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Description of key information

No carcinogenic potential was observed with Silicic acid, aluminum sodium salt (CAS 1344-00-9, NAS) in a whole live study in rats after intrapleural administration. This study concluded that NAS is not carcinogenic in rats in that it does not induce mesotheliomas following intrapleural injection.


The same result was obtained in long-term feeding studies with structurally related silicon dioxide in mice and rats.

Key value for chemical safety assessment

Carcinogenicity: via oral route

Link to relevant study records

Referenceopen allclose all

Endpoint:
carcinogenicity: oral
Type of information:
migrated information: read-across from supporting substance (structural analogue or surrogate)
Adequacy of study:
key study
Reliability:
2 (reliable with restrictions)
Rationale for reliability incl. deficiencies:
other: Comparable to guideline study with acceptable restrictions
Reason / purpose for cross-reference:
reference to same study
Qualifier:
equivalent or similar to guideline
Guideline:
OECD Guideline 453 (Combined Chronic Toxicity / Carcinogenicity Studies)
Deviations:
yes
Remarks:
Group sizes smaller than recommended: effectively 20/sex/dose for terminal sacrifice; recommended 50 (note: Sufficient biostatistical power can never be achieved for substances that have no or a very low cancerogenic potential.)
GLP compliance:
not specified
Species:
rat
Strain:
Fischer 344
Sex:
male/female
Details on test animals or test system and environmental conditions:
TEST ANIMALS
- Source: Funabashifarm Animal Co. Ltd. Japan
- Age at study initiation: 3 weeks
- Weight at study initiation: 117 - 150 g (male rats); 92 - 126 g (female rats)
- Fasting period before study:
- Housing: 2 rats/cage
- Diet: ad libitum
- Water: ad libitum
- Acclimation period: 2 weeks


ENVIRONMENTAL CONDITIONS
- Temperature (°C): 23 +-1
- Humidity (%): 50 +-10 %
- Air changes (per hr):
- Photoperiod (hrs dark / hrs light): 10 dark / 14 light
Route of administration:
oral: feed
Analytical verification of doses or concentrations:
no
Duration of treatment / exposure:
103 weeks with interim kill after 6 and 12 months (10 animals each)
Frequency of treatment:
daily
Post exposure period:
none
Remarks:
Doses / Concentrations:
1.25, 2.5 and 5 %
Basis:
nominal in diet
No. of animals per sex per dose:
40
Control animals:
yes
Sacrifice and pathology:
GROSS PATHOLOGY: Yes
HISTOPATHOLOGY: Yes
Statistics:
Fisher´s exact test and Cochran-Armitage test for trend
Clinical signs:
no effects observed
Mortality:
no mortality observed
Body weight and weight changes:
no effects observed
Food consumption and compound intake (if feeding study):
no effects observed
Food efficiency:
not specified
Water consumption and compound intake (if drinking water study):
no effects observed
Ophthalmological findings:
not examined
Haematological findings:
no effects observed
Clinical biochemistry findings:
no effects observed
Urinalysis findings:
not examined
Behaviour (functional findings):
not examined
Organ weight findings including organ / body weight ratios:
effects observed, treatment-related
Gross pathological findings:
no effects observed
Histopathological findings: non-neoplastic:
no effects observed
Histopathological findings: neoplastic:
no effects observed
Details on results:
Result (carcinogenicity): negative:
The tumour responses in the silica-fed rats were not statistically significantly different from the controls (Fisher´s exact test and Cochran-Armitage test for trend) (see also: IARC 1997, p. 171).

Dose descriptor:
NOAEL
Remarks:
(highest dose level tested)
Effect level:
5 other: % in the diet
Sex:
male/female
Remarks on result:
other:
Remarks:
Effect type: other: carcinogenicity and toxicity (migrated information)
Dose descriptor:
NOAEL
Remarks:
(highest dose level tested: 5 % in the diet)
Effect level:
ca. 1 800 - ca. 3 000 mg/kg bw/day (actual dose received)
Sex:
male
Basis for effect level:
other: Specific silica intake decreased over time during growth and aging in relation to the relative reduction in food intake (see Report, Tab. 7)
Remarks on result:
other:
Remarks:
Effect type: other: carcinogenicity and toxicity (migrated information)
Dose descriptor:
NOAEL
Remarks:
(highest dose level tested: 5 % in the diet)
Effect level:
ca. 1 800 - ca. 3 200 mg/kg bw/day (actual dose received)
Sex:
female
Basis for effect level:
other: Specific silica intake decreased over time during growth and aging in relation to the relative reduction in food intake (see Report, Tab. 8)
Remarks on result:
other:
Remarks:
Effect type: other: carcinogenicity and toxicity (migrated information)

The mean cumulative intake was 143.46, 279.55 and 581.18 g/rat in males
and 107.25, 205,02 and 435.33 g/rat in females, respectively.

