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Toxicological information

Repeated dose toxicity: inhalation

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Administrative data

Endpoint:
repeated dose toxicity: inhalation
Remarks:
combined repeated dose and carcinogenicity
Type of information:
migrated information: read-across from supporting substance (structural analogue or surrogate)
Adequacy of study:
weight of evidence
Reliability:
2 (reliable with restrictions)
Rationale for reliability incl. deficiencies:
other: Acceptable, well documented study report which meets basic scientific principles.
Cross-reference
Reason / purpose:
reference to same study

Data source

Reference
Reference Type:
publication
Title:
Effects of the inhalation of dusts from calcium silicate insulation materials in laboratory rats
Author:
Bolton R.E, Addison J, Davis J.M.E, Donaldson K, Jones A.D, Miller B.G. and A Wright
Year:
1986
Bibliographic source:
Env Res 39, 26-43

Materials and methods

Test guideline
Qualifier:
no guideline followed
Principles of method if other than guideline:
Male Wistar SPF rats were exposed to three different calcium silicate dusts at a concentration of 10 mg/m3 for 12 months, after which some animals were killed and the others were kept for their full lifespan. Detailed histopathological and haematological examinations were carried out after the animals died.
GLP compliance:
not specified
Limit test:
no

Test material

Reference
Name:
Unnamed
Type:
Constituent
Details on test material:
Three different calcium silicate insulation materials were selected for the study. The main component of the material was the 11 Å form of the mineral tobermorite (Ca5(OH)2Si6O16*4H2O.
Calcium carbonate and quartz are used in the commercial manufacture of tobermorite, and residues are normally found in the final products.
Other components present in the calcium silcate insulation materials tested were man made mineral fibers, cellulose fibers, amorphous silica and haematite.

The three types (A, B and C) of calcium silicate insulation material were supplied as standard product slabs, 50 mm thick, which were then sawn to smaller pieces. A cloud of airborne dust was generated using a rotating wire brush.

Test animals

Species:
rat
Strain:
Wistar
Sex:
male
Details on test animals and environmental conditions:
Wistar SPF rats of the AF/HAN strain were used.
TEST ANIMALS
- Source: no data
- Age at study initiation: no data
- Weight at study initiation: no data
- Fasting period before study: no data
- Housing: 48 animals were placed in each of the four inhalation chambers
- Diet (e.g. ad libitum): yes (standard pellet laboratory diet)
- Water (e.g. ad libitum): tap water
- Acclimation period: no data


ENVIRONMENTAL CONDITIONS: no data


IN-LIFE DATES: From: end of 12 month exposure period To: full lifespan, however the final surviving animals from all groups were killed 19 months after the end of the dustiness phase

Administration / exposure

Route of administration:
inhalation: dust
Type of inhalation exposure:
not specified
Vehicle:
other: unchanged (no vehicle)
Remarks on MMAD:
MMAD / GSD: no data
Details on inhalation exposure:
INHALATION:
A rotating wire brush was used for generation of a cloud of airborne dust containing a wide range of particle sizes. A jet of compressed air was used to carry the dust into the chamber ventilation air flow.

Analytical verification of doses or concentrations:
yes
Details on analytical verification of doses or concentrations:

Airborne sust samples were taken regularly from each chamber throughout the exposure phase. These were used to provide estimates of the total and respirable mass concentrations, size distributions and the mineral composition of the dusts.
Duration of treatment / exposure:
Inhalation: 7h/day
Frequency of treatment:
Inhalation: 5 days/week for a total of 224 days over an elapsed period of 12 months.
Doses / concentrations
Remarks:
Doses / Concentrations:
inhalation: 10 mg/m3
Basis:
analytical conc.
No. of animals per sex per dose:
Inhalation: 48 males per substanse (3 test substances + control, altogether 192 animals)
Control animals:
yes, concurrent no treatment
Details on study design:
INHALATION:
- Dose selection rationale: The dose of 10 mg/m3 of respirable dust was selected to provide a direct comparison with the known effects of prolonged exposure to similar concentrations of asbestos dusts.

Positive control:
No

Examinations

Observations and examinations performed and frequency:
CAGE SIDE OBSERVATIONS: No data


DETAILED CLINICAL OBSERVATIONS: No data


BODY WEIGHT: Yes
- Time schedule for examinations: monthly


FOOD EFFICIENCY:
No data


WATER CONSUMPTION AND COMPOUND INTAKE (if drinking water study): No data


OPHTHALMOSCOPIC EXAMINATION: No data

HAEMATOLOGY: Yes
- Time schedule for collection of blood: 5 days before the start of inhalation and 3 days after the end of the 12 month exposure. period when 12 animals/group were killed.
- Anaesthetic used for blood collection: No data
- Animals fasted: No data
- How many animals: 12 / group, 48 in total
- Parameters checked : haemoglobin and estimation of packed cell volume after hematocrit centrifugation. A more detailed hematological examination was undertaken 12 animals. At the end of the 12 month eposure 12 animals/group (48 rats in total) were killed and haematological analyses were carried out (table 1).


