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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: see 'Remark'
Remarks:
Study follows acceptable test methods and sufficient information is available for interpretation. The study is included in the peer reviewed Food and Chemical Toxicology Journal. Read-across from the results on the test substance has been made to the registered substance based on the similar structure of the two substances.
Cross-reference
Reason / purpose for cross-reference:
reference to same study

Data source

Reference
Reference Type:
publication
Title:
Unnamed
Year:
1991
Report date:
1991

Materials and methods

Test guideline
Qualifier:
no guideline followed
Principles of method if other than guideline:
No test guideline was provided.
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:
silicon dioxide (amorphous)
Constituent 2
Reference substance name:
Pyrogenic (fumed) amorphous silica
IUPAC Name:
Pyrogenic (fumed) amorphous silica
Constituent 3
Reference substance name:
Aerosil 200
IUPAC Name:
Aerosil 200
Test material form:
aerosol dispenser: not specified
Remarks:
migrated information: aerosol
Details on test material:
Specifications of the amorphous silica:

Characteristic: Aerosil 200
Structure: Amorphous
BET-surface area (m^2/g): 200
Behaviour against water: Hydrophilic
Mean primary particle size (nm): 12
Primary particle shape: Spherical
Agglomeration size (µm): N/A
pH value: 3.6-4.3
SiO2 content (%): >99.8
Sodium sulphate (%): N/A
Chloride (ppm): <250

Test animals

Species:
rat
Strain:
Wistar
Sex:
male/female
Details on test animals or test system and environmental conditions:
6 week old male (n = 490) and female (n = 490) SPF-bred Wistar rats (Cpb: WU, Wistar random) were purchased from the TNO Central Institute for the Breeding of Laboratory Animals. They were housed singly in stainless-steel wire cages in Hazleton H 1000 inhalation chambers throughout the whole 13 week exposure period. The chambers were kept at 21-23°C, and 65-75% relative humidity, with an air-flow of approximately 40 m^3/hr. The rats were provided ad lib with unfluoridated tap-water and fed the Institute's stock diet for rats. During exposure the rats were deprived of food and water. After the exposure period those rats that were retained for the post-treatment periods were transferred from the inhalation chambers to an animal room and housed in wire-mesh, stainless-steel cages, five males and five females to a cage.

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:
The very small primary particles (<6-about 45 nm, calculated as the arithmetic mean of transmission electron micrograph magnifications) form agglomerates and aggregates. Because of the weakness of the bonds and the electrostatic charge of the particles it was impossible to determine the aerodynamic agglomerate/aggregate size distribution in the test atmospheres. The range of the geometric agglomerate/aggregate size distribution was 1 to about 120 µm for the amorphous silicas with maxima at about 10 and 100 µm. Aerosols were generated using the Institute's dust generators, which were composed of a dust feed mechanism and an atomizer operated by compressed air. The concentrations of test material in the test atmospheres were determined by gravimetry. Samples of the test atmospheres were drawn through glass fibre filters (Sartorius SM 13430). The filters were weighed just before and after sampling.
Analytical verification of doses or concentrations:
yes
Details on analytical verification of doses or concentrations:
The concentrations of test material in the test atmospheres were determined by gravimetry.
Duration of treatment / exposure:
13 weeks
Frequency of treatment:
6 hours per day, 5 days per week
Doses / concentrationsopen allclose all
Remarks:
Doses / Concentrations:
1 mg/m^3
Basis:
nominal conc.
Remarks:
Doses / Concentrations:
6 mg/m^3
Basis:
nominal conc.
Remarks:
Doses / Concentrations:
30 mg/m^3
Basis:
nominal conc.
No. of animals per sex per dose:
70 males and 70 females
Control animals:
yes, concurrent no treatment
Details on study design:
There were three test groups, one positive control group and one blank control group each containing 70 males and 70 females. The rats were exposed for 6 hr/day, 5 days/week for 13 weeks to 1, 6 or 30 mg/m^3. After the exposure period and 13, 26, 39 and 52 weeks after exposure 20, 10, 10, 10 and 20 rats/sex/group, respectively, were killed.
Positive control:
70 males and 70 female rats were exposed to 60 mg/m^3 of quartz.

