Dichloro(diphenyl)silane

Endpoint summary

Description of key information

RDT oral (OECD TG 408), rat: NOAEL local = 40 mg/kg bw/day, NOAEL systemic = 40 mg/kg bw/day

Key value for chemical safety assessment

Repeated dose toxicity: via oral route - systemic effects

Link to relevant study records

Reference

Endpoint:

sub-chronic toxicity: oral

Type of information:

experimental study

Adequacy of study:

key study

Study period:

27 Apr - 01 Sept 2020

Reliability:

1 (reliable without restriction)

Rationale for reliability incl. deficiencies:

guideline study

Qualifier:

according to guideline

Guideline:

OECD Guideline 408 (Repeated Dose 90-Day Oral Toxicity Study in Rodents)

Version / remarks:

25 June 2018

Deviations:

no

GLP compliance:

yes (incl. QA statement)

Remarks:

Bayerisches Landesamt für Gesundheit und Lebensmittelsicherheit, Schwabach, Germany

Limit test:

no

Species:

rat

Strain:

Wistar

Remarks:

Crl:WI(Han)

Sex:

male/female

Details on test animals or test system and environmental conditions:

TEST ANIMALS
- Source: Charles River, Sulzfeld, Germany
- Females: nulliparous and non-pregnant: yes
- Age at study initiation: approx. 7-8 weeks old
- Weight at study initiation: males: 163 – 202 g (mean: 181.7 g, ± 20 % = 145.3 – 218.0 g); females: 121 – 164 g (mean: 142.6 g, ± 20 % = 114.1 – 171.2 g)
- Fasting period before study: not reported
- Housing: 5 animals / sex / group / cage in IVC cages (type IV, polysulphone cages) on Altromin saw fibre bedding
- Diet: Altromin 1324 maintenance diet for rats and mice (Altromin Spezial-futter GmbH & Co. KG, Lage, Germany) provided ad libitum
- Water: tap water, sulphur acidified to a pH of approximately 2.8 provided ad libitum
- Acclimation period: at least 5 days

DETAILS OF FOOD AND WATER QUALITY: Drinking water, municipal residue control, microbiological controls at regular intervals;
Certificates of food, water and bedding are filed for two years at BSL Munich and afterwards archived at Eurofins BioPharma Product Testing Munich GmbH.

ENVIRONMENTAL CONDITIONS
- Temperature (°C): 22 ± 3
- Humidity (%): 55 ± 10
- Air changes (per hr): 10
- Photoperiod (hrs dark / hrs light): 12 / 12

Route of administration:

oral: gavage

Vehicle:

corn oil

Remarks:

dried and de-acidified

Details on oral exposure:

PREPARATION OF DOSING SOLUTIONS: The test item was weighed into a glass vial on a suitable precision balance and the dried and de-acidified vehicle was added to give the appropriate final concentration of the test item. The formulation was alternately vortexed and/or stirred until visual homogeneity was achieved. After homogenization the formulation was overlaid with argon or nitrogen to prevent instability caused by repeated contact of the test item formulation with air. Formulates were kept under magnetic stirring during the daily administration.

VEHICLE
- Justification for use and choice of vehicle (if other than water): This vehicle was selected in consultation with the sponsor based on the test item’s characteristics. Corn oil was filtered through a mixture of activated silica gel 60 and aluminum oxide (1:1, volume/volume), which had been filled into a glass chromatography column to three quarters of its height. For filtering, a vacuum of 75 mbar was applied. The dried and de-acidified vehicle was overlaid with argon or nitrogen and stored until usage.
- Concentration in vehicle: 2.5, 10 and 31.25 mg/mL
- Amount of vehicle: 4 mL/kg bw
- Lot/batch no.: MKCK6411

Analytical verification of doses or concentrations:

yes

Details on analytical verification of doses or concentrations:

Before the beginning of the treatment period, formulation samples were prepared and analysed in order to obtain knowledge about stability and homogeneity of the test item in the selected vehicle as part of a separate GLP study.
The prestart homogeneity investigation was included on the samples collected from various levels (top, middle and bottom) of high-dose and low-dose groups.
As the test item was shown to be homogenous (after 30 min without stirring), samples were not collected during the study for the investigation of homogeneity and only samples were taken for substance concentration.
Concentration analysis of formulation samples was performed at three concentrations, 2.5 mg/mL, 10 mg/mL and 31.25 mg/mL in weeks 1, 5, 9 and the last week of the study. The mean recoveries observed for the low-dose group were between 90.5% and 109.9% of the nominal value, between 82.6% and 97.2% of the nominal value for the mid-dose group and between 93.8% and 103.8% of the nominal value for the high-dose group. The mean recoveries observed in the low-, mid- and high-dose groups were 98.3%, 90.9%, and 99.1% of the nominal concentration, respectively.
Nominal concentrations were confirmed for all dose groups, as measured concentrations were within the acceptance criterion of 15%. However, one sample (no. 11, mid-dose week 3) did not meet this criterion with a recovery of 82.6%. Since overall mean recovery was within acceptance criteria, no further actions were taken.

Duration of treatment / exposure:

90 days; animals in the recovery group were observed for a period of 28 days following the last administration.

Frequency of treatment:

once daily, 7 days/week

Dose / conc.:

10 mg/kg bw/day (actual dose received)

Dose / conc.:

40 mg/kg bw/day (actual dose received)

Dose / conc.:

125 mg/kg bw/day (actual dose received)

No. of animals per sex per dose:

10 animals/sex/dose (treatment and control groups)
5 animals/sex/dose (recovery group)

Control animals:

yes, concurrent vehicle

Details on study design:

- Dose selection rationale: Doses were selected based on a 14-day range finding study in rats with dose levels of 25, 50, 100, 500 and 375 mg/kg bw/day. In this study, mortality occurred in 2/2 males and 2/2 females at the dose of 500 mg/kg bw/day and 1/2 females at 375 mg/kg bw/day, inflammatory lesions in the stomach and, small and large intestine were considered as the cause of morbidity. Adverse clinical signs were observed at 500 mg/kg bw/day in both males and females including, increased salivation (slight), apathy, hypotonia (muscle), reduced spontaneous activity (slight/severe), slow movements, piloerection (moderate) and half eyelid close (both), hypothermia, lacrimation (left) on treatment days. No treatment-related mortality or marked clinical signs were observed at up to 100 mg/kg bw/day. Treatment did not affect the body weight gain at up to 100 mg/kg bw/day in males and females and body weight was comparable to the respective controls. Test item-related gross lesions were noted in the stomach and, small and large intestine at ≥375 mg/kg bw/day and these were evident during the histopathological examination. The test item caused inflammatory and degenerative findings in the stomach of animals at 375 and 500 mg/kg bw/day. Based on the histopathological data, that no adverse effects were noted up to and including 100 mg/kg bw/day.

