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Toxicological information

Repeated dose toxicity: oral

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Administrative data

Endpoint:
chronic toxicity: oral
Type of information:
experimental study
Adequacy of study:
key study
Reliability:
2 (reliable with restrictions)
Rationale for reliability incl. deficiencies:
other: Comparable to guideline study, based on scientific standards, documentation limited, acceptable for assessment
Cross-reference
Reason / purpose:
reference to same study

Data source

Referenceopen allclose all

Reference Type:
other company data
Title:
Unnamed
Year:
1953
Report Date:
1953
Reference Type:
study report
Title:
Unnamed
Year:
1956
Report Date:
1956

Materials and methods

Test guideline
Qualifier:
equivalent or similar to
Guideline:
OECD Guideline 452 (Chronic Toxicity Studies)
Deviations:
yes
Remarks:
limited group size (15 + 15); limited examinations
GLP compliance:
no

Test material

Reference
Name:
Unnamed
Type:
Constituent
Details on test material:
- Name of test material (as cited in study report): Silene EF
- Substance type: inorganic
- Physical state: solid; white powder
- Analytical purity:
- Impurities (identity and concentrations):
- Composition of test material, percentage of components: SiO2 (64 %); CaO (18 %); Al2O3 (0.6 %); MgO (0.1 %); NaCl (1.5 %);
- loss at 105 °C: 5 %
- loss on ignition: 15 %
- pH ~10 (5 % water suspension)
- surface area: 80 m2/g

Test animals

Species:
rat
Strain:
other: albino, Carworth Farm strain
Sex:
male/female
Details on test animals and environmental conditions:
TEST ANIMALS
- Source:
- Age at study initiation: weanling
- Weight at study initiation: averages 70 - 73 g (m, f)
- Fasting period before study: no
- Housing: individual
- Diet: ad libitum
- Water: ad libitum
- Acclimation period: no data


ENVIRONMENTAL CONDITIONS: no data

Administration / exposure

Route of administration:
oral: feed
Vehicle:
other: gelatine (15 g/100 mL water)
Details on oral exposure:
DIET PREPARATION
- Rate of preparation of diet (frequency): weekly
- Particular measures: Based on results from the pre-test, the test compound had be administered in moist form
in order to suppress its alkalinity and dustability
- Mixing appropriate amounts: Appropriate amounts of the Silene-gelatine mixtures were mixed
with the basic diet in a twin-shell blender on w/w basis.
The amount of gelatine added to all diets including controls remained constant
throughout the whole experiment.

- Storage temperature of food: no data

- Dosage regimen: The high-dose groups had accustom to the diet containing higher levels of Silene:
Therefore, gradual increase in Silene content:
7.5% group: increase from 5 to 7.5 % after 3 wks;
10% group: increase from 5 to 7.5 % after 3 wks, further increase from 7,5 to 10 % after 10 wks.


Analytical verification of doses or concentrations:
no
Duration of treatment / exposure:
2 years
Frequency of treatment:
continuous
Doses / concentrations
Remarks:
Doses / Concentrations:
1.0, 5.0, 7.5, and 10 % (w/w) in feed, 7.5 and 10 % after an acclimation period to higher levels (see "Diet Preparation" above)
Basis:
nominal in diet
No. of animals per sex per dose:
15
Control animals:
yes, concurrent vehicle
Details on study design:
Post-exposure period: no data

Examinations

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


DETAILED CLINICAL OBSERVATIONS: Yes
- Time schedule:


BODY WEIGHT: Yes (see report, Table 41, 43, )
- Time schedule for examinations: weekly


FOOD CONSUMPTION AND COMPOUND INTAKE (if feeding study) (see Report, Table 42, 44, 45)
- Food consumption for each animal determined and mean daily diet consumption calculated as g food/kg body weight/day: Yes (Table 45 + 46)
- Compound intake calculated as time-weighted averages from the consumption and body weight gain data: Yes (Table 45)


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 (Report, Table 46: for wks 0 - 26 and 0 - 52)


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


OPHTHALMOSCOPIC EXAMINATION: No


HAEMATOLOGY: Yes
- Time schedule for collection of blood: start, 13, 52 and 104 wks
- Anaesthetic used for blood collection: No data
- Animals fasted: No
- How many animals: start (5 m, 5 f), 13, 52 and 104 wks (3 m, 3 f each group and interval)
- Parameters checked in table 47 were examined: hemoglobin, total red and white blood cell count, differential leukocyte picture


CLINICAL CHEMISTRY: No data


URINALYSIS: Yes (pH measurement)
- Time schedule for collection of urine: during wk 102
- Metabolism cages used for collection of urine: No, individually, in void urine of 5 m and 5 f of each group
- Animals fasted: No
- Parameters checked in table 48 were examined: pH


