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EC number: 236-704-1
CAS number: 13465-77-5
No data are available for the repeated dose oral toxicity of
hexachlorodisilane, therefore good quality data for the hydrolysis
product, polysilicic acid (equivalent to SAS) have been read-across to
address the potential for systemic toxicity. In a repeat dose 90-day
oral toxicity study (Kim et al., 2014) with Sprague-Dawley rats, two
forms of synthetic amorphous silica (SAS and NM-202; differing in
particle size and specific surface area) were administered (vehicle:
water) by oral gavage for 90 consecutive days at a dose of 500, 1000 or
2000 mg/kg bw/day (10 animals/sex/group). The particles were described
as either 20 or 100 nm in diameter. Extra animals were included in the
control (received water only) and highest dose groups to allow for a
two-week post-exposure recovery period. Observations were made according
to OECD TG 408. For 20 and 100 nm silica samples the findings were
sporadic and without a dose-response, so were concluded by the study
authors not to be treatment-related. The NOAEL for both particle sizes
was therefore concluded to be ≥2000 mg/kg bw/day. For local effects a
good quality study on hydrogen chloride is available. In a 90-day
repeated dose inhalation study in rats and mice (Toxigenics, 1983), 31
males and 21 females of each species/strain were exposed to test
concentrations of 0, 10, 20 and 50 ppm hydrogen chloride gas (HCl).
Treatment was whole-body exposure for six hour per day, 5 days per week.
The No Observed Adverse Effect Concentration (NOAEC) for systemic
effects was determined to be 20 ppm (approximately 30 mg/m3) based on
decreased body weight following exposure to 50 ppm. No NOAEC for local
effects was established as irritant/corrosive effects were observed at
all dose levels tested. No suitable dermal data are available.
There are no
adequate long term repeated dose toxicity data on hexachlorodisilane
so good quality data for the hydrolysis products polysilicic acid
(equivalent to synthetic amorphous silica) and hydrogen chloride
have been used to assess the potential for adverse effects following
exposure to hexachlorodisilane.
It is considered not to be either ethical or technically feasible to
perform repeated dose toxicity testing with hexachlorodisilane by
any route of exposure due to its known corrosive properties, which
dominate the toxicity profile of this substance. Following repeated
oral dosing, the corrosive nature of the product could affect the
lining of the stomach, giving rise to hyperplasia and a subsequent
reduced food intake. This would confound the interpretation of any
systemically driven effects. A guideline-compliant repeated-dose
inhalation study should elicit systemic toxicity at the highest test
concentration. Since the local corrosive effects of
hexachlorodisilane would be significant a valid inhalation study
according to the relevant guidelines is technically not feasible to
do. It is also unlikely that any systemic effects would be seen at
dose levels made sufficiently low (<10
ppm) to prevent the known corrosive effects and/or distress
in the test species. This has been confirmed in a 28-day inhalation
study with another chlorosilane, dichloro(dimethyl)silane (WIL,
2014), in which there were no effects of treatment on clinical
signs, body weight or food consumption that would indicate a
systemic effect. Furthermore, the histopathology in the study
indicated that the local effects in the upper respiratory tract were
similar to HCl. It is therefore concluded that local effects caused
by HCl will dominate the inhalation toxicity profile of
With regard to the dermal and inhalation routes, due to the known
corrosive effects of hexachlorodisilane, appropriate H-phrases and
P-statements are included in the labelling, meaning that repeated
skin and inhalation exposure is not expected. Any accidental skin
contact or inhalation exposure could cause severe local effects but
would be unlikely to cause any systemic effects.
There are no adequate
repeat-dose toxicity data on hexachlorodisilane so good quality data for
synthetic amorphous silica (CAS 112926-00-8) have been used to assess
the general systemic oral toxicity of hexachlorodisilane. Local effects
from the hydrolysis product, hydrogen chloride (HCl) are not addressed
by these data (see section on local effects below).
Hexachlorodisilane, like all inorganic chlorosilanes, is a severely
corrosive substance that is decomposed by water. The reaction is highly
exothermic (Merck, 2013).
Hydrolysis half-life is estimated to be less than 5s at 25°C and pH 4, 7
and 9. The
estimated half-lives of the substance at 25ºC and pH 4, 7 and 9 are
approximately 5 seconds, producing hexahydroxydisilane and hydrogen
hydrolysis of the Si-Si bonds in hexahydroxydisilane is expected to
happen rapidly and produces monosilicic acid.
Monosilicic acid condenses to insoluble polysilicic acid [equivalent to
synthetic amorphous silica (SAS)] at concentrations higher than 100-150
mg/l ‘SiO2 equivalent’ in water (Holleman-Wiberg,
2001). At very high concentration, polysilicic acid can condense to
silicon dioxide (SiO2).
Hexahydroxydisilane is also likely to form condensation products
(polyhydroxy-polysilanes) at similar concentrations (in terms of SiO2
equivalents). The structure and predicted properties of the Si-Si
containing hydrolysis products (polyhydroxy-polysilanes) and
(poly)silicic acid are very similar, and distinguishing between them
would be very difficult analytically. The hydrolysis products of
hydrochloric acid and (poly)silicic acid are significant for the
chemical safety assessment (CSR).
