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Toxicological information

Repeated dose toxicity: inhalation

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Administrative data

Endpoint:
sub-chronic toxicity: inhalation
Type of information:
migrated information: read-across from supporting substance (structural analogue or surrogate)
Adequacy of study:
key study
Reliability:
2 (reliable with restrictions)
Rationale for reliability incl. deficiencies:
other: Study was conducted using a method equivalent to OECD Testing Guideline 413 and meets acceptable scientific standards.

Data source

Reference
Reference Type:
publication
Title:
Subchronic inhalation toxicity of amorphous silicas and quartz dust in rats
Author:
Reuzel P. et al
Year:
1991
Bibliographic source:
Fd Chem Toxic 29: 341-356

Materials and methods

Test guideline
Qualifier:
according to guideline
Guideline:
OECD Guideline 413 (Subchronic Inhalation Toxicity: 90-Day Study)
Deviations:
yes
Remarks:
no ophthalmological examination performed
GLP compliance:
not specified
Limit test:
no

Test material

Constituent 1
Chemical structure
Reference substance name:
Silicon dioxide
EC Number:
231-545-4
EC Name:
Silicon dioxide
Cas Number:
7631-86-9
Molecular formula:
O2Si
IUPAC Name:
dioxosilane
Test material form:
solid: particulate/powder
Remarks:
migrated information: powder
Details on test material:
- Name of test material: Aerosil 200 - Degussa AG (Frankfurt am Main, Germany)
- Physical state: solid
- Analytical purity: >99.8%

Test animals

Species:
rat
Strain:
Wistar
Sex:
male/female
Details on test animals or test system and environmental conditions:
TEST ANIMALS
- Source: TNO Central Institute for the Breeding of Laboratory Animals
- Age at study initiation: 6 weeks
- Weight at study initiation:
- Fasting period before study:
- Housing: singly during exposure period, five males and five females per cage after exposure period
- Diet: ad libitum
- Water: ad libitum

ENVIRONMENTAL CONDITIONS
- Temperature (°C): 21°C - 23°C
- Humidity (%): 65% - 75%
- Air changes: 40 m3 per hour

Administration / exposure

Route of administration:
inhalation: aerosol
Type of inhalation exposure:
whole body
Vehicle:
air
Remarks on MMAD:
MMAD / GSD: Mean primary particle size: 12 nm
Details on inhalation exposure:
GENERATION OF TEST ATMOSPHERE / CHAMBER DESCRIPTION
- System of generating particulates/aerosols: Dust feed mechanism + atomizer operated by compressed air

TEST ATMOSPHERE
- Sampling: using a Sartorius SM 13430
- Brief description of analytical method used: gravimetry
Analytical verification of doses or concentrations:
yes
Duration of treatment / exposure:
13 weeks of exposure. Termination at the end of the exposure or 13, 26, 39 or 52 weeks after the end of exposure
Frequency of treatment:
6 hours/day, 5 days/week
Doses / concentrations
Remarks:
Doses / Concentrations:
1, 6, and 30 mg/m3 (Aerosil 200)
Basis:
nominal conc.
No. of animals per sex per dose:
70 males and 70 females per concentration (including control group).
Control animals:
yes, concurrent no treatment
Details on study design:
- Dose selection rationale: a 14-day dose range finding study was performed before the main study. It was found that a concentration of 17 mg/m3 induced slight adverse effects. The concentration of 6 mg/m3 was chosen as it was the German Threshold Limit Value for inert dust such as Aerosil 200. The concentration of 30 mg/m3 was chosen in order to generate adverse effects (but no mortality).

Examinations

Observations and examinations performed and frequency:
DETAILED CLINICAL OBSERVATIONS: Yes
- Time schedule: Daily

BODY WEIGHT: Yes
- Time schedule for examinations: Weekly during exposure, once every 4 weeks during the recovery period.

FOOD CONSUMPTION:
- Food consumption for each animal determined and mean daily diet consumption calculated as g food/kg body weight/day: No data

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: Yes / No / No data

WATER CONSUMPTION: No data

OPHTHALMOSCOPIC EXAMINATION: No data

HAEMATOLOGY: Yes
- Time schedule for collection of blood: every 13 weeks
- Anaesthetic used for blood collection: No data
- Animals fasted: No data
- How many animals: 10 rats/sex/concentration
- Parameters examined: cell counts, haemoglobin content, packed cell volume, white-cell counts, differential white-cell counts, prothrombin time, and thrombocytes.

CLINICAL CHEMISTRY: Yes
- Time schedule for collection of blood: every 13 weeks
- Animals fasted: No data
- How many animals: 10 rats/sex/concentration
- Parameters examined: albumin, alkaline phosphatase, alanine aminotransferase, aspartate aminotransferase, urea, total protein, creatinine, total bilirubin, calcium, potassium, sodium, inorganic phosphate, cholesterol and glucose

URINALYSIS: Yes
- Time schedule for collection of urine: every 13 weeks
- Metabolism cages used for collection of urine: No data
- Animals fasted: No data
- Parameters examined: appearance, volume, density and pH, analysis for protein, occult blood, glucose, ketones, sediment

NEUROBEHAVIOURAL EXAMINATION: No data
Sacrifice and pathology:
GROSS PATHOLOGY: Yes
HISTOPATHOLOGY: Yes
Other examinations:
- Collagen content in lungs
- Silicon content in lungs
- Silicon in lymph nodes associated to the lungs
Statistics:
Body weight: analysis of co-variance and Dunnett's multiple comparison test
Organ weight: analysis of variance and Dunnett's multiple comparison test
Haematology: analysis of variance and Dunnett's multiple comparison test
Biochemistryy: analysis of variance and Dunnett's multiple comparison test
Hhistopathological changes: analysis of incidence using the Fisher exact probability test