Positive control:

None

Observations and examinations performed and frequency:

CAGE SIDE OBSERVATIONS: Yes
- Time schedule: General clinical observations were made at least once a day, preferably at the same time each day and considering the peak period of anticipated effects after dosing. The health condition of the animals was recorded. Twice daily all animals were observed for morbidity and mortality except on weekends and public holidays when observations were made once daily.

DETAILED CLINICAL OBSERVATIONS: Yes
- Time schedule: Once before the first administration and at least once a week thereafter
- Detailed cage side observations (outside home cage in a standard arena) included: response to handling, body position, spontaneous locomotor activity, ataxic gait, hypotonic gait, twitches, tremors, seizures unusual behaviour, stereotypical behaviour, faeces consistency, abnormal vocalization, aggressiveness/irritability and grooming.

BODY WEIGHT: Yes
- Time schedule for examinations: The body weight was recorded once before the assignment to the experimental groups, on the first day of administration and weekly during the treatment and recovery periods.

FOOD CONSUMPTION: Yes
- Time schedule for examinations: Weekly during the treatment and recovery periods

OPHTHALMOSCOPIC EXAMINATION: Yes
- Time schedule for examinations: Ophthalmological examinations, using an ophthalmoscope were made on all animals before the first administration and in the last week of the treatment period as well as at the end of the recovery period in the recovery animals.
- Dose groups that were examined: All groups

HAEMATOLOGY: Yes
- Time schedule for collection of blood: Haematological parameters were examined at the end of the treatment and recovery periods prior to or as part of the sacrifice of the animals
- Anaesthetic used for blood collection: Yes, ketamine/xylazin
- Animals fasted: Yes
- How many animals: All surviving animals
- Parameters checked in table 1 were examined.

CLINICAL CHEMISTRY: Yes
- Time schedule for collection of blood: Parameters of clinical biochemistry were examined at the end of the treatment and recovery periods prior to or as part of the sacrifice of the animals
- Animals fasted: Yes
- How many animals: All surviving animals
- Parameters checked in table 2 were examined.

URINALYSIS: Yes
- Time schedule for collection of urine: Prior to sacrifice
- Metabolism cages used for collection of urine: Yes
- Animals fasted: Yes
- Parameters checked in table 3 were examined.

NEUROBEHAVIOURAL EXAMINATION: Yes
- Time schedule for examinations: Once before the first exposure and towards the end of the exposure period but not earlier than in week 11 as well as in the last week of the recovery period multiple detailed behavioural observations were made outside the home cage using a functional observational battery of tests
- Dose groups that were examined: All surviving animals
- Battery of functions tested included detailed cage side observations considering spontaneous activity, lethargy, recumbent position, convulsions, tremors, apnoea, asphyxia, vocalisation, diarrhoea, changes in skin and fur, eyes and mucous membranes (salivation, discharge), piloerection and pupil size.

IMMUNOLOGY: No

OTHER: For an evaluation of test item-related effects on the pituitary-thyroid axis and thyroid hormones, serum samples of all animals were retained at the end of treatment (80 animals) and recovery (20 animals). T3 (triiodothyronine), T4 (L-thyroxine) and TSH (thyroid-stimulating hormone) serum levels were determined in the main study animals.

Sacrifice and pathology:

GROSS PATHOLOGY: Yes (see table 4); one day after the last administration (study day 91), all surviving animals of the treatment period and 4 weeks after the last administration, all surviving animals of the recovery period were sacrificed using anaesthesia (ketamine/xylazin) followed by exsanguination. They were then subjected to a detailed gross necropsy which included careful examination of the external surface of the body, all orifices and the cranial, thoracic and abdominal cavities and their contents. Vaginal smears were examined on the day of necropsy to determine the stage of estrous cycle. Special attention was given to the gastrointestinal tract in order to assess possible corrosive effects.
The wet weight of the organs (see table 4) of all sacrificed animals was recorded as soon as possible. Paired organs were weighed together. Weight of the thyroid/parathyroid glands was measured after fixation. Organ weights of animals found dead or euthanized for animal welfare reasons were not recorded.
The tissues in Table 5 from all animals were preserved in 4% neutral-buffered formaldehyde except eyes, testes and epididymides which were fixed in Modified
Davidson’s fixative for approximately 24 hours before they were transferred to 70% ethanol.

HISTOPATHOLOGY: Yes (see table 5); organs listed in Table 5 were examined histopathologically after preparation of paraffin sections and hematoxylin-eosin staining for the animals of the control and high-dose groups sacrificed at the end of the treatment period and any animal found dead or euthanized before the planned day of sacrifice.
For testis, a detailed qualitative examination was made, taking into account the tubular stages of the spermatogenic cycle at evaluation of additional haematoxylin-PAS (Periodic Acid Schiff) stained slides.
For organs and tissues showing treatment-related changes in the high-dose group, these examinations were extended to animals of all other dosage groups, as well as to animals subjected to necropsy at the end of the recovery period.
Any gross lesion macroscopically identified was examined microscopically in all animals. Discoloration possibly due to the test item was evaluated in the organs of all dose groups.

Other examinations:

EXAMINATIONS OF FERTILITY PARAMETERS
Vaginal smears were examined on the day of necropsy to determine the stage of estrous cycle in all female animals of the main and recovery groups.

