Dichlorosilane

Endpoint summary

Description of key information

No data are available for the repeated dose oral toxicity of dichlorosilane, therefore good quality data for the precipitated hydrolysis product, synthetic amorphous silica (SAS), have been read-across to address the potential for systemic toxicity. In a repeat dose 90-day oral toxicity study (Kim et al., 2014) with Sprague-Dawley rats, two forms of synthetic amorphous silica (SAS and NM-202; differing in particle size and specific surface area) were administered (vehicle: water) by oral gavage for 90 consecutive days at a dose of 500, 1000 or 2000 mg/kg bw/day (10 animals/sex/group). The particles were described as either 20 or 100 nm in diameter. Extra animals were included in the control (received water only) and highest dose groups to allow for a two-week post-exposure recovery period. Observations were made according to OECD TG 408. For 20 and 100 nm silica samples the findings were sporadic and without a dose-response, so were concluded by the study authors not to be treatment-related. The NOAEL for both particle sizes was therefore concluded to be ≥2000 mg/kg bw/day. For local effects, a good quality study on hydrogen chloride is available. 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. 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. No suitable dermal data are 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

Type of information:

experimental study

Adequacy of study:

key study

Study period:

No data

Reliability:

2 (reliable with restrictions)

Rationale for reliability incl. deficiencies:

guideline study

Qualifier:

according to guideline

Guideline:

OECD Guideline 408 (Repeated Dose 90-Day Oral Toxicity Study in Rodents)

GLP compliance:

yes

Limit test:

no

Species:

rat

Strain:

Sprague-Dawley

Sex:

male/female

Details on test animals or test system and environmental conditions:

TEST ANIMALS
- Source: Orient Bio, Korea
- Age at study initiation: 6 weeks old at purchase
- Weight at study initiation: 187.9-205.3 g for males and 143.3-167.1 g for females
- Fasting period before study: No
- Housing: Two animals per cage were housed in stainless steel wire cages
- Diet (e.g. ad libitum): Ad libitum
- Water (e.g. ad libitum): Ad libitum
- Acclimation period: 8 days

ENVIRONMENTAL CONDITIONS
- Temperature (°C): 21.5-23.3
- Humidity (%): 42.0-51.4
- Air changes (per hr): 10-15
- Photoperiod (hrs dark / hrs light): 12/12

IN-LIFE DATES: No data

Route of administration:

oral: gavage

Vehicle:

other: Distilled water

Details on oral exposure:

PREPARATION OF DOSING SOLUTIONS: Colloidal silica NPs with 20 nm and 100 nm diameters were diluted in distilled water and each of the tested doses were formulated by dilution of the highest dose with distilled water. Working samples of each dose formulation were prepared daily during the study. The formulated test particles were homogenised by vortexing just prior to administration.

Analytical verification of doses or concentrations:

no

Duration of treatment / exposure:

90 days

Frequency of treatment:

Daily

Dose / conc.:

500 mg/kg bw/day (actual dose received)

Remarks:

20 nm particles

Dose / conc.:

1 000 mg/kg bw/day (actual dose received)

Remarks:

20 nm particles

Dose / conc.:

2 000 mg/kg bw/day (actual dose received)

Remarks:

20 nm particles

Dose / conc.:

500 mg/kg bw/day (actual dose received)

Remarks:

100 nm particles

Dose / conc.:

1 000 mg/kg bw/day (actual dose received)

Remarks:

100 nm particles

Dose / conc.:

2 000 mg/kg bw/day (actual dose received)

Remarks:

100 nm particles

No. of animals per sex per dose:

Control and 2000 mg/kg bw/day: 15 (includes 5 animals for the recovery group);
500 and 1000 mg/kg bw/day: 10

Control animals:

yes, concurrent vehicle

Details on study design:

- Dose selection rationale: Doses were based on the results from a 14-day repeated dose toxicity study (details in Kim et al., 2014) in which no significant adverse effects were observed at doses of 1000 and 2000 mg/kg bw/day.
- Post-exposure recovery period in satellite groups: Control and highest dose group had 5 extra animals each, which were observed for a recovery period of two weeks following the 90-day treatment period.

