Silicic acid, aluminum magnesium sodium salt

Carcinogenicity

Description of key information

Based on structure analogy of amorphous sodium aluminosilicate, no carcinogenicity is expected from the exposure to silicic acid, aluminium magnesium sodium salt.

Taking into account that orally ingested aluminium from sodium silicoaluminate is poorly bioavailable, absorbed and rapidly excreted, no risk potential of aluminium will occur. Sodium and magnesium are natural constituents of the regular human diet.

Key value for chemical safety assessment

Carcinogenicity: via oral route

Endpoint conclusion

Endpoint conclusion:

no study available

Carcinogenicity: via inhalation route

Link to relevant study records

Reference

Endpoint:

carcinogenicity, other

Remarks:

other: intrapleural injection

Type of information:

experimental study

Adequacy of study:

key study

Study period:

Dec. 1, 1982 - Jan. 22, 1986; experimental phase: Jan. 10, 1983 - Jan. 22, 1986

Reliability:

2 (reliable with restrictions)

Rationale for reliability incl. deficiencies:

comparable to guideline study with acceptable restrictions

Justification for type of information:

Test material ist different from reference substance but comparable, see chapter 13, attachment 'Analogue Approach Justification'

Reason / purpose for cross-reference:

read-across: supporting information

Qualifier:

equivalent or similar to guideline

Guideline:

OECD Guideline 451 (Carcinogenicity Studies)

Deviations:

yes

Remarks:

- Special design/comparative study focussed on induction of mesothelioma; therefore, intrapleural application, one dose only, one sex only / no haematology, clinical chemistry and urinalysis

Principles of method if other than guideline:

Method: Special test design, whole-life study
Comprehensive test programme and comparative study including various silicates (crystalline and amorphous) as well as quartz and TiO2. Fibrous minerals, UICC crocidolite (blue asbestos) and Oregon erionite (fibrous zeolite) served as positive control substances.

GLP compliance:

yes

Specific details on test material used for the study:

amorphous sodium aluminosilicates (ASA)
ASA was supplied by Crosfield Chemicals as a slurry. On receipt the sample was allocated a unique sample number 13,499T2. The slurry was maintained in a disperse state using a magnetic stirrer.

Species:

rat

Strain:

Wistar

Sex:

male/female

Details on test animals or test system and environmental conditions:

TEST ANIMALS
- Source: Unilever Environ. Safety Laboratory Breeding Unit
- Age at study initiation: 8 weeks
- Fasting period before study: no
- Housing: groups of 10 animals
- Diet: ad libitum
- Water: ad libitum


ENVIRONMENTAL CONDITIONS
- Temperature (°C): 21 ± 2
- Humidity (%): 55 ± 10
- Photoperiod (hrs dark / hrs light): 12 / 12

Route of administration:

other: intrapleural injection

Vehicle:

other: suspension in saline

Details on exposure:

Test materials were administered as a suspension in sterile saline by a single intra-pleural injection under halothane anaesthesia during the 8th week of life.

Analytical verification of doses or concentrations:

no

Duration of treatment / exposure:

One time exposure, after that the animals were allowed to live their whole life-span or maximally 3 years.

Frequency of treatment:

single dose

Post exposure period:

The rats were allowed to live out their lives until they showed signs of distress at which point they were sacrificed.

Dose / conc.:

20 other: mg/animal (nom.)

No. of animals per sex per dose:

50
positive and negative control groups: 30

Control animals:

other: negative controls: saline, TiO2 (20 mg), Dorentrup quartz (20 mg)

Details on study design:

Dose selection rationale: cancerogenic dose for fibrous materials

Positive control:

UICC crocidolite
Oergon erionite

Observations and examinations performed and frequency:

CAGE SIDE OBSERVATIONS: Yes, daily for signs of ill-health and reaction to treatment.

DETAILED CLINICAL OBSERVATIONS: Yes, at weighing

BODY WEIGHT: Yes, before and directly after treatment, then weekly

Sacrifice and pathology:

A detailed necropsy (including histopatholgy) was conducted but particular attention was paid to possible neoplasia, especially in and around the pleural cavity. The key end-point was the percentage incidence of pleural (intra-thoracic) mesotheliomas.

Statistics:

Analysis of survival data, neoplastic conditions and associated pre-neoplastic condition: tumours were evaluated by giving a "Peto score" (Peto R. et al. 1980) for malignancy and cause of death. 39 groupings of tumours and hyperplasia used for statistical analysis (Appendix 18).

