Registration Dossier

Administrative data

Description of key information

There are no repeated dose oral, inhalation or dermal studies available for dichloro(methyl)(phenyl)silane. Data waivers are in place for oral and dermal repeated dose toxicity endpoints (see attachment to data waiver for repeated dose toxicity: oral).

A 14-day non-GLP dose range-finding study was conducted with dichloro(methyl)(phenyl)silane (CAS 149-74-6) based on guideline OECD 407 but modified to realise a staggered dose selection depending on substance related effects. Additional histopathology examinations were performed for precise NOAEL justification, but a NOAEL could not be determined. Test item-related gross lesions were noted in the stomach, small and large intestine at ≥ 250 mg/kg bw/day and these were evident during histopathological examination. At the microscopic examination, specific findings were found, starting at the dose of 50 mg/kg bw/day. These findings included inflammatory and degenerative lesions which consisted of erosions, inflammation, hyperplasia, ulceration, hyperkeratosis, single cell necrosis and epithelial degeneration (Bioservice, 2019).

The analogous substance trichloro(propyl)silane was tested in a 7-day dose range-finding study (non-GLP; Bioservice, 2018) in order to determine appropriate doses (to avoid corrosive effects) for administration in repeated dose toxicity tests. In this study a NOAEL could not be determined due to the corrosive effects of the test substance on the gastrointestinal and respiratory tracts. All animals administered the tests substance were sacrificed on study day 2 due to ethic reasons. The findings at pathology and histopathology showed signs of corrosion which was considered to be related to the hydrolysis product hydrochloric acid.

Since the local corrosive effects of chlorosilanes are significant, valid oral or inhalation studies according to the relevant guidelines are technically not feasible. It is also unlikely that any systemic effects would be observed at doses made sufficiently low to prevent the known corrosive effects and/or distress in the test species. Indeed, ECHA’s Executive Director made the following statement in his decision (No. ED/49/2015) for trichlorosilane “ECHA notes that the Contested Decision should not have provided the option of carrying out the PNDT study on the registered substance, which is corrosive and consequently can only be tested at very low concentrations. In a PNDT study, which normally requires high systematic availability of the tested substance, the very low concentrations would almost certainly lead to a negative result”.

 

To support this conclusion a 28-day inhalation study with another chlorosilane, dichloro(dimethyl)silane (CAS 75-78-5, WIL, 2014) is used to demonstrate that local effects are dominated by generation of the hydrolysis product, HCl, and that there are no adverse systemic effects.

 

In a well conducted 90-day gas inhalation study (Toxigenics, 1984) 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, which was observed with a LOAEC of 10 ppm.

A good quality 90-day repeated inhalation study for hydrogen chloride has been used to assess the local effects of dichloro(methyl)(phenyl)silane. In a 90-day repeated inhalation study with HCl, no serious adverse systemic effects were observed in rats and mice exposed up to 50 ppm (approximately 70 mg/m3) for 6 hours per day, 5 days per week. The only significant adverse finding relating to systemic toxicity was decreased body weight at the highest dose level. Local effects on the nasal turbinates of mice were observed at all dose levels tested (10, 20 and 50 ppm). Testing with HCl at higher test concentrations is neither ethically nor technically feasible since severe corrosive effects would lead to discomfort and distress in the test animals. The author of this CSR considers that the apparent systemic effects at 50 ppm in the study were most likely secondary to local corrosive effects at this dose level.

Following uptake of HCl, hydrogen and chloride ions from will enter the body’s natural homeostatic processes and significant systemic effects are unlikely.

Key value for chemical safety assessment

Repeated dose toxicity: via oral route - systemic effects

Endpoint conclusion
Endpoint conclusion:
no study available
System:
gastrointestinal tract

Repeated dose toxicity: inhalation - systemic 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:
2 (reliable with restrictions)
Rationale for reliability incl. deficiencies:
study well documented, meets generally accepted scientific principles, acceptable for assessment
Qualifier:
equivalent or similar to
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 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):
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.
Mortality:
mortality observed, treatment-related
Description (incidence):
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.
Body weight and weight changes:
effects observed, treatment-related
Description (incidence and severity):
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 and compound intake (if feeding study):
effects observed, treatment-related
Description (incidence and severity):
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.
Food efficiency:
not examined
Water consumption and compound intake (if drinking water study):
not examined
Ophthalmological findings:
not examined
Haematological findings:
no effects observed
Description (incidence and severity):
There were no treatment-related effects.
Clinical biochemistry findings:
no effects observed
Description (incidence and severity):
There were no treatment-related effects.
Urinalysis findings:
no effects observed
Behaviour (functional findings):
not examined
Immunological findings:
not examined
Organ weight findings including organ / body weight ratios:
effects observed, treatment-related
Description (incidence and severity):
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 pathological findings:
no effects observed
Description (incidence and severity):
There were no treatment-related effects.
Histopathological findings: non-neoplastic:
effects observed, treatment-related
Description (incidence and severity):
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.
Histopathological findings: neoplastic:
not examined
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:
no
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:
no adverse effect observed

