Zeolite, cuboidal, crystalline, synthetic, non-fibrous

Repeated dose toxicity: inhalation

Administrative data

Endpoint:

chronic toxicity: inhalation

Type of information:

experimental study

Adequacy of study:

key study

Study period:

Feb. 28, 1976 - Feb. 8, 1978

Reliability:

2 (reliable with restrictions)

Rationale for reliability incl. deficiencies:

study well documented, meets generally accepted scientific principles, acceptable for assessment

Remarks:

But the results of this study have to be considered with some caution due to chronic pneumonia that affected almost all animals.

Data source

Reference

Reference 1

Reference Type:

study report

Title:

Unnamed

Year:

1979

Report date:

1979

Reference 2

Reference Type:

publication

Title:

Zeolithe A - A Phosphate Substitute for Detergents: Toxicological Investigation

Author:

Gloxhuber et al.

Year:

1982

Bibliographic source:

Fd. Chem Toxic. Vol. 21, No. 2, pp. 209-220

Report date:

1982

Reference 3

Reference Type:

study report

Title:

Unnamed

Year:

1977

Report date:

1977

Reference 4

Reference Type:

study report

Title:

Unnamed

Year:

1978

Report date:

1978

Reference 5

Reference Type:

study report

Title:

Unnamed

Year:

1979

Report date:

1979

Materials and methods

Test guideline

Qualifier:

no guideline followed

Principles of method if other than guideline:

chronic inhalation study in rats: 1 dose and 1 control group (and one additional dose and one additional control group after 14 months), 3 whole body inhalations per week.
Due to chronic pneumonia that affected almost all animals about the 20th month of the experiment, the final sacrifice was performed after 22 months.

GLP compliance:

no

Limit test:

yes

Test material

Test material information

Constituent 1

Reference substance name:

Zeolite, cuboidal, crystalline, synthetic, non-fibrous

EC Number:

930-915-9

Cas Number:

1318-02-1

Molecular formula:

M2/nO • Al2O3 • ySiO2 • wH2O (n is the valency of the cation M, predominantly Na, y can range from 0.64 to 8.8, and w is the number of water molecules (general formula) Na: 1.34 - 24.02%, Al: 2.20 - 39.51%, Si: 15.52 - 68.64% (general composition); additionally, depending on the water quality: Ca, Mg and K might be present below 6%

IUPAC Name:

Zeolite, cuboidal, crystalline, synthetic, non-fibrous

Test material form:

solid: particulate/powder

Remarks:

no surface treatment

Specific details on test material used for the study:

SASIL (A Zeolite)
charge F-325, fine white powder, particle size to over 80% between 1 and 6 µm.

Test animals

Species:

rat

Strain:

Wistar

Sex:

male/female

Details on test animals or test system and environmental conditions:

- HAN 67 SPF Wistar rats with an average body weight of 139-154 g (main group) and 125-130 g (additional group) at the start of the experiment
- keeping: conventionally under daylight
- feed: ALTROMIN 1324 and water ad libitim. During inhalations food and water were withdrawn from the animals.

Administration / exposure

Route of administration:

inhalation: dust

Type of inhalation exposure:

whole body

Remarks:

inhalation chamber

Vehicle:

air

Analytical verification of doses or concentrations:

yes

Details on analytical verification of doses or concentrations:

gravimetric measurements of the amount of dust and dose

Duration of treatment / exposure:

main groups: 22 months
additional groups: 8 months

Frequency of treatment:

on Mondays, Wednesdays and Fridays for 5 hours each

Doses / concentrations

Dose / conc.:

20 mg/m³ air (nominal)

No. of animals per sex per dose:

15 in treatment and control groups (main groups for 22 months)
15 males and 10 females in treatment and control groups (additional groups for 8 months)

Control animals:

yes, concurrent vehicle

Details on study design:

inhalation chambers: 24°C; relative humidity 55%; in wire cages; 5 test animals or 5 control animals per cage.

Examinations

Observations and examinations performed and frequency:

daily observation
weighted once per week until week 23, thereafter every fortnight, and beginning with the 32nd week of the experiment once per month

Sacrifice and pathology:

All rats were dissected at the end of the experiment and the internal organs, especially the target organs, histologically examined. 2 male controls were also microbiologically examined due to infectious disease of airways of all rats.
Due to chronic pneumonia that attacked about the 20th month of the experiment almost all animals, the final sacrifice was performed already after 22 months.

Results and discussion

Results of examinations

Clinical signs:

effects observed, non-treatment-related

Description (incidence and severity):

10 months after the start of the experiment, the first cases of respiratory diseases were observed. The affected rats began to sneeze briefly,
there were convulsions of coughing with whistling sounds in the expirium. The animals lost weight and sat apathetically in a crouching position in the cages. After occurrence of the marked dyspnea some rats developed a reddish discharge from the nose. These observations concerned both the test animals and the controls evenly. Reinforced hygiene measures did not help. The chronic pneumonia attacked about the 20th month of the experiment almost all animals

Mortality:

mortality observed, non-treatment-related

Description (incidence):

Mortality occured in treated and control animals.

Body weight and weight changes:

effects observed, non-treatment-related

Description (incidence and severity):

The average body weights of the two groups of animals were more or less parallel during the experiment, and taking the age of the animals into account
it was without any special features. The slight deviations from the 11th month onward were not significant and did not occur substance-specific, but rather due to the moribund state of some rats.

