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EC number: 231-545-4 | CAS number: 7631-86-9
- Life Cycle description
- Uses advised against
- Endpoint summary
- Appearance / physical state / colour
- Melting point / freezing point
- Boiling point
- Density
- Particle size distribution (Granulometry)
- Vapour pressure
- Partition coefficient
- Water solubility
- Solubility in organic solvents / fat solubility
- Surface tension
- Flash point
- Auto flammability
- Flammability
- Explosiveness
- Oxidising properties
- Oxidation reduction potential
- Stability in organic solvents and identity of relevant degradation products
- Storage stability and reactivity towards container material
- Stability: thermal, sunlight, metals
- pH
- Dissociation constant
- Viscosity
- Additional physico-chemical information
- Additional physico-chemical properties of nanomaterials
- Nanomaterial agglomeration / aggregation
- Nanomaterial crystalline phase
- Nanomaterial crystallite and grain size
- Nanomaterial aspect ratio / shape
- Nanomaterial specific surface area
- Nanomaterial Zeta potential
- Nanomaterial surface chemistry
- Nanomaterial dustiness
- Nanomaterial porosity
- Nanomaterial pour density
- Nanomaterial photocatalytic activity
- Nanomaterial radical formation potential
- Nanomaterial catalytic activity
- Endpoint summary
- Stability
- Biodegradation
- Bioaccumulation
- Transport and distribution
- Environmental data
- Additional information on environmental fate and behaviour
- Ecotoxicological Summary
- Aquatic toxicity
- Endpoint summary
- Short-term toxicity to fish
- Long-term toxicity to fish
- Short-term toxicity to aquatic invertebrates
- Long-term toxicity to aquatic invertebrates
- Toxicity to aquatic algae and cyanobacteria
- Toxicity to aquatic plants other than algae
- Toxicity to microorganisms
- Endocrine disrupter testing in aquatic vertebrates – in vivo
- Toxicity to other aquatic organisms
- Sediment toxicity
- Terrestrial toxicity
- Biological effects monitoring
- Biotransformation and kinetics
- Additional ecotoxological information
- Toxicological Summary
- Toxicokinetics, metabolism and distribution
- Acute Toxicity
- Irritation / corrosion
- Sensitisation
- Repeated dose toxicity
- Genetic toxicity
- Carcinogenicity
- Toxicity to reproduction
- Specific investigations
- Exposure related observations in humans
- Toxic effects on livestock and pets
- Additional toxicological data
Repeated dose toxicity: oral
Administrative data
- Endpoint:
- short-term repeated dose toxicity: oral
- Type of information:
- experimental study
- Adequacy of study:
- key study
- Study period:
- Jan, 20 - Oct. 13, 2011; experimental phase: Jan. 26 - May 3, 2011
- Reliability:
- 1 (reliable without restriction)
- Rationale for reliability incl. deficiencies:
- guideline study
Data source
Reference
- Reference Type:
- study report
- Title:
- Unnamed
- Year:
- 2 011
- Report date:
- 2011
Materials and methods
Test guideline
- Qualifier:
- according to guideline
- Guideline:
- OECD Guideline 407 (Repeated Dose 28-Day Oral Toxicity Study in Rodents)
- Version / remarks:
- 2008
- GLP compliance:
- yes (incl. QA statement)
Test material
- 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: nanoform, no surface treatment
- Details on test material:
- Precipitated, CAS-No.: 112926-00-8, Surface area / BET [m2/g]: 160
Constituent 1
- Specific details on test material used for the study:
- NM-200, supplied by JRC, Ispra, on behalf of the sponsor, CEFIC, The European Chemical Industry Council
Test animals
- Species:
- rat
- Strain:
- Wistar
- Details on species / strain selection:
- purchased from: Charles River Deutschland, Sulzfeld, Germany
- Sex:
- male
- Details on test animals or test system and environmental conditions:
- Animals were housed in groups of 5 per cage in Makrolon Type IV cages in animal room T1.044 in the conventional area. Absorbent softwood was used as bedding material in the cages (Lignocel BK 8-15, ssniff GmbH, Soest, Germany). Drinking water from the Hannover city water supplier was offered fresh weekly, in Makrolon bottles (approximately 300 ml), ad libitum. Food was offered ad libitum fresh weekly. The diet used (ssniff R/M-H) was supplied by ssniff GmbH, Soest, Germany. The temperature in the animal room was set at 22 ± 2°C and the rel. humidity at 30 - 70%. The animal room lighting was a 12-hour light/dark cycle controlled by an automatic timing device.
