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Toxicological information

Repeated dose toxicity: oral

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Administrative data

Endpoint:
short-term repeated dose toxicity: oral
Type of information:
migrated information: read-across from supporting substance (structural analogue or surrogate)
Adequacy of study:
supporting study
Reliability:
2 (reliable with restrictions)
Rationale for reliability incl. deficiencies:
other: Basic data given

Data source

Reference
Reference Type:
publication
Title:
Characterization and toxicological behavior of synthetic amorphous hydrophobic silica
Author:
Lewinson, J. et al.
Year:
1994
Bibliographic source:
Regul Toxicol Pharmacol. 20(1 Pt 1):37-57

Materials and methods

Principles of method if other than guideline:
Repeated dose 35- and 56-day oral toxicity in rodents
GLP compliance:
not specified

Test material

Reference
Name:
Unnamed
Type:
Constituent
Details on test material:
- Name of test material (as cited in study report): Aerosil R 972 (Fumed Hydrophobic Silica)
- Analytical purity: >99.8%

Test animals

Species:
rat
Strain:
Wistar
Sex:
male/female
Details on test animals and environmental conditions:
TEST ANIMALS
- Weight at study initiation: 120 +/- 5 g and 130 +/-5 g (group identity unspecified)
- Diet (e.g. ad libitum): powder diet Altromin (Altromin GmbH, Germany)
- Water (e.g. ad libitum): ad libitum


ENVIRONMENTAL CONDITIONS
- Temperature (°C): 23 +/- 2

Administration / exposure

Route of administration:
oral: feed
Vehicle:
unchanged (no vehicle)
Details on oral exposure:
DIET PREPARATION
- Rate of preparation of diet (frequency): weekly
- Mixing appropriate amounts with (Type of food): The test substance was mixed with the powder diet Altromin, supplied by Fa. Altromin GmbH, taking into account the increasing body weight and the decreasing food intake of the animals.
Analytical verification of doses or concentrations:
not specified
Duration of treatment / exposure:
5 weeks in the low- and mid-dose groups and 8 weeks in the high-dose group
Frequency of treatment:
continuous
Doses / concentrationsopen allclose all
Remarks:
Doses / Concentrations:
0, 500, 1000, 2000 mg/kg bw
Basis:
nominal in diet
Remarks:
Doses / Concentrations:
4000 mg/kg bw
Basis:
nominal in diet
Remarks:
Doses / Concentrations:
8000 mg/kg bw
Basis:
nominal in diet
Remarks:
Doses / Concentrations:
16000 mg/kg bw
Basis:
nominal in diet
No. of animals per sex per dose:
10
Control animals:
yes, plain diet
Details on study design:
- Dose selection rationale: The administered doses were 0, 500,1000, and 2000 mg/kg bw. Because the animals tolerated 2000 mg/kg bw, the high dose was elevated to 4000 mg/kg bw after 14 days, to 8000 mg/kg bw after another 14 days, and finally to 16000 mg/kg bw.

Examinations

Observations and examinations performed and frequency:
CAGE SIDE OBSERVATIONS: Yes
- Time schedule: daily


BODY WEIGHT: Yes
- Time schedule for examinations: weekly


FOOD CONSUMPTION AND COMPOUND INTAKE (if feeding study):
- Time schedule for examinations: daily and weekly


HAEMATOLOGY: Yes
- Time schedule for collection of blood: At the beginning and at the end of the experiment
- Anaesthetic used for blood collection: Yes (ether)
- How many animals: 5 animals from each group
- Parameters examined: hemoglobin, erythrocytes, leukocytes, and blood smear
Sacrifice and pathology:
GROSS PATHOLOGY: Yes
HISTOPATHOLOGY: Yes. Kidney and liver samples were fixed in 10% formalin and stained with hematoxylin/eosin after Hotchkiss (PAS staining).

Results and discussion

Results of examinations

Details on results:
CLINICAL SIGNS AND MORTALITY
Only after the stepwise increase of the high dose to 16000 mg/kg bw (corresponding to approximately 25% of the daily food intake) were treatment-related effects observed. These included shyness, dirty fur, reduced activity, cachexia, and hemorrhage in the mucous membranes of the eyes and nose. Two males and two females died with severe cachexia in week 8 (days 9 and 13 after administration of 16000 mg/kr bw).

BODY WEIGHT AND WEIGHT GAIN
The administration of 16000 mg/kg bw caused a pronounced reduction of the body weight. After a dose of 8000 mg/kg bw, the body weight was only slightly influenced.

FOOD CONSUMPTION AND COMPOUND INTAKE (if feeding study)
The administration of 16000 mg/kg bw caused decreased food intake.

HAEMATOLOGY
No significant changes were observed in the examined hematological parameters.

GROSS PATHOLOGY
No significant changes were observed after macroscopic evaluation of the treated animals.

HISTOPATHOLOGY: NON-NEOPLASTIC
Microscopic examinations of the liver of rats consuming the highest doses (2000-16000 mg/kg bw) revealed severe atrophy in the epithelium of the liver. Condensation of the cytoplasm, loss of the basophilic structure and hyperchromatic and contracted nuclei occurred in the liver cells. Glycogen could not be detected with PAS staining. To a lesser degree these changes were sporadically seen in two females of the mid-dose group (1000 mg/kg bw). No treatment-related changes were found in the kidneys of any animal. No treatment-related effects were observed in the low-dose group (500 mg/kg bw).

Effect levels

open allclose all
Dose descriptor:
NOEL
Effect level:
500 mg/kg bw/day (nominal)
Sex:
male/female
Dose descriptor:
LOEL
Effect level:
1 000 mg/kg bw/day (nominal)
Sex:
female
Basis for effect level:
other: sporadical histopathological changes in the liver (atrophy of the epithelium, decrease of the basophilic nuclei and of the glycogen content)

Target system / organ toxicity

Critical effects observed:
not specified

Applicant's summary and conclusion

Conclusions:
The results of this study demonstrate that the lethal dose range begins at approximately 16000 mg/kg bw for hydrophobic silicas. It should be noted that the acceptance of the treated diet was strongly reduced and that the fraction of the test substance in the diet amounted to approximately 25% by weight. Malnutrition can also cause changes similar to those found, such as weight loss, cachexia, and decrease of the glycogen content in the liver cells. Therefore, it is not clear wether the test substance in a very high dose, the reduced food intake, or the two combined caused the described effects. At a dose of 1000 mg/kg bw in two female rats, similar histopathological changes in the liver (atrophy of the epithelium, decrease of the basophilic nuclei and of the glycogen content) were sporadically found in a slighter degree than in the high-dose group animals. Therefore, the lowest-observed effect level (LOEL) in this study was 1000 mg/kg bw and the no-observed effect level (NOEL) was 500 mg/kg bw.