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Description of key information

In a 90-day inhalation study with hydrogen chloride in rats and mice (Toxigenics, 1983) 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, the Lowest Observed Adverse Concentration (LOAEC) was 10 ppm (15 mg/m³). Local effects attributable to the generation of hydrogen chloride were recorded at comparable concentrations. In 28-day repeated dose inhalation study in rats and mice respectively with dichloro(dimethyl)silane (WIL, 2014), local effects attributable to the generation of hydrogen chloride were recorded at comparable concentrations.

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:
other: rat and mouse

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 repeated dose data are available for [2-(perfluorohexyl)ethyl]trichlorosilane. Good quality data from the hydrolysis product hydrogen chloride has been used to assess the potential for adverse effects following exposure to [2-(perfluorohexyl)ethyl]trichlorosilane. Data on the structural analogue [2-(perfluorohexyl)ethyl]triethoxysilane was also available and it was included to this dataset but it was not considered further due to the fact that corrosion is the predominant effect of the registered substance and that oral exposure is not relevant to humans. In this Combined Repeated Dose Oral Toxicity Study with the Reproduction / Developmental Toxicity Screening Test, conducted according to an appropriate OECD test guideline and in compliance with GLP,  the reported NOAEL value for target organ toxicity for [2-(perfluorohexyl)ethyl]triethoxysilane was 50 mg/kg bw/day based on neurotoxicity (Eurofins, 2017).

 

Overview

It is considered not to be either ethical or technically feasible to perform repeated dose toxicity testing with [2-(perfluorohexyl)ethyl]trichlorosilane by any route of exposure due to its known corrosive properties. 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 confound the interpretation of any systemically driven effects. A guideline-compliant repeated-dose inhalation study should elicit systemic toxicity at the highest test concentration. Since the local corrosive effects of [2-(perfluorohexyl)ethyl]trichlorosilane would be significant a valid inhalation study according to the relevant guidelines is technically not feasible to do. It is also 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 (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 local effects in the upper respiratory tract were similar to HCl. It is therefore concluded that local effects caused by HCl will dominate the inhalation toxicity profile of [2-(perfluorohexyl)ethyl]trichlorosilane.

With regard to the dermal and inhalation routes, due to the known corrosive effects of [2-(perfluorohexyl)ethyl]trichlorosilane, appropriate H-phrases and P-statements are included in the labelling, meaning that repeated skin and inhalation exposure is not expected. Any accidental skin contact or inhalation exposure could cause severe local effects but would be unlikely to cause any systemic effects.

 

Inhalation route

Hydrogen Chloride

As has already been described above, [2-(perfluorohexyl)ethyl]trichlorosilane is a severely corrosive substance that is decomposed by water, producing HCl. For local effects it is appropriate to read across results of a 90-day inhalation toxicity study on HCl, which demonstrates the severe corrosive effects of HCl in the respiratory tract.

In a 90-day repeated dose inhalation study in rats and mice (Toxigenics, 1983), 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 hours per day, 5 days per week. Fifteen 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 sacrificedin 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.

Ninety 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 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.

Dichloro(dimethyl)silane

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. 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. 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.

 

Oral route

[2-(perfluorohexyl)ethyl]trichlorosilane

(CAS 78560-45-9) is a highly moisture-sensitive liquid that hydrolyses rapidly in contact with water (estimated half-life of <5 seconds at 25°C and pH 4, 7 and 9) and produces hydrogen chloride (HCl) as one of the primary hydrolysis products. Hydrolysis is complete within few minutes.

The leading health effect of this substance, which is part of the chlorosilanes substance group, is corrosivity. This view is supported by test results with different chlorosilanes and another corrosive silane, which hydrolyses rapidly to acetic acid. The substance is classified in accordance with Regulation (EC) No 1272/2008 as Skin Corrosive Category 1A (H314) and Corrosive to the respiratory tract (EUH071).