Observations and examinations performed and frequency:

CAGE SIDE OBSERVATIONS: Yes
- Time schedule: All animals were observed once daily after treatment for well-being, mortality and clinical signs of toxicity (no further detail).

DETAILED CLINICAL OBSERVATIONS: It is not clear how detailed the observations were as they were not described in the publication.

BODY WEIGHT: Yes
- Time schedule for examinations: Once per week.

FOOD CONSUMPTION:
- Food consumption for each animal determined and mean daily diet consumption calculated as g food/kg body weight/day: yes, but g food per rat calculated.

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: Yes
- Time schedule for examinations: Daily, calculated by difference between supplied amounts and remaining amounts measured the next day.

OPHTHALMOSCOPIC EXAMINATION: Yes
- Time schedule for examinations: Last week of 90-day treatment period
- Dose groups that were examined: Control and highest dose groups

HAEMATOLOGY: Yes
- Time schedule for collection of blood: Night before scheduled necropsy
- Anaesthetic used for blood collection: Yes (isoflurane)
- Animals fasted: Yes
- How many animals: All animals
- Parameters checked in table 1 were examined.

CLINICAL CHEMISTRY: Yes
- Time schedule for collection of blood: Night before scheduled necropsy
- Animals fasted: Yes
- How many animals: All animals
- Parameters checked in table 1 were examined.

URINALYSIS: Yes
- Time schedule for collection of urine: For five animals per group of each sex during the last week of the 90-day treatment period. Total urine volume was calculated from the urine collected over a 24-h period.
- Metabolism cages used for collection of urine: Yes, for five animals from the control and highest dose group over a 3-h sampling period.
- Animals fasted: No data
- Parameters checked in Table 1 were examined.

NEUROBEHAVIOURAL EXAMINATION: No

Sacrifice and pathology:

GROSS PATHOLOGY: Yes (see Table 2), on moribund or dead animals, and on all animals at the end of the 90-day exposure period.
HISTOPATHOLOGY: Yes (see Table 2), tissues from the control and highest dose group were examined histopathologically.

Statistics:

Body weight values, feed and water consumption data, hematological data, blood biochemistry data, and organ weight values were analysed for homogeneity of variance using Levene’s test. One-way analysis of variance was performed to evaluate the significance of differences. If the variance was homogeneous and a significant difference was identified, Scheffe’s multiple comparison test was performed as a post hoc test. If the variance was not homogeneous, the data were analysed using Dunnett’s T3 test. Analysis of data from the recovery groups was performed using the Student’s t-test. All analyses were performed using Statistical Package for the Social Sciences version 19.0 software (SPSS Inc, Chicago, IL, USA).

Clinical signs:

no effects observed

Mortality:

no mortality observed

Body weight and weight changes:

no effects observed

Food consumption and compound intake (if feeding study):

no effects observed

Food efficiency:

not examined

Water consumption and compound intake (if drinking water study):

no effects observed

Ophthalmological findings:

not specified

Description (incidence and severity):

Examination conducted but results not discussed.

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:

no effects observed

Gross pathological findings:

no effects observed

Histopathological findings: non-neoplastic:

no effects observed

Histopathological findings: neoplastic:

not examined

Details on results:

CLINICAL SIGNS AND MORTALITY: Irrespective of particle size, there were no animal deaths and no treatment-related clinical signs during the experimental period for rats of either sex. There were a few occurrences of salivation, loss of fur and wound scratching in the 2000 mg/kg bw/day group for 20 nm silica. However, due to the sporadic nature there was no dose-dependency, so the study authors concluded that these observations were not related to treatment.

BODY WEIGHT AND WEIGHT GAIN: Regardless of SiO2 particle size, there were no statistically significant differences in body weight between treated rats and their respective control groups, for either males or females.

FOOD CONSUMPTION: There were sporadic increases in food consumption for 20 nm silica and sporadic increases in food consumption for 100 nm silica. Therefore the authors concluded that these differences were not treatment-related.

WATER CONSUMPTION: There were sporadic decreases in water consumption for 20 nm and 100 nm silica, but these were not considered to be treatment-related.