Examinations

Observations and examinations performed and frequency:
Clinical observations were made daily. Body weights were recorded weekly during the exposure period and once every 4 weeks thereafter. Haematological and urinary parameters were determined in 10 rats/sex/ group at 13 week intervals. Haematological determinations include cell counts, haemoglobin content, packed cell volume, white-cell counts, differential white-cell counts, prothrombin time, thrombocytes, albumin, alkaline phosphatase, alanine aminotransferase, aspartate aminotransferase, urea, total protein, creatinine, total bilirubin, calcium, potassium, sodium, inorganic phosphate, cholesterol and glucose. Urinary parameters included appearance, volume, density and pH, analysis for protein, occult blood, glucose and ketones and microscopy of sediment.


Sacrifice and pathology:
From 50% of the rats killed at each stage the following tissues and organs were collected and preserved in 4% aqueous, neutral phosphate buffered formaldehyde solutions: lungs, mediastinal and hylus lymph nodes, trachea, larynx, adrenals, aorta, axillary lymph nodes, brain (brainstem, cerebrum and cerebellum), caecum, co-agulating glands, colon, duodenum, epididymides, eyes, heart, ileum, jejunum, kidneys, liver, mammary glands, mesenteric lymph nodes, nose (nasal cavity), oesophagus, ovaries, pancreas, parathyroids, parotid salivary glands, pharynx, pituitary, prostate, rectum, seminal vesicles, skeletal muscle (thigh), skin/subcutis (flank), spinal cord, spleen, sternum with bone marrow, stomach, sublingual salivary glands, testes, thymus (if identifiable), thyroid, urinary bladder and uterus. The lungs, adrenals, brain, heart, kidneys, liver, spleen, testes and thymus were weighed. The lungs were fixed by intratracheal inflation with the fixative under 10 cm water pressure. Tissues required for microscopic examination were embedded in Paraplast, sectioned at 5 µm and stained with haematoxylin and eosin. Histopathological examin- ation was carried out on all tissues and organs collected at the end of the exposure period, and on the respiratory tract and regional lymph nodes collected after 13, 26, 39 and 52 weeks of observation.
Other examinations:
The collagen and silicon content in the lungs and associated lymph node was also observed from the other 50% of rats killed at each stage.
Statistics:
Body weights were analysed by an analysis of co-variance (Cochran, 1957) followed by the Dunnett's multiple comparison test (Dunnett, 1955). Analysis of variance (Steel and Torrie, 1960) followed by the Dunnett's multiple comparison test were applied to the organ weights, and haematological and biochemical data. Incidences of histopathological changes were analysed by the Fisher exact probability test (Siegel 1956).

