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Toxicological information

Repeated dose toxicity: oral

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Administrative data

Endpoint:
chronic toxicity: oral
Remarks:
combined repeated dose and carcinogenicity
Type of information:
migrated information: read-across from supporting substance (structural analogue or surrogate)
Adequacy of study:
weight of evidence
Reliability:
2 (reliable with restrictions)
Rationale for reliability incl. deficiencies:
other: acceptable well documented study report which meets basic scientific principles read-across to synthetic amorphous silica
Cross-reference
Reason / purpose:
reference to same study

Data source

Reference
Reference Type:
publication
Title:
Oral ingestion of Syloid to mice and rats and its chronic toxicity and carcinogenicity.
Author:
Takizawa, Y., Hirasawa, F., et al.
Year:
1988
Bibliographic source:
Acta Medica et Biologica 36 (1): 27-56.

Materials and methods

Test guideline
Qualifier:
equivalent or similar to
Guideline:
OECD Guideline 452 (Chronic Toxicity Studies)
GLP compliance:
not specified

Test material

Reference
Name:
Unnamed
Type:
Constituent
Details on test material:
- Name of test material (as cited in study report): tradename: Syloid 244
- Molecular formula (if other than submission substance): SiO2 x H2O
- Molecular weight (if other than submission substance):
- Smiles notation (if other than submission substance):
- InChl (if other than submission substance):
- Structural formula attached as image file (if other than submission substance): see Fig.
- Substance type:
- Physical state: fine white silica powder
- Analytical purity:
- Impurities (identity and concentrations):
- Composition of test material, percentage of components:
- Isomers composition:
- Purity test date:
- Lot/batch No.: Lot No. JC-2108
- Expiration date of the lot/batch:
- Radiochemical purity (if radiolabelling):
- Specific activity (if radiolabelling):
- Locations of the label (if radiolabelling):
- Expiration date of radiochemical substance (if radiolabelling):
- Stability under test conditions:
- Storage condition of test material:
- Other: Food grade, micronized; source Fuji Davison Chemical Ltd, Japan

Test animals

Species:
other: mice and rats
Strain:
other: B6C3F1 mice and Fisher rats
Sex:
male/female
Details on test animals and environmental conditions:
TEST ANIMALS
- Source: Funabashifarm Animal Co. Ltd, Japan
- Age at study initiation: mice 4 weeks, rats 3 weeks
- Weight at study initiation: male-mice 21.0-27.3 g, female-mice 16.0-19.9 g; male-rats 117-150 g, female-rats 92.0- 126 g
- Fasting period before study:
- Housing: in wire-mesh cages, separated according to sex, 5 mice per cage, 2 rats per cage
- Diet (e.g. ad libitum):
- Water (e.g. ad libitum): tap water ad lipidum
- Acclimation period: 1 week for mice; 2 weeks for rats


ENVIRONMENTAL CONDITIONS
- Temperature (°C): 23.1+-1
- Humidity (%): 50+-10
- Air changes (per hr): air-conditioned
- Photoperiod (hrs dark / hrs light): artifical fluorescent lighting daily for a continuous 14-hour period


IN-LIFE DATES: From: To:

Administration / exposure

Route of administration:
oral: feed
Details on oral exposure:
PREPARATION OF DOSING SOLUTIONS:


DIET PREPARATION
- Rate of preparation of diet (frequency): prepared weekly
- Mixing appropriate amounts with (Type of food):
- Storage temperature of food:


VEHICLE
- Justification for use and choice of vehicle (if other than water):
- Concentration in vehicle:
- Amount of vehicle (if gavage):
- Lot/batch no. (if required):
- Purity:
Duration of treatment / exposure:
93 weeks for mice and 103 weeks for rats
Frequency of treatment:
daily
Doses / concentrationsopen allclose all
Remarks:
Doses / Concentrations:
0, 1.25, 2.5, 5%
Basis:
nominal in diet
Remarks:
Doses / Concentrations:
0, 2500, 5000, 10000 mg/kg bw/day (for mice)
Basis:
nominal in diet
Remarks:
Doses / Concentrations:
0, 625, 1250, 2500 mg/kg bw/day (for rats)
Basis:
nominal in diet
No. of animals per sex per dose:
mice and rats were dined into dosage groups of 10 animals each
Control animals:
yes

Examinations

Observations and examinations performed and frequency:
CAGE SIDE OBSERVATIONS: Yes
- Time schedule: daily for survival
- Cage side observations checked in table [No.?] were included.