At necropsy (one day after the last administration) and at the end of the recovery period, the left epididymis and left testis of the groups 1 and 4 males were separated and used for evaluation of sperm parameters (main and recovery). Epididymal sperm motility and testicular sperm count were evaluated in all male animals.

Sperm morphology slides were prepared from all male animals of the control and high-dose groups (main and recovery).

Statistics:

A statistical assessment of the results of the body weight, food consumption, parameters of haematology, blood coagulation and clinical biochemistry and absolute and relative organ weights were performed for each gender by comparing values of dosed with control animals using either a parametric one-way ANOVA and a post-hoc Dunnett Test or a non-parametric Kruskal-Wallis Test and a post-hoc Dunn’s Test, based on the results of homogeneity and normality tests. Furthermore, statistical comparisons of data acquired during the recovery period may be performed with a Student’s t-Test or Mann-Whitney U-Test when appropriate.

Clinical signs:

effects observed, treatment-related

Description (incidence and severity):

No test item-related adverse clinical findings were observed in any of the treated groups.
Moving the bedding was observed at the low- (not in females), mid- and high-dose groups at post dose observation. This is assumed to be an indication of discomfort caused by a local reaction to the test item. Slight to moderate or severe salivation was observed at post dose observation in all the dose levels (not in low-dose females) and subsided later during the treatment or recovery period.
The severity of salivation (slight or moderate or severe) increased more in the high-dose groups (12/15 males and 11/15 females) when compared to lower dose levels (3/10 low-dose males and 4/10 mid-dose females) during the treatment period. Increased salivation and moving the bedding are deemed to be treatment-related local reactions to the test item but are not considered as toxicologically relevant.
There were no test item-related clinical signs observed during the weekly detailed clinical examinations during the study.

Mortality:

no mortality observed

Description (incidence):

No test item-related mortality was observed during the study period. All animals survived until the end of the treatment or the recovery period.

Body weight and weight changes:

effects observed, non-treatment-related

Description (incidence and severity):

No test item-related effects on body weight were observed during the treatment or recovery period of the study in the control, as well as in all dose groups.
There were variations in mean body weight gain over the study period in both males and females at the end of the treatment and recovery periods, however these changes were mainly due to changes observed in mean body weight gain in control animals and not related to treatment-related effects.

Food consumption and compound intake (if feeding study):

no effects observed

Description (incidence and severity):

No test item-related effects on food consumption were observed during the treatment or recovery period of the study in control, as well as in all dose groups in both males and females.

Food efficiency:

not examined

Water consumption and compound intake (if drinking water study):

not examined

Ophthalmological findings:

no effects observed

Description (incidence and severity):

No toxicologically relevant effects determined via ophthalmoscopy examinations were observed in the control or any of the dose groups at the end of the treatment or recovery period.

Haematological findings:

effects observed, non-treatment-related

Description (incidence and severity):

At the end of the treatment or recovery period, no test item-related effect on haematological parameters was found and no test item-related effect on coagulation
parameters was noted.
A slight but statistically significant increase in mean haemoglobin was observed in females of the mid- and high-dose groups (4.7 and 4.3% respectively above control). A moderate but statistically significant increase in mean percent monocytes was observed in high-dose females (60.9% above control) which was not significant in mid-dose females (38.4% above control). At the end of recovery, high-dose males showed moderate but statistically significant decreases in mean percent monocytes (44.5% below control) and in high-dose female, a slight but statistically significant decrease in mean MCV was observed (3.6% below control). No statistical
significance was observed in coagulation parameters at end of treatment and recovery periods in either sex.
In males, a dose-dependent increase in WBC count was observed in all dose levels (3.2%, 13.3% and 32.8% above control) when compared to control. A moderate decrease in mean percent eosinophils was observed in all dose groups (24.6%, 46.2% and 27.7%
below control) when compared to control. Similarly, a decreased mean percent of neutrophils in high-dose (24.8%), monocytes in low-dose (11.9%), basophils in mid-dose (11%) and leucocytes in low-dose groups (13%) was observed at the end of treatment.
In females, a dose dependent increase in WBC count was observed in all dose levels (8.8%, 19.4% and 68.9% above control) when compared to controls. A moderate decrease in mean percent eosinophils was observed in low-dose and mid-dose groups (28.8% and 15.4% below control) when compared to controls. Similarly, a decreased mean percent of neutrophils in all groups (17%, 11.4% and 26%), an increase in monocytes in mid-dose and high-dose group (38.4% and 60.9%), an increase in basophils in all groups (150%, 50% and 175%) and a decrease in leucocytes in all groups (23%, 14.3% and 14.3%) was observed at the end of treatment.
In males, increased WBC count (56.2%) and platelet count (22.3%) and decreased mean percent eosinophils (45.7%), neutrophils (14.6%), monocytes (44.5%), basophils (57.1%) and leucocytes (20%) were observed in the high-dose group. In females, increased mean percent eosinophils (22%), monocytes (14.9%), basophils (60%) and a decrease in leucocytes (46.7%) were observed in the high-dose group at the end of recovery period.
The slight changes with or without achieving statistical significance in differential blood cell counts do not indicate acute or chronic inflammation and are considered not to be an adverse effect of treatment with the test item. All the haematological values are within the historical control range for this strain of rat.
Mean coagulation parameters were found to be comparable at the end of the treatment and recovery periods. No statistically significant changes were observed. All the values are within the range of historical control data and no test item-related effect on coagulation parameters was observed.

