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Repeated dose toxicity: inhalation

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Administrative data

sub-chronic toxicity: inhalation
Type of information:
migrated information: read-across based on grouping of substances (category approach)
Adequacy of study:
key study
Study period:
2 (reliable with restrictions)
Rationale for reliability incl. deficiencies:
other: comparable to guideline study with acceptable restrictions
Reason / purpose for cross-reference:
reference to same study

Data source

Referenceopen allclose all

Reference Type:
study report
Report date:
Reference Type:
Subchronic inhalation toxicity of amorphous silicas and quartz dust in rats
Reuzel, P.G.J.; Bruijntjes, J.P.; Feron, V.J.; Woutersen, R.A.
Bibliographic source:
Fd. Chem. Toxic., 29, 341-354

Materials and methods

Test guideline
according to guideline
OECD Guideline 413 (Subchronic Inhalation Toxicity: 90-Day Study)
Principles of method if other than guideline:
Comparative study including Aerosil R974 (fumed, hydrophobic), Sipernat 22S (precipitated, hydrophil) as well as quartz (crystalline). Special modifications as compared with standard study: Examinations primarily focused upon changes in the lung, respiratory tract, and regional (hilus and mediastial) lymph nodes, including collagen and silica determinations in the lung. Post-exposure recovery period up to one year was enclosed: 10 m / 10 f animals per group sacrificed after 13 wks, 50 m / 50 f animals per group were kept for a recovery period of at most 52 wks (13, 26, 39, and 52 wks). Haematology and urinalysis were conducted 5x periodically up to week 65 (including recovery). Blood chemistry was carried out group-wise on autopsy after defined intervals up to week 66 (including recovery).
GLP compliance:
Limit test:

Test material

Constituent 1
Reference substance name:
EC Number:
Cas Number:
Details on test material:
- Name of test material (as cited in study report): Aerosil 200
- Analytical purity: 99.8 % SiO2

Test animals


Administration / exposure

Route of administration:
inhalation: aerosol
Type of inhalation exposure:
whole body
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)(comp. Degussa AG 1987, part I, p. 62) 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 (Degussa 1987, p. 13).
Analytical verification of doses or concentrations:
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 / concentrations
Doses / Concentrations:
1.3, 5.9 or 31 mg/m3
analytical conc.
No. of animals per sex per dose:
no data
Control animals:

Results and discussion

Results of examinations

Clinical signs:
no effects observed
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:
Effect level:
1.3 mg/m³ air (analytical)
not specified
Dose descriptor:
Effect level:
5.9 mg/m³ air (analytical)
not specified
Dose descriptor:
Effect level:
1.3 mg/m³ air (analytical)
not specified

Target system / organ toxicity

Critical effects observed:
not specified

Any other information on results incl. tables


The respiration rate showed a concentration-related increase when compared to the controls (only qualitatively evaluated); the body-weight gain was slightly depressed. (Degussa 1987, p. 27)


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.


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 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.


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 (p. 51).

Applicant's summary and conclusion