Silicon dioxide

Carcinogenicity

Description of key information

The data set compiles 2 studies on different forms of SAS substance (BET range from 90 to 350 m³/g) in animals. 2 Studies conducted in 1988 according to OECD guideline 453 (Klimisch score 2) did not show evidence of significant carcinogenicity after chronic oral application to both rats and mice. No alteration in survival rate, bodyweight, food consumption, behaviour, organ weights or blood chemistry were observed. Gross or microscopic changes or neoplasms were not detected in any of the examined tissues. The NOEL for rats and mice was determined as 5% in the diet.

Key value for chemical safety assessment

Carcinogenicity: via oral route

Link to relevant study records

Reference

Reference 1

Endpoint:

carcinogenicity: oral

Type of information:

experimental study

Adequacy of study:

key study

Study period:

May 7, 1984 - May 8, 1986

Reliability:

2 (reliable with restrictions)

Rationale for reliability incl. deficiencies:

comparable to guideline study with acceptable restrictions

Reason / purpose for cross-reference:

reference to same study

Reason / purpose for cross-reference:

reference to other 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

Specific details on test material used for the study:

Syloid 244

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

Dose / conc.:

12 500 ppm (nominal)

Dose / conc.:

25 000 ppm (nominal)

Dose / conc.:

50 000 ppm (nominal)

No. of animals per sex per dose:

40 - 41

Control animals:

yes, plain diet

Observations and examinations performed and frequency:

daily: survival
weekly: body weight (bi-weekly after week 55), food consumption

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:

mortality observed, non-treatment-related

Description (incidence):

Survival rate was greatest in 5% group, followed by the control, 1.25% and 2.5% dosage groups.

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:

effects observed, non-treatment-related

Description (incidence and severity):

Occasional erratic variations in hematologic profiles were observed in the treated groups: high WBC at 24 months in male groups of 1.25% dosage, and low RBC, HGB, and HCT at 24 months in the female 2.5% dosage group. The very high value for WBC in male rats of the 1.25% group looks as if it had one or two values, perhaps because of technical errors. However, no significance could be attached to the difference.

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

Description (incidence and severity):

lower liver weights in the 2.5% and 55 female dosage groups after 12 and 24 months

Gross pathological findings:

no effects observed

Histopathological findings: non-neoplastic:

not specified

Histopathological findings: neoplastic:

effects observed, non-treatment-related

Description (incidence and severity):

The incidence of tumors was the greatest in the genital organs, next in the skin. The other organs showed relatively low incidence. The histopathological findings of main tumors were as follows:
a. Adenomas/adenocarcinomas of mammary gland were found 7/19 (36.8%) in the control male group, 8/18 (44.4%) in the 1.25% group, 1/18 (5.6%) in the 2.5% group, and 1/17 (5.9%) in dosage male groups. The results of the Cochran-Armitage test for positive dose-related trends in the incidence of tumors of each group were not significant.
b. Seminomas of testes occurred highly in each treated male that died during the period of 12 to 24 months. However, no significance can be attached to these findings.
c. The incidence of clitoral adenomas in male rats varied according to dosage; those in the control group showed the highest value of 10/17 (58.8%), followed by 8/17 (47.1%) for the 1.25% dosage group, 7/20 (35%) for the 2.5% dosage group, and 5/21 (23.8%) for the 5% dosage group. The result of the Cochran-Armitage test for negative dose-related trends in the females was significant (P<0.05). However, the incidences showed no significant differences between the control and treated groups.

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:

50 000 ppm (nominal)

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)
   

Conclusions:

The occasional presence of some neoplasms did not reveal any consistent, dose-related trends in any group. It was concluded that proper dietary administration of micronized silica had proven to be generally safe with no long-term toxic effects.

Executive summary:

A long-term bioassay of chronic toxicity was conducted by orally administering Syloid 244 to rats.