(Note: Misprint for substance uptake by males, 2.5 %, in Tab. 7: 179.55 must read 279.55 g/rat.)

The average doses of the male and female 5%-groups were approx. 1800 to 2000 mg/(kg bw*d)

after week 15 of the study start, while they were distinctly higher in the juvenile phase of life

(comp. Report, Tab. 7 and 8).

Specific silica intake decreased over time during growth and aging in relation to the relative reduction

in food intake. A reasonable average of 2000 mg/(kg bw*d) is estimated from the experimental data.

This estimate relates to a mean body weight of 400 g and 300 g for males and females, respectively

(see Report, Tab. 7 and 8), which agrees fairly well with the growth curves (comp. Report, Fig. 5 and 6) .


No significant variations in survival rats were observed in males, while the female survival rats 

were decreased but not statistic significant different from the control group. In body weight, food intake 

or in hematology and clinical chemistry parameters no relevant changes were seen. Lower liver weights

were noted from 12 to 24 months in the 2.5 and 5 % female dose group. 

In histopathological examination the tumour incidence was the greatest in testes, mammmary gland 

(incidence in the controls higher than in the treatment groups) and prepuce (males) and mammary 

gland and clitoris (incidence in the controls higher than in the treatment groups) in females.
(see also IARC 1997)
   

Endpoint:
carcinogenicity: oral
Type of information:
read-across from supporting substance (structural analogue or surrogate)
Adequacy of study:
key study
Reliability:
2 (reliable with restrictions)
Rationale for reliability incl. deficiencies:
other: Comparable to guideline study with acceptable restrictions
Reason / purpose for cross-reference:
reference to same study
Qualifier:
equivalent or similar to guideline
Guideline:
OECD Guideline 453 (Combined Chronic Toxicity / Carcinogenicity Studies)
Deviations:
yes
Remarks:
Group sizes smaller than recommended: effectively 20/sex/dose for terminal sacrifice; recommended 50 (note: Sufficient biostatistical power can never be achieved for substances that have no or a very low cancerogenic potential.)
GLP compliance:
not specified
Species:
mouse
Strain:
B6C3F1
Sex:
male/female
Details on test animals or test system and environmental conditions:
TEST ANIMALS
- Source: Funabashifarm Animal Co. Ltd. Japan
- Age at study initiation: 4 weeks
- Weight at study initiation: 21 - 27.3 g (male mice); 16 - 19.9 g (female mice)
- Fasting period before study:
- Housing: 5 mice/cage
- Diet: ad libitum
- Water: ad libitum
- Acclimation period: 1 week


ENVIRONMENTAL CONDITIONS
- Temperature (°C): 23 +-1
- Humidity (%): 50 +-10 %
- Air changes (per hr):
- Photoperiod (hrs dark / hrs light): 10 dark / 14 light
Route of administration:
oral: feed
Analytical verification of doses or concentrations:
no
Duration of treatment / exposure:
93 weeks with interim kill after 6 and 12 months, 10 animals each
Frequency of treatment:
daily
Post exposure period:
none
Remarks:
Doses / Concentrations:
1.25, 2.5 and 5 %
Basis:
nominal conc.
No. of animals per sex per dose:
40
Control animals:
yes
Sacrifice and pathology:
GROSS PATHOLOGY: Yes
HISTOPATHOLOGY: Yes
Statistics:
Fisher´s exact test and Cochran-Armitage test for trend
Clinical signs:
no effects observed
Mortality:
no mortality observed
Body weight and weight changes:
effects observed, treatment-related
Food consumption and compound intake (if feeding study):
no effects observed
Food efficiency:
not specified
Water consumption and compound intake (if drinking water study):
not specified
Ophthalmological findings:
not examined
Haematological findings:
no effects observed
Clinical biochemistry findings:
not specified
Urinalysis findings:
not examined
Behaviour (functional findings):
not examined
Organ weight findings including organ / body weight ratios:
no effects observed
Gross pathological findings:
no effects observed
Histopathological findings: non-neoplastic:
no effects observed
Histopathological findings: neoplastic:
no effects observed
Details on results:
Result (carcinogenicity): negative:
The tumour responses in the silica-fed mice were not statistically significantly different from the controls (Fisher´s exact test and Cochran-Armitage test for trend) (see also: IARC 1997, p. 171).
Dose descriptor:
NOAEL
Remarks:
(highest dose level tested)
Effect level:
5 other: % in the diet
Sex:
male/female
Remarks on result:
other:
Remarks:
Effect type: other: carcinogenicity and toxicity (migrated information)
Dose descriptor:
NOAEL
Remarks:
(highest dose level tested: 5 % in the diet)
Effect level:
ca. 5 000 - ca. 7 000 mg/kg bw/day (actual dose received)
Sex:
male
Basis for effect level:
other: Specific silica intake decreased over time during body-weight gain in relation to the relative reduction in food intake (see Report, Tab. 2)
Remarks on result:
other:
Remarks:
Effect type: other: carcinogenicity and toxicity (migrated information)
Dose descriptor:
NOAEL
Remarks:
(highest dose level tested: 5 % in the diet)
Effect level:
ca. 4 000 - ca. 13 000 mg/kg bw/day (actual dose received)
Sex:
female
Basis for effect level:
other: Specific silica intake decreased over time during body-weight gain in relation to the relative reduction in food intake (see Report, Tab. 3)
Remarks on result:
other:
Remarks:
Effect type: other: carcinogenicity and toxicity (migrated information)