Clinical biochemistry findings:

effects observed, treatment-related

Description (incidence and severity):

A slight but statistically significant decreased mean ASAT value was observed in high-dose males (24% below control) and in high-dose females (20.4% below control) when compared to controls. A slight but statistically significant decrease in mean creatinine was observed in low-dose and high-dose females (17.2% and 15.3% respectively below control). A slight but statistically
significant increase in mean potassium was observed in mid-dose and high-dose females (12.6% and 22.7% respectively, above control) when compared to controls at the end of treatment period. In correlation with the histopathological findings of liver and kidneys, the statistical significance is considered to be of toxicological relevance in the high-dose group.
A slight but statistically significant decreased mean ASAT value was observed in high-dose males (17.2% below control) and in high-dose females without significance (10.9% below control) when compared to controls at the end of recovery. A slight but statistically
significant decrease in mean total bilirubin was observed in high-dose males (12.3% below control) when compared to controls at the end of recovery.
At the end of the recovery period, the mean ALAT, creatinine, alkaline phosphatase, urea and HDL were found to be slightly decreased without achieving statistical significance in high-dose males. In females, mean ALAT, glucose, ASAT and triglycerides were found to be slightly decreased without achieving statistical significance. All these values were within the historical control data range for this strain of rat.

Urinalysis findings:

effects observed, non-treatment-related

Description (incidence and severity):

Urinalysis showed the presence of bilirubin in two low-dose group females and one high-dose group male but not in the control group animals. These changes
are slight and not considered to be test item-related.
All other urinalysis parameters measured at the end of the treatment and recovery periods were without specific changes to the respective control group and no test item-related effects on urinary parameters were found.

Behaviour (functional findings):

effects observed, treatment-related

Description (incidence and severity):

Overall, no toxicologically relevant effects were observed via functional observation battery examinations in the treatment or recovery control or dose groups.
Before the first treatment, statistically significantly lower faecal consistency was found in low-dose males (14.3% below control). Statistically significant increase in urination was observed in low-dose males on week 13 (475% above control). Statistically significant lower startle response was observed in high-dose males on week 13 (20% below control). A statistically significant increase in changes in skin was observed in high-dose females on week 13. A statistically significant increase in defecation was observed in mid-dose females on week 13 (350% above control).
At the end of the recovery period, a statistically significant increase in urination was observed in high-dose males on week 17 (233% above control). Statistically significant decrease in animal sleeping (100% below control) and increase in animal moving in cages (150% above control) were observed in high-dose females on week 17. Statistically significant increase in changes in skin was observed in high-dose females on week 17.

Immunological findings:

not examined

Organ weight findings including organ / body weight ratios:

effects observed, treatment-related

Description (incidence and severity):

In the organ weight determinations of animals sacrificed at the end of the treatment period, the following organ weight changes were considered to be related to treatment with the test item:
Statistically significant increases in relative kidney weights of females of mid- and high-dose groups. There was also a tendency for increases in absolute kidney weights in females of the high-dose group, as well as in absolute and relative kidney weights in males of the high-dose group, although these were not statistically significant.
Statistically significant increases in absolute and relative liver weights in both sexes of the high-dose group and a slight but statistically significant increase in relative weights in females of the mid-dose group. Females of the mid-dose group showed a slightly higher group mean value of absolute liver weights when compared to the control, although this was not statistically significant.
A slightly but statistically significant higher absolute and relative mean liver weight was observed in males of the high-dose group (11% and 11.7-14.6%) when compared to control. A moderately but statistically significant higher absolute and relative mean liver weight were observed in females of the high-dose group (34.4% and 34.6-38.9%) and relative mean liver weight in the mid-dose group (19.2%) when compared to control at the end of treatment period.
A slight but statistically significantly higher relative mean kidneys weight was observed in females of the mid-dose (9.9-16.2%) and high-dose groups (13.1-16.6%) when compared to control.
A moderately but statistically significantly higher absolute and relative mean spleen weight were observed in males of the high-dose group (25.4% and 22.2-23.3%) when compared to control at the end of recovery period. A moderate decrease in mean absolute and relative weight of thymus was observed in low-dose females (20% and 16-20.5%) at the end of treatment when compared to control. A slight increase in mean absolute and relative weight of adrenal glands was observed in mid-dose (15 and 18.7-26.3%) and high-dose females (11.8% and 12.7-16.1%) at the end of treatment when compared to control.
A moderate increase in mean absolute and relative weight of thymus was observed in high-dose males (36.3% and 28.2-30.3%) and females (19.4% and 16.1-17.2%) at the end of recovery period when compared to control. A moderate increase in mean absolute and relative weight of adrenal glands was observed in high-dose males (13.2% and 15.9-17.2%) at the end of recovery period when compared to control.
A slight but statistically significantly higher relative mean ovarian weight was observed in females of the high-dose group (18-22.5%) when compared to control. A slight to moderate increase in absolute and relative mean uterine with cervix weight was observed in females of the high-dose main and recovery groups, when compared to the controls. The differences between test item-treated females and control animals in mean weight of the uterus and ovaries were not considered toxicologically relevant as female reproductive organs undergo variable changes depending on the stage of the oestrous cycle.
In organ weight determinations of animals sacrificed at the end of the recovery period, there were no statistically significant differences in the liver and kidney weights of both sexes.
In the groups subjected to necropsy at the end of the recovery period, statistically significant increases in absolute and relative spleen weights were detected in the high-dose females. No treatment-related histomorphologic findings were observed in organs of the
hematolymphoid system of the high-dose animals sacrificed at the end of the treatment period, and therefore, the increase in spleen weight was deemed to be incidental and of no toxicological relevance.

Gross pathological findings:

effects observed, non-treatment-related

Description (incidence and severity):

No treatment-related macroscopic findings were observed in any of the dose groups in both sexes at necropsy of the end of treatment and recovery periods.
Macroscopic findings recorded at necropsy at the end of the treatment period were spotted thymus in one high-dose female and abnormal red colored mandibular lymph node in one high-dose female and at the end of recovery period a uterus dilatation on both sides was recorded in one high-dose female. These were considered to be incidental findings.

Neuropathological findings:

not examined

Histopathological findings: non-neoplastic:

effects observed, treatment-related

Description (incidence and severity):

The test item-related microscopic changes were observed in the kidney, urinary bladder, liver, adrenal glands, jejunum, stomach and nasal cavity in the high-dose group.