A well conducted and reported acute oral study with another chlorosilane (dichloro(3-chloropropyl)methylsilane (CAS 7787-93-1)) is available (Hüls AG, 1997). The study was conducted in compliance with OECD 423, and in accordance with GLP. The test substance was administered neat (no vehicle) to Wistar rats via oral gavage at single doses of 2000 (3 males), 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 non-GLP 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 (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

[2-(perfluorohexyl)ethyl]trichlorosilane

should be expected to be at least as severe as those for triacetoxy(ethyl)silane. Therefore, this study substantiates the conclusions on the lack of scientific feasibility of testing

[2-(perfluorohexyl)ethyl]trichlorosilane

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 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.

A regulatory driven 7-day dose-range-finding (DRF) study (BSL Bioservice, 2018) with trichloro(propyl)silane (CAS 141-57-1) was conducted in order to determine again the feasibility of dosing chlorosilanes (at low doses to avoid corrosive effects) in repeated dose oral toxicity tests.In this 7-day dose range-finding study, 30, 60 or 120 mg/kg bw/day of neat trichloro(propyl)silane were administered by oral gavage to Wistar rats (3 animals/sex/dose, except the low dose which used 5 animals/sex). The control animals were handled identically but sterile water was administered. The lowest dose (30 mg/kg bw/day) of trichloro(propyl)silane was based on the lowest technically achievable dose volume (5 µL).

During the administration period, the animals were observed daily for signs of toxicity. Following two days of administration, all animals administered trichloro(propyl)silane were euthanized prior to study completion date due to animal welfare reasons. The surviving control animals were sacrificed as scheduled on study day 7. All animals were subject to macroscopic examination and full histopathology of the trachea, lungs, oesophagus, stomach and intestine.

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 oesophagus, stomach and lungs were recorded at necropsy. Most notably, semi-solid content and foam formation was observed at the entrance of oesophagus 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 the oesophagus, stomach, trachea and lungs. In summary, the histopathological findings were as follows:

Oesophagus:

  • Inflammatory and/or degenerative lesions in all test item-treated animals,
  • Hyperacute lesions: mucosal degeneration (coagulation necrosis),
  • Acute inflammation in one low-dose female,
  • Necrotizing inflammation in remaining animals. In one case the necrosis/inflammation associated with ulveration and oesophageal perforation.

Trachea:

  • Acute inflammation or necrotizing inflammation in a few animals throughout all test item-treated groups.  

Lungs:

  • Multifocal peribronchiolar inflammation was recorded in the lungs of one high-dose animal affecting mainly the alveoli connecting the terminal end sacs associated with bronchiolar epithelium degeneration.
  • Deposition of cellular detritus associated with degenerated epithelium on one mid-dose animal.

Stomach:

  • Inflammatory and degenerative lesions affected both the forestomach and the glandular stomach, consisting of inflammation and ulceration.

The observed corrosive effects of trichloro(propyl)silane can be directly related to the facile hydrolysis of the parent substance. The formation of hydrochloric acid explains all recorded findings in the DRF study. Based on the results of the DRF study with trichloro(propyl)silane, it was concluded that further testing with this test item in animal studies would not be scientifically justifiable and in contradiction with animal welfare policy. This study further substantiates the premise that local corrosive effects of chlorosilanes in the gastrointestinal tract 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.

 

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

  • All chlorosilanes are classified as corrosive to the skin and respiratory tract.
  • 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)).
  • For chlorosilanes, in general, it can be derived based on all available data 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.
  • In the 7-day DRF study with trichloro(propyl)silane severe corrosive effectshave been observed after 1-2 exposure days. Therefore, it is expected that corrosive effects will be observed at low doses for all chlorosilanes during repeated dose toxicity studies requiring dosing of experimental animals for 28 to 90 days.

Justification for classification or non-classification

The available read-across data on hydrogen chloride and dichlorosilane indicate that [2(perfluorohexyl)ethyl]trichlorosilane does not require classification for repeated dose toxicity according to Regulation (EC) No. 1272/2008.