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EC number: 236-828-6
CAS number: 13501-76-3
There are no measured repeated dose toxicity data on (3-chloropropyl)diethoxymethylsilane, therefore, the structural analogue substance (3-chloropropyl)trimethoxysilane (CAS: 2530-87-2) has been used to assess the systemic toxicity potential of (3-chloropropyl)diethoxymethylsilane (MW ratio: target/source = 1.06).Repeated dose toxicity:Inhalation, subchronic:according to OECD TG 413 in rats: NOAEC = 804.6 mg/m³ (99.7 ppm)MW corrected NOAEC = 853.38 mg/m³Inhalation, subacute:according to OECD TG 422 in rats: NOAEC = ≥804.6 mg/m³ (99.7 ppm) MW corrected NOAEC = ≥ 853.38 mg/m³
were chosen as key when the available study was of relevance and of
sufficient quality for classification, labelling and for risk
No adequate repeated-dose toxicity data are
available for (3-chloropropyl)diethoxymethylsilane, therefore good
quality inhalation data for the analogue substance
(3-chloropropyl)trimethoxysilane (CAS: 2530-87-2) have been read-across.
Both substances hydrolyse to produce structurally similar silanol
hydrolysis products, (3-chloropropyl)methylsilanediol and
(3-chloropropyl)silanetriol, with the other hydrolysis products being
ethanol and methanol respectively. Since neither methanol or ethanol
would contribute to general toxicity effects in rodents at the dose
levels tested, it is considered that the observed toxicological effects
are due to the action of the (3-chloropropyl)silyl moiety, although the
specific toxicological mechanism cannot be determined from the available
information. Both substances have log Kow in the range that
is favourable for absorption across the respiratory tract (ethoxy log
kow= 4.2 and methoxy log kow= 0.56). No acute inhalation toxicity data
are available for either substance, but acute oral and dermal LD50 values
for both substances in rats are > 2000 mg/kg. It is therefore considered
valid to read-across the results for the trimethoxy analogue to fill
data gaps for the registered substance. Additional information is given
in a supporting report (PFA, 2013s)attached in Section 13 of the IUCLID
5 dossier. The molecular weight difference between
target and source chemical is 210.77/198.72 = 1.06.
key 90- day whole-body inhalation (vapour) study in rats, which was
conducted in accordance with OECD TG 413 with the structural analogue
substance (3 -chloropropyl)trimethoxysilane is available. Microscopic
examinations did not reveal any adverse findings in females exposed to
0.5 or 5 ppm. Eight of 10 male animals in the 0.5 ppm exposure group
were reported as normal. The two remaining male animals exhibited
minimal chronic cystitis of the urinary bladder. Nine of 10 male animals
were reported as normal in the 5.0 ppm exposure group. The remaining
male animals exhibited minimal chronic cystitis of the urinary bladder.
Treatment-related histopathological effects were observed in the 99.7
animals. Increased incidence of hyperplasia of the urinary bladder
epithelium was noted in both sexes of this group (Dow Corning
is not known whether the urinary bladder was inflated by a fixative
before microscopic examination. Without inflation of the urinary bladder
the relevance of the hyperplasia is questionable. Based on the
fact that the hyperplasia of the bladder was mild /minimal and in some
cases associated with a minimal inflammation (cystitis) it can be
presumed that if the stimulus for the hyperplastic changes is removed
the hyperplasia will resolve within a matter of weeks and the urinary
bladder will return to a normal histological appearance.
A minimal/mild change of the urinary bladder not associated with any
clinical symptoms or changes in urine parameters does not reflect a
marked organ dysfunction. Therefore, the mild/minimal hyperplastic
effects are not considered as adverse and the NOAEC is 99.7 ppm (804.6mg/m³).The
NOAEC for the target chemical is 853.38 mg/m³.
supporting 28-day whole body inhalation (vapour) study in rats, which
was conducted in accordance with OECD TG 422 with the structural
-chloropropyl)trimethoxysilane is also available. Rats were exposed up
to and including the highest concentration of 99.7 ppm (804.6 mg/m³).
There were no signs of general toxicity in the study and therefore based
on these results the NOAEC was established to be ≥ 99.7 ppm (≥804.6
mg/m³). The NOAEC
for the target chemical is ≥ 853.38 mg/m³ (RCC,
To reduce animal testing REACH
recommends to make use of a read-across approach where appropriate based
on the high accordance in properties relevant for the specific endpoint.
In the case of repeated dose toxicity relevant properties are
structural similarity as well as physical-chemical and basic
toxicological parameters in the same range. In the following paragraphs
the read-across approach for (3-chloropropyl)diethoxymethylsilane (CAS
13501-76-3) is evaluated point by point.
After inhalation exposure, both
(3-chloropropyl)diethoxymethylsilane (CAS 13501-76-3) and
(3-chloropropyl)trimethoxysilane (CAS 2530-87-2) are supposed to
hydrolyse rapidly to similar silanol hydrolysis products, namely
(3-chloropropyl)methylsilanediol and (3-chloropropyl)silanetriol. The
non-silanol hydrolysis products, ethanol and methanol, are not expected
to contribute to any adverse effects for systemic toxicity at the
relevant dose levels. This is discussed further below.
The half-lives of (3-chloropropyl)diethoxymethylsilaneat
25°C are3.8 h at pH 7 (see
Section 5.1.2).As the hydrolysis reaction may be acid or
base catalysed, the rate of reaction is expected to be slowest at pH 7
and increases as the pH is raised or lowered.
Reaction rate increases with
temperature therefore hydrolysis will be faster at physiologically
relevant temperatures compared to standard laboratory conditions. Under
ideal conditions, hydrolysis rate can be recalculated according to the
DT50(X °C) = DT50(T)
x e(0.08 (T-X))
Where T = temperature for which data
are available and X = target temperature.