Clinical signs:

not specified

Mortality:

mortality observed, non-treatment-related

Description (incidence):

The survival in all UICC crocidolite groups was significantly (p <0.01) worse than in any non-crocidolite group. There were no substantial differences in survival in the 7 groups which did not receive either Oregon erionite or UICC crocidolite. 52% -60% of deaths were due to neoplasia but none were due to mesotheliomas.
The percentage of deathes due to neo-plastic conditions was only sligthly elevated in ASA-treated males compared to saline controls (29% to 26%, repectively) and not at all in treated females (s. also below: "Relevance of carcinogenic effects / potential")

Body weight and weight changes:

not specified

Food consumption and compound intake (if feeding study):

not specified

Food efficiency:

not specified

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

not specified

Ophthalmological findings:

not examined

Haematological findings:

not examined

Clinical biochemistry findings:

not examined

Urinalysis findings:

not examined

Behaviour (functional findings):

not examined

Immunological findings:

not examined

Organ weight findings including organ / body weight ratios:

not specified

Gross pathological findings:

effects observed, treatment-related

Description (incidence and severity):

White test material was present and occasional slight intra-thoracic adhesions present.

Neuropathological findings:

not examined

Histopathological findings: non-neoplastic:

effects observed, treatment-related

Description (incidence and severity):

Test material was occasionally present, and there was infrequent slight pleural/pericardial thickening composed of macrophages with or without connective tissue.

Histopathological findings: neoplastic:

effects observed, non-treatment-related

Description (incidence and severity):

There was an increase in liver cell tumours for the sexes combined, and a reduction in incidence of thyroid follicular tumours in the sexes combined. Neither represented convincing evidence of a treatment-related effect. (s. also below: "Relevance of carcinogenic effects / potential")
The intra-pleural injection of non-fibrous Crosfield ASA did not result in any convincing effect on tumour incidence at any site. In particular, there were no pleural mesotheliomas.

Other effects:

effects observed, non-treatment-related

Description (incidence and severity):

When non-fibrous ASA was given in conjunction with UICC crocidolite, there was no evidence that it acted together with the fibrous mineral as co-carcinogen, there being no increase in the number of mesotheliomas in groups treated with UICC crocidolite in combination with non-fibrous Crosfield ASA in comparison with the groups treated with UICC crocidolite alone or in combination with titanium dioxide or Dorentrup quartz 12.
Furthermore, the combination of ASA with UICC crocidolite did not result in a shortening of the latent period for the induction of mesotheliomas. In fact, the combination of the material with UICC crocidolite caused a reduction in the age adjusted incidence of mesotheliomas.

Details on results:

CLINICAL SIGNS AND MORTALITY
- SURVIVAL (Tab. 2 and 4):
ASA-treated animals as well as all other groups having been treated with non-fibrous material showed normal survival 
as compared to the saline control.

- CAUSES of MORTALITY (Tab. 7 and 8):
There was no shift towards neoplastic lesions as primary cause of mortality 
due to treatment with non-fibrous material, ASA and untreated control groups:
52 - 60 % of all deaths were due to neoplasia but none were caused by mesothelimas.

HISTOPATHOLOGY: NON-NEOPLASTIC
- LOCAL NON-NEOPLASTIC, REACTIVE REPONSE
Test material was occasionally present intra-thoracically. There was infrequent slight pleural/pericardial thickening
composed of macrophages with or without connective tissue.(p. 15), occasionally associated with slight intra-thoracic adhesions (p. 12).
There was a trend to form nodules (Tab.5/6).
On the other hand, quartz elicited much more extensive granulomatous, fibroblastic reactions with dense deposition of collagen
forming nodules, also involving the mediastinal lymph nodes which were enlarged, intra-thoracic adhesions, hydrothorax and
accumulation of macrophages and mononuclear cells (p. 12/15).


HISTOPATHOLOGY: NEOPLASTIC
- MESOTHELIOMAS (Tab. 10)
No pleural mesotheliomas appeared in the saline group. 
No pleural mesotheliomas were induced by ASA and the other non-fibrous minerals including TiO2 and quartz, 
apart from a single benign testicular mesothelioma (unrelated to treatment).

- ACTION in COMBINATION of non-fibrous with crocidolite (fibrous mineral) (Tab. 10):
The results corresponded to those found with asbestos alone (77 - 87% vs,. 87% mesoteliomas).
Hence, a statement on co-carcinogenic or promoter-like interaction is not possible, as the the tumour yields were already
at the maximum limit for crocidolite alone.