The mean cumulative intake after 93 weeks was 38.45, 79.78 and 160 g/mouse in males and 37.02, 72.46 and 157.59 g/mouse in females, respectively. 


 


The average doses of the male and female 5%-groups were approx. 5800 and 4500 mg/(kg bw*d) after week 15 - 20 of the study start, while they were distinctly higher in the juvenile phase of life, in particular in the female group (comp. Report, Tab. 2 and 3).


Specific silica intake decreased over time during growth and aging in relation to the relative reduction in food intake. A reasonable average of 5800 and 4500 mg/(kg bw*d) is estimated from the experimental data (see Report, Tab. 2 and 3). These estimates largely relate to a mean body weight of 42 g and 45 g for males and females, respectively, from week 15 through 93, which agrees fairly well with the growth curves (comp. Report, Fig. 1 and 2).

In the 2.5 and 5 % groups the food consumption increased, but this was 
accompanied by a decreased body-weight gain in the 5-% group from week 15 through 50 (males, <0.01) and from week 30 through 50 (females, p<0.05). 


No differences in mean body weights were found in the second half of the investigation (see Report Fig. 1 and 2 / Tab. 2 and 3).

No significant difference in survival rats or behaviour was observed. 


No dose-related alteration in hematologic parameters was evident. 


None of the changes in organ weights were sex- or dose-related. 

At the histopathological examination, tumors were found in the 
hematopoietic organs, particularly malignant lymphoma/leukemia, which occurred in 7/20 (38 %) in the female groups of the 2.5 % dose group.  

The results of the Cochran-Armitage test for positive dose-related trends 
in the incidence of tumors were not significant. 



Females: In the lungs, the frequency of adenocarcinomas was 1/16 (6.25 %) 
for the control, 1/19 (5.3 %) for the 1.25-%, 0/20 for the 2.5-%, and 


1/20 (5 %) for the 5-% dosage groups of females (no adenomas). 

Males: In the lungs, the frequency of adenocarcinomas was 1/16 (6.25) for 
the control, 2/17 (11.8 %) for the 1.25-%, 3/14 (21.4 %) for the 2.5-%, 


and 3/16 (18.8 %) for the 5-% dosage groups of males. 

In the liver, the correlation of hyperplastic nodules/hepatocellular 
carcinoma/hemangioma/fibrosarcoma in the treated groups, as compared with 


the control group was relatively low. 

Non-neoplastic lesions were observed in the subcutis, lungs, kidneys, and 
liver in the treated groups.


But these were considered to be of no toxicological significance.
 

Endpoint conclusion
Endpoint conclusion:
no adverse effect observed
Study duration:
chronic
Species:
other: mice and rats
Quality of whole database:
reliability 2

Carcinogenicity: via inhalation route

Endpoint conclusion
Endpoint conclusion:
no study available

Carcinogenicity: via dermal route

Endpoint conclusion
Endpoint conclusion:
no study available

Justification for classification or non-classification

As no carcinogenic potential was observed, there is no need for classification

Additional information

Negative findings in a rat carcinogenicity model after comparative intrapleural treatment with various types of materials (including Silicic acid, aluminum sodium salt (CAS 1344-00-9, NAS)) [Chamberlain 1999] and the absence of a mutagenic potential underline that Silicic acid, aluminum sodium salt (CAS 1344-00-9, NAS) is not cancerogenic.


Negative results were also found after long-term oral administration of the structure-analogous synthetic amorphous silica (SAS) (up to 5 % in the diet given to rats and mice, corresponding to average daily doses of 2000 mg/kg bw in rats and 4500 to 5800 mg/kg bw in mice, female and male, respectively) [Takizawa et al. 1988].


In the synopsis of all studies, it is concluded that there is no evidence of a carcinogenic potential arising from the ingestion of synthetic amorphous Silicic acid, aluminum sodium salt (CAS 1344-00-9, NAS).