Cordierite (Mg2[Al4O3(SiO3)5])

Repeated dose toxicity: oral

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:

key study

Reliability:

2 (reliable with restrictions)

Rationale for reliability incl. deficiencies:

other: Study was conducted using a method equivalent to OECD Testing Guideline 453 and meets acceptable scientific standards.

Data source

Reference

Reference Type:

publication

Title:

Oral ingestion of syloid to mice and rats and its chronic toxicity and carcinogenicity.

Author:

Takizawa, Y. 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

Guideline:

OECD Guideline 453 (Combined Chronic Toxicity / Carcinogenicity Studies)

Deviations:

yes

Remarks:

no urinalysis was performed

GLP compliance:

no

Limit test:

yes

Test material

Test material information

Constituent 1

Reference substance name:

Silicon dioxide

EC Number:

231-545-4

EC Name:

Silicon dioxide

Cas Number:

7631-86-9

Molecular formula:

O2Si

IUPAC Name:

dioxosilane

Test material form:

solid: particulate/powder

Remarks:

migrated information: powder

Details on test material:

- Substance name: Syloid 244
- Supplier: Fuji Davison Chemical Ltd, Japan
- Lot/batch No.: JC-2108

Test animals

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: male: 117g to 150g; female: 92.0g to 126g
- Fasting period before study: Not provided
- Housing: 2 animals per cage
- Diet: ad libitum
- Water: ad libitum
- Acclimation period: 2 weeks

ENVIRONMENTAL CONDITIONS
- Temperature: 23 +/- 1°C
- Humidity: 50 +/- 10%
- Air changes (per hr): Not provided
- Photoperiod: 10 hrs dark / 14 hrs light

Administration / exposure

Route of administration:

oral: feed

Vehicle:

unchanged (no vehicle)

Details on oral exposure:

DIET PREPARATION
- Rate of preparation of diet (frequency): weekly

Analytical verification of doses or concentrations:

no

Duration of treatment / exposure:

Duration: 103 weeks. Some specimens were sacrificed after 6 and 12 months.

Frequency of treatment:

Continuous administration through diet.

Doses / concentrations

Remarks:

Doses / Concentrations:
1.25, 2.5 and 5 %
Basis:
nominal in diet

No. of animals per sex per dose:

40 animals per sex for 1.25%, 2.5%, and the control. 41 animals per sex for 5%.

Control animals:

yes, plain diet

Examinations

Observations and examinations performed and frequency:

Physical examinations and observations:
- Survival: daily
- Body weights: weekly for the first 55 weeks then biweekly
- Food consumption: weekly
- Unusual signs: routinely
- Other: some specimen were sacrificed to collect experimental data after 26 and 52 weeks.

Clinical laboratory procedure:
- Haematology: Erythrocytes, haemoglobin, leukocytes, and haematocrit at termination
- Clinical chemistry: aspartate transaminase, alanine transaminase, serum inorganic phosphorus, total protein, albumin, lactic dehydrogenase, alkali phosphatase, total bilirubin, total cholesterol, high density lipoprotein cholesterol, low density lipoprotein cholesterol, triglyceride, , blood urea nitrogen, uric acid, creatinine, and calcium on serum separated from the blood after clotting at termination

Sacrifice and pathology:

- Sacrifice: by etherization after overnight fasting.
- Gross examination: lungs, bronchus, heart, kidneys, liver, spleen, brain, stomach, colon, intestines, pancreas, adrenal glands, pituitary, thyroid, salivary glands, thymus, testes, prostate, bladder, ovaries, uterus, oviducts, femoral bones, mammary glands, skin, and subcutis.
- Microscopic examination: liver, kidneys, spleen, heart, and brain fixed in cold, neutrally-buffered solution of formalin, embedded in paraffin, sectioned, and stained with hematoxylin-eosin

Statistics:

Significance of differences tested by using Student's t-analysis variance test.
Chi-square test of significance (p<0.05) by Mantel-Hanszel was employed to compare the survival date exclusive of sacrificed specimens.
Prevalence rates expressed as percentages of tumor groups and non-tumor groups.
Significance of differences between means of prevalence tested by using Fischer's exact test.
Percentages of frequencies of tumor analyzed by using the Cochran-Armitage test for trend in proportion.

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

Food efficiency:

not examined

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:

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:

CLINICAL SIGNS AND MORTALITY
- Deaths in male groups compared to control group (non-significant)
- Highest survival rates in the 5% group (non dose-related)

FOOD CONSUMPTION AND COMPOUND INTAKE
Mean cumulative intake of the substance at the end of the 103 weeks:
- 1.25%: 143.46g (male) and 107.25g (female)
- 2.5%: 179.55g (male) and 205.02g (female)
- 5%: 581.18g (male) and 435.33g (female)

HAEMATOLOGY
- Sporadic variations in haematologic profiles observed in the treated groups (non-significant)

CLINICAL CHEMISTRY
- Changes observed in aspartate transaminase, albumin, alanine transaminase, lactic dehydrogenase, total protein, total bilirubin, low-density lipoprotein cholesterol, and triglyceride (non biologically significant)
- No changes observed in creatinine, urea, and bilirubin.

ORGAN WEIGHTS
- Lower liver weight noted from 52 weeks to 103 weeks in female rats compared with treated groups dosed at 2.5% and 5% (non sex or dose-related)
- No sex or dose-related hypertrophy or atrophy.

HISTOPATHOLOGY: NEOPLASTIC
- Greatest tumor incidence in genital organs (non significant)
- Relatively low incidence in other organs (non significant)

Effect levels

1

Dose descriptor:

NOAEL

Remarks:

highest dose evaluated

Effect level:

ca. 1 700 - ca. 3 000 mg/kg bw/day (actual dose received)

Sex:

male

Basis for effect level:

other: highest dose evaluated: 5% concentration in diet

2

Dose descriptor:

NOAEL

Remarks:

highest dose evaluated

Effect level:

ca. 1 700 - ca. 3 000 mg/kg bw/day (actual dose received)

Sex:

female

Basis for effect level:

other: highest dose evaluated: 5% concentration in diet

Target system / organ toxicity

Critical effects observed:

not specified

Applicant's summary and conclusion

Conclusions:

The NOAEL was 5% of the substance in diet, which corresponds to a dose between 1700 and 3000 mg/kg bw/day for both male and female and is the highest concentration evaluation during this study.

Executive summary:

Chronic toxicity of the read-across substance silicon dioxide branded as Syloid 244 following an oral exposure was determined according to a method similar to the OECD Guideline for Testing of chemicals 453. Syloid 244 was orally administrated in diet to Fisher rats - which is the preferred species for this study - for 103 weeks at dose levels of 0, 1.25, 2.5, and 5%. Clinical observations were performed routinely throughout the study. Body weight were calculated weekly for the first 55 weeks then biweekly. Food consumption was determined weekly. Haematology and clinical chemistry was performed at termination.

Lungs, bronchus, heart, kidneys, liver, spleen, brain, stomach, colon, intestines, pancreas, adrenal glands, pituitary, thyroid, salivary glands, thymus, testes, prostate, bladder, ovaries, uterus, oviducts, femoral bones, mammary glands, skin, and subcutis were extracted for gross examination. Microscopic examination was performed on liver, kidneys, spleen, heart, and brain.

Animals were sacrificed after 6 and 12 months to obtain additional intermediate data.

No significant or dose-related alterations were observed in food consumption, body and organ weights, haematology, clinical chemistry, and during the histopathology.

The NOAEL was 5% of the substance in diet, which corresponds to a dose between 1700 and 3000 mg/kg bw for both male and female and is the highest concentration evaluation during this study.