(3-chloropropyl)diethoxymethylsilane the hydrolysis half-life at 37.5°C
and pH 7 (relevant for lungs and blood) is 2.3 hours and 5 s at 37.5°C
and pH 2 (relevant for stomach).
For the read-across substance,
(3-chloropropyl)trimethoxysilane, the corresponding half-lives are 53
min (20°C, pH 7), 17 min (37°C, pH 7), and 5 s (37.5°C, pH 2),
Analogue approach justification
Both the registration and read-across
substances are structurally similar, containing a 3-chloropropyl moiety
and 2-3 alkoxy (-OX) groups. The two substances hydrolyse rapidly to
produce similar hydrolysis products(3-chloropropyl)methylsilanediol and
These substances are part of an
analogue group of chloroalkoxysilanes. The read-across substance was
selected as the most appropriate based on chemical structure.
Further information is given in a
supporting report attached to Section 13 of the IUCLID5 dossier (PFA,
(b) Similar physicochemical
A data matrix is attached in Section
13 of the IUCLID dossier, and the key physicochemical parameters are
Si hydrolysis product
Molecular weight (parent substance)
log Kow (parent)
log Kow (silanol hydrolysis product)
Water sol (parent)
Water sol (silanol hydrolysis product))
60 000 mg/l
1 000 000 mg/l
Vapour pressure (parent)
Hydrolysis t1/2 at pH 7 and 25°C
Hydrolysis t1/2 at pH 2 and 37.5°C
Hydrolysis t1/2 at pH 7 and 37°C
(c) Similar toxicokinetics
and (3-chloropropyl)trimethoxysilane have similar vapour pressures,
indicating that exposure as a vapour is possible. The predicted water
solubility and the log Kow indicate that absorption from the
respiratory tract epithelium by passive diffusion is possible.
(d) Similar acute toxicity
A key acute oral limit test which was
conducted in compliance with GLP and according to the now deleted OECD
TG 401 is available on (3-chloropropyl)diethoxymethylsilane. Two out of
five males died when dosed at 2000 mg/kg bw and the macroscopic
examination of the two perished animals showed the most severe lesions
in the stomach and the intestine. The mucosa of these tissues showed
hyperaemia and haemorrhages. No macroscopic abnormalities were observed
in animals killed on day 14. All animals showed severe clinical symptoms
in the first six hours after treatment with the test substance. The
symptoms seen were padding movements, gait abnormality; decreased
activity and squatting position. 24 and 48 hours after treatment most of
the animals showed still the described clinical signs. Only one male and
one female showed these signs 72 hours after treatment with the test
substance. Milder clinical signs like piloerection were observed until
day 7. After 7 days until the end of the observation period there were
no more signs of systemic reaction to treatment. The LD50 to
rats of (3-Chloropropyl)diethoxymethylsilane was found to be > 2000
A key acute dermal toxicity study
which was conducted in compliance with GLP and according to OECD TG 402
is available on (3-chloropropyl)diethoxymethylsilane, there was no
mortality or any systemic effects seen at 2000 mg/kg bw (24 hour
exposure) (LD50> 2000 mg/kg bw).
In an acute oral
toxicity study with(3-chloropropyl)trimethoxysilanethe
LD50 (rat) was determined to be >2000 mg/kg day. Three older studies
support this conclusion, although much higher dose levels were tested
than required by current guidelines.In addition theLD50
(rat) was determined to be >2000 mg/kg after dermal exposure. Two
older studies support this conclusion, although much higher dose levels
were tested than required by current guidelines.
In conclusion, both substances have
low potential for acute toxicity.
e) Discussion of repeated systemic
toxicity of the non-silanol hydrolysis products
The repeated dose toxicity of the
non-silanol hydrolysis products, methanol and ethanol, has been
extensively studied. It is beyond the scope of this assessment to review
all of the available data in detail. However, the key findings from the
disseminated REACH dossiers and OECD SIAR reports (OECD 2004a and OECD
2004b) are reported here to support read-across arguments.
The majority of repeated dose toxicity
information for methanol comes from inhalation studies in rats and
Generally effects noted include nasal
irritation in rats (but not monkeys), CNS depression, effects on body
and organ weight and in some cases effects on clinical chemistry
parameters. Studies were conducted up to significant doses and generally
effects when noted, are considered adverse only at upper end of the dose
ranges studied e.g 650 mg/m³ in monkeys, 13 000 mg/m³ in rats.
Methanol is not classified for
repeated dose toxicity in Annex VI of Regulation (EC) No 1272/2008.
Generally in repeat dose studies in
animals with ethanol very large doses are used, and often specific
endpoints relating to known effects in humans are the primary focus of
such studies. However, adverse effects on the liver have been noted in
animals but only at very high doses >8 g/kg/day.
Ethanol is not classified for repeated
dose toxicity in Annex VI of Regulation (EC) No 1272/2008.
In conclusion, the oral NOAEL in rats
for methanol is greater than the dose that is expected to be generated
from hydrolysis of (3-chloropropyl)trimethoxysilane in the lung.
Similarly, ethanol generated from hydrolysis of
(3-chloropropyl)diethoxymethylsilane would not be expected to contribute
to the observed toxicity in rats at the dose levels used.
Based on the fact
that the urinary bladder effects were minimal and are expected to be
reversible for the structural analogue substance
3-chloropropyltrimethoxysilane (CAS: 2530-87-2), there is no proposal to
classify for specific target organ effects following repeated exposures
according to EC Regulation 1272/2008 for the registered substance.
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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