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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: Comparable to guideline study with acceptable restrictions.

Data source

Reference
Reference Type:
publication
Title:
Subchronic inhalation toxicity of amorphous silicas and quartz dust in rats.
Author:
Reuzel, P.G.J. et al.
Year:
1991
Bibliographic source:
Fd Chem Toxic 29: 341-354

Materials and methods

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

Test material

Reference
Name:
Unnamed
Type:
Constituent
Details on test material:
- Name of test material (as cited in study report): Aerosil 200
- Analytical purity: 99.8 % SiO2

Test animals

Species:
rat
Strain:
Wistar
Sex:
male/female

Administration / exposure

Route of administration:
inhalation: aerosol
Type of inhalation exposure:
whole body
Vehicle:
other: unchanged (no vehicle)
Remarks on MMAD:
MMAD / GSD: Not given; The very small primary particles (<6-approx. 45 nm, calculated as the arithmetic mean of transmission electron micrograph magnification) form agglomerates and aggregates. Because of the weakness of bonds and the electrostatatic charge of particles, it was impossible to determine the aerodynamic agglomerate/aggreagate size distribution in the test atmosphere. The range of the geometric agglomerate/aggregate size distribution was 1 to about 120 μm for the amorphous silicas with a maximum at approx. 10 µm.
Details on inhalation exposure:
Inhalation chamber: Single housing during exposure. Dust generator with compressed air atomizer producing an aerosol which was mixed with air to achieve desired silica levels. Silica concentration was measured gravimetrically.
Analytical verification of doses or concentrations:
yes
Details on analytical verification of doses or concentrations:
mean concentrations were determined by gravimetry
Duration of treatment / exposure:
13 weeks
Frequency of treatment:
6 hours/day, 5 days/week
Doses / concentrationsopen allclose all
Remarks:
Doses / Concentrations:
1.3, 5.9 or 31 mg/m3
Basis:
analytical conc.
Remarks:
Doses / Concentrations:
1, 6 or 30 mg/m3
Basis:
nominal conc.
No. of animals per sex per dose:
not specified
Control animals:
yes

Examinations

Observations and examinations performed and frequency:
see "Any other informations on materials and methods"
Sacrifice and pathology:
GROSS PATHOLOGY: Yes
HISTOPATHOLOGY: Yes

Results and discussion

Results of examinations

Clinical signs:
no effects observed
Mortality:
no mortality observed
Body weight and weight changes:
effects observed, treatment-related
Food consumption and compound intake (if feeding study):
not specified
Food efficiency:
not specified
Water consumption and compound intake (if drinking water study):
not specified
Ophthalmological findings:
not examined
Haematological findings:
effects observed, treatment-related
Clinical biochemistry findings:
effects observed, treatment-related
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

Effect levels

open allclose all
Dose descriptor:
NOAEC
Effect level:
1.3 mg/m³ air (analytical)
Sex:
not specified
Dose descriptor:
LOAEC
Effect level:
5.9 mg/m³ air (analytical)
Sex:
not specified
Dose descriptor:
NOEC
Effect level:
< 1.3 mg/m³ air (analytical)
Sex:
not specified

Target system / organ toxicity

Critical effects observed:
not specified

Any other information on results incl. tables

CLINICAL OBSERVATION

The respiration rate showed a concentration-related increase when compared to the controls (only qualitatively evaluated); the body-weight gain was slightly depressed.

HAEMATOLOGY / BLOOD CHEMISTRY

Red blood cell count and hemoglobin were statistically higher in males exposed to 30 mg/m3, but not in females.

White blood cell count due to increases in the numbers of neutrophilic leukocytes were elevated in both males and females of the 6- and 30-mg groups, but concentration-response relationship was poor. After 3 months recovery, these blood parameters normalized.

Blood chemistry and urine analysis were without significant findings.

PATHOLOGY

At autopsy after exposure, swollen and spotted lungs and enlarged mediastinal lymph nodes were observed, the degree of severity being treatment-related. At 6 and 30 mg/m3, the lung weights and the collagen content in the lungs were clearly increased, most pronounced in males showing this effect also at the 1-mg/m3 level. The above-mentioned effects gradually subsided after the exposure period, but in males exposed to 6 and 30 mg/m3 the collagen content was still above control values at the end of the study.

SILICA DEPOSITION

Silica could be detected in lungs only in relatively small amounts at the end of the exposure period, on the average 0.2 mg in all animals of the 30-mg groups. Only one male exposed to 30 mg/m3 showed a small amount of silica in the regional lymph node. During the post-exposure observation period, no silica could be recovered from any animal.

HISTOLOGY

The microscopic examination at the end of exposure period showed accumulation of alveolar macrophages and granular material, cellular debris, polymorphonuclear leucocytes, increased septal cellularity, alveolar bronchialisation, focal interstitial fibrosis, cholesterol clefts and granulomalike lesions in the lung. The granuloma-like lesions did not show fibroblastic activity and hyalinization and regressed during recovery. Accumulation of macrophages was seen in the mediastinal lymph node (disappeared after wk 39 post-exposure). Treatment-related, microscopic changes in the nasal region were occasionally found at the end of exposure period such as focal necrosis slight atrophy of the olfactory epithelium. All types of pulmonary lesions were more marked in males than in females. A level of 1.3 mg/m3 induced only slight changes, which generally recovered quickly, therefore the NOEL is lower than 1.3 mg/m3. During the post-exposure observation period the changes in lungs and lymph nodes recovered totally or partly. Interstitial fibrosis was not noted directly after the exposure period, but appeared with a delay, for the first time observed after 13 wks postexposure: increasing incidence especially in 30-mg rats, and a few in the 6-mg group (p. 44), but decreased in severity and frequency until the end of the study.

Applicant's summary and conclusion