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Diss Factsheets

Toxicological information

Repeated dose toxicity: other routes

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Administrative data

Endpoint:
repeated dose toxicity: other route
Remarks:
combined repeated dose and carcinogenicity
Type of information:
migrated information: read-across based on grouping of substances (category approach)
Adequacy of study:
key study
Reliability:
2 (reliable with restrictions)
Rationale for reliability incl. deficiencies:
other: Reliable with restrictions.

Data source

Referenceopen allclose all

Reference Type:
study report
Title:
Unnamed
Year:
1992
Reference Type:
study report
Title:
Unnamed
Year:
1991

Materials and methods

Test guideline
Qualifier:
according to guideline
Guideline:
other:
Principles of method if other than guideline:
Method:Twenty hamsters received intratracheal administration of man-made calcium sulfate fiber (D = 1.0 microns, L = 17.8 microns) for 5 weeks, after which they were observed for 2 years for tumor development.
GLP compliance:
not specified
Limit test:
yes

Test material

Constituent 1
Reference substance name:
Calcium sulfate
EC Number:
231-900-3
EC Name:
Calcium sulfate
Cas Number:
7778-18-9
IUPAC Name:
calcium sulfate
Details on test material:
- Name of test material: Calcium sulfate
- CAS number :7778-18-9
- EC Number: 231-900-3
- Molecular formula (if other than submission substance): CaSO4
- Molecular weight (if other than submission substance): 136.14 g/mol
- Smiles notation (if other than submission substance): [Ca+2].[O-]S([O-])(=O)=O
-InChl (if other than submission substance):=1/Ca.H2O4S/c;1-5(2,3)4/h;(H2,1,2,3,4)/q+2;/p-2
- Structural formula attached as image file (if other than submission substance): see Fig.1
- Substance type:inorganic
- Physical state:solid
- Appearance: white solid
- Density -2.96 g/cm3)
- Melting point-1460 °C
- Solubility in water - 2.1 g/L (20 °C
- Synonyms: Plaster of Paris, Drierite,, Gypsum

Test animals

Species:
hamster, Syrian
Strain:
other: hamster, Syrian
Sex:
female
Details on test animals or test system and environmental conditions:
Species/strain: Syrian hamster
Sex: Female
Number of animals: 20 females/group
Age/Weight at study initiation: Age not indicated; 80 g
ADMINISTRATION / EXPOSURE
Route of administration: intratracheal intubation
Exposure period: 5 weeks
Frequency of treatment: once weekly
Post-exposure observation period: 2 years after the first administration.
Doses: total dose10 mg/animal (0.20 ml fiber suspension and 0.3 ml air per dose).
Control group: yes, untreated
Particle size: mean D 1.0 µm, L 17.8 µm (respirable)
CLINICAL OBSERVATIONS AND FREQUENCY
- Mortality/clinical signs: frequency not indicated
- Body weight: frequency not indicated
PATHOLOGICAL EXAMINATIONS
- Macroscopic examinations: all moribund animals and surviving animals at termination of the study were subjected to routine autopsies.
- Microscopic examinations: all organs were fixed and subjected to histopathological examinations using hematoxylin eosin stain and other special stains.

Administration / exposure

Route of administration:
other: Intratracheally
Vehicle:
unchanged (no vehicle)
Analytical verification of doses or concentrations:
not specified
Duration of treatment / exposure:
5 weeks
Frequency of treatment:
Frequency of treatment:2 mg/animal each week for 5 weeks
Doses / concentrations
Remarks:
Doses / Concentrations:
Dose:10 mg/animal total
No. of animals per sex per dose:
twenty female animals
Control animals:
yes, concurrent no treatment
Details on study design:
ADMINISTRATION / EXPOSURE
Route of administration: intratracheal intubation
Exposure period: 5 weeks
Frequency of treatment: once weekly
Post-exposure observation period: 2 years after the first administration.
Doses: total dose10 mg/animal (0.20 ml fiber suspension and 0.3 ml air per dose).
Control group: yes, untreated
Particle size: mean D 1.0 µm, L 17.8 µm (respirable)
CLINICAL OBSERVATIONS AND FREQUENCY
- Mortality/clinical signs: frequency not indicated
- Body weight: frequency not indicated
PATHOLOGICAL EXAMINATIONS
- Macroscopic examinations: all moribund animals and surviving animals at termination of the study were subjected to routine autopsies.
- Microscopic examinations: all organs were fixed and subjected to histopathological examinations using hematoxylin eosin stain and other special stains.