DETAILED CLINICAL OBSERVATIONS: Yes / No / No data
- Time schedule:

BODY WEIGHT: Yes
- Time schedule for examinations: with mice 0, 5, 15, 30, 50, 81 and 93 weeks after feeding; with rats 0, 5, 15, 30, 50, 81 and 103 weeks after feeding


FOOD CONSUMPTION AND COMPOUND INTAKE (if feeding study):
- Food consumption for each animal determined and mean daily diet consumption calculated as g food/kg body weight/day: Yes / No / No data
- Compound intake calculated as time-weighted averages from the consumption and body weight gain data: Yes / No / No data


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: Yes / No / No data


WATER CONSUMPTION AND COMPOUND INTAKE (if drinking water study): Yes / No / No data
- Time schedule for examinations:


OPHTHALMOSCOPIC EXAMINATION: No
- Time schedule for examinations:
- Dose groups that were examined:


HAEMATOLOGY: Yes
- Time schedule for collection of blood: 6, 12 and 21 months for mice and 6, 12 and 24 months for rats
- Anaesthetic used for blood collection: Yes (identity) / No / No data
- Animals fasted: Yes / No / No data
- How many animals: 89/160 male mice and 105/158 female mice; 118/161 male rats and 123/161 female rats
- Parameters checked in table [No.?] were examined: erythrocytes (RBC), hemoglobin (Hb), leucocytes (WBC) and hematocrit (Ht)


CLINICAL CHEMISTRY: Yes
- Time schedule for collection of blood: 6, 12 and 21 (mice) or 24 (rats) months
- Animals fasted: Yes / No / No data
- How many animals: 89/160 male mice and 105/158 female mice; 118/161 male rats and 123/161 female rats
- Parameters checked in table [No.?] were examined: aspartate transaminase (AST), alanine transaminase (ALT), serum inorganic phosphorus (IP), total protein (TP), albumin (ALB), lactic dehydrogenase (LDH), alkali phosphatase (ALP), total bilirubin (TB), total cholesterol (T-Cho), high density lipoprotein cholesterol (HDL-C), low density lipoprotein cholesterol (LDL-C), triglyceride (TG), blood urea nitrogen (BUN), uric acid (UA), creatine (Cre), and calcium (CA) on serum separated from the blood after clotting


URINALYSIS: No
- Time schedule for collection of urine:
- Metabolism cages used for collection of urine: Yes / No / No data
- Animals fasted: Yes / No / No data
- Parameters checked in table [No.?] were examined.


NEUROBEHAVIOURAL EXAMINATION: No
- Time schedule for examinations:
- Dose groups that were examined:
- Battery of functions tested: sensory activity / grip strength / motor activity / other:


OTHER:
Sacrifice and pathology:
GROSS PATHOLOGY: Yes
HISTOPATHOLOGY: Yes
Statistics:
The mean and standard deviations of various measured parameters were calculated for each dose group. The significant difference between the control and the compound-treated groups was tested by Student's t-analysis variance test (P<0.05*; P<0.01**). The chi-square test of significance (P<0.05) by Mantel-Hanszel was employed to compare the survival date exclusive of sacrificed specimens. Prevalence rates were cited as percentages of tumor groups and non-tumor groups in cases of post-mortem examination. The significance of differences between the two means of prevalence was tested by Fisher's exact test for fourfold tables. The percentages of the frequencies of tumor in specific tissues were analysed by the Cochrane-Armitage test for linear trend in proportion with continuity correction.

Results and discussion

Results of examinations

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
Water consumption and compound intake (if drinking water study):
not examined
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:
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:

CLINICAL SIGNS AND MORTALITY:
Most of the mice remained in good health, appeared to be active, and showed normal behavior throughout the treatment. No significant difference in survival rates for each group was observed.
In rats, no physical or behavioral signs of pharmacologic effects were observed during the treatment. In male rats over a perioid of 48 weeks, the mean survival rates in treated groups was greatest in the 5%, followed by the control and 1.25 or 2.5% dosage groups. However, the variations were not significant between the control and treated groups. While the female survival rates of 5%, 2.5%, and 1.25% groups were 0.875, 0.80, and 0.65 respectively, these were not statisticall and significantly different from the values observed in the control group.