NEUROBEHAVIOURAL EXAMINATION: No


OTHER:
ANALYSIS of the FECES (see Report, Table 49)
- silicon dioxide content: prior to termination of the experiment

ANALYSIS of TISSUE Sections (see Report, Table 52)
- silicon dioxide content: upon termination of the experiment
(kidney, liver, spleen, cardiac muscle, skeletal muscle, and testes:
from 6 m and 6 f of each dose level, tissues of 3 animals of each sex pooled for analysis (2 replicates)
Sacrifice and pathology:
GROSS PATHOLOGY: Yes

ORGAN WEIGHTS: Yes (see table 51)
liver, kidneys, and spleen (both sexes, each group)

HISTOPATHOLOGY: Yes (see table 50)
Tissues from 6 m and 6 f each dose level and control preserved in formalin:
thyroid, lung, heart, liver, kidney, stomach, large and small intestine, pancreas, spleen,
adrenal, urinary bladder, gonads, bone marrow, and skeletal muscle
Statistics:
no data, arithmetic means plus S.D., Fisher Student test for pH in urine

Results and discussion

Results of examinations

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):
effects observed, treatment-related
Food efficiency:
effects observed, treatment-related
Water consumption and compound intake (if drinking water study):
not examined
Ophthalmological findings:
not examined
Haematological findings:
no effects observed
Clinical biochemistry findings:
not specified
Urinalysis findings:
effects observed, treatment-related
Behaviour (functional findings):
not examined
Organ weight findings including organ / body weight ratios:
no effects observed
Gross pathological findings:
effects observed, treatment-related
Histopathological findings: non-neoplastic:
no effects observed
Histopathological findings: neoplastic:
no effects observed
Details on results:
CLINICAL SIGNS AND MORTALITY
survival comparable to controls for all dose groups (Tab. 45)
Prior to death: weight loss and signs of pneumonitis in majority of animals due to overwhelming respiratory infection


BODY WEIGHT AND WEIGHT GAIN
1 %: comparable to control (m + f)
5 %: males with very slight retardation, not statistically significant;
females with growth retardation until wk 52, from wk 78 - 80 comparable to control
7.5 %: males with significant growth retardation (bw approx. -9 % at termination)
females comparable to development in the 5% group
10 %: males and females significant growth retardation, less pronounced in females (bw approx. -11 % for males at termination)


FOOD CONSUMPTION AND COMPOUND INTAKE (if feeding study)
Food consumption increased at 5 % and higher due to the increase in inert fraction in the diet.
Compound intake: mean daily intake calculated per rat based on food consumption

FOOD EFFICIENCY
decreased dose-related:
1 %: no significant difference from the control, or only slight decreasing trend (Table 46)
5 %: ~90 % of control (m); ~85 % of control (f)
7.5 % ~82 % of control (m); ~75 % of control (f)
10 % ~70 % of control (m); ~70 % of control (f)


URINALYSIS
slightly increasing trend in the high-dose groups as compared to controls (Teb. 48).


ORGAN WEIGHTS
no effect discernible (Tab. 51)


GROSS PATHOLOGY
1 and 5%: No gross lesions attributable to the treatment
10 % level: Calculi consisting of high concentration of CaCO3 and some SiO2 in the intestine or
brittle in the urinary bladder in isolated cases, which may have caused the animals´death.
7.5 and 10 % level: Supply of body fat somewhat less than of controls
Bile-duct dilations and dilation of the portal vein (histologically: impression of cholangitis)
in isolated cases (not noted in other groups);
tissue nodules in the liver in isolated cases (not noted in other groups).


HISTOPATHOLOGY: NON-NEOPLASTIC
comparable to controls



OTHER FINDINGS

SILICON in TISSUES (see also 7.1 Toxikokinetics...)
There was a dose-related increase of Si in the kidney and liver, but not in the other organs examined:
The increase was more marked in males than in females.

Kidney at 5 % level: approx. 3x background (m), no or only slight increase (f)
at 10 % level: approx. 20x background (m), approx. 15x background (f)

Liver at 5 % level: approx. 2x background (m), no or only slight increase (f)
at 10 % level: approx. 3x background (m), approx. 3x background (f)




Effect levels

open allclose all
Dose descriptor:
NOAEL
Effect level:
5 other: % in diet
Sex:
male/female
Dose descriptor:
LOAEL
Effect level:
7.5 other: % in diet
Sex:
male/female
Basis for effect level:
other: body weight; gross pathology
Dose descriptor:
NOAEL
Effect level:
ca. 2 500 - ca. 3 200 mg/kg bw/day (nominal)
Sex:
male/female
Basis for effect level:
other: estimated from Report: Compound consumed per rat (Tab. 45) related to mean body weights (Tables 43 and 44)

Target system / organ toxicity

Critical effects observed:
not specified

Applicant's summary and conclusion