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EC number: 220-449-8
CAS number: 2768-02-7
There are no measured data
on the toxicokinetics of trimethoxy(vinyl)silane.
The following summary has
therefore been prepared based on the predicted and measured
physicochemical properties of the registered substance and its
hydrolysis product (see Table 5.1.2 below). The data have been
used in algorithms which are the basis of many physiologically
based pharmacokinetic and toxicokinetic (PBTK) prediction models.
Although these algorithms provide quantitative outputs, for the
purposes of this summary only qualitative statements or
predictions will be made because of the remaining uncertainties
that are characteristic of prediction models.
The main input variable for
the majority of the algorithms is the log Kow. By using this and,
where appropriate, other known or predicted physicochemical
properties of trimethoxy(vinyl)silane or its hydrolysis product,
reasonable predictions or statements may be made about their
potential absorption, distribution, metabolism and excretion
hydrolyses very rapidly in contact with water (half-life
approximately 0.1 hours at pH 7 and at 20-25°C), generating
vinylsilanetriol and methanol. Direct exposure of workers and the
general population to the parent substance or its hydrolysis
products might occur via the inhalation and dermal routes.
Exposure of the general population via the environment might occur
via the oral route but would be limited to the hydrolysis product
due to the very rapid hydrolysis.
The toxicokinetics of
methanol have been reviewed in other major reviews and are not
considered further here.
not relevant due to very rapid hydrolysis in contact with water
1.0E+06 mg/L (QSAR)
640 Pa at 10°C, 1190 Pa at 20°C and 6000 Pa at 50°C (EU Method A.4)
0.017 Pa at 25°C (QSAR)
-2.0 at 20°C (QSAR)
Molecular weight (g/mol)
0.1 hour at pH 7 and at 20-25°C
Direct oral exposure is not
expected for this substance. However, oral exposure to the
hydrolysis product is potentially possible via the environment.
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 g/mol) through
aqueous pores or carriage of such molecules across membranes with
the bulk passage of water (Renwick, 1993).
Therefore, if oral exposure
to parent did occur, molecular weight of trimethoxy(vinyl)silane
(148.24 g/mol) is in the favourable range and would favour
absorption, so systemic exposure by this route is likely. At pH 2
in the stomach, the parent compound is predicted to hydrolyse into
the hydrolysis product vinylsilanetriol within 5 seconds at the
temperature of 37.5°C. Vinylsilanetriol has a favourable molecular
weight and water solubility values for absorption so systemic
exposure to this would also be likely.
Signs of systemic toxicity
were evident in the acute toxicity (Bushy Run Research Center,
1984) and repeat dose toxicity (Hashima Laboratories, 2005) oral
studies, which indicates systemic exposure to either the parent or
There are supporting
toxicokinetic data on two related alkoxysilane substances that
show rapid absorption of alkoxysilanes following oral
In the first toxicokinetic
test (Charles River, 2017), diethoxy(dimethyl)silane (CAS 78-62-8)
was administered as a single oral gavage dose (1000 mg/kg bw) to
male and female rats (2/sex). Blood samples were collected at 0.5,
1, 2, 4, 6 and 24 hours after dosing. The peak plasma
concentration was reached rapidly, at the first blood collection
point, just half an hour after dosing.
In a toxicokinetic test on morpholinotriethoxysilane
(CAS 21743-27-1), the radiolabelled test substance was
administered by oral gavage to mice (12/sex) as a single dose of
2000 mg/kg bw (Harlan Laboratories, 2009). Three male and three
female animals were sacrificed one and four hours after test
substance administration, and terminal blood, femur, stomach,
combined gastrointestinal (GI) tract contents, small intestine,
large intestine, liver and kidney were collected. Terminal blood,
femur, stomach, small intestine, large intestine, combined GI
tract contents, liver, kidney as well as urine and faeces were
collected from the remaining animals 24 hours after
administration. Overall significant mean levels of the test
item were found in blood and plasma as early as 1 hour after
application. This indicates that after oral administration the
test item was rapidly absorbed in significant amounts.
If dermal exposure were to
occur, in practice this would be to the parent compound as well as
the hydrolysis product.
The fat solubility and the
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.
Due to the likely very rapid
hydrolysis of the parent substance, trimethoxy(vinyl)silane, on
contact with skin, systemic exposure via this route is predicted
to be minimal. The hydrolysis product vinylsilanetriol is highly
soluble, and the log Kow value (-2.0) indicates it will
not be lipophilic enough to cross the stratum corneum and
therefore dermal absorption into the blood is unlikely to occur.
