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EC number: 242-056-0
CAS number: 18171-19-2
are no in vivo data on the toxicokinetics of 3-chloropropyl(dimethoxy)methylsilane.
following summary has therefore been prepared based on validated
predictions of 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 3-chloropropyl(dimethoxy)methylsilane
or its hydrolysis products, reasonable predictions or
statements may be made about their potential ADME properties.
is a moisture-sensitive, volatile liquid that
hydrolyses rapdily in contact with water (half-life approximately 1.3
hour at pH 7, predicted), generating methanol and 3-chloropropyl(methyl)silanediol.
Human exposure can occur via the inhalation
or dermal routes. Relevant inhalation exposure would be to the parent
and hydrolysis products.
The toxicokinetics of
methanol have been reviewed in other major reviews and are not
considered further here.
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 must be assumed to be possible for all
substances that have appreciable solubility in water or lipids. 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,
significant oral exposure is not expected for
3-chloropropyl(dimethoxy)methylsilane, should it occur then with a
solubility of 370 mg/l and a molecular weight of 182.72 g/mol it is
reasonable to assume systemic exposure will occur also.
For the hydrolysis product,3-chloropropyl(methyl)silanediol,
oral exposure to humans following hydrolysis in the
gastro-intestinal tract or via the environment may be relevant. With a
higher solubility (60000 mg/l) and lower molecular weight (154.67 g/mol)
than the parent, should oral exposure to 3-chloropropyl(methyl)silanediol
occur then it is reasonable to assume systemic exposure will
and to a greater extent than the parent.
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
The water solubility (370
mg/l) and log Kow (3.2) of the parent substance are therefore
favourable for dermal absorption, but this will be limited by the
hydrolysis of this substance.
The predicted water
solubility (60000 mg/l) of the hydrolysis product, 3-chloropropyl(methyl)silanediol,
is favourable for absorption across the skin but the log Kow of
0.8 is less so. Therefore, some absorption across the skin may occur but
possibly to a lesser extent than the parent.
once hydrolysis has occurred on the skin, absorption is likely to be
reduced. The available reliable skin irritation study did not provide
evidence of absorption as there were no systemic clinical effects
reported. Also, there were no systemic effects observed following a
dermal application of the related 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 3-chloropropyl(dimethoxy)methylsilane
results in a blood:air coefficient of approximately 46:1
meaning that, if lung exposure occurred there would be uptake in to the
systemic circulation. The high water solubility of the hydrolysis
results in a markedly higher blood:air partition coefficient
(approximately 2.1E+07:1) so once hydrolysis has occurred, as it would
be expected to in the lungs, then significant uptake would be expected
into the systemic circulation. However, the high water solubility of 3-chloropropyl(methyl)silanediol
may lead to some of it being retained in the mucus of the
lungs so once hydrolysis has occurred, absorption is likely to slow down.
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 3-chloropropyl(dimethoxy)methylsilane
predicts that, should systemic exposure occur, distribution
would primarily be into fat, with potential distribution into liver,
muscle, brain and kidney but to a much lesser extent.
For the hydrolysis product, 3-chloropropyl(methyl)silanediol,
it is predicted there may be some distribution into fat but
minimal distribution into the other main body compartments with
tissue:blood partition coefficients of less than 1.
Table 1: Tissue:blood
are no data regarding the metabolism of
3-chloropropyl(dimethoxy)methylsilane. Genetic toxicity tests in
vitro showed no observable differences in effects with and without
metabolic activation for 3-chloropropyl(dimethoxy)methylsilane. 3
-Chloropropyl(dimethoxy)methylsilane hydrolyses rapidly to
3-chloropropyl(methyl)silanediol and methanol in the presence of
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% lipids.
this algorithm, the soluble fraction of
3-chloropropyl(dimethoxy)methylsilane in blood is approximately 8.0%
while the corresponding value for the hydrolysis product,
3-chloropropyl(methyl)silanediol, is approximately 96%. Therefore, these
figures suggest that the hydrolysis
product is likely to be effectively eliminated via the kidneys in urine
but the parent substance would be predicted to not be as readily
eliminated from the body. However, as the parent is hydrolysed, the
hydrolysis product will be excreted via urine, and accumulation is
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