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:
2 (reliable with restrictions)
Rationale for reliability incl. deficiencies:
study well documented, meets generally accepted scientific principles, acceptable for assessment
Qualifier:
equivalent or similar to
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 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):
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.
Mortality:
mortality observed, treatment-related
Description (incidence):
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.
Body weight and weight changes:
effects observed, treatment-related
Description (incidence and severity):
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 and compound intake (if feeding study):
effects observed, treatment-related
Description (incidence and severity):
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.
Food efficiency:
not examined
Water consumption and compound intake (if drinking water study):
not examined
Ophthalmological findings:
not examined
Haematological findings:
no effects observed
Description (incidence and severity):
There were no treatment-related effects.
Clinical biochemistry findings:
no effects observed
Description (incidence and severity):
There were no treatment-related effects.
Urinalysis findings:
no effects observed
Behaviour (functional findings):
not examined
Immunological findings:
not examined
Organ weight findings including organ / body weight ratios:
effects observed, treatment-related
Description (incidence and severity):
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 pathological findings:
no effects observed
Description (incidence and severity):
There were no treatment-related effects.
Histopathological findings: non-neoplastic:
effects observed, treatment-related
Description (incidence and severity):
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.
Histopathological findings: neoplastic:
not examined
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:
no
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

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

A 14-day non-GLP dose range-finding study was conducted with dichloro(methyl)(phenyl)silane (CAS 149-74-6) based on guideline OECD 407 but modified to realise a staggered dose selection depending on substance related effects. Additional histopathology examinations were performed for precise NOAEL justification, but a NOAEL could not be determined. The aim of this study was to assess the possible health hazards which could arise from repeated exposure of dichloro(methyl)(phenyl)silane via oral administration to rats over a period of 14 days to establish a dose range for a pre-natal developmental toxicity study. The test item was administered in corn oil, in order to minimise local effects, daily in doses of 50, 100, 250, 375 and 500 mg/kg bw/day to 2 male and 2 female rats per dose. Animals of an additional control group were handled identically as the dose groups but received vehicle only.

During the period of administration, the animals were observed precisely each day for signs of toxicity. Animals that were euthanised for animal welfare reasons were examined macroscopically. At the end of the study, the surviving animals and these from the control group were sacrificed and observed macroscopically.

A full histopathological evaluation of the tissues (trachea, lungs, oesophagus, stomach and intestine) was performed on all animals. Organs showing gross alterations upon necropsy were also examined histopathologically.

By study day 5 all male and female rats from 500 mg/kg bw/day group and one male from 375 mg/kg bw/day group were euthanized in a moribund condition due to animal welfare reasons. One female rat at 375 mg/kg bw/day was found dead on treatment day 11. Inflammatory lesions of the stomach were considered to be the cause of mortality.

Treatment with dichloro(methyl)(phenyl)silane caused adverse clinical signs in male and females at 500 mg/kg bw/day. Clinical signs like moving the bedding, increased salivation (slight to moderate), prone position, moderate piloerection, apathy, abnormal breathing, reduced spontaneous activity (slight to severe), slow movements, wasp waist (slight), hypothermia, both eyelids closed, nasal discharge, lack of defecation, lacrimation and dehydration were observed. 

Treatment with dichloro(methyl)(phenyl)silane in males at 375 mg/kg bw/day showed the clinical signs of increased salivation (slight to moderate), apathy, prone position, abnormal breathing, nasal discharge, moderate reduced spontaneous activity, both eyelids closed, lack of defecation, lacrimation, hypothermia, wasp waist (moderate), moderate piloerection, slow movements and dehydration. One female showed moving the bedding during treatment day 7-10 and it was found dead on treatment day 11.

There were no adverse clinical signs in animals at 50 mg/kg bw/day, 100 mg/kg bw/day and 250 mg/kg bw/day. There were no clinical signs at 50 mg/kg bw/day during the entire treatment period in both male and female. Moving the bedding and slight to moderate salivations was transiently observed in all male and female animals at 100 and 250 mg/kg bw/day. This is assumed to be due to discomfort caused by a local reaction to dichloro(methyl)(phenyl)silane.

Males of the control, 50 mg/kg bw/day, 100 mg/kg bw/day and 250 mg/kg bw/day groups tended to gain body weight throughout the study period. Males at 375 mg/kg bw/day and 500 mg/kg bw/day showed a tendency towards a loss of body weight. Body weight change of test item-treated females showed no trend towards body weight loss. Mean body weight gain of test item treated groups was comparable to control females.

Mean food consumption from treatment day 1 to 14 was found to be comparable up to 250 mg/kg bw/day when compared to control both in male and female. At 375 mg/kg bw/day, both male and female had shown slightly lowered food consumption when compared to control. Animals at 500 mg/kg bw/day were euthanized due to animal welfare reasons; food consumption was not reported in both male and female.

Treatment with dichloro(methyl)(phenyl)silane had no dose-dependent effect on haematology and clinical biochemistry parameters in any of the test item-treated groups. Differences between test item-treated males and females and their respective controls showed no dose-dependency or consistency and thus were not considered toxicologically relevant.

