Zeolite, cuboidal, crystalline, synthetic, non-fibrous

Repeated dose toxicity: other routes

Administrative data

Endpoint:

chronic toxicity: other route

Remarks:

single intratracheal administration

Type of information:

experimental study

Adequacy of study:

supporting study

Reliability:

4 (not assignable)

Rationale for reliability incl. deficiencies:

secondary literature

Cross-reference

Cross-reference 1

Reason / purpose for cross-reference:

reference to other study

Reference

Endpoint:

carcinogenicity, other

Remarks:

intraperitoneal

Type of information:

experimental study

Adequacy of study:

supporting study

Reliability:

4 (not assignable)

Rationale for reliability incl. deficiencies:

secondary literature

GLP compliance:

not specified

Specific details on test material used for the study:

Zeolite A (batch F 197)

Species:

rat

Strain:

Wistar

Sex:

male

Route of administration:

intraperitoneal

Vehicle:

other: 0.5 ml of Tyrode’s Solution

Frequency of treatment:

once

Post exposure period:

up to 24 months

Dose / conc.:

50 other: mg (total dose)

No. of animals per sex per dose:

70 (males only)

Control animals:

yes, concurrent vehicle

Positive control:

yes, Quartz DQ 12

Observations and examinations performed and frequency:

Health and body weight were checked regularly.

Sacrifice and pathology:

At autopsy, the mesentery and abdominal lymph nodes were weighed and the mesentery, various lymph nodes, liver, spleen, kidney, adrenals, lungs and trachea were examined histologically.

Clinical signs:

no effects observed

Mortality:

mortality observed, non-treatment-related

Body weight and weight changes:

no effects observed

Histopathological findings: non-neoplastic:

effects observed, non-treatment-related

Histopathological findings: neoplastic:

effects observed, treatment-related

Description (incidence and severity):

With the exception of one suspected benign lymphangioma in the control group, tumours were found, at the scheduled autopsies, only in the Zeolithe-A group. These consisted of a parafollicular adenoma of the thyroid in one of the ten rats examined histologically at month 18 and a follicular adenocarcinoma of the thyroid, a phaeochromocytoma of the adrenal gland and nine benign lymphangiomas of the mesenteric lymph nodes in the 23 rats examined at 2 yr.

Critical effects observed:

yes

Lowest effective dose / conc.:

50 other: g (total dose)

System:

immune system

Organ:

lymph node

Treatment related:

yes

Relevant for humans:

presumably yes

Among the 11 spontaneous deaths occurring up to wk 104 in the 70 male Wistar rats injected ip with a Zeolithe A Suspension, one case of leukaemia and one of enteritis were diagnosed. The Cause of the other nine deaths remained obscure because of advanced autolysis. Of the 40 rats in the quartz group, two were found severely autolysed and two had to be killed, one with a reticulum-cell sarcoma and one with a nephroblastoma. One of the 40 conlrols died prematurely with colonic atonia. Zeolite A-treated and control rats did not differ with regard to general behaviour and body weight, but in the quartz group the body-weight gain was slower and some cases of a circumscribed alopecia occurred. At 3 months, fat deposition in the omentum and mesentery was inconspicuous in the Zeolite A group, but typical nodules were visible in the quartz group. The weight of mesentery plus omenturn in the quartz group differed significantly from that of the controls at months 6 and 18. The silicotic mesentery in the quartz group consisted mainly of nodules of connective tissue and considerably enlarged lymph nodes, while the mesenteric fat deposits in the Zeolithe A group resembled those of thc controls. Some rats of the Zeolithe A group showed punctiform adhesions of the gut and liver.

In Ihe histological examinations, cell accumulalions consisting mainly of macrophages and sometimes of macrophages and lymphocytes were found fairly regularly 3, 6, 18 and 24 months after the administration of Zeolithe A. The accumulations were embedded between the omental fat cells and sometimes contained a greyish-white substance within the macrophage cytoplasm. No specific reaction or formation of connective tissue was found in or around these accumulations. In some cases well-circumscribed accumulations of macrophages surrounded by a fibrous capsule and showing no morphological connection with the omentum occurred. Within the fibrous capsule, vascular connections and connective tissue in different stages were seen. The macrophages within the capsules contained intracellular deposits of a greyish crystalline substance, which, after 6, 18 and 24 months became exposed due to lysis and degeneration of the macrophages. No additional activation of the mesenchyma or connective tissue was induced at any time of the study. Both forms of cell or substance accumulation were observed in all groups more or less frequently and irregularly.

The lymph nodes examined, among them mediastinal lymph nodes, often contained circumscribed accumulations of macrophages in the paracortical area. These macrophages sometimes showed substantial inclusions, but no connective-tissue formation was observed. The surfaces of the spleen, liver and kidney showed more or less regularly circumscribed or laminar layers of connective tissue. Always on the kidney but seldom on the spleen and liver, this connective tissue contained substantial greyish deposits, which were similar to the encapsulated omental deposits described above. These deposits did not progress with time nor influence the underlying parenchyma.

In the group treated with Quartz DQ 12, quartz-typical areas with central necrosis and hyalinization prevailed in the mesentery and omentum. Characteristic silicotic granulomas were found to a comparable extent in the lymph nodes, liver and spleen. In the control group treated with Tyrode‘s Solution isolated accumulations of macrophages were found in the mesentery and omenturn, and in the lymph nodes small circumscribed accumulations of macrophages were seen in the paracortical area.

With the exception of one suspected benign lymphangioma in the control group, tumours were found, at the scheduled autopsies, only in the Zeolithe-A group. These consisted of a parafollicular adenoma of the thyroid in one of the ten rats examined histologically at month 18 and a follicular adenocarcinoma of the thyroid, a phaeochromocytoma of the adrenal gland and nine benign lymphangiomas of the mesenteric lymph nodes in the 23 rats examined at 2 yr.