The acute dermal toxicity
study (Bushy Run Research Center, 1984) showed evidence of
systemic toxicity at high doses of parent test substance, implying
that dermal absorption of substance-related material had occurred.
The pH of the airway surface
liquid has been determined to be in the range 6.7-7 (Jayaraman
et al.,2000), without significant inter- or intraspecies
The predicted hydrolysis
half-life at 37.5ºC and pH 7 (relevant for lungs and blood) is
approximately 2 minutes. This prediction is based on a weight of
evidence of data from validated QSAR estimation method and
measured data (reliability 4 due to lack of methodology details),
and the following principle. As the hydrolysis reaction may be
acid or base catalysed, the rate of reaction is expected to be
slowest at around pH 7 and increase as the pH is raised or
lowered. For an acid-base catalysed reaction in buffered solution,
the measured rate constant is a linear combination of terms
describing contributions from the uncatalyzed reaction as well as
catalysis by hydronium, hydroxide, and general acids or bases.
kH3O+[H3O+] + kOH-[OH-]
+ ka[acid] + kb[base]
This chemical reaction is
independent of enzymatic involvement. It is reasonable to assume
that the parent and hydrolysis products of trimethoxy(vinyl)silane
will be present in the airway surface liquid, without significant
variation between individuals.
Proving the hydrolysis rate
in the lungs of experimental animals in vivo would present
many complicated (possibly insurmountable) technical difficulties,
and therefore the presence of parent and hydrolysis product is
assumed as a worst-case scenario.
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’s Law coefficient and the octanol: air
partition coefficient (Koct: air) as independent variables.
Using these values for
trimethoxy(vinyl)silane predicts a blood: air partition
coefficient of approximately 62:1 meaning that, in steady state,
approximately 98% of this substance will be in blood and
approximately 2% in air, and therefore if lung exposure occurs the
majority of parent substance available would be absorbed. However,
hydrolysis is expected. For the hydrolysis product,
vinylsilanetriol, the predicted blood: air partition coefficient
is approximately 5.3 E+08:1 meaning that systemic exposure is even
more likely. Again, this prediction is based on physicochemical
properties and is not expected to vary between individuals.
It is also important to
consider the water solubility of trimethoxy(vinyl)silane and its
hydrolysis product with respect to dissolving in the mucous of the
respiratory tract. The parent is expected to hydrolyse in the
aqueous mucous. The hydrolysis product is highly soluble in water
and therefore also expected to be present in the mucous lining
following inhalation of trimethoxy(vinyl)silane, from which there
is potential for passive absorption.
The key inhalation study on
trimethoxy(vinyl)silane (Bushy Run Research Center, 1990) showed
adverse systemic effects, specifically involving the kidneys and
bladder. These findings are reliable evidence that the test
substance was absorbed following inhalation exposure.
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
trimethoxy(vinyl)silane (log Kow = 1.1) predicts that,
should systemic exposure occur, potential distribution into the
main body compartments would be minimal.
Similarly, for the
hydrolysis products, distribution into the main body compartments
is predicted to be minimal.
Table: 5.1.3 Tissue:
blood partition coefficients
Additionally, there is a
supporting study on a structurally-related substance (morpholinotriethoxysilane,
CAS 21743-27-1) which show that there is no bioaccumulation
in any organ (Harlan Laboratories, 2009). In this test (described
plasma concentrations declined during the 24 h observation period
to approximately 6.8% of the peak value in male mice and to 6.0%
of the peak value in female mice. A comparable effect was seen in
all tissues analysed. Together with excretion data (described
later) these findings provide supporting evidence for the
conclusion that trimethoxy(vinyl)silane is not expected to
accumulate in any organ or tissue.
There are no data on the
metabolism of trimethoxy(vinyl)silane. However, it will hydrolyse
to form methanol and vinylsilanetriol once absorbed into the body.
Genetic toxicity tests in vitro showed no observable
differences in effects with and without metabolic activation.
within an analogue group of substances for which, in general,
there is no evidence of any significant biodegradation once
hydrolysis and subsequent biodegradation of alkoxy/acetoxy groups
has been taken into account (PFA, 2013f). In a ready
biodegradation study with trimethoxy(vinyl)silane, the
biodegradation observed is attributable to the non-silanol
hydrolysis product (methanol). Mass-balance
calculation has been undertaken to determine the percentage by
weight of the parent substance that is associated with the
biodegradable by-product. Once the biodegradation of the
hydrolysed methoxy- groups is taken into account, there is no
evidence of any biodegradation of the silanol
hydrolysis product, vinylsilanetriol. This observation is
supported by studies with silanols that are structurally similar
to vinylsilanetriol. Studies with hydroxytrimethylsilane (CAS
1066-40-6) and dimethylsilanediol (CAS 1066-42-8) show no evidence
of biodegradation (Clarke, 2008; Dow Corning Corporation, 1984). It
is therefore concluded that the substance and its silanol
hydrolysis product are not recognised by biological systems
containing all the mammalian enzymes and metabolic systems.