In the kidney, there was diffuse vacuolation of the proximal tubular cells in both sexes of the high-dose group This vacuolation caused tubular cell hypertrophy in most of the affected animals. These findings were not associated with further evidence of degenerative changes, and therefore, deemed not to be of an adverse nature, but an adaptive response to an increased demand of tubular functions such as transcellular transport and metabolism. Increased or increase tendency of kidney weights recorded in mid- and high-dose groups were likely to be associated with tubular cell hypertrophy and an increased demand of tubular functions.

In the urinary tract, there was also diffuse, simple urothelial hyperplasia in the urinary bladder and this was observed in both sexes in the high-dose group. In some affected cases, edema and/or mononuclear cell infiltration in the submucosa/lamina propria were also involved in the lesions.

In the stomach, there was increased incidence and/or severity of inflammatory and the reactive changes in the forestomach of both sexes at the high dose. The findings consisted of multifocal inflammatory cell infiltration, submucosal edema, and focal to multifocal hyperplasia of the squamous epithelium with hyperkeratosis. In a single case (one male), there was also ulceration. These effects were considered to be the lesions caused by the corrosive or irritative properties of the test item. Glandular stomach erosion was
observed in one male in the low-dose group. However this finding was not considered to be related to the local exposure of the test item

The histological findings that were considered to be related to the properties of the test item were also observed in the nasal cavity of both sexes of the high-dose group. The findings consisted of regenerated olfactory and/or respiratory epithelium, accompanied by mucosal to submucosal mixed inflammatory cell infiltration in some cases. The cause of nasal cavity lesions was deemed to be a consequence of incidental influx or retrograde uptake of the test item formulation.

Lipid accumulation in the lamina propria mucosa of the jejunum was observed in both sexes at the high dose. The minimal centrilobular hepatocellular hypertrophy in itself was considered to be of an adaptive nature but not adverse. Meanwhile, in the liver of the high-dose group, there was increased incidence and severity of hepatocellular fatty change in multifocal or patchy manner. Increased or increase tendency of liver weights recorded in mid- and high-dose groups were considered to be associated with these findings most likely to be of metabolic nature in the liver. In addition, the incidence and/or severity of fatty change in zona fasciculata of the adrenal gland were increased in both sexes at the high dose. Thus, the effects to lipid biosynthesis and/or metabolism were suggested.

Any findings mentioned above, irrespective of whether it was of a systemic or local nature, or primary or secondary nature of the treatment-related effects, recovered or tended to recover after a 28-day withdrawal period.

The testis was checked for completeness of cell populations and the stages, also taking into account any degenerative tubular changes and the interstitial cell structure. As a result, there were no differences of toxicological concern in the incidence and severity of
findings between control and HD group animals sacrificed at the end of the treatment period, and no test item-related effects on the testicular histomorphology were observed.

The histopathology examination also revealed that any histomorphologic changes elicited by the test item disappeared or recovered with its discontinuation of its administration.

Histopathological findings: neoplastic:

not examined

Other effects:

effects observed, non-treatment-related

Description (incidence and severity):

Hormone analysis (T3, T4, TSH) in serum samples did not show an effect related to the test item at the end of the treatment and recovery periods.

There were no statistical significances and no test item-related effects on mean testis weight, mean testicular sperm count and mean testicular sperm motility for all main study and recovery dose groups. in the treatment groups and recovery groups.
At the end of recovery, a slight but statistically significant increase in mean abnormal and a decrease in normal sperms/findings were observed in the high-dose group, hence lower main (low and mid) dose groups were analyzed for sperm morphology. Mean total number of abnormal and normal sperms/findings (sperm morphology) in all the dose groups were found to be comparable to control at the end of treatment period when compared to concurrent controls. Statistical changes observed in high-dose recovery males were found to be within the normal range of historical control data for this strain. In addition, no treatment related effects on the testicular histomorphology were observed during histopathological evaluations in control and high-dose groups.
No test item-related effects on estrous cycle on the day of necropsy were observed for both the main treatment or recovery females of the study in control, as well as in all dose groups.

Key result

Dose descriptor:

LOAEL

Remarks:

local

Effect level:

125 mg/kg bw/day (actual dose received)

Based on:

test mat.

Sex:

male/female

Basis for effect level:

histopathology: non-neoplastic

Key result

Dose descriptor:

LOAEL

Remarks:

systemic

Effect level:

125 mg/kg bw/day (actual dose received)

Based on:

test mat.

Sex:

male/female

Basis for effect level:

histopathology: non-neoplastic

Key result

Dose descriptor:

NOAEL

Remarks:

local/systemic

Effect level:

40 mg/kg bw/day (actual dose received)

Based on:

test mat.

Sex:

male/female

Basis for effect level:

other: no adverse effects observed

Key result

Critical effects observed:

yes

Lowest effective dose / conc.:

125 mg/kg bw/day (actual dose received)

System:

hepatobiliary

Organ:

liver

Treatment related:

yes

Dose response relationship:

yes

Relevant for humans:

not specified

Conclusions:

In an OECD 408 compliant study conducted according to GLP, the NOAEL for local (forestomach) and systemic toxicity (liver) was established at 40 mg/kg bw/day in rats administered dichloro(diphenyl)silane (CAS 80-10-4).

Endpoint conclusion

Endpoint conclusion:

adverse effect observed

Dose descriptor:

NOAEL

40 mg/kg bw/day

Study duration:

subchronic

Species:

rat

Quality of whole database:

The available information comprises an adequate and reliable study, and is thus sufficient to fulfil the standard information requirements set out in Annex VIII-IX, 8.6, of Regulation (EC) No 1907/2006.