 

Conclusions:

Although nine benign lymphangiomas of the mesenteric lymph nodes in 23 treated rats examined at 2 years were found, according to the MAK commission's report, these results were not used in the assessement of the carcinogenic potential of zeolites, because the study was insufficiently documented.

Executive summary:

A Suspension of 50 mg Zeolite A was injected intraperitoneally into male Wistar rats. Because, according to the MAK report, this study was inadequately documented, it was not used for the assessment of the carcinogenic potential of zeolites. 

Cross-reference 2

Reason / purpose for cross-reference:

reference to other study

Reference

Endpoint:

carcinogenicity, other

Remarks:

intraperitoneal

Type of information:

experimental study

Adequacy of study:

supporting study

Reliability:

4 (not assignable)

Rationale for reliability incl. deficiencies:

secondary literature

Reason / purpose for cross-reference:

reference to other study

GLP compliance:

not specified

Specific details on test material used for the study:

Zeolite A (batch F 197)

Species:

mouse

Sex:

male

Route of administration:

intraperitoneal

Vehicle:

other: 0.2 ml Tyrode’s solution

Frequency of treatment:

once

Post exposure period:

up to 18 months

Dose / conc.:

10 other: mg (total dose)

No. of animals per sex per dose:

70 (males only)

Control animals:

yes, concurrent vehicle

Positive control:

yes, 10 mg Quartz DQ 12

Observations and examinations performed and frequency:

Health and body weight were checked regularly.

Sacrifice and pathology:

At autopsy, the mesentery and abdominal lymph nodes were weighed and the mesentery, various lymph nodes, liver, spleen, kidney, adrenals, lungs and trachea were examined histologically.

Mortality:

mortality observed, non-treatment-related

Histopathological findings: non-neoplastic:

effects observed, non-treatment-related

Histopathological findings: neoplastic:

effects observed, non-treatment-related

Critical effects observed:

no

As in the rats, two different forms of cellular accumulation were observed in the omenturn. Additional formation of connective tissue or other mesenchymal activity was not induced by these accumulations. Spots of conneclive tissue occurred on the parenchymatous organs, especially the spleen, but substantial deposits were observed only on the spleen. In the animals of the quartz group, typical areas were evident and a  circumscribed granulomatous peritonitis was diagnosed in some animals. Additionally, a generalized amyloidosis was observed in some mice after 18 months. In the control group, isolated accumulations of macrophages
were observed in the omenturn and mesntery, and in all the groups age-related tumours such as adenoma and adenocarcinoma of the lung and kidney or haemangiosarcoma of the liver occurred. Lymphadenosis was found to be the cause of high mortality in this study.

Conclusions:

Age-related tumors were seen in all groups, including control. Therefore no assessement of the carcinogenic potential of Zeolite A is possible.

Executive summary:

In a study in male mice 10 mg Zeolithe A and 10 mg Quartz DQ 12were administered ip to groups of 70 and 30 animals, respectively. The control group (40 animals) received only the vehicle solution. In all groups age-related tumours such as adenoma and adenocarcinoma of the lung and kidney or haemangiosarcoma of the liver occurred.

Data source

Reference

Reference 1

Reference Type:

review article or handbook

Title:

Zeolithe, synthetisch, nicht faserförmig

Author:

MAK commission

Year:

2014

Bibliographic source:

MAK, 56. Lieferung, 2014

Reference 2

Reference Type:

publication

Title:

Unnamed

Year:

1983

Materials and methods

GLP compliance:

not specified

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:

Zeolite A (batch F 197)

Test animals

Species:

rat

Strain:

Wistar

Sex:

male/female

Administration / exposure

Route of administration:

other: intratracheal

Vehicle:

other: Tyrode’s Solution at 25% concentration

Duration of treatment / exposure:

one time exposure, 24 months of post-exposure

Frequency of treatment:

once

Doses / concentrations

Dose / conc.:

50 other: mg (total dose)

No. of animals per sex per dose:

25

Control animals:

yes, concurrent vehicle

other:

Examinations

Sacrifice and pathology:

The lungs and thymus were weighed and the trachea lung and mediastinal lymph nodes were fixed in 10% formaldehyde and examined microscopically. The total
numbers of rats examined histologically after intratracheal administration of Zeolithe A, quartz or Tyrode’s solution (controls) were 17, 14 and 9, respectively.

Results and discussion

Results of examinations

Histopathological findings: non-neoplastic:

effects observed, non-treatment-related

Description (incidence and severity):

At both 18 and 24 months after the administration of Zeolithe A, various forms of chronic reaction were observed in the lungs. In addition to circumscribed focal alveolitis, small areas of connective tissue near the bronchioli were observed, resulting in a deformation of the lung structure. In contrast to the situation
in the quartz-treated rats, which showed severe silicosis, these alterations occupied only a small part of the lung parenchyma and showed no signs of progression. As after the ip administration of Zeolithe A, accumulations of macrophages containing substantial deposits were observed. In the corresponding mediastinal lymph nodes, a similar deposit was seen and
formation of single collagenous fibres occurred.

Target system / organ toxicity

Critical effects observed:

no

Applicant's summary and conclusion

Conclusions:

The MAK report on workplace safety concludes that in this study compared to the quartz group, whose animals showed severe silicosis, these changes only affected a small part of the lung parenchyma and were not progressive.

Executive summary:

A chronic study of the effects of intratracheal administration of Zeolite A was performed on male and female Wistar rats. The alterations observed occupied only a small part of the lung parenchyma and showed no signs of progression.