Results and discussion

Results of examinations

Clinical signs:
effects observed, treatment-related
Description (incidence and severity):
During exposure, there was a concentration-related increase in the respiration rate of animals exposed to the test substance. The respiration rate quickly returned to normal after exposure had ended.
Mortality:
mortality observed, treatment-related
Description (incidence):
During exposure, there was a concentration-related increase in the respiration rate of animals exposed to the test substance. The respiration rate quickly returned to normal after exposure had ended.
Body weight and weight changes:
effects observed, treatment-related
Description (incidence and severity):
At the end of the exposure period, body-weight gain was 5-10% lower in male rats exposed to 30 mg/m^3 of the test substance. Body weights returned to normal after the exposure period.
Food consumption and compound intake (if feeding study):
not examined
Description (incidence and severity):
Rats did not have access to food during exposure.
Food efficiency:
not examined
Description (incidence and severity):
Rats did not have access to food during exposure.
Water consumption and compound intake (if drinking water study):
not examined
Description (incidence and severity):
Rats did not have access to water during exposure.
Ophthalmological findings:
not examined
Haematological findings:
effects observed, treatment-related
Description (incidence and severity):
Red blood cell counts, haemoglobin content and packed cell volumes slightly increased in males exposed to 30 mg/m^3 of the test substance. After 13 weeks of non-exposure these parameters had returned to normal.
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
Description (incidence and severity):
At the end of the exposure period lung weight had increase. The increases were statistically significant in comparison with the controls, except in the 1 mg/m^3 exposure group. The increase was greater in males than in females.
Gross pathological findings:
effects observed, treatment-related
Description (incidence and severity):
Most of the rats which were killed at the end of exposure had swollen and spotted lungs with a spongy consistency and/or irregular surface and enlarged lung-associated lymph nodes. These effects had dissapeared after 26 weeks post-exposure.
Histopathological findings: non-neoplastic:
not examined
Histopathological findings: neoplastic:
not examined
Details on results:
The increase in lung weight decreased within 13 weeks post-exposure, with the exception of the 30 mg/m^3 exposure group, where the lung weight was higher than the controls 26 weeks post-exposure. Microscopic changes were mainly observed in the lungs. Changes in rats killed at the end of the exposure period comprised slight to severe accumulation of alveolar macrophages, intra-alveolar granular material, cellular debris and polymorphonuclear leucocytes in the alveolar spaces, and increased septal cellularity, seen as an increase in the number of type II pneumocytes and macrophages within the alveolar walls. In general, the most severe changes were found in rats exposed to Aerosil 200 and quartz (positive control), compared with the other amorphous silica substances tested (see the other study records for this endpoint).

Effect levels

Dose descriptor:
NOAEL
Remarks on result:
not determinable
Remarks:
no NOAEL identified

Target system / organ toxicity

Critical effects observed:
not specified

Any other information on results incl. tables

Granulomas, seen as aggregates of macrophage-like cells were scattered throughout the lungs of a few rats exposed to 30 mg /m3 of the test substance. Silicosis was observed in the positive control group i.e. the quartz treated group, but not in any of the groups exposed

Applicant's summary and conclusion

Conclusions:
The test substance was found to induce changes in the lungs after the 13 week exposure period e.g. granulomatous lesions. Silicosis was observed only in the positive control group (exposed to quartz). Although the test substance was very quickly cleared from the lungs and regional lymph nodes, the changes in these organs were only partly reversed during the post-exposure period in rats exposed to 30 mg/m^3.
Executive summary:

The chronic inhalation toxicity of the test substance was determined using male and female Wistar rats, which were exposed to concentrations of 1, 6 and 30 mg/m3 of pyrogenic silica 6 hours per day, five days per week for 13 weeks. Positive controls were exposed to 60 mg/m3 of crystalline silica (quartz), negative controls were exposed to clean air. Clinical signs, body weight, haematology, biochemistry, urinalyses, organ weights, retention of test material in the lungs and regional lymph nodes, collagen content of the lungs, and gross and microscopic pathology were determined in order to disclose possible adverse effects and to study the reversibility, stability or progression of the effects. The test substance induced increases in lung weight, pulmonary lesions and granulomatous lesions. Silicosis was observed only in quartz-exposed animals. Although the test substance was very quickly cleared from the lungs and regional lymph nodes, the changes in these organs were only partly reversed during the post-exposure period in rats exposed to 30 mg/m3. The results of this study revealed that only quartz induced progressive lesions in the lungs resembling silicotic nodules. The structure of both pyrogenic silica (silicon dioxide) and silicic acid, aluminium, calcium, sodium salt are macromolecular skeletons of silicon and oxygen. In the silicic acid, aluminium, calcium, sodium salt the metal cations bind ionically to negatively charged oxygens in the structure. The inclusion of the metal cations to the structure of pyrogenic silica (silcon dioxide) would not change the toxicity of the substance, or the behaviour of the substance once inhaled.