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Administrative data

Description of key information

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

 

Since the local corrosive effects of chlorosilanes would be 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.

Following uptake of HCl, hydrogen and chloride ions 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

Endpoint conclusion
Endpoint conclusion:
no study available

Repeated dose toxicity: inhalation - local effects

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

There are no repeated dose toxicity data on dichloro(diphenyl)silane.

Oral Route

Dichloro(diphenyl)silane (CAS 80-10-4) is a highly moisture-sensitive liquid that hydrolyses rapidly in contact with water (measured half-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.

A well conducted and reported acute oral study with another chlorosilane is the study available for dichloro(3-chloropropyl)methylsilane (CAS 7787-93-1) (Hüls AG, 1997). The study was conducted in compliance with OECD 423, and in accordance with GLP. The test substance (unchanged, no vehicle) was administered to Wistar rats via oral gavage at doses of 2000 (3 males only), 200 (3 males and 3 females), and 25 (3 males and 3 females) mg/kg bw. The dose of 2000 mg/kg bw caused severe signs of toxicity including heavy breathing, squatting position and gait abnormalities in all animals. Two of the three males tested died within one hour post-administration. The surviving rat showed severe symptoms at three hours post-administration and was euthanized for humane reasons. The dose of 200 mg/kg bw showed signs of toxicity including squatting position, abnormal gait, sedation, salivation, piloerection, body weight loss and emaciation that persisted until day 6 or 8 in treated male animals. One male died on day 6 post-administration. The rest of the animals were euthanized for humane reasons. Since no death occurred in male rats within the first 24 hours post-treatment, three females were treated with the test substance in the same way. The dose of 200 mg/kg bw resulted in severe signs of toxicity in all of the female animals and all three of them were euthanized on day 6 post-administration for humane reasons. The dose of 25 mg/kg bw showed no clinical signs of toxicity in any of the male rats whereas body weight loss was noted in female animals and one of the animals was emaciated at the end of the 14-day observation period. Severe macroscopic lesions were observed in the animals treated with 2000 or 200 mg/kg bw at necropsy. Inflammatory lesions of the digestive system were predominant. Perforation of the oesophagus or the stomach was also observed, associated with fibrinous inflammation of the adjacent tissues. Multifocal thickening of the gastric wall was observed in male animals treated with 25 mg/kg bw test substance. Severe emaciation, haemorrhages in the small intestine, not filled stomach and caecum, dark red lung and bloody nose were observed in one female treated with 25 mg/kg bw. Based on the macroscopic and clinical observations observed in the study by Hüls AG (1997), the corrosive nature of the test substance is evident even at the low dose of 25 mg/kg bw.

In a seven-day range-finding study (Sprague-Dawley rats, oral gavage, no vehicle, 20 -1000 mg/kg bw/day) on triacetoxy(ethyl)silane (CAS 17689-77-9) conducted to determine the appropriate doses for administration in an OECD 422 study, which was therefore not conducted to a guideline or to GLP (DCC, 2004), a NOAEL could not be determined due to the corrosive effects of this substance on the oesophagus and stomach. On the basis of this result it was concluded that it was not feasible to conduct the OECD 422 study. The corrosive effects of triacetoxy(ethyl)silane are due to hydrolysis of the parent substance, which generates acetic acid. Since acetic acid is a ‘weaker’ acid than HCl the corrosive properties of dichloro(diphenyl)silane should be expected to be at least as severe as those for triacetoxy(ethyl)silane. Therefore, this study substantiates the conclusions on the scientific feasibility of testing dichloro(diphenyl)silane in oral repeated dose toxicity studies.

The study on dichloro(3-chloropropyl)methylsilane (Hüls AG, 1997) shows that a practical and humane dose range for subsequent longer term studies is likely to be below the limit of technical practicality and toxicological significance. Other common corrosive effects observed in acute studies with other chlorosilanes include glandular stomach erosion, massive burns to abdominal organs, enlarged organs and blood-filled intestines. Overall, based on the available studies, it is evident that local corrosive effects of chlorosilanes in the gastrointestinal tract do occur at low doses and supports the conclusion that testing of chlorosilanes in repeated dose toxicity studies via the oral route is unethical and scientifically unjustified.

Therefore, a 7-day dose-range-finding (DRF) study with trichloro(propyl)silane (CAS 141-57-1) is in progress, with an expected completion date of 30th June 2017. A decision on whether a 28-day DRF study with trichloro(propyl)silane is scientifically justified will be based on the extent of corrosion observed in the on-going 7-day study. This stepwise approach is being used to investigate the corrosive effects of trichloro(propyl)silane, which is representative of other registered chlorosilanes, following repeated oral gavage administration to rats. 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 silicon-containing 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.

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)silaneand 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.