- OTHER TUMORS (Tab. 9)
The treatment with the test minerals, irrespective of the fibrous or non-fibrous nature, did not influence the pattern of prevalence 
of isolated spontaneous tumors other than mesotheliomas (most of them thyroid follicular tumors).

Relevance of carcinogenic effects / potential:

The test item does not induce mesotheliomas and does not act as tumor promotor:
- The percentage of deaths due to neo-plastic conditions was only sligthly elevated in ASA-treated males compared to saline controls: 29% to 26%, respectively (cf. Table 7).
- The percentage of deaths due to neo-plastic conditions was the same in ASA-treated females compared to saline controls: both 44% (cf. Table 8).
- The number of intra-thoracic tumours was sligthly decreased in ASA-treated rats compared to saline controls: 7 to 8, respectively, both of a total number of 100 rats each (cf. Table 9).
- There was no incidence of mesothelioma in ASA-treated rats (cf. Table 10).

Key result

Dose descriptor:

NOAEL

Effect level:

>= 20 other: mg/animal

Sex:

male/female

Basis for effect level:

gross pathology

histopathology: neoplastic

histopathology: non-neoplastic

mortality

Key result

Critical effects observed:

no

1.  No intra-thoracic mesotheliomas occurred in the saline-treated control group nor in the groups treated with titanium dioxide or Dorentrup quartz.

2.    Intra-thoracic mesotheliomas were induced in rats treated with Oregon erionite and UICC crocidolite, the latter either alone or in combination with the aluminosilicate.

3.   No intra-thoracic mesotheliomas occurred in any of the groups treated with ASA test materials or the control non-fibrous erionite.

4.  There was no evidence that co-treatment of rats with UICC crocidolite and ASA caused an increase in the incidence of intra-thoracic mesotheliomas.

5.   There was no evidence that co-treatment of rats with UICC crocidolite and ASA caused a shortening in the latency period of intra-thoracic mesotheliomas.

6.  In rats treated with ASA there was no increase in the incidence of tumours of any type at extra-thoracic sites.

Conclusions:

The results of the study indicate that ASA is not carcinogenic in the rat in that it does not induce mesotheliomas following intrapleural injection, and that the substance does not act as co-carcinogen with UICC crocidolite in that the incidence of mesotheliomas did not increase following co-injection into the pleural cavity. Neither did the substances act as tumour promoter in that it did not shorten the latency period of UICC crocidolite-induced mesotheliomas following co-injection into the pleural cavity. (s. also above: "Relevance of carcinogenic effects / potential")

Executive summary:

The purpose of the study was to determine:

•  The carcinogenic potentials of non-fibrous crystalline zeolites and amorphous sodium aluminosilicates (ASA), comparing them with a known carcinogenic fibrous zeolite.

• Whether crystalline zeolites and ASA act together with fibrous minerals as co-carcinogens.
•  Whether crystalline zeolites and ASA can reduce the latent period for the induction of mesotheliomas (tumours of the pleura).

Only the results on ASA (structurally relateted to SMAS) are documented here.

Endpoint conclusion

Endpoint conclusion:

no adverse effect observed

Study duration:

chronic

Species:

rat

Quality of whole database:

RL2

Carcinogenicity: via dermal route

Endpoint conclusion

Endpoint conclusion:

no study available

Justification for classification or non-classification

There is no need for classification of silicic acid, aluminium magnesium sodium salt as carcinogen.

Additional information

Oral

no study available

Other routes: intrapleural application (used as substitute for an inhalation study)

Amorphous sodium aluminosilicates (ASA), which is structurally related to SMAS, did not induce mesotheliomas and did not act as tumour promotor:

- The percentage of deaths due to neo-plastic conditions was only slightly elevated in ASA-treated males compared to saline controls: 29% to 26%, respectively.

- The percentage of deaths due to neo-plastic conditions was the same in ASA-treated females compared to saline controls: both 44%.

- The number of intra-thoracic tumours was slightly decreased in ASA-treated rats compared to saline controls: 7 to 8, respectively, both of a total number of 100 rats each.

- There was no incidence of mesothelioma in ASA-treated rats.

 

Overall conclusions: The results of the study indicate that ASA is not carcinogenic in rat in that it does not induce mesotheliomas following intrapleural injection, and that the substance does not act as co-carcinogen with UICC crocidolite in that the incidence of mesotheliomas did not increase following co-injection into the pleural cavity. Neither did the substance act as tumour promoter in that it did not shorten the latency period of UICC crocidolite-induced mesotheliomas following co-injection into the pleural cavity.