Administration / exposure
- Route of administration:
- oral: gavage
- Vehicle:
- other: a solution of methylhydroxypropylcellulose (0.5 %) in deionised water (Milli-Q, Millipore)
- Duration of treatment / exposure:
- 28 d
- Frequency of treatment:
- daily
Doses / concentrationsopen allclose all
- Dose / conc.:
- 100 mg/kg bw/day (nominal)
- Dose / conc.:
- 300 mg/kg bw/day (nominal)
- Dose / conc.:
- 1 000 mg/kg bw/day (nominal)
- Dose / conc.:
- 1 000 mg/kg bw/day (nominal)
- Remarks:
- recovery group
- No. of animals per sex per dose:
- 5 (males only)
- Control animals:
- yes, concurrent vehicle
- Details on study design:
- 14-day observation phase for some animals (5 treated and 5 control)
Examinations
- Observations and examinations performed and frequency:
- All animals were clinically observed in their cages at least once a day. Once a week, they were inspected outside their home cages and carefully examined for clinical symptoms, i.e. abnormalities concerning their general condition. This included inspection of skin, fur, eyes, visible mucous membranes, examination for pathomorphological changes (e.g. unusual breathing pattern, masses, nodules), abnormal behaviour and central nervous symptoms (e.g. changes in gait, posture or grooming activity, unusual response to handling, secretion/excretion abnormalities, clonic/tonic movements, stereotypies) and/or other clinical abnormalities.
- Sacrifice and pathology:
- Gross necropsy was performed on all rats.
Histopathological examination of the cerebrum, cerebellum, peripheral nerve, trachea, thyroid, lung, mandibular lymphnode, mesenteric lymphnode, thymus, heart, skeletal muscle, liver, spleen, spinal cord, adrenals, forestomach, glandular stomach, duodenum, jejunum, ileum, cecum, colon, rectum, kidneys, urinary bladder, eyes with optic nerve, testes, epididymis, coagulation glands, seminal vesicles, prostate, femur with bone marrow and joint was performed in 5 males of the high dose group 4 (1000 mg/kg bw Synthetic Amorphous Silica) and the control group 1 (vehicle). Gross findings of other organs were examined in addition. - Other examinations:
- Locomotor Activity
During the last week of treatment, spontaneous locomotor activity over 60 minutes using the „Motitest“ computerized light-beam system (TSE, Homburg/Ts., Germany) was determined. The data were analyzed in 15-minutes intervals. In addition, the total values for distance, time in rest, time in movement, rearing time, and number of rearings were determined. Additional testing for spontaneous locomotor activity in the two recovery groups was not performed in the second recovery week, because no significant statistical differences between the dose groups and the control group were determined in the first testing.
Hematological, clinical chemistry analyses (hematology and serum chemistry) were performed before final sacrifice for all animals:
- Erythrocyte count, hemoglobin, hematocrit, mean erythrocyte volume, mean erythrocyte hemoglobin mass, mean erythrocyte hemoglobin concentration, total and differential leukocyte count, platelet count, prothrombin time, and thromboplastin time were recorded.
- Aspartate aminotransferase (EC 2.6.1.1), alanine aminotransferase (EC 2.6.1.2), gammaglutamyl transferase (EC 2.3.2.2), alkaline phosphatase (EC 3.1.3.1), sorbitol dehydrogenase (EC 1.1.1.14), cholinesterase (EC 3.1.1.8), creatin kinase (EC 2.7.3.2), total bilirubin, urea, creatinine, total protein, albumin, cholesterol, glucose, sodium, potassium, calcium, chloride, inorganic phosphate and triglyceride were measured. Globulin and
albumin/globulin ratio were calculated from the albumin and total protein data.
Analysis of Silicon in tissue (blood, kidney and liver) was performed by ICP-MS. - Statistics:
- Differences between groups were considered case by case as statistically significant for p<0.05. Data were analyzed using analysis of variance. If the group means differed significantly according to the analysis of variance, the means of the treatment groups were compared with the means of the control group, using DUNNETT's modification of the t-test. Kruskal-Wallis ANOVA and Mann-Whitney U-test were applied in the case of non-homogeneous data. The statistical evaluation of the histopathological findings was done with the two-tailed FISHER test using the PROVANTIS system. For comparisons of semiquantitative data, the Chi-square test was used.
Results and discussion
Results of examinations
- Clinical signs:
- no effects observed
- Mortality:
- no mortality observed
- Body weight and weight changes:
- effects observed, non-treatment-related
- Description (incidence and severity):
- The only statistically significant difference in body weight gain was observed in the mid-dose group between day 7 and 14. It was not dose dependent and transient and therefore considered to be incidental and of no toxicological relevance.
- Food consumption and compound intake (if feeding study):
- no effects observed
- Haematological findings:
- effects observed, non-treatment-related
- Description (incidence and severity):
- A slight but significant decrease was found in the partial thromboplastin time (PTT) in the mid dose group. The white blood cell count (WBC) and the lymphocyte count (LYMC) were significantly decreased in the mid dose group. However, the relative lymphocyte count (LYM) was unchanged. As all values were within the normal range, these changes are considered to be of minor toxicological relevance.
