Zeolite, cuboidal, crystalline, synthetic, non-fibrous

Carcinogenicity

Description of key information

No indication of carcinogenicity was found in any reliable study.

 

Oral

There is only one study available in a type A zeolite. Here, in all doses groups, tumor rates and tumor spectra were within normal limits for the laboratory rat of the Wistar strain. Furthermore, neither the individual findings nor the summation showed a dose-dependent accumulation of tumorous changes. Therefore, the test substance was in the dosage of 10 - 1000 ppm for rats under the experimental conditions neither carcinogenic nor did it induce hyperplastic reactions. 

 

Inhalation

Again, only one study in a type A zeolite is available. 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. The NOAEL was equal or greater than 20 mg/m³.

 

Other routes

There are two reliable studies in the intraperitoneal route. In the first, the carcinogenicity of a type A zeolite was studied in the peritoneum of 586 BALBlC male mice after a single intraperitoneal or intraabdominal wall injection. After single application the test substance did not show carcinogenicity within 23 months.
In another study which allowed rats to live out their lives until they showed signs of distress at which point they were sacrificed, it was concluded that two forms of zeolite and sodium aluminosilicate were not carcinogenic in the rat and that they did not induce mesotheliomas following intrapleural injection.

Key value for chemical safety assessment

Carcinogenicity: via oral route

Link to relevant study records

Reference

Endpoint:

carcinogenicity: oral

Type of information:

experimental study

Adequacy of study:

supporting study

Reliability:

2 (reliable with restrictions)

Rationale for reliability incl. deficiencies:

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

Qualifier:

no guideline followed

Principles of method if other than guideline:

combined chronic toxicity and carcinogenicity study, substance administered orally in the diet, 3 main and 3 satellite group plus controls, up to 104 weeks of treatment

GLP compliance:

not specified

Specific details on test material used for the study:

Sasil (A Zeolite)

Species:

rat

Strain:

Wistar

Sex:

male/female

Details on test animals or test system and environmental conditions:

Wistar rat of the MuRa SPF 67 strain, c. 5-6 weeks old
Total number of rats at the start of the experiment: 520
Acclimatisation time: 1 week to 10 days
Temperature: 21 */- 2 °C
Relative humidity: 50 +/- 5 %
Light/dark: 14/10 h
Diet: Altromin #1324 (ad libitum)

Route of administration:

oral: feed

Analytical verification of doses or concentrations:

yes

Details on analytical verification of doses or concentrations:

There was a good correlation between dosages in the average substance intake during the experiment, as follows:
Group 2: 0.62 (males) and 0.65 (females) mg/kg bw/d
Group 3: 6.00 (males) and 6.53 (females) mg/kg bw/d
Group 4: 58.47 (males) and 62.15 (females) mg/kg bw/d

But the determination of Sasil in rat feed proved to be very problematic due to the high content of aluminium and silicon in the normal rat diet, and therefore seemed, if at all, only feasible at the dosage of 1000 ppm Sasil for rat food.

Duration of treatment / exposure:

up to 104 weeks

Frequency of treatment:

Substance was added to the feed, which was available ad libitum.

Dose / conc.:

10 ppm (nominal)

Remarks:

Group 2

Dose / conc.:

100 ppm (nominal)

Remarks:

Group 3

Dose / conc.:

1 000 ppm (nominal)

Remarks:

Group 4

No. of animals per sex per dose:

4 main groups, 50 males and 50 females per group
and 4 satellite groups, 15 males and 15 females per group

Control animals:

yes, plain diet

Observations and examinations performed and frequency:

All signs of illness or symptoms of toxicity combined with changes in behavior were documented on a daily basis.
During the first 2 months, each rat was weighted weekly, until week 18 every 14 days, from there to the end of the experiment every 4 weeks.
Water consumption was visually estimated in the group with the highest dosage and control every week.

For each main group, a satellite group was installed consisting of 15 male and 15 female animals. These rats were investigated in certain
intervals. The satellite groups were excluded in the evaluation of the tumor quotas.

Sacrifice and pathology:

Histopathology: 10 males and 10 females of groups 1 and 4
Carcinogenicity: All animals of groups 2 and 3 and the other animals of groups 1 and 4.

After 78 weeks, the satellite groups were killed. There was a detailed macroscopic assessment of the dissected animals with identification of organ weights. The internal organs and tissues were removed and fixed, but not histologically examined.

Any rat that showed symptoms of intoxication or spontaneous illness was killed. All killed animals and the animals that were found dead were dissected.