OPHTHALMOSCOPIC EXAMINATION: The results of the ophthalmic examination were not reported.

HAEMATOLOGY: In the high dose recovery group for 20 nm silica there were statistically significant increases in lymphocyte counts compared with the control recovery group. There were no findings for the groups treated with 100 nm silica.

CLINICAL CHEMISTRY: No differences between treated and control animals were observed for 20 nm silica. For females of the high dose recovery group treated with 100 nm silica, aspartate aminotransferase and creatine kinase concentrations were statistically significantly decreased compared with the controls.

URINALYSIS: There were no statistically significant differences in urinalysis parameters in any treated group compared with the respective control groups for either 20 nm or 100 nm silica.

ORGAN WEIGHTS: For 20 nm silica relative liver weight was statistically significantly decreased in males of the highest dose group compared with the control group. Absolute and relative lung weights were statistically significantly increased in males of the high dose recovery group compared with the controls. For 100 nm silica there was a statistically significantly increase in absolute weights of kidney, lung and submandibular glands in the male high dose recovery group. In the same group relative weights of kidneys and lungs were statistically significantly increased. Females in the high dose recovery group had statistically significantly decreased absolute and relative ovary weights. These data are summarised in Table 3 and 4. No other details are available. The study authors concluded that due to the sporadic nature of the organ weight findings they were not due to treatment.

GROSS PATHOLOGY: Pale yellowish discoloration on the posterior surface of the left lateral lobe of the liver was observed in one male animal from the 20 nm silica 500 mg/kg group. With regard to 100 nm silica, a small-sized right testis and epididymis were observed in one male from the 500 mg/kg group. A light yellow discoloration of the left lateral lobe of the liver (about 1 mm diameter), and a light yellow-coloured cyst with adjacent fat near the right kidney were also observed in another male in the 1000 mg/kg group. In addition, a small-sized left ovary was observed in one female from the 2000 mg/kg recovery group. However, there was no dose-dependency, so the study authors concluded that they were not related to treatment.

HISTOPATHOLOGY: Granulomatous inflammation was observed in one male rat from the 1000 mg/kg bw/day group and two from the 2000 mg/kg bw/day group treated with 20 nm silica. Chronic bronchioalveolar inflammation was observed in one male rat from the 2000 mg/kg bw/day group treated with 20 nm silica. There were no adverse findings from the groups treated with 100nm silica. These lesions were observed in four cases in total and were minimal to mild in severity.

Key result

Dose descriptor:

NOAEL

Effect level:

>= 2 000 mg/kg bw/day (actual dose received)

Based on:

test mat.

Sex:

male/female

Basis for effect level:

other: There were no observed adverse effects following repeated oral exposure to two different sizes of colloidal silica particles (20 and 100 nm).

Critical effects observed:

no

Table 3 Organ weights and organ weight to body weight ratios of male rats in the 90-day gavage study (main group) of 20 nm SiO2 nanoparticles*

	0 (vehicle control)	500 mg/kg bw/day	1000 mg/kg bw/day	2000 mg/kg bw/day
Number of animals	10	10	10	10
Male
Necropsy body weight	565.9±43.4	553.7±45.1	529.1±48.4	526.6±48.9
Liver
Absolute (g)	14.70±1.90	13.65±1.26	13.11±1.94	12.59±1.71
Relative (%)	2.59±0.18	2.47±0.14	2.47±0.16	2.38±0.11^a

*Organ (absolute) weights and body weights are given in grams: organ weight to body (relative) weights are given as mg organ weight/g body weight (mean ± standard deviation); ^aP<0.05 significantly different from control, by Scheffe’s test.