Reference 2

Endpoint:

carcinogenicity: oral

Type of information:

experimental study

Adequacy of study:

supporting study

Study period:

May 7, 1984 - May 8, 1986

Reliability:

2 (reliable with restrictions)

Rationale for reliability incl. deficiencies:

comparable to guideline study with acceptable restrictions

Reason / purpose for cross-reference:

reference to same study

Reason / purpose for cross-reference:

reference to other 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

Specific details on test material used for the study:

Syloid 244

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.

Dose / conc.:

12 500 ppm (nominal)

Dose / conc.:

25 000 ppm (nominal)

Dose / conc.:

50 000 ppm (nominal)

No. of animals per sex per dose:

38-40

Control animals:

yes, plain diet

Observations and examinations performed and frequency:

daily: survival
weekly: body weight (bi-weekly after week 55), food consumption

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:

mortality observed, non-treatment-related

Body weight and weight changes:

effects observed, treatment-related

Description (incidence and severity):

During the initial 61-week period, the control and treated groups grew at essentially the same rate. No significant variations in body weight were observed throughout this study between the control and treated groups of 1.25% and 2.5% dosages. However, at the end of the initial 10-week period (p<0.01), the 5% dosage group showed lower growth rate as compared to the control group. At 81 weeks, an increase in food consumption in the control groups was evident in the treated male groups of 2.5% and 5% dosages. It is of interest to note that increased food consumption in the treated group of 5% dosage was accompanied by decreased body weight.

Food consumption and compound intake (if feeding study):

effects observed, treatment-related

Description (incidence and severity):

s. above

Food efficiency:

not specified

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

not specified

Ophthalmological findings:

not examined

Haematological findings:

effects observed, non-treatment-related

Description (incidence and severity):

The mean HCT and MCV at 12 months in females showed a somewhat lower level in comparison with the normal group. How¬ever, there was no evidence of dose-related alteration of hematologic profiles at the end of the 12- and 21-month treatments.

Clinical biochemistry findings:

not specified

Urinalysis findings:

not examined

Behaviour (functional findings):

no effects observed

Organ weight findings including organ / body weight ratios:

no effects observed

Gross pathological findings:

effects observed, treatment-related

Description (incidence and severity):

Abnormal atrophy or hypertrophy of the organs, which deviated significantly from the limits established by the normal group, was sporadically found only at the end of 6 weeks in the 2.5% and 5% dosage groups. However, none of these changes were sex- or dose-related.

Histopathological findings: non-neoplastic:

effects observed, non-treatment-related

Description (incidence and severity):

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.

Histopathological findings: neoplastic:

effects observed, non-treatment-related

Description (incidence and severity):

Tumors attributed to the treatment of SYLOID were found in the hematopoietic organs, particularly malignant lymphoma/leuiemia, which occurred in 7/ 20 (35%) in the female groups of the 2.5% dosage group. The results of the Cochran- Armitage test for positive dose-related trends in the incidence of tumors were not significant.
In the lungs, the frequency of adenoma/adenocarcinoma 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. The incidence of the lung adenomas in females was greater than that of males. However, none of these findings were sex- or dose-related.
In the liver, the correlation of hyperplastic nodules/hepato cellular carcinoma/ hemangioma/fibrosarcoma in the treated groups, as compared with the control group, was relatively low.

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).

Key result

Dose descriptor:

NOAEL

Remarks:

(highest dose level tested)

Effect level:

50 000 ppm (nominal)

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.
 

Conclusions:

The occasional presence of some neoplasms did not reveal any consistent, dose-related trends in any group. It was concluded that proper dietary administration of micronized silica had proven to be generally safe with no long-term toxic effects.

Executive summary:

A long-term bioassay of chronic toxicity was conducted by orally administering Syloid 244 to mice.

Justification for classification or non-classification

The available studies did not evidence any carcinogenic potential. According to Annex I of the Regulation (EC) 1272/2008 and GHS (Globally Harmonized Classification System), the test substance therefore requires no classification and has no mandatory label requirement.