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EC number: 252-558-1
CAS number: 35435-21-3
There are no in vivo or in
vitro data on the toxicokinetics of
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 Kow
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.
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
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.
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,
(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
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 Kow
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
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 Kow
(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
Dermal toxicity studies did not
show signs of systemic toxicity, therefore it is not possible to judge
whether any absorption occurred.
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.
The absorbed material is likely to
be in the form of the parent and hydrolysis products. The log Kow
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 (Kow) 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
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
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
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.
see .pdf attachment in Section 13.
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
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.
Enck P, Merlin V, Erckenbrecht JF,
et al. Stress effects on gastrointestinal transit in the rat. Gut
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