Table 4 Organ weights and organ weight to body weight ratios for the recovery group in the 90-day gavage study of SiO2 nanoparticles*

	0 (vehicle control)	2000 mg/kg bw/day
Number of animals	5	5
SiO2 (20 nm)
Male
Necropsy body weight	569.8±38.4	545.9±35.0
Lung
Absolute (g)	1.61±0.07	1.81±0.12^a
Relative (%)	0.28±0.02	0.33±0.02^a
SiO2 (100 nm)
Male
Necropsy body weight	577.4±60.5	603.3±22.0
Kidney
Absolute (g)	3.27±0.21	3.69±0.21^a
Relative (%)	0.57±0.03	0.61±0.02^a
Lung
Absolute (g)	1.62±0.09	1.93±0.08^a
Relative (%)	0.28±0.02	0.32±0.02^a
Submaxillary gland
Absolute (g)	0.78±0.04	0.96±0.12^a
Relative (%)	0.14±0.01	0.16±0.02
Female
Necropsy body weight	303.9±47.8	304.9±16.9
Ovary
Absolute	0.094±0.009	0.066±0.022^a
Relative	0.0314±0.0040	0.0217±0.0069^a

*Organ (absolute) weights and body weights are given in grams: organ weight to body (relative) weights are given as mg organ weights/g body weight (mean ± standard deviation); ^aP<0.05, significantly different from control by Scheffe’s test.

Conclusions:

Based on a 90-day oral repeated dose toxicity study conducted to OECD test guideline 408 and to GLP, the NOAEL for 20nm and 100nm colloidal silica particles is ≥2000 mg/kg bw/day in Sprague-Dawley rats.

Endpoint conclusion

Endpoint conclusion:

no adverse effect observed

Dose descriptor:

NOAEL

2 000 mg/kg bw/day

Study duration:

subchronic

Species:

rat

Quality of whole database:

The key study was conducted according to OECD TG 408 and to GLP, without any significant deviations and is therefore the most suitable key study for the repeat dose oral toxicity endpoint.

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:

2 (reliable with restrictions)

Rationale for reliability incl. deficiencies:

study well documented, meets generally accepted scientific principles, acceptable for assessment

Qualifier:

equivalent or similar to guideline

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 or test system 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 (nominal)

Dose / conc.:

20 ppm (nominal)

Dose / conc.:

50 ppm (nominal)

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:

no

Conclusions:

In a well conducted 90-day gas inhalation study (reliability score 1) the systemic NOAEC for hydrogen chloride was 20 ppm (30 mg/m3) 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:

mouse

Quality of whole database:

The key study was conducted according to OECD TG 413 and to GLP, without any significant deviations and is therefore the most suitable key study for the repeat dose inhalation local toxicity endpoint.

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 adequate long-term repeated dose toxicity data on dichlorosilane so good quality data for the hydrolysis products polysilicic acid (equivalent to synthetic amorphous silica) and hydrogen chloride have been used to assess the potential for adverse effects following exposure to dichlorosilane.

Overview

It is considered not to be ethical to perform repeated dose toxicity testing with dichlorosilane by any route of exposure due to its known corrosive properties, which dominates the toxicity profile of this substance. 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 dichlorosilane 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 dichlorosilane.

With regard to the dermal and inhalation routes, due to the known corrosive effects of dichlorosilane, 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.

ORAL ROUTE

SYSTEMIC EFFECTS

There are no adequate repeat-dose toxicity data on dichlorosilane so good quality data for synthetic amorphous silica (CAS 112926-00-8) have been used to assess the general systemic oral toxicity of dichlorosilane. Local effects from the hydrolysis product, hydrogen chloride (HCl) are not addressed by these data (see section on local effects below).

Dichlorosilane, like all inorganic chlorosilanes, is a severely corrosive substance that is decomposed by water, producing silicic acid and HCl. The reaction is highly exothermic (Merck, 2013). Hydrolysis half-life is approximately 5 seconds at 25°C and pH 4, 7 and 9. The initial products of hydrolysis are hydrogen chloride and silanediol. The silanediol is expected to react rapidly to produce hydrogen and monosilicic acid. Hydrogen would be released to the atmosphere immediately.

 

Monosilicic acid condenses to insoluble polysilicic acid [equivalent to synthetic amorphous silica (SAS)] at concentrations higher than 100-150 mg/l ‘SiO₂ equivalent’ in water (Holleman-Wiberg, 2001). At very high concentration, polysilicic acid can condense to silicon dioxide (SiO₂). The hydrolysis products of hydrochloric acid and (poly)silicic acid are significant for the chemical safety assessment (CSR).