Food consumption and compound intake (if feeding study):

effects observed, non-treatment-related

Description (incidence and severity):

After taking the animals out of the chambers and they were transferred to their stay cages, the feed consumption and water consumption increased for about 2 hours, obsered both in the experimental and control animals.

Food efficiency:

not examined

Water consumption and compound intake (if drinking water study):

effects observed, non-treatment-related

Description (incidence and severity):

After taking the animals out of the chambers and they were transferred to their stay cages, the feed consumption and water consumption increased for about 2 hours, obsered both in the experimental and control animals.

Ophthalmological findings:

not examined

Haematological findings:

not examined

Clinical biochemistry findings:

not examined

Urinalysis findings:

not examined

Behaviour (functional findings):

no effects observed

Description (incidence and severity):

The animals calmed down quickly after onset of inhalation and lay isolated, rarely in small groups, with normal breathing frequency, in the cages. The rats did not show aggressiveness. There were no abnormalities with regard to excrement or urine output. The experimental animals cleaned themselves more often than the controls and closed their eyes during the inhalation time and also in the in the activity phase more often (avoidance of conjunctival foreign body reactions due to SASIL).

Immunological findings:

not examined

Organ weight findings including organ / body weight ratios:

not examined

Gross pathological findings:

effects observed, non-treatment-related

Description (incidence and severity):

The rats showed macroscopically almost without exception bronchiectasis, purulent slimy exudates in the trachea and in the large
bronchial branches. Some of the lungs were atelectatic bloated, the individual gray-red lung lobes partially to completely hepatized. The mediastinal lymph nodes were mostly enlarged and dark to black.

Neuropathological findings:

not examined

Histopathological findings: non-neoplastic:

effects observed, non-treatment-related

Description (incidence and severity):

All animals examined, i.e. controls and experimental animals showed bronchopneumonia in various stages corresponding to the picture of chronic murine pneumonia.
But there were no histological indications either for fibrogenic, silicogenic or carcinogenic effects provoked by SASIL.

Histopathological findings: neoplastic:

effects observed, non-treatment-related

Description (incidence and severity):

Different kinds of tumors were observed in five treated and in five control animals.
There were no histological indications either for fibrogenic, silicogenic or carcinogenic effects provoked by SASIL.

Description (incidence and severity):

The test substance ws deposited in alveolar epihelias near the alveolar septum, in alveolar macrophages or alveolar epithelia in the alveoli, or in macrophages in the perivascular or peribronchial lymph sheaths. In the further consequence the substance was also deposited in the paracortical area
of the mediastinal lymph node.

Details on results:

A histopathological examination of some rats came to the following conclusion:
"The findings suggest a soluble dust, the initially clear fibrotic reaction of which was in regression.
In the periportal and mediastinal lymph nodes, individual and groups of macrophages were found that contained the material (SASIL). The dust centers showed no fibrotic tendency after the test period. They were fitted into the local network of reticular fibers. An increase in reticular and collagen fibers could certainly be ruled out. Thus, the material behaved like inert dust in the lymph nodes.

Another histopathological examination of 6 Sasil-treated and 4 control rats concluded that after 22 months of administration the inhaled Sasil did not cause tumors in the six experimental animals of the treated group and did not produce fibrosis in the lungs and regional mediastinal lymph nodes.

Effect levels

Dose descriptor:

NOAEL

Effect level:

>= 20 mg/m³ air (nominal)

Sex:

male/female

Basis for effect level:

histopathology: neoplastic

histopathology: non-neoplastic

Target system / organ toxicity

Critical effects observed:

yes

Lowest effective dose / conc.:

20 mg/m³ air (nominal)

System:

respiratory system: lower respiratory tract

Organ:

lungs

Treatment related:

no

Dose response relationship:

no

Relevant for humans:

no

Any other information on results incl. tables

The results of this inhalation experiment allowed to conclude that the test substance after chronic inhalation in the lungs was neither silicogenic nor fibrogenic. No tumorous changes were found pathologically or histologically in the respiratory tract or in other associated locations observed. The quality of those tumors observed and their temporal occurrence gave no indications of a carcinogenic activity of the test substance.

Applicant's summary and conclusion

Conclusions:

The experiment had to be interrupted after 22 months of inhalation, since the rats developed chronic murine pneumonia.
But the findings suggested that SASIL neither produces fibrogenic nor carcinogenic effects.

Executive summary:

The aim of this investigation was to determine whether SASIL produces fibrotic or silicotic changes after repeated inhalation, and if it might produce tumors. For this purpose main groups of 15 male and 15 female Wistar rats were exposed to an aerosol of zeolite A at an average concentration of 20 mg/m³ for five hours a day, three days a week for a schedulded time period of 24 months. The control group received pure air. One additional dose group was dosed beginning after the 14th month of the experiment. Due to chronic pneumonia that affected almost all animals about the 20th month of the experiment, the final sacrifice was performed already after 22 months for the main groups (i.e. 8 months of administration for the additional group).

The results of this inhalation experiment allowed to conclude that the test substance after chronic inhalation in the lungs was neither silicogenic nor fibrogenic. No tumorous changes were found pathologically or histologically in the respiratory tract or in other associated locations observed.