Trichloro(3,3,4,4,5,5,6,6,7,7,8,8,8-tridecafluorooctyl)silane

Endpoint summary

Key value for chemical safety assessment

Effects on fertility

Description of key information

No reproductive toxicity data are available for [2-(perfluorohexyl)ethyl]trichlorosilane (CAS 78560-45-9; EC 278-947-6).

A Combined Repeated Dose Toxicity Study with the Reproduction / Developmental Toxicity Screening Test with triethoxy(3,3,4,4,5,5,6,6,7,7,8,8,8-tridecafluorooctyl)silane (CAS 51851-37-7, EC 257-473-3) is included in this dossier for information only. The study was conducted according to the appropriate OECD 422 Test Guideline and in compliance with GLP. No adverse effects were observed on male and female fertility or fetus development at any dose tested (Eurofins, 2017, reliability 1).

Effect on fertility: via oral route

Endpoint conclusion:

no study available

Effect on fertility: via inhalation route

Endpoint conclusion:

no study available

Effect on fertility: via dermal route

Endpoint conclusion:

no study available

Additional information

It is considered not to be either ethical or technically feasible to perform reproductive toxicity testing with [2-(perfluorohexyl)ethyl]trichlorosilane (CAS 78560-45-9; EC 278-947-6) by any route of exposure at toxicologically relevant doses or concentrations due to its known corrosive properties.

Data on the structural analogue [2-(perfluorohexyl)ethyl]triethoxysilane (CAS 51851-37-7, EC 257-473-3) was also available and it was included in this dataset but not considered further due to the fact that corrosion is the predominant effect 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 developmental toxicity for [2-(perfluorohexyl)ethyl]triethoxysilane was ≥125 mg/kg bw/day (the highest dose tested; Eurofins, 2017, reliability 1).

Limited data are available regarding the reproduction and development of animals following oral, dermal or inhalation exposure to hydrogen chloride or hydrochloric acid, however, protons and chloride ions both exist as normal constituents of body fluid in animals, hence low concentrations of hydrogen chloride appear not to cause adverse effects in animals. Therefore, hydrogen chloride would not contribute to any reproductive toxicity (fertility or developmental) effects at the dose levels tested.

[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; EC 232-136-3)) is available (Hüls AG, 1997, reliability 1). The study was conducted in compliance with OECD Test Guideline 423 (although current Guideline dose levels were not used) 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, reliability 1), 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, EC 241-677-4) conducted to determine the appropriate doses for administration in an OECD 422 study (DCC, 2004, reliability 2), 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 developmental toxicity studies.

The study on dichloro(3-chloropropyl)methylsilane (Hüls AG, 1997, reliability 1) 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 developmental toxicity studies via the oral route is unethical and scientifically unjustified.

A regulatory driven 7-day dose-range-finding (DRF) study (BSL Bioservice, 2018, reliability 2) with trichloro(propyl)silane (CAS 141-57-1, EC 205-489-6) was conducted in order to again determine 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 developmental 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 effects have 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.

Effects on developmental toxicity

Description of key information

No developmental toxicity data are available for [2-(perfluorohexyl)ethyl]trichlorosilane (CAS 78560-45-9; EC 278-947-6).

A Combined Repeated Dose Toxicity Study with the Reproduction / Developmental Toxicity Screening Test with triethoxy(3,3,4,4,5,5,6,6,7,7,8,8,8-tridecafluorooctyl)silane (CAS 51851-37-7, EC 257-473-3) is included in this dossier for information only. The study was conducted according to the appropriate OECD 422 Test Guideline and in compliance with GLP. No adverse effects were observed on male and female fertility or fetus development at any dose tested (Eurofins, 2017, reliability 1) .

Effect on developmental toxicity: via oral route

Endpoint conclusion:

no study available

Effect on developmental toxicity: via inhalation route

Endpoint conclusion:

no study available

Effect on developmental toxicity: via dermal route

Endpoint conclusion:

no study available

Additional information

It is considered not to be either ethical or technically feasible to perform developmental toxicity testing with [2-(perfluorohexyl)ethyl]trichlorosilane (CAS 78560-45-9; EC 278-947-6) by any route of exposure at toxicologically relevant doses or concentrations due to its known corrosive properties.

Data on the structural analogue [2-(perfluorohexyl)ethyl]triethoxysilane (CAS 51851-37-7, EC 257-473-3) was also available and it was included in this dataset but not considered further due to the fact that corrosion is the predominant effect 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 developmental toxicity for [2-(perfluorohexyl)ethyl]triethoxysilane was ≥125 mg/kg bw/day (the highest dose tested; Eurofins, 2017, reliability 1).

Limited data are available regarding the reproduction and development of animals following oral, dermal or inhalation exposure to hydrogen chloride or hydrochloric acid, however, protons and chloride ions both exist as normal constituents of body fluid in animals, hence low concentrations of hydrogen chloride appear not to cause adverse effects in animals. Therefore, hydrogen chloride would not contribute to any reproductive toxicity (fertility or developmental) effects at the dose levels tested.

[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; EC 232-136-3)) is available (Hüls AG, 1997, reliability 1). The study was conducted in compliance with OECD Test Guideline 423 (although current Guideline dose levels were not used) 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, reliability 1), 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, EC 241-677-4) conducted to determine the appropriate doses for administration in an OECD 422 study (DCC, 2004, reliability 2), 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 developmental toxicity studies.

The study on dichloro(3-chloropropyl)methylsilane (Hüls AG, 1997, reliability 1) 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 developmental toxicity studies via the oral route is unethical and scientifically unjustified.

A regulatory driven 7-day dose-range-finding (DRF) study (BSL Bioservice, 2018, reliability 2) with trichloro(propyl)silane (CAS 141-57-1, EC 205-489-6) was conducted in order to again determine 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 developmental 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 effects have 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 information on hydrogen chloride indicates that [2(perfluorohexyl)ethyl]trichlorosilane does not require classification for reproductive or developmental toxicity according to Regulation (EC) No. 1272/2008.