 

Monosilicic acid and polysilicic acid are naturally occurring substances which are ubiquitous in the environment. Soluble monosilicic acid is the major bioavailable form of silicon and plays an important role in the biogeochemical cycle of silicon (ECETOC, 2006). Typical background concentrations of monosilicic acid in the environment are up to 75 mg/l ‘SiO₂equivalent’ in river water and up to 14 mg/l ‘SiO₂equivalent’ in seawater (Iler, 1979).

 

The literature gives various values for the solubility of silicic acid, determined indirectly as ‘SiO₂ equivalent’ because the soluble species cannot be directly measured:

 

The solubility of monosilicic acid according to Alexander et al., (1954) at 25 °C:

• 150 mg/l ‘SiO₂ equivalent’ at pH 2.0 and pH 3.0
• 130 mg/l ‘SiO₂ equivalent’ at pH 4.2
• 110 mg/l ‘SiO₂ equivalent’ at pH 5.7
• 100 mg/l ‘SiO₂ equivalent’ at pH 7.7
• 490 mg/l ‘SiO₂ equivalent’ at pH 10.3
• 1120 mg/l ‘SiO₂ equivalent’ at pH 10.6

 

The solubility of monosilicic acid according to Goto and Okura (1953) at 25 °C:

• 120 mg/l ‘SiO₂ equivalent’ at pH 2.0
• 150 mg/l ‘SiO₂ equivalent’ at pH 7.0

 

The solubility of monosilicic acid according to Elmer and Nordberg, (1958) at neutral pH:

• 170 mg/l ‘SiO₂ equivalent’ at 35 °C
• 270 mg/l ‘SiO₂ equivalent’ at 65 °C
• 465 mg/l ‘SiO₂ equivalent’ at 95 °C

 

With the described properties of dichlorosilane in mind it is not possible to conduct 90-day repeated dose toxicity studies in experimental animals due to the corrosive nature of this substance. Nor can the hydrolysis product, monosilicic acid, be tested as it is not possible to isolate this substance. However, we know from physicochemical properties that following ingestion of dichlorosilane, the conditions in the stomach are such that following an initial rapid hydrolysis to soluble monosilicic acid, this monomer will start to condense to form insoluble polysilicic acid (equivalent to SAS). This condensation will start to occur once the concentration of monosilicic acid reaches approximately 100-150 mg/l in the gastric juices.

Monosilicic acid (soluble silica) undergoes condensation reactions in solution at about 100 -150 mg/l ‘SiO₂ equivalent’. The solubility of monosilicic acid in water is 150 mg/l ‘SiO₂ equivalent'.

Following dosing by oral gavage, partitioning will occur between the dose vehicle and the aqueous environment in the stomach.

Mass dosed (in mg/day) = Body weight (in kg) x dose level (in mg/kg bw/day)

 

Dose concentration (in mg/l) = mass dosed (in mg/day) ÷ volume (in l)

So, the dose level (mg/kg bw/day) required to reach the dose concentration of 150 mg/l 'SiO₂ equivalent', the estimated (conservative) maximum concentration of silicic acid that can occur in the stomach before condensation to insoluble polysilicic acid (equivalent to SAS) begins is calculated as follows:

Body weight of rat = 0.3 kg

Dose level = X                                                        

Estimated aqueous volume = 0.0015 l                                                                      

Dose concentration = 150 mg/l

150 mg/l = 0.3 kg x dose level (mg/kg bw/day) ÷ 0.0015l

Dose level = 0.75 mg/kg bw/day 'SiO₂ equivalent'

Therefore, based on a condensation limit of 150 mg/l, the maximum dose level that could be used in practice to ensure exposure mainly to monosilicic acid in the stomach of experimental animals is approximately 0.75 mg/kg bw/day or less of 'SiO₂ equivalent'.

A correction for molecular weight gives a maximum dose level for dichlorosilane:

Mr [dichlorosilane]               =             101.01 g/mol

Mr [silicon dioxide]                         =             60.08 g/mol

Dose level [dichlorosilane]        =            [Dose level [silicon dioxide]  x  Mr [dichlorosilane]]

                                                                                                         Mr [silicon dioxide]

 

                                                            =            (0.75 mg/kg bw/day) x (101.01 g/mol)

                                                                                                         (60.08 g/mol)

 

                                                            =             1.26 mg/kg bw/day

Therefore, based on a condensation limit of 150 mg/l the maximum dose level of dichlorosilane that could theoretically be dosed to ensure exposure mainly to monosilicic acid is approximately 1.3 mg/kg bw/day.

