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Administrative data

Description of key information

There are no repeated dose oral, inhalation or dermal studies available for trichloro(4 -methylphenyl)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

Link to relevant study records
Reference
Endpoint:
sub-chronic toxicity: inhalation
Type of information:
read-across from supporting substance (structural analogue or surrogate)
Adequacy of study:
weight of evidence
Justification for type of information:
Study included to support data waiver.
Reason / purpose:
read-across source
Reason / purpose:
read-across source
Dose descriptor:
NOAEC
Effect level:
20 ppm
Based on:
test mat.
Sex:
male/female
Basis for effect level:
body weight and weight gain
Remarks on result:
other:
Remarks:
CAS 7647-01-0, Toxigenics, 1984
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.
Remarks on result:
other:
Remarks:
CAS 7647-01-0, Toxigenics, 1984
Dose descriptor:
NOAEC
Basis for effect level:
other: local irritant effects noted in the nasal cavity at both 5 and 25 ppm (26 or 132 mg/m3) DCDMS. Similar findings recorded for 50 ppm HCl, which were generally comparable in incidence and severity to 25 ppm DCDMS.
Remarks on result:
not determinable
Remarks:
CAS 75-78-5, WIL, 2014
Critical effects observed:
not specified
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 trichloro(4-methylphenul)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

No data on repeated dose toxicity is available for trichloro(4 -methylphenyl)silane (CAS 701-35-9).

 

Oral route

Trichloro(4 -methylphenyl)silane (CAS 701-35-9) is a highly moisture-sensitive liquid that hydrolyses rapidly in contact with water (half-life <1 min at pH 7) to 4 -methylphenylsilanetriol and hydrogen chloride (HCl). As the substance is corrosive, risk management measures are in place at industrial sites to prevent the potential for human exposure to trichloro(4 -methylphenyl)silane. Due to the corrosive nature of the substance it is considered not to be either ethical or scientifically justified to perform repeated dose toxicity testing with trichloro(4 -methylphenyl)silane by any route of exposure. As an example, following repeated oral dosing, the corrosive nature of the product could affect the lining of the stomach, giving rise to hyperplasia and a subsequent reduced food intake. This would make the interpretation of any systemic findings difficult.

 

This is supported by a 7 -day range-finding study on triacetoxy(ethyl)silane (CAS 17689 -77 -9) (DCC, 2004).In this 7-day range-finding study (Sprague-Dawley rats, oral gavage, no vehicle, 20, 100, 500, and 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, 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 trichloro(4 -methylphenyl)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 trichloro(4 -methylphenyl)silane in oral repeated dose toxicity studies.

Furthermore, this is also supported by regulatory driven 7 -day dose-range-finding (DRF) study according to OECD 407 with trichloro(propyl)silane (CAS 141-57-1). In this study (Wistar rats, oral gavage, no vehicle, 30, 60, 120 mg/kg bw/day) on trichloro(propyl)silane (CAS 141 -57 -1) conducted to determine the appropriate doses for administration in further repeated dose toxicity studies, which was therefore not conducted to GLP. This study was terminated after 2 days of dosing for animal welfare reasons and a NOAEL could not be determined due to the corrosive effects of this substance on the oesophagus and stomach.

From the results of the DRF study with trichloro(propyl)silane, it was concluded that further testing with this test item in animal studies would be unethical and scientifically not justified.

 

Both studies further substantiate the premise 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.

 

Inhalation route

 

A guideline-compliant repeated-dose inhalation study should elicit systemic toxicity at the highest test concentration. Since the local corrosive effects of trichloro(4 -methylphenyl)silane would be significant, it is unlikely that any systemic effects would be seen at dose levels made sufficiently low (<10 ppm) to prevent the known corrosive effects and/or distress in the test species. This has been confirmed in a 28-day inhalation study with another chlorosilane, dichloro(dimethyl)silane (CAS 75-78-5, WIL, 2014) in which there were no effects of treatment on clinical signs, body weight or food consumption that would indicate a systemic effect. Furthermore, the histopathology in the study indicated that the effects in the upper respiratory tract were similar to HCl. It is therefore concluded that the hydrolysis product HCl will dominate the inhalation toxicity profile of trichloro-p-tolylsilane. Local effects from hydrogen chloride are addressed by good quality data for that substance (Toxigenics Inc, 1984) and the 4-week dichloro(dimethyl)silane study (WIL, 2014). With regard to the dermal route, due to the known corrosive effects of trichloro(4 -methylphenyl)silane, appropriate H-phrases and P-statements are included in the labelling, meaning that repeated skin contact can be excluded.

 

 Thus, the hazard profile of trichloro(4 -methylphenyl)silane is solely driven by the hydrolysis product HCl and can be assessed qualitatively and quantitatively by considering the HCl produced by hydrolysis. Further repeated-dose animal studies should be omitted due to animal welfare.

 

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 extremison 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 urinalysis 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 the 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 (ca. 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.

 

In a 4-week repeated dose study (WIL, 2014) 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 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, with a clear dose-relationship in incidence and severity between the 5 and 25 ppm dichloro(dimethyl)silane groups for the majority of findings. Exposure to 25 ppm (132 mg/m³) dichloro(dimethyl)silane or 50 ppm hydrogen chloride was also associated with interstitial edema 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 25 ppm dichloro(dimethyl)silane and 50 ppm 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 25 ppm dichloro(dimethyl)silane group compared with the 50 ppm HCl group. 

 

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.