Registration Dossier

Administrative data

Description of key information

NOAEL (rats) = 159 mg/kg bw/day 

Key value for chemical safety assessment

Repeated dose toxicity: via oral route - systemic effects

Link to relevant study records

Referenceopen allclose all

Endpoint:
sub-chronic toxicity: oral
Type of information:
experimental study
Adequacy of study:
key study
Reliability:
2 (reliable with restrictions)
Rationale for reliability incl. deficiencies:
other: see 'Remark'
Remarks:
Only two standard parameters were studied: body weight and survival. Background concentration in the diet varied between 0.1 and 1.0% of SiO2 (w/w). Nitrogen and phosphorous retention/excretion was measured only in the males at the end of the exposure period.
Principles of method if other than guideline:
Oral exposure of weanling rats via drinking water for 180 days.
The study was conducted to assess the influence of silica in the diet on growth and nutrient balance.
GLP compliance:
no
Species:
rat
Strain:
Sprague-Dawley
Sex:
male/female
Details on test animals or test system and environmental conditions:
TEST ORGANISMS
- Age: Weanling
Route of administration:
oral: drinking water
Vehicle:
water
Duration of treatment / exposure:
180 d (m-f) + 17 days (m)
Frequency of treatment:
daily
Remarks:
Doses / Concentrations:
789.5 and 1587 mg sodium  silicate/L
Basis:
nominal in water
Remarks:
Doses / Concentrations:
600 and 1200 mg SiO2/l
Basis:

No. of animals per sex per dose:
6
Control animals:
yes
Details on study design:
Post-exposure period: no
Observations and examinations performed and frequency:
CLINICAL OBSERVATIONS AND FREQUENCY: 
- Mortality: registered with unknown frequency
- Body weight: registered every week
- Urinalysis: nitrogen and phosphorous registered daily from day 181-197 in males. 
Other examinations:
Analysis of faeces: nitrogen and phosphorous registered daily from day 181-197 in males.
Dose descriptor:
NOAEL
Effect level:
> 159 mg/kg bw/day (nominal)
Sex:
male/female
Basis for effect level:
other: no effects observed
Critical effects observed:
not specified

TOXIC RESPONSE/EFFECTS BY DOSE LEVEL: 
- Mortality and time to death: None
- Clinical signs: no effects
- Body weight gain: Some statistically significant differences in body weight between experimental groups and controls were registered, but these were small (6% or less), not consistent and not dose related.
- Urinalysis: significant, but not dose-related effects on nitrogen and  phosphorus retention (p<0.05)
- Other: In the male low dose group nitrogen retention was 50% lower that in the control group, while in the high dose
group no such difference was observed. In a repeat experiment no clear and significant differences in nitrogen
retention were found. In both experiments phosphorous retention seemed somewhat increased in the male high dose
groups (approximately 12%), while in the low dose groups no effect of treatment was seen.

Endpoint:
sub-chronic toxicity: oral
Type of information:
experimental study
Adequacy of study:
key study
Reliability:
2 (reliable with restrictions)
Rationale for reliability incl. deficiencies:
other: Study performed according to basic scientific principles.
Qualifier:
equivalent or similar to guideline
Guideline:
OECD Guideline 408 (Repeated Dose 90-Day Oral Toxicity Study in Rodents)
Deviations:
not specified
GLP compliance:
no
Limit test:
no
Species:
rat
Strain:
Wistar
Sex:
male/female
Details on test animals or test system and environmental conditions:
TEST ORGANISMS
- Age: 7 weeks
Route of administration:
oral: drinking water
Vehicle:
water
Analytical verification of doses or concentrations:
not specified
Duration of treatment / exposure:
3 months
Frequency of treatment:
daily
Remarks:
Doses / Concentrations:
200, 600 and 1800 ppm
Basis:
nominal in water
No. of animals per sex per dose:
5
Control animals:
yes
Observations and examinations performed and frequency:
- Clinical signs: daily
- Mortality: daily
- Body weight: once a week
- Food consumption: once a week
- Water consumption: measured daily 
- Haematology: after the test period erythrocytes and leukocytes were counted, hemoglobin value, blood cell volume and leukocyte percentage
- Biochemistry:  after the test period gamma-GOT, gamma-GPT and alkali phosphatase activity measurement
- Urinalysis: after the test period measurements were made on pH-value, sugar, protein, ketone and blood value.
Sacrifice and pathology:
- Macroscopic: wet weight of liver, kidney, heart, lung, spleen, suprarenal glands, thymus, thyroid gland, testicles and ovaries. Also dissected: pancreas, intestines, stomachs, bone marrow.
- Microscopic: liver, kidney, heart, lung, spleen, suprarenal glands, thymus, thyroid gland, testicles and ovaries were fixed with 10% formalin, packed in paraffin, cut into thin sections and subjected to hematoxylin and eosin staining.
Dose descriptor:
NOAEL
Effect level:
> 227 - 237 mg/kg bw/day (nominal)
Sex:
male/female
Basis for effect level:
other: overall effects
Critical effects observed:
not specified

No clearly treatment related effects at tested dose levels of 200, 600 and 1800 ppm (corresponding to 26.4, 76.2 and
227.1 mg/kg/day, respectively, for males; and 32.1, 97.6 and 237.2  mg/kg/day, respectively, for females).


TOXIC RESPONSE/EFFECTS BY DOSE LEVEL: 
- Mortality and time to death: None
- Clinical signs: No effects
- Body weight gain: No effects
- Food/water consumption: No effects
- Clinical chemistry: No effects
- Haematology: No effects
- Urinalysis: No effects
- Organ weights: No effects
- Gross pathology: No effects
- Histopathology: Except for the kidneys, no morphological changes have  been observed in the organs examined. The observed

histological changes in the kidneys (tubule wall calcinosis, glomerular swelling, tubule  swelling, weakening of the renal tubule cell

walls and dilation of the  tubule lumen) were not dose-related and occurred also in the controls.  Cylindrical inclusions in the renal

tubular cells were only observed in  the medium dosage group.