System:

hepatobiliary

Organ:

liver

Repeated dose toxicity: inhalation - systemic effects

Endpoint conclusion

Endpoint conclusion:

no study available

Repeated dose toxicity: inhalation - local effects

Link to relevant study records

Reference

Endpoint:

sub-chronic toxicity: inhalation

Type of information:

experimental study

Adequacy of study:

key study

Study period:

1 May 1983 to 18 August 1983

Reliability:

1 (reliable without restriction)

Rationale for reliability incl. deficiencies:

comparable to guideline study

Qualifier:

equivalent or similar to guideline

Guideline:

OECD Guideline 413 (Subchronic Inhalation Toxicity: 90-Day Study)

GLP compliance:

yes

Limit test:

no

Species:

other: rat and mouse

Strain:

other: Sprague-Dawley rats, Fischer-344 rats, and B6C3F1 mice

Sex:

male/female

Details on test animals or test system and environmental conditions:

TEST ANIMALS
- Source: No data
- Age at study initiation: No data
- Weight at study initiation: No data
- Fasting period before study: No
- Housing: Individually housed in 8 cubic meter stainless steel and glass inhalation chambers.
- Diet (e.g. ad libitum): Ad libitum
- Water (e.g. ad libitum): Ad libitum
- Acclimation period: One week

ENVIRONMENTAL CONDITIONS
- Temperature (°C): Data could not be found in report supplied
- Humidity (%): Data could not be found in report supplied
- Air changes (per hr): Data could not be found in report supplied
- Photoperiod (hrs dark / hrs light): 12/12

IN-LIFE DATES: From: 20 September 1984 To: 20 December 1984

Route of administration:

inhalation: gas

Type of inhalation exposure:

whole body

Vehicle:

clean air

Details on inhalation exposure:

GENERATION OF TEST ATMOSPHERE / CHAMBER DESCRIPTION
- Exposure apparatus: Animals were housed and exposed in 8 cubic meter stainless steel and glass inhalation chambers.
The test substance was first passed through a regulator and was maintained at a pressure of 50 psig. It was then passed through a flowmeter which measured the flow rate. The gas was then mixed with a supply of filtered, dry air, introduced at the top of the inhalation chamber and exhausted at the bottom. The negative pressure of each test chamber was maintained at 0.1 inches of water. The control chamber was maintained at a positive pressure of 0.02 inches of water.

TEST ATMOSPHERE
- Brief description of analytical method used: Analyses of chamber scrub samples were performed throughout the study by a method involving the titration of dissolved chlorides with a dilute solution of mercuric nitrate in the presence of a mixed diphenylcarbazone-bromophenol blue indicator. Each test chamber was sampled approximately once per hour. The control chamber was sampled once daily.

Analytical verification of doses or concentrations:

yes

Details on analytical verification of doses or concentrations:

Analyses of chamber scrub samples were performed throughout the study by a method involving the titration of dissolved chlorides with a dilute solution of mercuric nitrate in the presence of a mixed diphenylcarbazone-bromophenol blue indicator. Each test chamber was sampled approximately once per hour. The control chamber was sampled once daily.

Duration of treatment / exposure:

90 days

Frequency of treatment:

six hours, five days per week

Dose / conc.:

10 ppm

Remarks:

target concentration

Dose / conc.:

20 ppm

Remarks:

target concentration

Dose / conc.:

50 ppm

Remarks:

target concentration

No. of animals per sex per dose:

31 males and 21 females of each species/strain

Control animals:

yes, concurrent vehicle

Details on study design:

- Dose selection rationale: No data
- Rationale for selecting satellite groups: Interim sacrifice group of 15 males and 10 females sacrificed after the fourth exposure.

Observations and examinations performed and frequency:

CAGE SIDE OBSERVATIONS: Yes
- Time schedule: At least twice daily for mortality and clinical signs of toxicity.

DETAILED CLINICAL OBSERVATIONS: Yes
- Time schedule: Weekly

BODY WEIGHT: Yes
- Time schedule for examinations: All animals: just prior to the first exposure (day 1), then weekly, and a final fasted body weight measurement was obtained prior to the 90-day sacrifice.

FOOD CONSUMPTION:
- Just prior to the first exposure (day 1), then weekly for each animal.

FOOD EFFICIENCY:
- Body weight gain in kg/food consumption in kg per unit time X 100 calculated as time-weighted averages from the consumption and body weight gain data: No

WATER CONSUMPTION: No

OPHTHALMOSCOPIC EXAMINATION: No

HAEMATOLOGY: Yes
- Time schedule for collection of blood: At 90 days.
- Anaesthetic used for blood collection: Yes (ether)
- Animals fasted: Yes, for approximately 12 hours.
- How many animals: 10 males and 10 females
- Parameters checked in table 1 were examined.

CLINICAL CHEMISTRY: Yes
- Time schedule for collection of blood: At 90 days.
- Animals fasted: Yes, for approximately 12 hours.
- How many animals: 10 males and 10 females
- Parameters checked in table 1 were examined.

URINALYSIS: Yes, in 10 males and 10 females.
- Time schedule for collection of urine: At 90 days.
- Metabolism cages used for collection of urine: Yes
- Animals fasted: Yes, for approximately 12 hours.
- Parameters checked in table 1 were examined.

NEUROBEHAVIOURAL EXAMINATION: No

Sacrifice and pathology:

15 males and 10 females per group per strain/species were sacrificed the day following the fourth exposure for pathological examination. After 90 days of exposure 10 males and 10 females per group per strain/species (same animals as those for clinical pathology) were sacrificed for pathological examination.

At the day 5 interim sacrifice the nasal turbinates, trachea, lung and gross lesions were examined microscopically. Organs and tissues examined microscopically at 90 days are summarised in Table 2.

Statistics:

Parametric data such as body weight and food consumption were analysed using an analysis of variance (ANOVA). Statistically significant differences that were noted were further studied by either Tukey's (equal populations) or Scheffe's (unequal populations) Test of Multiple Comparison. Non-parametric data such as organ weight ratios were analysed using a Kruskal-Wallis ANOVA and a Test of Multiple Comparison. Discontinuous data such as appropriate incidences of histopathological findings were compared using CHI-SQUARE or Fischer's Exact Probability Test.