Results and discussion

Results of examinations

Clinical signs:
effects observed, treatment-related
Mortality:
mortality observed, treatment-related
Body weight and weight changes:
effects observed, treatment-related
Food consumption and compound intake (if feeding study):
not examined
Food efficiency:
not examined
Water consumption and compound intake (if drinking water study):
not examined
Ophthalmological findings:
not examined
Haematological findings:
effects observed, treatment-related
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:
effects observed, treatment-related
Histopathological findings: non-neoplastic:
effects observed, treatment-related
Histopathological findings: neoplastic:
no effects observed
Details on results:
CLINICAL SIGNS AND MORTALITY
- Dose-related increase of the respiration rate. The respiration rate returned to normal at the end of exposure.

BODY WEIGHT AND WEIGHT GAIN
- Body weight of male rats exposed to 30mg/m3 was 5% - 10% lower at the end of exposure compared with control group. Body weight returned to normal after 13 weeks post exposure.

HAEMATOLOGY
- Neutrophilic leucocyte count was higher for rats exposed to 30 mg/m3 compared with control group (non-significant). It returned to normal after 13 weeks post exposure.
- Red blood cell count, haemoglobin content, and packed cell volume slightly increased in males exposed to 30 mg Aerosil 200/m3 compared with control group. They returned to normal after 13 weeks post exposure.

CLINICAL CHEMISTRY
- No adverse effects observed compared with control group.

URINALYSIS
- No adverse effects observed compared with control group.

ORGAN WEIGHTS
- Rats exposed to 6 and 30 mg/m3 showed significantly heavier lungs compared with control group, with a greater increase in male rats compared with female rats, and greater increase in rats exposed to 30 mg/m3 compared to rats exposed to 6 mg/m3. It returned to normal after 13 weeks post exposure for rats exposed to 6 mg/m3.

GROSS PATHOLOGY
- Swollen/spongy lungs in rats exposed to the test item. It returned to normal after 26 weeks.

HISTOPATHOLOGY: NON-NEOPLASTIC
- Miscrocopic changes were observed in the lungs compared with the control group at the end of exposure. These changes were dose-related and caused by an inflammatory reaction induced by the test item. Most changes returned to normal during the recovery period.

OTHER FINDINGS
- Lung collagen content: Animals exposed to the test item had higher lung collagen content compared with the control group, with the highest result being obtained for rats exposed to 30 mg/m3 and higher lung collagen content in male rats when compared in female rats. It returned to normal after 52 weeks only for animal exposed to 1 mg/m3.
- Silicon in the lungs and associated lymph nodes: The test item was quickly cleared from the lung and associated lymph nodes.

Effect levels

open allclose all
Dose descriptor:
NOAEC
Remarks:
local
Effect level:
1.3 mg/m³ air (analytical)
Sex:
male/female
Basis for effect level:
other: Mean concentration of the test item of atmosphere when the target concentration was 1 mg/m3
Dose descriptor:
NOAEL
Remarks:
systemic
Effect level:
5.9 mg/L air (analytical)
Sex:
male/female
Basis for effect level:
other: Mean concentration of the test item of atmosphere when the target concentration was 5.9 mg/m3

Target system / organ toxicity

Critical effects observed:
not specified

Applicant's summary and conclusion

Conclusions:
The NOAEL of the substance has been determined to be 1.3 mg/m3 for local effects (on the respiratory tract) and 31 mg/m3 for systemic effects.
Executive summary:

Subchronic toxicity of the read-across substance silicon dioxide branded as Aerosil 200 following an inhalation exposure was determined according to a method similar to the OECD Guideline for Testing of chemicals 413. Wistar rats were exposed to Aerosil 200 as an aerosol 6 hours/day, 5 days/week, for 13 weeks, at dose levels of 0, 1, 6, and 30 mg/m3. Rats were sacrificed at the end of exposure or 13, 26, 39 or 52 weeks after the end of exposure. Clinical observations were performed daily. Body weight were calculated weekly during the exposure then once every 4 weeks during the recovery period. Haematology and clinical chemistry were evaluated, and urinalysis performed once every 13 weeks. Gross pathology and histopathology were performed on sacrificed animals, along with calculation of collagen content in lungs, and silicon content in lungs and associated lymph nodes.

A dose-related increase of the respiration rate was observed in treated animals. Macroscopic and microscopic changes were observed in the lungs are considered to be related to an inflammatory pulmonary reaction, along with the higher neutrophilic leucocyte count seen in rats treated at 30 mg/m3. No effects were identified in the clinical biochemistry and the urinalysis. Red blood cell count, haemoglobin content, and packed cell volume slightly increased in males exposed to 30 mg/m3 of the substance.

Animals exposed to the test item had higher lung collagen content.

During the recovery period, most adverse effects identified in treated animals disappeared and the lungs were cleared from the test.

Systemic effects on haematology parameters were identified at the highest dose of 31 mg/m3. Therefore, the NOAEL has been determined to be 5.9 mg/m3 for systemic effects.

A dose of 1.3 mg/m3 only induced slight local effects that recovered quickly. Therefore, the NOAEL has been determined to be 1.3 mg/m3 for local effects.

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