Monosilicic acid and polysilicic acid are naturally occurring substances
which are ubiquitous in the environment. Soluble monosilicic acid is the
major bioavailable form of silicon and plays an important role in the
biogeochemical cycle of silicon (ECETOC, 2006). Typical background
concentrations of monosilicic acid in the environment are up to 75 mg/l
‘SiO2equivalent’ in river water and up to 14 mg/l ‘SiO2equivalent’
in seawater (Iler, 1979).
The literature gives various values for the solubility of silicic acid,
determined indirectly as ‘SiO2 equivalent’ because the
soluble species cannot be directly measured:
The solubility of monosilicic acid according to Alexander et al.
(1954) at 25 °C:
The solubility of monosilicic acid according to Goto and Okura (1953) at
The solubility of monosilicic acid according to Elmer and Nordberg
(1958) at neutral pH:
With the described properties of hexachlorodisilane in mind it is not
possible to conduct 90-day repeated dose toxicity studies in
experimental animals due to the corrosive nature of this substance. Nor
can the hydrolysis product, monosilicic acid, be tested as it is not
possible to isolate this substance. However, we know from
physicochemical properties that following ingestion of
hexachlorodisilane, the conditions in the stomach are such that
following an initial rapid hydrolysis to soluble monosilicic acid, this
monomer will start to condense to form insoluble polysilicic acid
(equivalent to SAS). This condensation will start to occur once the
concentration of monosilicic acid reaches approximately 150 mg/l in the
Monosilicic acid (soluble silica) undergoes
condensation reactions in solution at about 100-150 mg/l ‘SiO2
equivalent’. The solubility of monosilicic acid in water is 150 mg/l ‘SiO2
Following dosing by oral gavage, partitioning will occur between the
dose vehicle and the aqueous environment in the stomach.
Mass dosed (in mg/day) = Body weight (in kg) x dose level (in mg/kg
Dose concentration (in mg/l) = mass dosed (in mg/day) ÷
volume (in l)
So, the dose level (mg/kg bw/day) required to reach the dose
concentration of 150 mg/l 'SiO2 equivalent', the estimated
(conservative) maximum concentration of silicic acid that can occur in
the stomach before condensation to insoluble polysilicic acid
(equivalent to SAS) begins is calculated as follows:
Body weight of rat = 0.3 kg
Dose level = X
Estimated aqueous volume = 0.0015 l
Dose concentration = 150 mg/l
150 mg/l = 0.3 kg x dose level (mg/kg bw/day) ÷
Dose level = 0.75 mg/kg bw/day 'SiO2 equivalent'
Therefore based on a condensation limit of 150 mg/l, the maximum dose
level that could be used in practice to ensure exposure mainly to
monosilicic acid in the stomach of experimental animals is approximately
0.75 mg/kg bw/day or less of 'SiO2 equivalent'.
A correction for molecular weight gives a maximum dose level for
Mr [hexachlorodisilane] = 268.89 g/mol
Mr [silicon dioxide] = 60.08 g/mol
Dose level [hexachlorodisilane] = [Dose
level [silicon dioxide] x Mr [hexachlorodisilane]]
Mr [silicon dioxide]
mg/kg bw/day) x (268.89 g/mol)
= 3.36 mg/kg bw/day
Therefore based on a condensation limit of 150 mg/l the maximum dose
level of hexachlorodisilane that could theoretically be dosed to ensure
exposure mainly to monosilicic acid is approximately 3 mg/kg bw/day.
For comparison purposes, using the above calculation, the following
shows the dose concentrations for the dose levels typically used in
experimental animal studies (100, 300 and 1000 mg/kg bw/day).
Body weight = 0.3 kg
Total amount dosed = 30 mg
Estimated aqueous volume = 1.5 ml
= 20,000 mg/l
= 0.3 kg
Total amount dosed
= 90 mg
Estimated aqueous volume
= 1.5 ml
= 60,000 mg/l
= 0.3 kg
Total amount dosed
= 300 mg
= 200,000 mg/l
Therefore dosing at these dose levels clearly gives a dose concentration
in the stomach that far exceeds the dose at which condensation to
polysilicic acid (equivalent to SAS) starts to occur. Consequently, the
majority of the dose in the stomach will be present as insoluble
polysilicic acid (equivalent to SAS). In all cases only approximately
150 mg/l will be present as soluble monosilicic acid.
Overall, it can be concluded that gavaging hexachlorodisilane at doses
unlikely to cause local corrosive effects and at doses that give mainly
soluble monosilicic acid (2 mg/kg bw/day or less) would be unethical
based on animal usage. However, because the vast majority of a gavaged
dose will rapidly condense to insoluble polysilicic acid it is
appropriate to use toxicology data on SAS to address the potential for
oral toxicity of hexachlorodisilane.