Clinical signs:

effects observed, treatment-related

Description (incidence and severity):

Local effects

Mortality:

mortality observed, treatment-related

Description (incidence):

Local effects

Body weight and weight changes:

effects observed, treatment-related

Food consumption and compound intake (if feeding study):

effects observed, treatment-related

Food efficiency:

not examined

Water consumption and compound intake (if drinking water study):

not examined

Ophthalmological findings:

not examined

Haematological findings:

no effects observed

Clinical biochemistry findings:

no effects observed

Urinalysis findings:

no effects observed

Behaviour (functional findings):

not examined

Organ weight findings including organ / body weight ratios:

effects observed, treatment-related

Gross pathological findings:

no effects observed

Histopathological findings: non-neoplastic:

effects observed, treatment-related

Description (incidence and severity):

Relating to local effects

Histopathological findings: neoplastic:

not examined

Details on results:

CLINICAL SIGNS AND MORTALITY: 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

BODY WEIGHT AND WEIGHT GAIN: 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.

FOOD CONSUMPTION: 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 expsoure-related.

HAEMATOLOGY: there were no treatment-related effects.

CLINICAL CHEMISTRY: there were no treatment-related effects.

URINALYSIS: there were no treatment-related effects.

ORGAN WEIGHTS: decrease liver weight 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.

GROSS PATHOLOGY

HISTOPATHOLOGY: 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.

Dose descriptor:

NOAEC

Effect level:

20 ppm

Based on:

test mat.

Sex:

male/female

Basis for effect level:

other: Systemic NOAEC based on reduced body weights at 50 ppm.

Dose descriptor:

LOAEC

Effect level:

10 ppm

Based on:

test mat.

Sex:

male/female

Basis for effect level:

other: Local LOAEC based on irritant/corrosive effects seen at all dose levels tested in mice.

Critical effects observed:

not specified

Conclusions:

In a well conducted 90-day gas inhalation study (reliability score 1) the systemic NOAEC for hydrogen chloride was 20 ppm based on decreased body weight following exposure to 50 ppm (6 hours/day, 5 days/week) in rats and mice. The main adverse findings related to irritant/corrosive effects on the nasal turbinates in mice.

Endpoint conclusion

Endpoint conclusion:

adverse effect observed

Dose descriptor:

LOAEC

15 mg/m³

Study duration:

subchronic

Species:

rat

Quality of whole database:

The study was well documented and meets generally accepted scientific principles, and conducted in compliance with GLP. The relevance of these data for hazard assessment of dichloro(diphenyl)silane is discussed in the endpoint summary.

Repeated dose toxicity: dermal - systemic effects

Endpoint conclusion

Endpoint conclusion:

no study available

Repeated dose toxicity: dermal - local effects

Endpoint conclusion

Endpoint conclusion:

no study available

Additional information

Oral route

A reliable subchronic study in rats according to OECD TG 408 and in compliance with GLP is available by the oral route for dichloro(diphenyl)silane (BSL, 2021). Based on the results of a dose-range finding study (BSL, 2019) male and female Wistar rats were administered the test substance at dose levels of 10, 40 and 125 mg/kg bw/day for 90 days. The control group received the vehicle dried and deacidified corn oil. A recovery group was included in the control and high dose group and observed for a period of 28 days following the last administration.

No test item-related mortality was observed during the treatment and recovery periods and no adverse clinical findings were found during the observation period, weekly detailed clinical observation and functional observation and ophthalmoscopy in the last week of the treatment period or recovery period. There were no test item-related effects on body weight development and food consumption in any of the dose groups when compared to controls in both males and females. No test item-related adverse effects were observed in haematology, coagulation and urinalysis parameters in any of the dose groups. Furthermore, no test item-related effects were observed for thyroid hormone analysis. In correlation to the histopathological findings in the liver and kidneys, the changes observed in mean ASAT, creatinine and potassium were considered to be test item-related in the high-dose group. Fertility parameters in males were not affected by treatment with the test item and no test item-related effects on the testicular histomorphology were observed. No test item-related changes were observed on the estrous cycle in all dose groups at the end of the treatment and recovery periods. There were no macroscopic changes that could be attributed to treatment with the test item. Test item-related organ weight increases were observed in the liver and kidneys in the mid-dose and high-dose groups at the end of the treatment period. At the end of the recovery period, there were no statistically significant differences in the liver and kidney weights of both sexes.

Histological findings related to treatment with the test item were seen in several organs of the high-dose group (kidney, urinary bladder, liver, adrenal glands, jejunum, stomach and nasal cavity).

There was diffuse vacuolation of the proximal tubular cells in both sexes of the high-dose group in the kidney. This vacuolation caused tubular cell hypertrophy in most of the affected animals. These findings were not associated with further evidence of degenerative changes, and therefore were deemed not to be of an adverse nature, but an adaptive response to an increased demand of tubular functions such as transcellular transport and metabolism.

In the urinary tract, there was also diffuse, simple urothelial hyperplasia in the urinary bladder and was observed in both sexes in the high-dose group. In some affected cases, edema and/or mononuclear cell infiltration in the submucosa/lamina propria were also involved in the lesions.

In the stomach, there was increased incidence and/or severity of inflammation and reactive changes in the forestomach of both sexes at the high dose. The findings consisted of multifocal inflammatory cell infiltration, submucosal edema, and focal to multifocal hyperplasia of the squamous epithelium with hyperkeratosis. In a single case (one male), there was also ulceration. These effects were considered to be the lesions caused by the corrosive or irritative properties of the test item.

The histological findings that were considered to be related to the physiocochemical properties of the test item were also observed in the nasal cavity of both sexes of the high-dose group. The findings consisted of regenerated olfactory and/or respiratory epithelium, accompanied by mucosal to submucosal mixed inflammatory cell infiltration in some cases. The cause of nasal cavity lesions was deemed to be a consequence of incidental influx or retrograde uptake of the test item formulation.