After 104 weeks of treatment, all surviving rats of the main groups were killed. The internal organs were macroscopically assessed in detail. In addition, the inner organs of animals in which no tumours were observed, were weighed. The tissues of all dosages and controls were histological examined.

Other examinations:

The animals were weekly observed for eye changes. Final assessments were carried out before and during sacrifice as well as in histological examinations.

Before the first treatment and during weeks 6, 26 and 78, blood samples of the satellite groups were investigated. Blood tests were carried out on 10 males and 10 female animals of the highest dosage and control satellite groups.
Biochemical and urinary examinations of the satellite groups were performed in weeks 6, 26 and 78.
Blood samples of the main groups were examined in week104. Biochemical and urinary examinations of the main groups were performed in week 104.

Clinical signs:

not examined

Dermal irritation (if dermal study):

not examined

Mortality:

mortality observed, non-treatment-related

Description (incidence):

A good survival rate or low spontaneous mortality was achieved across all groups.

Body weight and weight changes:

effects observed, treatment-related

Description (incidence and severity):

Main groups: no effects observed
Satellite groups: In the case of female animals, significantly lower weights compared to controls were observed, as follows:
Group 2 in the 78th week and on section day. Group 3 in the 12th, 18th, 22nd, 30th, 70th, 74th and 78th week of treatment and on
section day. Group 4 in the 16th, 18th, 22nd, 62nd, 70th and 74th week of treatment and on Section day.

Food consumption and compound intake (if feeding study):

effects observed, non-treatment-related

Food efficiency:

not examined

Ophthalmological findings:

not examined

Haematological findings:

effects observed, treatment-related

Description (incidence and severity):

Satellite groups: In the 26-week examination, a lower but comparable number of platelets were observed in both group 1 and group 4.
Main groups: In the final examinations, the male animals of group 4 showed leukopenia. In comparison with controls, the number of leukocytes was also lower on average in the other test groups. An explanation could not be found and other findings were normal.

Clinical biochemistry findings:

effects observed, non-treatment-related

Description (incidence and severity):

Satellite groups: During the experiment, significant differences were calculated for a few parameters compared to controls. However, these differences either showed no dose relationship or were within the limits for rats of that age.
Main groups: An increased content of silicon was found in the kidneys in the male animals of group 4 at the end of the experiment. In females, the aluminium content in the urine was increased. However, these differences were not significant.

Urinalysis findings:

effects observed, non-treatment-related

Description (incidence and severity):

At the end of the experiment, protein, in some cases blood, ketone bodies, parasite eggs, leukocytes and erythrocytes in the urinary sediment were observed regardless of the dosage. These findings are well known in older animals, as the rats increasingly develop spontaneous desease of the kidneys in old age.

Behaviour (functional findings):

no effects observed

Description (incidence and severity):

The behaviour of the rats was during the entire application time without any special features. The animals could be handled without problems and showed in no phase of the experiment any form of conspicuousness in the cages.

Immunological findings:

not examined

Organ weight findings including organ / body weight ratios:

effects observed, non-treatment-related

Description (incidence and severity):

Findings showed no toxicological relevant meaning.

Gross pathological findings:

effects observed, non-treatment-related

Description (incidence and severity):

Among the main findings in the respiration tract of the experimental and control group was a low to moderate, interstitial chronic pneumonia with sporadic formation of chronic pleurisy. This finding was largely in line with the image of a chronic, non-progressive viral disease of the respiratory tract.
The findings in the gastrointestinal tract, including liver and pancreas, were similarly developed in all animals of both groups. While ulcerations in the fore stomach of the rat are among the known diseases of the stomach, the gastritis of the fundus gland is a relatively rare finding. Both findings occurred dose-independently and also in the control group. The same applies to the findings in the liver, pancreas and spleen.
Pyelitis with concretion, pyelitis without concretion or concretion alone occurred in both experimental and control animals in varying accumulations. A qualitative change in the formation of concretion was not observed in the animals of the experimental group. Similarly, there were no effects in the form of stone formations in the renal pelvis or in the bladder or changes in the bladder epithelium. The pathological-anatomical and histological findings of the animals also did not reveal a dose-dependent disease of the genitourinary tract.

Neuropathological findings:

not examined

Histopathological findings: non-neoplastic:

effects observed, non-treatment-related

Description (incidence and severity):

No histological findings were found in group 4 that indicated a chronic toxic effect induced by the substance.