The key study is a repeated dose 90-day oral toxicity study in rats (Kim
et al., 2014) conducted according to OECD test guideline 408 and in
compliance with GLP. In this study two forms of synthetic amorphous
silica (described as SAS and NM-202; differing in particle size and
specific surface area) were administered (vehicle: water) by oral gavage
for 90 consecutive days at a dose of 500, 1000 or 2000 mg/kg bw/day (10
animals/sex/group). A number of control and high dose group animals were
used for a two-week post-exposure recovery group follow-up. All findings
were sporadic and without a dose-response, so were concluded by the
study authors not to be treatment-related. The NOAEL for SAS was
therefore concluded to be ≥2000 mg/kg bw/day.
As has already been described
above, hexachlorodisilane is a severely corrosive substance that
is decomposed by water, producing silicic acid and HCl. For local
effects it is appropriate to read across results of a 90-day inhalation
toxicity study on HCl, which demonstrates the severe corrosive effects
of HCl in the respiratory tract.
In a 90-day repeated dose inhalation study in rats and mice
(Toxigenics, 1983), 31 males and 21 females of each species/strain
were exposed to test concentrations of 0, 10, 20 and 50 ppm hydrogen
chloride gas (HCl). Treatment was whole-body exposure for six hour
per day, 5 days per week. Fifteen males and 10
females from each group were sacrificed after four exposures and the
nasal turbinates, trachea, lung and gross lesions were examined
microscopically. In general, all animals in the high dose group
showed adverse findings after 4-days exposure. One female high dose
mouse was found dead on study day 12, and four low dose male mice
were found dead on study day 92. In addition, one high dose female
mouse was sacrificed in extremis on study day 20. One high
dose female Sprague-Dawley rat was found dead on study day 4.
However, the study authors noted that the deaths did not appear to
be related to exposure to HCl. Clinical signs were consistent with
the irritant/corrosive properties of HCl (appendage, tail or lip
injury in the form of toe missing/swollen/open/gelatinous,
scabbed/deformed/lesion, crusty nose, tissue mass, mouth injury,
scabbed nose, crusty muzzle, red stained fur, nasal discharge,
crusty eye, poor coat quality); some of the observed injuries may
have been mechanical and not related to test material exposure.
Ninety days exposure to 50 ppm HCl resulted in decreased body
weights in all four strains after four exposures. Following 90 days
of exposure B6C3F1 male and female mice and male Sprague-Dawley rats
exposed to 50 ppm had biologically significant decreases in body
weight. After four days of exposure there were statistically
significant decreases in food consumption for high dose male
Sprague-Dawley rats and male Fischer 344 rats. After 90 days high
dose mice had the largest reduction in food consumption. The rats
did not show a consistent reduction in food consumption that could
be deemed exposure-related. There were no treatment-related effects
on the haematology, clinical chemistry or urinalysis parameters that
were examined. Decreased liver weights were observed in high dose
male and female mice and Fischer 344 female rats. The authors noted
that this might have been due to the overall reduced body weights.
Animals exposed to all concentrations of HCl had minimal to mild
rhinitis, which occurred in the anterior portion of the nasal cavity
and was dose and time related. Mice also developed varying degrees
of cheilitis with accumulations of haemosiderin-laden macrophages
involving the perioral tissues at 50 ppm. At all exposure
concentrations mice developed oesinophilic globules in epithelial
cells lining the nasal turbinates after 90 days of exposure. The No
Observed Adverse Effect Concentration (NOAEC) for systemic effects
was determined to be 20 ppm (approximately 30 mg/m3)
based on decreased body weight following exposure to 50 ppm. No
NOAEC for local effects was established as irritant/corrosive
effects were observed at all dose levels tested.
Alexander G.B., Heston W.M. and Iler R.K. (1954) J. Phys. Chem., 58, 453.
Cotton F.A. and Wilkinson G. (1999) Advanced Inorganic Chemistry, 6thEdition,
ECETOC (2006) Synthetic Amorphous Silica (CAS No. 7631 -86 -9), JACC
REPORT No. 51
Elmer and Nordberg (1958) J. Am.Chem. Soc.,
Goto K. and Okura T. (1953) Kagaku, 23, 426.
Holleman-Wiberg, (2001) Inorganic Chemistry, Academic Press, p.
Iler, Ralph K. (1979) The Chemistry of Silica: Solubility,
Polymerization, Colloid and Surface Properties and Biochemistry of Silica,
Wiley, p. 13.
Jones, R. G., Wataru, A., and Chojnowski, J. (2000) Silicon-Containing
Polymers: The Science and Technology of Their Synthesis, Kluwer
Academic Press pp168-169
Merck Index (2013) Monograph Number. 8639 (15th Ed)
Based on the available read-across data from the hydrolysis products
insoluble polysilicic acid [equivalent to synthetic amorphous silica
(SAS)] and hydrogen chloride, hexachlorodisilane does not require
classification for specific organ toxicity following repeated
administration according to Regulation (EC) No. 1272/2008.
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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