Examinations

Observations and examinations performed and frequency:
Twenty hamsters received intratracheal administration of man-made calcium sulfate fiber (D = 1.0 microns, L = 17.8 microns) for 5 weeks, after which they were observed for 2 years for tumor development.
Three out of twenty animals were found to have tumors. Chronic alveolitis was also seen with macrophage and neutrophile aggregation and endemateous thickening of the alveolar walls. Changes appeared too mild to foster a pneumoconiosis such as asbestos.
Sacrifice and pathology:
PATHOLOGICAL EXAMINATIONS
- Macroscopic examinations: all moribund animals and surviving animals at termination of the study were subjected to routine autopsies.
- Microscopic examinations: all organs were fixed and subjected to histopathological examinations using hematoxylin eosin stain and other special stains.

Results and discussion

Results of examinations

Clinical signs:
no effects observed
Description (incidence and severity):
No acute deaths were noted after the administrations of fibers.
Mortality:
no mortality observed
Description (incidence):
No acute deaths were noted after the administrations of fibers.
Body weight and weight changes:
no effects observed
Description (incidence and severity):
comparable between the groups.
Food consumption and compound intake (if feeding study):
no effects observed
Description (incidence and severity):
comparable between the groups.
Food efficiency:
no effects observed
Description (incidence and severity):
comparable between the groups.
Water consumption and compound intake (if drinking water study):
no effects observed
Description (incidence and severity):
comparable between the groups.
Ophthalmological findings:
effects observed, treatment-related
Description (incidence and severity):
Three out of twenty animals were found to have tumors. Chronic alveolitis was also seen with macrophage and neutrophile aggregation and endemateous thickening of the alveolar walls.
Haematological findings:
effects observed, treatment-related
Description (incidence and severity):
Three out of twenty animals were found to have tumors. Chronic alveolitis was also seen with macrophage and neutrophile aggregation and endemateous thickening of the alveolar walls.
Clinical biochemistry findings:
effects observed, treatment-related
Description (incidence and severity):
Three out of twenty animals were found to have tumors. Chronic alveolitis was also seen with macrophage and neutrophile aggregation and endemateous thickening of the alveolar walls.
Urinalysis findings:
not examined
Behaviour (functional findings):
effects observed, treatment-related
Description (incidence and severity):
Three out of twenty animals were found to have tumors. Chronic alveolitis was also seen with macrophage and neutrophile aggregation and endemateous thickening of the alveolar walls.
Organ weight findings including organ / body weight ratios:
no effects observed
Description (incidence and severity):
comparable between the groups.
Gross pathological findings:
effects observed, treatment-related
Description (incidence and severity):
Three out of twenty animals were found to have tumors.
Histopathological findings: non-neoplastic:
effects observed, treatment-related
Description (incidence and severity):
Chronic alveolitis was  seen with macrophage and neutrophile aggregation and endemateous thickening of the alveolar walls 
Histopathological findings: neoplastic:
effects observed, treatment-related
Description (incidence and severity):
Chronic alveolitis was  seen with macrophage and neutrophile aggregation and endemateous thickening of the alveolar walls 
Details on results:
- Mortality and time to death: No acute deaths were noted after the administrations of fibers. Mortality was comparable between the groups.
- Body weight gain: comparable between the groups.
PATHOLOGICAL EXAMINATIONS
The number of tumor bearing hamsters in the calcium sulfate group was 3. Tumors were located in the rib (2; unspecified cell types), heart (1; anaplastic carcinoma) and kidney (1; dark cell carcinoma). In addition, chronic alveolitis with macrophage aggregation, and edematous thickening of alveolar walls with alveolitis was noted.
LOAEL:10 mg/kg bw

Effect levels

Dose descriptor:
LOAEL
Effect level:
10 mg/kg bw (total dose)
Based on:
test mat.
Sex:
female
Basis for effect level:
other: see 'Remark'

Target system / organ toxicity

Critical effects observed:
not specified

Applicant's summary and conclusion

Conclusions:
The number of tumor bearing hamsters in the calcium sulfate group was 3. Tumors were located in the rib (2; unspecified cell types), heart (1; anaplastic carcinoma) and kidney (1; dark cell carcinoma). In addition, chronic alveolitis with macrophage aggregation, and edematous thickening of alveolar walls with alveolitis was noted. LOAEL:10 mg/kg bw.