Synthetic amorphous magnesium silicate, with molar ratio (SiO2:MgO) range of 1.4-4

Carcinogenicity

Administrative data

Endpoint:

carcinogenicity, other

Remarks:

intra-pleural injection

Type of information:

experimental study

Adequacy of study:

key study

Study period:

10 Jan. 1983 - 22 Jan. 1986

Reliability:

2 (reliable with restrictions)

Rationale for reliability incl. deficiencies:

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

Data source

Reference

Reference Type:

study report

Title:

Unnamed

Year:

1995

Report date:

1995

Materials and methods

Test guideline

Test guideline 1

Qualifier:

no guideline available

Test guideline 2

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

Test material

Test material information

Constituent 1

Reference substance name:

Silicic acid, aluminum sodium salt

EC Number:

215-684-8

EC Name:

Silicic acid, aluminum sodium salt

Cas Number:

1344-00-9

Details on test material:

Crosfield ASA: Amorphous sodium aluminosilicate

Specific details on test material used for the study:

Crosfield ASA: Amorphous sodium aluminosilicate

Test animals

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
- Weight at study initiation: no data
- 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

Administration / exposure

Route of administration:

other: intra-pleural injection

Vehicle:

other: suspension in saline

Analytical verification of doses or concentrations:

no

Duration of treatment / exposure:

The animals were allowed to live their whole life-span or maximally 3 years.

Frequency of treatment:

single dose

Post exposure period:

see "Duration of treatment" and "Frequency of treatment"

Doses / concentrations

Remarks:

Doses / Concentrations:
20 mg/animal
Basis:
other: nominal dose

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:

crocidolite [blue asbestos] (20+40 mg) and erionite [fibrous zeolite] (20 mg)

Examinations

Observations and examinations performed and frequency:

CAGE SIDE OBSERVATIONS: Yes
daily

DETAILED CLINICAL OBSERVATIONS: Yes
at weighing

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

FOOD EFFICIENCY:
- Body weight gain in kg/food consumption in kg per unit time X 100 calculated as time-weighted averages from the consumption and body weight gain data: No data

OPHTHALMOSCOPIC EXAMINATION: No


HAEMATOLOGY: No


CLINICAL CHEMISTRY: No


URINALYSIS: No


NEUROBEHAVIOURAL EXAMINATION: No

Sacrifice and pathology:

GROSS PATHOLOGY: Yes
HISTOPATHOLOGY: Yes (see Appendix 8, Summaries Appendices 9 and 10 / 14 and 15)

Weight laid on intra-thoracic changes, in particular of the pleura.

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).

Results and discussion

Results of examinations

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

Organ weight findings including organ / body weight ratios:

not specified

Gross pathological findings:

effects observed, treatment-related

Histopathological findings: non-neoplastic:

effects observed, treatment-related

Histopathological findings: neoplastic:

no effects observed

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 mesotheliomas.

On the other hand, an increased fraction of the crocidolite-treated groups  died of mesotheliomas (67 - 87 %),
while among the rats treated with Oregon erionite, all deaths were due to mesotheliomas.


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).
The application of asbestos material distinctly produced pleural mesotheliomas in 71 - 93 % of the animals.

- 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% mesotheliomas).
Hence, a statement on co-carcinogenic or promoter-like interaction is not possible, as the tumour yields were already
at the maximum limit for crocidolite alone.
[see Table Histopathology for neoplastic effects under "Remarks on results..." ]

- 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).

Any other information on results incl. tables

Summary of incidences of mesotheliomas (from Report Vol. 1, Table 10)

Group Code	Treatment	Sex	No.	No. of rats with mesothelioma	Incidence [%]	Total incidence [%]
Test compounds
G	20 mg Crosfield ASA* (relevant test compound)	M	50	0	0	0
		F	50	0	0
D	20 mg non-fibrous erionite	M	50	0	0	0
		F	50	0	0
E	20 mg Degussa Sasil	M	50	1**	2	0
		F	50	0	0
F	20 mg AKZO zeolite	M	50	0	0	0
		F	50	0	0
Test controls
A	Saline control	M	50	0	0	0
		F	50	0	0
N	20 mg TiO2	M	3	0	0	0
		F	3	0	0
R	20 mg Dorentrup Quartz 12	M	30	0	0	0
		F	29	0	0
B	20 mg UICC crocidolite (pos. control 1)	M	30	28	93	87
		F	30	24	80
C	20 mg Oregon erionite (pos. control 2)	M	30	30	100	100
		F	30	30	100
P	20 mg TiO2 + 20 mg mg UICC crocidolite	M	30	26	87	82
		F	30	23	77
S	20 mg Dorentrup Quartz 12 + 20 mg mg UICC crocidolite	M	30	23	77	82
		F	29	24	83

* ASA = Amorphous sodium aluminosilicate

** benign testicular mesothelioma, not treatment related

Applicant's summary and conclusion

Executive summary:

A study was conducted based on OECD Guideline 451 using Crosfield ASA (Amorphous sodium aluminosilicate) in rats. A single dose of 20 mg/animal was administered by intra-pleural injection. There was no evidence that ASA acted as a carcinogen.