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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:
key study
Reliability:
2 (reliable with restrictions)
Rationale for reliability incl. deficiencies:
other: Comparable to guideline study with acceptable restrictions.
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. 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 453 (Combined Chronic Toxicity / Carcinogenicity Studies)
Deviations:
yes
Remarks:
- Group size was 10 animals/sex/dose at interim kills instead of 20 each. At terminal sacrifice 20/sex/dose as recommended. Urinanalysis not performed.
GLP compliance:
not specified
Limit test:
no

Test material

Reference
Name:
Unnamed
Type:
Constituent
Type:
Constituent
Details on test material:
- Name of test material (as cited in study report): Syloid 244, produced by Fuji Davidson Chemical Ltd.
- Physical state: fine white powder
- Analytical purity: no data
- Lot/batch No.: Lot No. JC-2108v

Test animals

Species:
rat
Strain:
Fischer 344
Sex:
male/female
Details on test animals 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)
- Housing: 2 rats/cage
- Diet: ad libitum
- Water: tap water; ad libitum
- Acclimation period: 2 weeks


ENVIRONMENTAL CONDITIONS
- Temperature (°C): 23 ± 1
- Humidity (%): 50 ± 10 %
- Photoperiod (hrs dark / hrs light): 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:
103 weeks, interim kill after 6 and 12 months (10 animals each)
Frequency of treatment:
daily
Doses / concentrations
Remarks:
Doses / Concentrations:
1.25, 2.5 and 5 %
Basis:
nominal in diet
No. of animals per sex per dose:
10
Control animals:
yes, concurrent no treatment
Details on study design:
Rats were separated according to sex, and by standard randomisation 2 rats were put in one cage. Rats were dined into dosage groups of 10 animals each.

Examinations

Observations and examinations performed and frequency:
CAGE SIDE OBSERVATIONS: Yes
- Time schedule: daily for survival and clinical signs


BODY WEIGHT: Yes
- Time schedule for examinations: weekly for the first 55 weeks, thereafter every two weeks


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 (weekly)
- Compound intake calculated as time-weighted averages from the consumption and body weight gain data: Yes


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


WATER CONSUMPTION AND COMPOUND INTAKE (if drinking water study): No data


OPHTHALMOSCOPIC EXAMINATION: No

HAEMATOLOGY: Yes
- Time schedule for collection of blood: 6, 12, and 24 months
- Parameters checked in table 9-1/9-2 were examined.


CLINICAL CHEMISTRY: yes (see Report p. 30)
- Time schedule for collection of blood: 6, 12 and 24 months

URINALYSIS: No


NEUROBEHAVIOURAL EXAMINATION: No


Sacrifice and pathology:
GROSS PATHOLOGY: Yes
HISTOPATHOLOGY: Yes
Statistics:
Student´s t-analysis variance test / Chi square test of Mantel-Hanszel for survival
Fisher´s exact test and Cochran-Armitage test for trend

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 specified
Water consumption and compound intake (if drinking water study):
not specified
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:
SUBSTANCE UPTAKE
The mean cumulative intake after 103 weeks 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) .

ORGAN WEIGHTS
Lower liver weights were noted from 12 to 24 months in the female 2.5 and 5 % dose groups (p =<0.01) (see Report Tab. 10-2).

HISTORICAL CONTROL DATA (if applicable): no data


Effect levels

open allclose all
Dose descriptor:
NOAEL
Effect level:
1 760 - 3 000 other: mg/kg bw and day
Sex:
male
Basis for effect level:
other: Daily intake of Syloid was distinctly higher in the initial phase of the lifespan study due to the body weights of the grow up animals.
Dose descriptor:
NOAEL
Effect level:
1 780 - 3 210 other: mg/kg bw and day
Sex:
female
Basis for effect level:
other: Daily intake of Syloid was distinctly higher in the initial phase of the lifespan study due to the body weights of the grow up animals.

Target system / organ toxicity

Critical effects observed:
not specified

Any other information on results incl. tables

The reduced liver weights in females (approx. -7 and -15 % after 12 and 24 months, respectively, independent of the dose) are not considered to be pathologically relevant.

Applicant's summary and conclusion