For comparison purposes, using the above calculation, the following shows the dose concentrations for the dose levels typically used in experimental animal studies (100, 300 and 1000 mg/kg bw/day).

Body weight                                = 0.3 kg

Total amount dosed                     = 30 mg

Estimated aqueous volume           = 1.5 ml

Dose concentration                      = 20,000 mg/l

Body weight                                = 0.3 kg

Total amount dosed                     = 90 mg

Estimated aqueous volume           = 1.5 ml

Dose concentration                     =  60,000 mg/l

Body weight                                 = 0.3 kg

Total amount dosed                      = 300 mg

Estimated aqueous volume           = 1.5 ml

Dose concentration                       = 200,000 mg/l

Therefore, dosing at these dose levels clearly gives a dose concentration in the stomach that far exceeds the dose at which condensation to polysilicic acid (equivalent to SAS) starts to occur. Consequently, the majority of the dose in the stomach will be present as insoluble polysilicic acid (equivalent to SAS). In all cases only approximately 150 mg/l will be present as soluble monosilicic acid.

Overall, it can be concluded that gavaging dichlorosilane at doses unlikely to cause local corrosive effects and at doses that give mainly soluble monosilicic acid (2 mg/kg bw/day or less) would be unethical based on animal usage. However, because the vast majority of a gavaged dose will rapidly condense to insoluble polysilicic acid, it is appropriate to use toxicology data on SAS to address the potential for oral toxicity of dichlorosilane.

The key study is a repeated dose 90-day oral toxicity study in rats (Kim et al., 2014) conducted according to OECD test guideline 408 and in compliance with GLP. In this study two forms of synthetic amorphous silica (described as SAS and NM-202; differing in particle size and specific surface area) were administered (vehicle: water) by oral gavage for 90 consecutive days at a dose of 500, 1000 or 2000 mg/kg bw/day (10 animals/sex/group). Several control and high dose group animals were used for a two-week post-exposure recovery group follow-up. All findings were sporadic and without a dose-response so were concluded by the study authors not to be treatment-related. The NOAEL for SAS was therefore concluded to be ≥2000 mg/kg bw/day.

 

INHALATION ROUTE

LOCAL EFFECTS

As has already been described above, dichlorosilane is a severely corrosive substance that is decomposed by water, producing silicic acid, HCl and hydrogen. Hydrogen would be immediately exhaled. 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.

Hydrogen chloride

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 hour 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 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.

 

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.

References

Alexander G.B., Heston W.M. and Iler R.K. (1954) J. Phys. Chem., 58, 453.

Cotton F.A. and Wilkinson G. (1999) Advanced Inorganic Chemistry, 6^thEdition, p271

ECETOC (2006) Synthetic Amorphous Silica (CAS No. 7631 -86 -9), JACC REPORT No. 51

Elmer and Nordberg (1958) J. Am.Chem. Soc., 41, 517

Goto K. and Okura T. (1953) Kagaku, 23, 426.

Holleman-Wiberg, (2001) Inorganic Chemistry, Academic Press, p. 865

Iler, Ralph K. (1979) The Chemistry of Silica: Solubility, Polymerization, Colloid and Surface Properties and Biochemistry of Silica, Wiley, p. 13.

Jones, R. G., Wataru, A., and Chojnowski, J. (2000) Silicon-Containing Polymers: The Science and Technology of Their Synthesis, Kluwer Academic Press pp168-169

Merck Index (2013) Monograph Number. 8639 (15th Ed)

Justification for classification or non-classification

Based on the available read-across data from the hydrolysis products insoluble polysilicic acid [equivalent to synthetic amorphous silica (SAS)] and hydrogen chloride, dichlorosilane does not require classification for specific organ toxicity following repeated administration according to Regulation (EC) No. 1272/2008.