BODY WEIGHT AND WEIGHT GAIN:
In mice, during the initial 61-week period, the control and treated groups grew at essentially the same rate. No significant variation 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, 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. Increased food consumption in the treated group of 5% dosage was accompanied by decreased body weight.
In rats, no consistent compound- or dose-related changes in growth rates were evident.

FOOD CONSUMPTION AND COMPOUND INTAKE (if feeding study):
In mice, the mean cumulative intake of SYLOID at the end of 93 weeks in the 1.25, 2.5 and 5% dietary levels was 38.45, 79.78 and 160.23 g/mouse in males, and 37.02, 72.46 and 157.59 g/mouse in females, respectively.
In rats, the mean cumulative intake of SYLOID at the end of 103 weeks for the 1.25, 2.5 and 5% dietary levels was 143.46, 179.55 and 581.18 g/rat in males, and 107.25, 205.02 and 435.33 g/rat in females, respectively.


FOOD EFFICIENCY

HAEMATOLOGY:
In mice, the mean HCT and MCV at 12 months in female mice showed a somewhat lower level in comparison with the normal group. However, there was no evidence of dose-related alteration of hematological profiles at the end of the 12- and 21-month treatments.
In rats, 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 has one or two values, perhaps because of technical errors. However, no significance can be attached to the difference.

CLINICAL CHEMISTRY: In rats, no biologically meaningful changes in TA, ALB, AST, ALT, ALP, T-BL and LDH were observed, although transient differences reaching statistical significance were frequently present. No noteworthy changes related to compound ingestion were observed in any parameters of renal analyses, such as BUN, CRE and UA.

ORGAN WEIGHTS: No noted atrophy or hypertrophy of the organs in each group was sex- or dose-related.


GROSS PATHOLOGY


HISTOPATHOLOGY: NON-NEOPLASTIC:
In mice, non-neoplastic lesions were observed in the subcutis, lungs, kidneys, and liver in the treated groups. These were considered to be of no toxicological significance.

HISTOPATHOLOGY: NEOPLASTIC (if applicable):
In mice, tumours 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 groups (not scientifically 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 hyperplasic nodules/hepato cellular carcinoma/hemangioma/fibrosarcoma in the treated groups, as compared with the control group, was relatively low.
In rats, the incidence of tumors was the greatest in the genital organs, next in the skin. The other organs showed relatively low incidence.
The occasional presence of some neoplasms did not reveal any consistent, dose-related trends in any group.


HISTORICAL CONTROL DATA (if applicable)


OTHER FINDINGS

Effect levels

open allclose all
Dose descriptor:
NOAEL
Remarks:
the highest dose tested
Effect level:
10 000 mg/kg bw/day (nominal)
Sex:
male/female
Basis for effect level:
other: for mice; Syloid
Dose descriptor:
NOAEL
Remarks:
the highest dose tested
Effect level:
2 500 mg/kg bw/day (nominal)
Sex:
male/female
Basis for effect level:
other: for rats; Syloid

Target system / organ toxicity

Critical effects observed:
not specified

Applicant's summary and conclusion

Conclusions:
Proper dietary administration of micronized silica (Syloid 244) was proven to be generally safe with no long-term effects.
Executive summary:

Food grade micronized silica gel (SYLOID®) was given in a feed to B6C3F1 mice and Fisher rats at dose levels of 0, 1.25, 2.5, and 5% (≈ 0, 2,500, 5,000, 10,000 mg/kg/day for mice and 0, 625, 1,250, 2,500 mg/kg/day for rats) for 93 and 103 weeks, respectively (Takizawa et al. 1988). Measurements: physical examinations and observations, clinical chemistry, post-mortem examination. There were no biological or any other meaningful alterations in body weight, food consumption or physical features of the exposed animals. No significant dose-related effects were seen at any dose level upon clinical laboratory examinations. The pathological examinations revealed no gross or microscopic changes in the tissues examined. The occasional presence of some neoplasms did not reveal any consistent, dose-related trends in any group.