Registration Dossier

Administrative data

Description of key information

According to ECHA decision number TPE-D-2114425282-58-01/F, there is an ongoing sub-chronic repeated dose toxicity study with the registration substance, conducted according to OECD TG 408 and in compliance with GLP. The study will be submitted as soon as possible once the final report is available.

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
Data waiving:
other justification
Justification for data waiving:
other:
Qualifier:
according to
Guideline:
OECD Guideline 408 (Repeated Dose 90-Day Oral Toxicity in Rodents)
Version / remarks:
25 June 2018
Deviations:
no
GLP compliance:
yes
Limit test:
no
Species:
rat
Strain:
Wistar
Remarks:
Crl: WI(Han)
Sex:
male/female
Details on test animals and environmental conditions:
TEST ANIMALS
- Source: Charles River, 97633 Sulzfeld, Germany
- Females nulliparous and non-pregnant: yes
- Age at study initiation: approx. 7-8 weeks
- Weight at study initiation:
- Fasting period before study: Not reported
- Housing: Housed in groups of 5 animals / sex / group / cage in IVC cages (type IV, polysulphone cages) on Altromin saw fibre bedding
- Diet: Altromin 1324 maintenance diet was available ad libitum
- Water: Tap water sulphur acidified to a pH of approximately 2.8 available ad libitum
- Acclimation period: At least 5 days

ENVIRONMENTAL CONDITIONS
- Temperature (°C): 22 ± 3
- Humidity (%): 55 ± 10
- Air changes (per hr): 10
- Photoperiod (hrs dark / hrs light): 12 hours light, 12 hours dark
Route of administration:
oral: gavage
Details on route of administration:
The test item formulation and vehicle were administered as a single daily dose to the animals by oral gavage. The application volume for all groups was 4 mL/kg body weight.
Vehicle:
corn oil
Details on oral exposure:
PREPARATION OF DOSING SOLUTIONS:
The test item was weighed into a tared plastic vial and the vehicle was added to give the appropriate final concentration of the test item. The formulation was vortexed and/or stirred until visual homogeneity was achieved. Formulates were constantly stirred until daily administration. The test item formulations were prepared freshly on each administration day before the administration procedure and administered directly after its preparation. The vehicle was used as control item.


VEHICLE
- Justification for use and choice of vehicle:
The vehicle was selected in consultation with the sponsor based on the test item’s characteristics.
Analytical verification of doses or concentrations:
yes
Details on analytical verification of doses or concentrations:
Before beginning of the treatment period, formulation samples were prepared and analysed in order to obtain knowledge about stability and homogeneity of the test item.
Duration of treatment / exposure:
90 days
Frequency of treatment:
Daily
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:
100 animals (50 males and 50 females) were included in the study (10 male and 10 female animals per group in the main study, 5 male and 5 female animals per recovery group).
Control animals:
yes, concurrent vehicle
Details on study design:
- Dose selection rationale: On the basis of a 14-day dose range finding study with dichloro(diphenyl)silane (CAS RN 80-10-4) in male and female Wistar rats with dose levels of 25, 50, 100, 500 and 375 mg/kg bw/day the following conclusions can be made: 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 stomach, 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, 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, the NOAEL was established at 100 mg/kg bw/day.
- Rationale for animal assignment (if not random): Before the first administration all animals to be used for the study were weighed and assigned to the experimental groups while achieving a mostly homogenous variation in body weight throughout the groups of males and females, respectively (randomisation will be performed with IDBS Workbook 10.1.2 or Ascentos 1.3.4 software).
- Fasting period before blood sampling for clinical biochemistry: Overnight
Positive control:
None
Observations and examinations performed and frequency:
CAGE SIDE OBSERVATIONS: Yes
- Time schedule: Once a day, preferably at the same time each day. Twice daily all animals were observed for morbidity and mortality except on weekends and public holidays when observations were made once daily
- Detailed cage side observations considering 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 were made outside the home cage in a standard arena once before the first administration and at least once a week thereafter.

DETAILED CLINICAL OBSERVATIONS: Yes
- Time schedule: 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 periods.

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:
- Food consumption for each animal determined and mean daily diet consumption calculated as g food/kg body weight/day: Yes

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: At the end of the treatment and recovery period prior to or as part of the sacrifice of the animals
- Anaesthetic used for blood collection: Yes; ketamine/xylazin
- Animals fasted: Yes; overnight
- How many animals: All surviving animals of the treatment period and 4 weeks after the last administration all surviving animals of the recovery period (study day 119)
- Parameters checked in tables 1 and 2 were examined.

CLINICAL CHEMISTRY: Yes
- Time schedule for collection of blood: At the end of the treatment and recovery period prior to or as part of the sacrifice of the animals
- Animals fasted: Yes; overnight
- How many animals: All surviving animals of the treatment period and 4 weeks after the last administration all surviving animals of the recovery period (study day 119)
- Parameters checked in table 3 were examined.

URINALYSIS: Yes
- Time schedule for collection of urine: Urinalysis performed on all animals prior to or as part of the scrifice of animals
- Metabolism cages used for collection of urine: Not specified
- Animals fasted: Not specified
- Parameters checked in table 5 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.
- Dose groups that were examined: All dose groups
- Battery of functions tested: 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 evalulations were made outside the home cage.

IMMUNOLOGY: No
Sacrifice and pathology:
GROSS PATHOLOGY: Yes. 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 (study day 119) were sacrificed using anesthesia (ketamine, xylazin) followed by exsanguination and were 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. All animals found dead and/or intercurrently euthanised for animal welfare reasons were subjected to a gross necropsy and the organs preserved for a histopathological examination. All macroscopic findings were recorded and organs showing gross abnormalities and all organs listed in Table 7 were preserved in 4% neutral-buffered formaldehyde except testes and epididymides, which were fixed in Modified Davidson’s fixative for approximately 24 hours before they were transferred to 70% ethanol. Organs that were weighed are presented in Table 6.

HISTOPATHOLOGY: Yes; organs presented in Table 7 were examined histopathologically after preparation of paraffin sections and haematoxylin-eosin staining for all animals sacrificed at the end of the treatment period and any animal found dead or euthanised before the planned day of sacrifice.
Other examinations:
Serum samples of all 100 animals, stored at < -15 C, were evaluated for test item-related effects on the pituitary-thyroid axis and thyroid hormones.. T3, T4 and TSH serum levels were determined for the main study animals (80 animals; Table 4).

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 group.

At necropsy (one day after the last administration) and at the end of the recovery period, left epididymis and left testis of the groups 1 and 4 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 groups 1 and 4 (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 were performed with a Student’s t-Test or Mann-Whitney U-Test when appropriate. These statistics were performed with Ascentos 1.3.4 software or GraphPad Prism V.6.01 software (p<0.05 is considered as statistically significant).
Endpoint conclusion
Endpoint conclusion:
no study available (further information necessary)

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:
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):
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

According to ECHA decision number TPE-D-2114425282-58-01/F, there is an ongoing sub-chronic repeated dose toxicity study with the registration substance, conducted according to OECD TG 408 and in compliance with GLP. The study will be submitted as soon as possible once the final report is available.

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.

There are no specific data for respiratory irritation, however the key acute inhalation study revealed signs of respiratory irritation/corrosion. Therefore 'EUH071 Corrosive to the respiratory tract' (1272/2008) is proposed in accordance with these data and those of related chlorosilane substances, based on the expected respiratory tract damage caused by the hydrolysis product HCl.

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, which also applies for oral studies. 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

In the absence of appropriate measured data, the substance is not classified for repeated dose toxicity.