Mean organ weights showed no dose-dependent differences between males and females treated with the test item and the respective control group. Organ weights from only one animal per sex were available at 375mg/kg/day as one male and one female rat were sacrificed due to animal welfare reasons prior to the scheduled sacrifice date.

Test item-related gross lesions were noted in the stomach consisting of masses, adhesions, abnormal surface, haemorrhage, abnormal color or discoloured foci, and enlargement at 250 mg/kg bw/day. At 375 or 500 mg/kg bw/day, there were changes (discoloration) in the duodenum and/or jejunum, and several cases of enlarged and/or abnormally coloured adrenal glands, and single cases of spleen adhesion and abnormal discoloration of lung.

Dichloro(methyl)(phenyl)silane caused inflammatory and degenerative findings in the stomach from animals at 50 mg/kg bw/day onwards. These findings consisted of inflammations in the forestomach submucosa and one case of forestomach ulceration at 50 mg/kg bw/day. In addition, there were single cases of inflammation in the serosa (i.e., peritonitis), and reactive changes in form of epithelial hyperplasia in the forestomach and increased hyperkeratosis of the forestomach epithelium in single cases.  At 100 mg/kg bw/day, the findings were similar but, in addition, there were single cases of minimal glandular stomach inflammation, degeneration of mucosal neck cells, and single cell necrosis of glandular mucosa cells.

At 250, 375 or 500 mg/kg, the aforementioned findings increased in incidence and severity. At 375 or 500 mg/kg, there were additional findings, i.e., degeneration of the forestomach epithelium, and glandular stomach erosion and ulceration. These findings caused in the 375 and 500 mg/kg bw/day groups  animals the early death in one animal of each sex from the 375 mg/kg bw/day group, and in all 500 mg/kg bw/day group animals. Inflammation and/or erosion were noted in single animals from 375 and 500 mg/kg bw/day groups, whereby the small intestine was involved at all segments.

Other related findings due to regurgitation consisted in the oesophagus of keratin desquamation in one male and both females of the 500 mg/kg bw/day group, single cases of larynx necrosis and inflammation in one 500 mg/kg bw/day group male, inflammatory secretion in the nasal cavities from one 500 mg/kg bw/day group female, and aspiration pneumonia in one375 mg/kg bw/day group female.  In addition, in one 375 mg/kg bw/day group male, the adhesion of the spleen was due to subcapsular inflammation. Gross lesions, enlargement of the adrenal glands were histologically due to diffuse hypertrophy of the zona fasciculata. The latter finding is deemed to be stress-related.

A 7-day dose range-finding study is available for the analogous substance, trichloro(propyl)silane (CAS 141-57-1) (Bioservice, 2018). The study was not conducted to a standard guideline or GLP, but the test procedure was in accordance with generally accepted scientific standards and was described in sufficient detail. The aim of this study was to assess the possible health hazards which could arise from repeated exposure of trichloro(propyl)silane via oral administration to rats over a period of 7 days. The test item was administered as provided daily in doses of 30, 60 and 120 mg/kg bw/day to 3 groups of rats, one dose level per group for a treatment period of 2 days. Animals of an additional control group were handled identically as the dose groups but received sterile water.

During the period of administration, the animals were observed precisely each day for signs of toxicity. Animals that were euthanised for animal welfare reasons were examined macroscopically. At the end of the study, the surviving animals from the control group were sacrificed and observed macroscopically.

A full histopathological evaluation of the tissues (trachea, lungs, esophagus, stomach and intestine) was performed on all animals. Organs showing gross alterations upon necropsy were also examined histopathologically.

All test item-treated animals had to be euthanized in extremis for animal welfare reasons latest on study day 2.

The observed clinical signs represented local toxicity, pain or were related to stress. The clinical observations were considered to be test item related and severe in extent.

Macroscopic local lesions in esophagus, stomach and lungs were recorded at necropsy. Most notably, semi-solid content and foam formation was observed at the entrance of esophagus and discoloration and /or erosion/ulceration of the stomach was observed in most animals and distributed among all dose groups.

Histopathological evaluation revealed signs of test item-related local toxicity including degenerative and inflammatory lesions in esophagus, stomach, trachea and lungs.

Dose range-finding studies for prenatal developmental toxicity studies (OECD 414) have also been conducted for another two chlorosilanes: trichloro(propyl)silane (CAS 141-57-1) and dichlorocyclohexylmethylsilane (CAS 5578-42-7). These dose range-finding studies have been added to this dataset to demonstrate consistency of effects among chlorosilane substances. For additional details please see the expert report attached to Section 13 of IUCLID (Weber, 2019). The summary also includes findings from a dose range-finding study for a Combined Repeated Dose Toxicity Study with the Reproduction/Developmental Toxicity Screening Test (OECD 422) with tert-butylchlorodimethylsilane (CAS 18162-48-6), which has not been added to the dataset.

Justification for classification or non-classification

The available data indicate that dichloro(methyl)(phenyl)silane does not need to be classified for specific target organ toxicity according to Regulation (EC) No 1272/2008.