The lipid accumulation in the lamina propria mucosa of the jejunum was observed in both sexes at the high-dose. The minimal centrilobular hepatocellular hypertrophy in itself was considered to be of an adaptive nature but not adverse. Meanwhile, in the liver of the high-dose group, there was both an increased incidence and severity of hepatocellular fatty change in multifocal or patchy manner. Increased or increased tendency of liver weights recorded in mid-dose and/or high-dose groups were considered to be associated with these findings most likely of a metabolic nature in the liver. In addition, the incidence and/or severity of fatty change in the zona fasciculata of the adrenal gland were increased in both sexes at the high-dose. Thus, the effects on lipid biosynthesis and/or metabolism were suggested.
All findings mentioned above, whether systemic or local, primary or secondary to the treatment-related effects, recovered or showed signs of recovery after a 28-day withdrawal period.

Under the conditions of this oral 90-day repeated dose toxicity study in rats the NOAEL for local (forestomach) and systemic toxicity (liver) was established at 40 mg/kg bw/day.

Inhalation route

Dichloro(diphenyl)silane (CAS 80-10-4) is a highly moisture-sensitive liquid that hydrolyses rapidly in contact with water (measuredhalf-life of 6 to 10 seconds at pH 4, 7 and 9 at 1.5°C) to diphenylsilanediol and hydrogen chloride (HCl). Hydrolysis is complete within few minutes.

In a 90-day repeated dose inhalation study in rats and mice (Toxigenics, 1984), 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. 15 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. 90-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 urinalyis 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.

With regard to the inhalation route of exposure, a guideline-compliant repeated-dose inhalation study should elicit systemic toxicity at the highest test concentration. Since the local corrosive effects of chlorosilanes would be significant, a valid inhalation study according to the relevant guidelines is technically not feasible. It is also unlikely that any systemic effects would be seen at dose levels made sufficiently low to prevent the known corrosive effects and/or distress in the test species. This hypothesis has been confirmed in a 28-day inhalation study with a chlorosilane, dichloro(dimethyl)silane (CAS 75-78-5, WIL, 2014). In this 4-week repeated dose study inhalation administration of dichloro(dimethyl)silane at targeted concentrations of 5 or 25 ppm (26 or 132 mg/m³) or hydrogen chloride at 50 ppm (75 mg/m³) to rats for 5 days per week for 4 weeks resulted in subacute inflammation, hyperplasia and/or hyperkeratosis of the squamous epithelium and mucous cell hyperplasia of the respiratory epithelium in the anterior nasal cavity. There was a clear dose-relationship in incidence and severity between the 26 or 132 mg/m³ dichloro(dimethyl)silane groups for the majority of findings. Exposure to 132 mg/m³ dichloro(dimethyl)silane or 75 mg/m³ hydrogen chloride was also associated with interstitial oedema and respiratory epithelial degeneration within the anterior nasal cavity and acute inflammation in the larynx. Generally the incidence and severity of effects were similar in the 132 mg/m³ dichloro(dimethyl)silane and 75 mg/m³ hydrogen chloride groups, or greater in the hydrogen chloride group. The incidence and severity of the effects in the hydrogen chloride exposed group were generally comparable to those noted in the 90-day inhalation study with hydrogen chloride (Toxigenics, 1983). Overall, the histopathology observations in the nasal cavity did not suggest a greater irritant effect for the 132 mg/m³ dichloro(dimethyl)silane group compared with the 75 mg/m³ hydrogen chloride group.

It is therefore concluded that hydrogen chloride will dominate the inhalation toxicity profile of chlorosilanes. Based on these conclusive data, repeated dose animal studies via the inhalation route with chlorosilanes are not considered to be ethically justifiable.

The available acute inhalation toxicity studies with chlorosilanes all meet the criteria for classification as either acutely toxic or harmful (LC50 below 20 mg/L with deaths occurring minutes after start of exposure). The local effects and mortalities observed in the studies can be attributed to hydrogen chloride (hydrolysis of the parent chlorosilanes would occur rapidly when inhaled, even if a mixture of parent and hydrolysis products were present in air) (Jean et al. 2006). The mortalities associated with the severe corrosive nature of chlorosilanes (rather than a systemic effect) have been confirmed by the findings from studies for at least fourteen chlorosilanes, which were performed according to the respective OECD guideline. In these studies, severe corrosive effects were observed even after short exposure times (e.g. 1 hour). The most common observations were respiratory irritation (labored breathing, rales, gasping and necrosis of the nose), dermal irritation, ocular effects (corneal opacities, lacrimation) as well as red/brown staining around the snout and/or eyes and scabs on snout. Substances causing these effects include the following: dichloro(methyl)(vinyl)silane (CAS 124-70-9), dichloro(dimethyl)silane (CAS 75-78-5), dichloro(methyl)silane (CAS 75-54-7), trichloro(vinyl)silane (CAS 75-94-5), chlorotri(3-methyl-propyl)silane (CAS 13154-25-1) or trichloro(methyl)silane (CAS 75-79-6). Most of the above mentioned indicators of toxicity showed marked resolution in those animals which survived to the end of the recovery period. Macroscopic observation of the animals also revealed lung injury (consolidation, haemorrhage, congestion, and ectasia), red or dark red discoloration of the lungs, fluid-filled pleural and thoracic cavities and trachea, periocular and perinasal encrustations and eye abnormalities. Substances causing the above macroscopic observations include the following: dichloro(dimethyl)silane (CAS 75-78-5), dichloro(methyl)(vinyl)silane (CAS 124-70-9), trichloro(vinyl)silane (CAS 75-94-5), dichloro(methyl)silane (CAS 75-54-7), trichloro(propyl)silane (CAS 141-57-1), chlorotrimethylsilane (CAS 75-77-4), chlorodimethylsilane (CAS 1066-35-9) or dichlorosilane (CAS 4109-96-0).The typical effects associated with exposure to corrosive substances were observed in the acute studies.

Overall, given the comparability of existing results for chlorosilanes and HCl, and the rapid hydrolysis of chlorosilanes in the atmosphere, the effects of HCl dominate local toxicity on the respiratory tract and therefore data for HCl can be used to assess the local repeated-dose toxicity of chlorosilanes.

Justification for classification or non-classification

The available oral repeated dose toxicity data of the registered substance do not meet the criteria for classification according to Regulation (EC) No. 1272/2008, and are therefore conclusive but not sufficient for classification.