Endpoint:
sub-chronic toxicity: oral
Type of information:
experimental study
Adequacy of study:
key study
Reliability:
2 (reliable with restrictions)
Rationale for reliability incl. deficiencies:
other: Study performed according to basic scientific principles, study report is unclear in some points.
Principles of method if other than guideline:
no data
GLP compliance:
no
Limit test:
no
Species:
mouse
Strain:
other: ddy
Sex:
male/female
Details on test animals or test system and environmental conditions:
TEST ORGANISMS
- Age: 4 weeks
Route of administration:
oral: drinking water
Vehicle:
water
Analytical verification of doses or concentrations:
not specified
Duration of treatment / exposure:
90 days
Frequency of treatment:
continuously
Remarks:
Doses / Concentrations:
300, 900, 2700 ppm (males), 333, 1000, 3000 ppm (females)
Basis:
nominal in water
No. of animals per sex per dose:
10
Control animals:
yes
Details on study design:
Post-exposure period: no
Observations and examinations performed and frequency:
CLINICAL OBSERVATIONS AND FREQUENCY: 
- Clinical signs: registered once daily
- Mortality: registered once daily
- Body weight: registered once a week
- Food consumption: registered once a week
- Water consumption: registered twice a week
- Haematology: erythrocyte count, leucocyte count, haemoglobin, haematocrit, blood serum protein content, leucocyte composition.
- Biochemistry: S-GOT, S-GTP, S-AlP (alkali phosphatase), bilirubin, blood glucose, BUN, cholesterol, A/G, potassium, sodium, chloride.
- Urinalysis: performed at the end of the study. pH, sugar (assumed to be glucose), protein, ketone, blood concentration, urinobilinogen.
Sacrifice and pathology:
ORGANS EXAMINED AT NECROPSY (MACROSCOPIC AND MICROSCOPIC): 
- Macroscopic: the wet weight of liver, kidney, spleen, suprarenal glands, thyroid glands, testicles, pituitary glands, heart, lung, brain, ovary was registered. The organs of the thoracic and abdominal cavity were examined macroscopically
- Microscopic: liver, kidney, spleen, suprarenal glands, thyroid glands, testicles, pituitary glands, heart, ovary, lung, brain, pancreas, stomach, duodenum, jejenum, ileum, cecum, rectum, urinary bladder, prostate, uterus, mammary glands, arteries, bone marrow, lymphatic glands were fixed in 10% formalin, packed in paraffin, cut into thin sections, subjected to haematoxylin and eosin staining and examined microscopically
Dose descriptor:
NOAEL
Effect level:
260 - 284 mg/kg bw/day (nominal)
Sex:
male/female
Basis for effect level:
other: overall effects
Dose descriptor:
LOAEL
Effect level:
716 - 892 mg/kg bw/day (nominal)
Sex:
male/female
Basis for effect level:
other: organ weights
Critical effects observed:
not specified

ACTUAL DOSE RECEIVED BY DOSE LEVEL BY SEX: 
males:
nominal dose   300       900       2700 ppm
actual intake  2.4-2.5   6.6-7.0   19.4-20.8 mg/animal/d
actual dose    96-100    264-280   776-832 mg/kg bw/d

females:
nominal dose   333       1000      3000 ppm
actual intake  2.2-2.6   6.5-7.1   17.9-22.3 mg/animal/d
actual dose    88-104    260-284   716-892 mg/kg bw/d
(calculations are based on an average body weight for mice of 25 g)

- Time of death: no mortality
- Number of deaths at each dose: no mortality


TOXIC RESPONSE/EFFECTS BY DOSE LEVEL: 
- Mortality and time to death: no mortality
- Clinical signs: no treatment-related effects
- Body weight gain: no treatment-related effects 
- Food/water consumption: there were no effects on food and water consumption. 
- Clinical chemistry: no effects 
- Haematology: There was an increase of the haematocrit level in the female high dose group. The leucocyte count in females
was significantly reduced in the low and medium dose group, and reduced in the highest dose group.
- Urinalysis: the protein concentration in all female exposure groups was slightly increased compared with the control group.
- Organ weights: the relative pituitary gland weight in females was reduced in all dose groups compared to the control, statistically significant only in the highest dose group. The relative liver weight in males was increased in all dose groups comparedto control group,significantly in the low and medium

dose group. With respect to the reproductive organs examined, the following wet  weights (g) were determined:

                   Testes             Ovaries
               right    left       right   left

control        0.13     0.14       8.4     7.3
2700 ppm     0.14     0.14       7.7     7.4
900 ppm       0.13     0.13       9.7     9.1
300 ppm       0.13     0.12       8.3     8.4

- Gross pathology: see histopathology
- Histopathology: no treatment-related effects

Additional information

Oral

Repeated oral dose toxicity studies with sodium silicate or sodium metasilicate ranging from 4 weeks to 180 days have been conducted with rats, mice, dogs and turkeys. Here, only the most relevant subchronic studies are described:

While in rats no treatment-related effects were noted, in female mice, a reduced pituitary glands weight was observed at 716 - 892 mg/kg bw/d (sodium metasilicate; 3 months exposure).

From these studies a NOAEL (90 d) of 227 - 237 mg/kg bw/d can be derived for rats. The NOAEL (90 d) for mice is 260 - 284 mg/kg bw/d. The NOAEL (180 d) for rats is 159 mg/kg bw/d.

Justification for classification or non-classification

The available data are conclusive but not sufficient for classification.