A determinant of the extent
of urinary excretion is the soluble fraction in blood. QPSRs as
developed by DeJongh 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%
Using the algorithm, the
soluble fraction of trimethoxy(vinyl)silane in blood is
approximately 92%. Similarly, for the hydrolysis product
vinylsilanetriol, the figure is >99% meaning that, once absorbed,
both the parent substance and hydrolysis product are likely to be
eliminated via the kidneys in urine, and accumulation is unlikely.
This prediction is supported
by in vivo toxicokinetic data on two related substances (morpholinotriethoxysilane
and diethoxy(dimethyl)silane). The details of these tests are
described above. With regard to excretion it has been demonstrated
that both of these substances are rapidly absorbed, but also
In the test conducted
by Harlan Laboratories (2009), morpholinotriethoxysilane peak
concentration to radioactivity in the blood, plasma, femur, liver
and kidney were found after just one hour. However, by 24 hours
after administration concentrations had declined to 6-7% of the
peak concentrations in plasma and tissues. After 24 hours 24.9%
and 17.4% of the applied dose was detected in urine, 3.4% and 9.8%
of the applied dose in cage wash of male and female mice,
respectively. Also, 63.8% and 64.2% of the applied dose was
excreted via faeces in male and female mice, respectively.
In the test conducted
by Charles River (2017), the maximum plasma concentration of
diethoxy(dimethyl)silane was measured at 1 hour after dosing (the
first sampling point). The test substance was also rapidly
eliminated with an individual half-life ranging between 1.06 to
1.27 hours for males and females, respectively.
In conclusion, rapid
absorption into the blood and fast elimination from the blood via
urine was observed with related alkoxysilane substances.
These findings support
the hypothesis that after hydrolysis, a water-soluble silanol is
formed (supported by log Kow calculation) which is
rapidly excreted from the body. Since, this hydrolysis occurs
without enzymatic involvement it is appropriate to reduce the
intraspecies assessment factor from 5 to 2.2 for workers and from
10 to 3.2 for the general population, by exclusion of the
toxicokinetic element of this assessment factor.
Charles River (2017) Single
Dose Pharmacokinetics of Diethoxy(dimethyl)silane
after Oral Administration in Male and Female Wistar Rats (non-GLP)
(ReachCentrum/Charles River, 2017) (Single Dose Pre-Study; final
study report not yet available).
Clarke, N (2008).
Trimethylsilanol (CAS No. 1066-40-6) Assessment of Ready
Biodegradability; CO2 in Sealed Vessels (CO2 Headspace
Test). Safepharm Laboratories Limited, Shardlow Business
Park, Shardlow, Derbyshire, DE72 2GD. Report number:
2581/0002. Report date: 2008-10-14.
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.
Corporation (1984) Twenty Day Biochemical Oxygen Demand of
Dimethylsilanediol with Bacterial Isolates Previously
Exposed to Silicones
Jayaraman, S.; Song,
Y.; Vetrivel, L.; Shankar, L. & Verkman, A. Noninvasive in vivo
fluorescence measurement of airway-surface liquid depth, salt
concentration, and pH Journal of Clinical Investigation, American
Society for Clinical Investigation, 2000, 107, 317-324.
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.
2013f, Peter Fisk Associates, Biodegradation Main Analogue Group
Renwick A. G. (1993)
Data-derived safety factors for the evaluation of food additives
and environmental contaminants.Fd. Addit. Contam.10: 275-305.
Information on Registered Substances comes from registration dossiers which have been assigned a registration number. The assignment of a registration number does however not guarantee that the information in the dossier is correct or that the dossier is compliant with Regulation (EC) No 1907/2006 (the REACH Regulation). This information has not been reviewed or verified by the Agency or any other authority. The content is subject to change without prior notice.Reproduction or further distribution of this information may be subject to copyright protection. Use of the information without obtaining the permission from the owner(s) of the respective information might violate the rights of the owner.
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