Dichlorocyclohexylmethylsilane

Endpoint summary

Description of key information

There are no repeated dose oral, inhalation or dermal studies available for dichloro(cyclohexyl)methylsilane. 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 based on guideline OECD 407 but modified to realise a staggered dose selection depending on substance related effects. Additional histopathology examinations were performed for precisely NOEAL justification, but a NOAEL could not be determined (Bioservice, 2019). In the study test item-related gross lesions were noted in the gastrointestinal organs at ≥ 175 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 inflammation, erosions, hyperplasia, ulceration and epithelial degeneration.

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 trichloro(propyl)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 form 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

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

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 exposure-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:

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

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 exposure-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:

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 the registered substance, dichloro(cyclohexyl)methylsilane (CAS 5578-42-7) based on guideline OECD 407 but modified to realise a staggered dose selection depending on substance related effects. Additional histopathology examinations were performed for precis NOAEL justification, but a NOAEL could not be determined (Bioservice, 2019). The aim of this study was to assess the possible health hazards which could arise from repeated exposure of dichloro(cyclohexyl)methylsilane via oral administration to rats over a period of 14 days and to establish dose ranges 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, 175 and 375 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 study, one female at 375 mg/kg bw/day was found dead on treatment day 9. Inflammatory lesions of the stomach were considered to be the cause of mortality, however all other animals survived until the scheduled sacrifice.

Treatment with test item did not show any adverse clinical signs in male and females of up to 375 mg/kg bw/day. Clinical signs like moving the bedding were transiently observed in all male and female animals of group 5-6 (175 or 375 mg/kg bw/day). This is assumed to be due to discomfort caused by a local reaction to the test item.

Treatment with test item in male and females did not affect the body weight gain and were found to be comparable with control. Males showed tendency to gain body weight throughout the study period.

Mean food consumption from treatment day 1 to 14 was found to be comparable up to 375 mg/kg bw/day when compared to control both in male and female. 

Treatment with test item 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 female was available from group 6 (375 mg/kg bw/day) as one female rats was found dead prior to the scheduled sacrifice date.

Test item-related gross lesions were noted in the stomach and large intestine at 175 or 375 mg/kg bw/day. Gross lesions in the stomach are consisting of abnormal surface and ulcerated gastric wall. In groups 6, gas filled stomach and colon was observed. Single incidence of abnormal colour (red) lungs was observed at 100 mg/kg bw/day and at 375 mg/kg bw/day.

Test item caused inflammatory and degenerative findings in the stomach from animals at 50 mg/kg bw/day onwards. These findings consisted at 50 mg/kg bw/day of acute inflammation in the glandular stomach mucosa and single cell necrosis in the glandular mucosa. At 100 mg/kg bw/day, there were forestomach ulceration, glandular stomach erosion, inflammations in the forestomach submucosa and/or epithelial hyperplasia of the forestomach in one male and two females.

From 175 to 375 mg/kg bw/day, the findings consisted of forestomach and glandular stomach ulceration, inflammation of the forestomach and/or glandular stomach submucosa, and squamous cell hyperplasia of the forestomach. In one case at 375 mg/kg bw/day, there was an inflammation in the serosa, i.e., peritonitis. The findings caused in the stomach from both mails and one female at 375 mg/kg bw/day, test item-related gross lesions consisting of crateriform or ulcerated surfaces.  

One of the females at 375 mg/kg bw/day was found dead during the course of the study. This female was affected by the aforementioned inflammatory lesions of the stomach. In addition, there was an acute necrotizing inflammation in the larynx and trachea. The inflammatory lesions in the larynx and trachea were deemed to be a consequence of aspiration. Furthermore, there was inflammatory secretion in the nasal cavities.

A 7-day dose range-finding study is available for trichloro(propyl)silane (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 euthanizedin 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.

Trichloro(propyl)silane is representative of other chlorosilanes because:

-         All chlorosilanes are moisture-sensitive liquids that hydrolyse very rapidly in contact with aqueous media and particularly under physiological conditions to generate hydrochloric acid and siliconcontaining hydrolysis products (Half-life (OECD 111): <1 minute at 25 °C and pH 4, 7 and 9; ≤ 5 seconds at 37.5 °C and pH 2 (predicted)).

-         The doses being investigated in the 7-day dose-range finding (DRF) study are based on the predicted amount of HCl that would be released, and the minimum possible dosing volume. For chlorosilanes, in general, it is expected that the highest dose that can be tested is limited by corrosion of gastrointestinal tract surfaces and therefore experimental animal welfare, and the lowest dose is restricted by the technical feasibility of dosing low volumes of the test substance to rats.

-         Therefore, the results of the 7-day DRF (and possibly the 28-day DRF) study with trichloro(propyl)silane and consideration of HCl release will form the basis of the justification for testing/ not testing this and other chlorosilanes, in full higher tier studies.

Dose range-finding studies for prenatal developmental toxicity studies (OECD 414) have also been conducted for another two chlorosilanes: dichloro(methyl)phenylsilane (CAS 149-74-6) and trichloro(propyl)silane (CAS 141-57-1). 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(cyclohexyl)methylsilane does not need to be classified for specific target organ toxicity according to Regulation (EC) No 1272/2008.