and HMDS. In all cases, non-conjugated silanol metabolites were detected in urine. It is therefore concluded that the primary hydrolysis product, 2,4,4-trimethylpentylsilanetriol, is the only significant metabolite of triethoxy(2,4,4-trimethylpentyl)silane.

The reactivity of triethoxy(2,4,4-trimethylpentyl)silane towards water suggests high reactivity to other biological nucleophils like protein-bound amino acids with hydroxyl groups. 2,4,4-Trimethylpentylsilanetriol lacks this reactivity and has a much lower tendency to be taken up into potential target tissues in the first place, judged by the reduced tissue-blood partition coefficients (see Table 1). Therefore, hydrolysis is considered a very efficient detoxification step.

This has direct implications for human risk assessment since assessment factors for toxicokinetic interspecies differences are per default set as the allometric scaling (AS) factor which in turn reflects the different caloric demand of different species. However, abiotic hydrolysis is clearly independent of caloric demand. It is a quasi-first order reaction since the reaction partner, water, is available in great excess. The hydrolysis rate therefore depends only on the concentration of the parent molecule. Hence, the metabolism of the parent does not underlie the AS principle when extrapolating dose descriptors from rodent studies to DNELs.

Figure 1: Predicted metabolism of triethoxy(2,4,4-trimethylpentyl)silane.

Please see .pdf attachment in Section 13.

Excretion

Following dermal exposure triethoxy(2,4,4-trimethylpentyl)silane is likely to be sloughed off with skin cells. The log Kow of this substance suggests a potential to remain in fatty tissues. However, systemically available test substance is likely to be excreted by the kidneys into urine. The high water solubility of (2,4,4-trimethylpentyl)silanetriol suggest that it is likely to be rapidly eliminated via the kidneys in urine. There is therefore no evidence to suggest that this substance will accumulate in the body.

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.

Enck P, Merlin V, Erckenbrecht JF, et al. Stress effects on gastrointestinal transit in the rat. Gut 1989;30:455-459.