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Key value for chemical safety assessment

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There are no in vivo data on the toxicokinetics of triethoxy(2,4,4-trimethylpentyl)silane. The following summary has therefore been prepared based on validated predictions of the physicochemical properties of the substance itself and its hydrolysis products. Triethoxy(2,4,4-trimethylpentyl)silane is a moisture-sensitive, volatile liquid that hydrolyses in contact with water (half-life 43 hours at pH 7 and 20-25°C), generating ethanol and 2,4,4-trimethylpentylsilanetriol. Human exposure can occur via the inhalation or dermal routes. Relevant inhalation and dermal exposure would be predominantly to the parent substance.

Absorption

Oral

Significant oral exposure is not expected for this substance.

Dermal

The molecular weight of triethoxy(2,4,4-trimethylpentyl)silane is not ideal for dermal absorption, but it would not preclude it. However, the measured water solubility (<0.1 mg/l) and calculated log Kow(>6.5) 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. Dermal toxicity studies did not show signs of systemic toxicity, therefore it is not possible to judge whether any absorption occurred.

Inhalation

The water solubility and log Kowof triethoxy(2,4,4-trimethylpentyl)silane suggest that it could be taken up by micellar solubilisation. It is unlikely to be absorbed across the respiratory tract epithelium by any other mechanism. There are no inhalation studies on triethoxy(2,4,4-trimethylpentyl)silane to check for signs of absorption.

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 triethoxy(2,4,4-trimethylpentyl)silane predicts that 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 18.7 to 5.5 for the remaining tissues. For the hydrolysis product, approximately the same proportion would distribute to liver, muscle, brain and kidney, whereas distribution would be 6-fold higher to fat.

Table 7.1.1: Tissue:blood partition coefficients

 

Log Kow

Kow

Liver

Muscle

Fat

Brain

Kidney

triethoxy(2,4,4-trimethylpentyl)silane

> 6.5

3.16E+06

8.9

5.5

113.9

18.7

8.2

2,4,4-trimethylpentyl silanetriol

0.9

7.94

0.9

0.9

6.2

1.0

0.9

 

 

Metabolism

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-trimethylpentyl silanetriol, 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-trimethylpentyl silanetriol 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-trimethylpentyl silanetriol, 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-Trimethylpentyl silanetriol 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 (seeTable 5.1.1). 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 below>

Excretion

Following dermal exposure triethoxy(2,4,4-trimethylpentyl)silane is likely to be sloughed off with skin cells. The log Kowof 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.