CLINICAL CHEMISTRY: / No data


URINALYSIS: No data


NEUROBEHAVIOURAL EXAMINATION: No data

OTHER: LUNG DUST ANALYSIS
- lungs were available from 6 of the 12 animals/group killed at the end of the exposure period. One lung/animal was assessed
-
Sacrifice and pathology:
GROSS PATHOLOGY: No data

HISTOPATHOLOGY: Yes
- tissues were taken from all major organs (no details given)
- speciemes were fixed in 10% formal saline and embedded in paraffin wax
- lungs were fixed by instillation prior to excision from the thoracic cavity
- hematoxylin and eosin stainings were routinely used
- for the study of pulmonary fibrosis Van Giesons's stain for collagen or Gordona and Sweet's reticulin stain were used
Statistics:
No data

Results and discussion

Results of examinations

Clinical signs:
no effects observed
Mortality:
no mortality observed
Body weight and weight changes:
no effects observed
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:
not examined
Urinalysis findings:
not examined
Behaviour (functional findings):
not examined
Organ weight findings including organ / body weight ratios:
no effects observed
Gross pathological findings:
no effects observed
Histopathological findings: non-neoplastic:
effects observed, treatment-related
Histopathological findings: neoplastic:
effects observed, treatment-related
Details on results:
HAEMATOLOGY: All the examined blood parameters fell within the normal ranges. The only effect was seen related to absolute number of white blood cells, which markedly increased in the dust exposed animal.

HISTOPATHOLOGY: NON-NEOPLASTIC
- All animals treated with calcium silicate materials showed dust-containing macrophages scattered throughout the alveolar regions of the lung, particularly close to the respiratory bronchioles. The frequency of dust-containing macrophages declined substantially after the end of the exposure period.
- Small amounts of interstitial fibrosis were found in 5 control and 13 dusted animals that had survived more than 10 months after the end of the exposure period.
- Animals exposed to sample A tended to have peribronchial areas of fibrosis not found in any of the other groups.
- The mediastinal lymph nodes from all dusted animals were found to contain some particulate material. This amount appeared to increase with time postexposure. Animals exposed to sample A had more extensive changes than the other groups.

OTHER FINDINGS
The lung dust analysis revealed that the lung residues of group C were very similar to those of the controls. The group B residues contained higher amounts of amorphous silica, but no other recognizable minerals. The group A residues contained a mixture of amorphous silica and quartz.

NEOPLASTIC EFFECTS: see Carcinogenicity

Effect levels

Dose descriptor:
NOAEC
Effect level:
ca. 10 mg/m³ air (analytical)
Sex:
male
Basis for effect level:
other: No signs of repeated dose toxicity

Target system / organ toxicity

Critical effects observed:
not specified

Any other information on results incl. tables

The peribronchial nodules found in animals exposed to sample A were the only pulmonary fibrotic lesions that appeared to be directly related to calcium silicate material exposure. However, these effetcs were supposed to be related to the detected quartz content of the lung dust after exposure to sample A.

The haematological information, indicating no differences between controls and exposed animals in most of the blood parameters, suggest that dust inhalation did not cause any marked systemic toxicity. However, the absolute numbers of white cells were significantly higher in the exposed groups than in the control group. Pulmonary dust accumulation is known to increase the number of neutrophils and macrophages, but there is no evidence that this alone produces changed levels in the numbers of circulating white blood cells. Anyhow this reaction was not considered to be serious, and the total levels were within the normal published range for rats.

Applicant's summary and conclusion

Conclusions:
Repeated exposure to calcium silicate dusts did not cause any signs of systemic toxicity. One of the substances tested caused peribronchial nodules, but these were supposed to be related to the higher quartz content of that specific substance (sample A).
Executive summary:

Male Wistar SPF rats were exposed to three different calcium silicate dusts at a concentration of 10 mg/m3 for 12 months, after which some animals were killed and the others were kept for their full lifespan. Detailed histopathological and haematological examinations were carried out after the animals died.

The haematological information, indicating no differences between controls and exposed animals in most of the blood parameters, suggest that dust inhalation did not cause any marked systemic toxicity.

Peribronchial nodules were found in animals exposed to sample A, but these effetcs were supposed to be related to the detected quartz content of the lung dust after exposure to sample A.

The absolute numbers of white cells were significantly higher in the exposed groups than in the control group. Pulmonary dust accumulation is known to increase the number of neutrophils and macrophages, but there is no evidence that this alone produces changed levels in the numbers of circulating white blood cells. Anyhow this reaction was not considered to be serious, and the total levels were within the normal published range for rats.