Histopathological findings: neoplastic:

effects observed, non-treatment-related

Description (incidence and severity):

In the evaluation of the tumor quality and tumor distribution, the test substance in the described test arrangement did not possess properties for hyperplastic and / or malignant tumors.

Relevance of carcinogenic effects / potential:

Tumor rates and tumor spectra were within normal limits for the laboratory rat of the Wistar strain. Furthermore, neither the individual findings nor the summation showed a dose-dependent accumulation of tumorous changes.

Key result

Dose descriptor:

NOAEL

Effect level:

>= 1 000 ppm

Sex:

male/female

Basis for effect level:

histopathology: neoplastic

histopathology: non-neoplastic

other:

Critical effects observed:

no

No critical effects to carcinogenicity were observed. Tumor rates and tumor spectra were within normal limits for the laboratory rat of the Wistar strain. Furthermore, neither the individual findings nor the summation showed a dose-dependent accumulation of tumorous changes. SASIL was in the dosage of 10 - 1000 ppm for rats under the experimental conditions neither carcinogenic nor did it induce hyperplastic reactions. Therefore, for carcinogenicity a NOAEL equal or greater the highest dosage is appropriate.

Conclusions:

The authors concluded that at the dose of 1000 ppm, clinical, haematological, biochemically and urologically no findings based on cumulative, chronic toxic effect of the test substance could have been observed. SASIL had been in the dosage of 10 - 1000 ppm for rats under the experimental conditions neither carcinogenic nor did it induce hyperplastic reactions.

Tumor rates and tumor spectra were within normal limits for the laboratory rat of the Wistar strain. Furthermore, neither the individual findings nor the summation showed a dose-dependent accumulation of tumorous changes. SASIL was in the dosage of 10 - 1000 ppm for rats under the experimental conditions neither carcinogenic nor did it induce hyperplastic reactions.

Executive summary:

In a chronic study in carcinogenicity Sasil was administered orally in the diet to rats for up to 104 weeks. Additionally to these main groups, there were also satellite groups which were treated for 78 weeks. No carcinogenic effects were observed.

Endpoint conclusion

Endpoint conclusion:

no adverse effect observed

Study duration:

chronic

Species:

rat

Quality of whole database:

reliability 2

Carcinogenicity: via inhalation route

Link to relevant study records

Reference

Endpoint:

carcinogenicity: inhalation

Type of information:

experimental study

Adequacy of study:

supporting 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

Reason / purpose for cross-reference:

read-across source

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:

not specified

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.

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.

Route of administration:

inhalation: dust

Type of inhalation exposure (if applicable):

whole body

Remarks:

inhalation chamber

Vehicle:

air

Details on exposure:

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

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

Post exposure period:

none

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

Observations and examinations performed and frequency:

cf. main study

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 after 22 months.

Description (incidence and severity):

cf. main study

Description (incidence and severity):

cf. main study

Description (incidence):

cf. main study

Description (incidence and severity):

cf. main study

Description (incidence and severity):

cf. main study

Description (incidence and severity):

cf. main study

Description (incidence and severity):

cf. main study

Description (incidence and severity):

cf. main study

Description (incidence and severity):

cf. main study

Description (incidence and severity):

cf. main study

Description (incidence and severity):

cf. main study

Description (incidence and severity):

cf. main study

Description (incidence and severity):

cf. main study

Description (incidence and severity):

cf. main study

Description (incidence and severity):

cf. main study

Description (incidence and severity):

cf. main study

Description (incidence and severity):

cf. main study

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.

Key result

Dose descriptor:

NOAEL

Effect level:

>= 20 mg/m³ air (nominal)

Sex:

male

Basis for effect level:

histopathology: neoplastic

Key result

Critical effects observed:

no

Both results, effect level and target / organ toxicity, only refer to carcinogenetic effects.

Conclusions:

The quality of those tumors observed and their temporal occurrence gave no indications of a carcinogenic activity of the test substance.

Executive summary:

These are the carcinogenetic results of a chronic inhalation study in rats. All other results can be found in the main study (Sasil, Gloxhuber 1978, Chronic, Rats, RL 2).

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. 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.

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.

Endpoint conclusion

Endpoint conclusion:

no adverse effect observed

Study duration:

chronic

Species:

rat

Quality of whole database:

reliability 2

Carcinogenicity: via dermal route

Endpoint conclusion

Endpoint conclusion:

no study available

Justification for classification or non-classification

As no carcinogenetic effects were observed in reliable studies, there is no need for classification.