- Clinical biochemistry findings:
- effects observed, non-treatment-related
- Description (incidence and severity):
- Cholinesterase (CHE) and glucose (GLUC) levels were marginally decreased in the mid dose group. However, all values were within the normal range and the changes reported above are thus considered to be incidental.
- Behaviour (functional findings):
- no effects observed
- Organ weight findings including organ / body weight ratios:
- no effects observed
- Gross pathological findings:
- effects observed, non-treatment-related
- Description (incidence and severity):
- No substance-related findings were observed.
Two animals (one male of group 2 (low dose), one male of group 5 (recovery control)) displayed an unilateral exophthalmus, probably caused by the previous retro-boulbous blood sampling.
One male of group 3 (mid dose) displayed a slight reduction in size of the prostate and the seminal vesicle. This alteration is considered to be an incidental finding, occasionally occurring in this strain.
One male of group 6 (recovery high dose) displayed a slight unilateral reduction in size of the testes and epididymis. This alteration is considered to be an incidental finding, occasionally occurring in this strain. - Neuropathological findings:
- no effects observed
- Description (incidence and severity):
- No influence on locomotor activity was observed.
- Histopathological findings: non-neoplastic:
- effects observed, non-treatment-related
- Description (incidence and severity):
- Substance-related findings were not observed in the histologically examined organs of males of the control and high dose group.
Lungs: Findings in the lungs occurred only in single animals of the control group like very slight focal bronchiolo-alveolar hyperplasia, slight alveolar histiocytosis (1/5), very slight pulmonary hemorrhage (1/5) and very slight/slight focal inflammatory cell infiltration (2/5).
Kidney: The finding of unilateral focal very slight tubular basophilia with nuclear crowding was seen in 1/5 males of the control group. Other degenerative changes of the kidneys such as unilateral slight focal subcapsular mononuclear cell infiltration associated with focal very slight fibrosis occurred in another control male, which showed a bilateral multifocal slight tubular dilatation in addition.
Liver: (Multi)focal very slight microgranulomas were diagnosed in 3/5 males of the control and in 5/5 males of the high dose group.
Prostate: 4/5 of the control animals and 5/5 of the high dose group animals showed very slight/slight (multi)focal inflammatory lesions.
Testes, Epididymis: Very slight/slight/moderate multifocal degeneration and depletion of germ cells was seen in 4/5 males of the control, and 4/5 males of the high dose group. Very slight/slight multifocal tubular atrophy was seen in 1/5 males of the control and in 2/5 males of the high dose group in addition. Intraluminal exfoliated degenerated germ cells were detected in the corresponding epididymis of 1/5 male of the control and 1/5 of the high dose group. A slight focal spermatic granuloma was noted in the epididymis of one control male. Very slight (multi)focal interstitial mononuclear cell infiltration was recorded in the epididymis of 1/5 males of the control and in 1/5 males of the high dose group. These alterations are considered to be incidental findings.
Other organs: Several other findings in various organs of the examined experimental groups were noted which also occurred incidentally and were not unusual for this strain and age. - Histopathological findings: neoplastic:
- no effects observed
- Other effects:
- effects observed, non-treatment-related
- Description (incidence and severity):
- Determination of silicon ion concentration: The ion concentrations in kidney, liver and blood were comparable in control animals (group 1) and high dose animals (group 4) and no treatment related changes were observed.
Effect levels
- Key result
- Dose descriptor:
- NOAEL
- Effect level:
- >= 1 000 mg/kg bw/day (nominal)
- Based on:
- test mat.
- Sex:
- male
- Basis for effect level:
- behaviour (functional findings)
- body weight and weight gain
- clinical biochemistry
- clinical signs
- food consumption and compound intake
- gross pathology
- haematology
- histopathology: neoplastic
- histopathology: non-neoplastic
- mortality
- neuropathology
- organ weights and organ / body weight ratios
- other: determination of silicon ion concentration
Target system / organ toxicity
- Key result
- Critical effects observed:
- no
Any other information on results incl. tables
No death occurred during the study and no adverse clinical symptoms were observed. No effects on food consumption or body weight were seen. The measurements of the spontaneous locomotor activity and the functional observational battery displayed no influence by the treatment. Evaluation of hematological and clinical chemistry parameters did not reveal any treatment related effects. Decreases of the partial thromboplastin time (PTT), white blood cell count (WBC) and lymphocyte count (LYMC) as well as cholinesterase (CHE) and glucose (GLUC) in group 3 (mid dose) after 28 d of exposure were considered not treatment related. Creatinin kinase (CK) and blood urea (UREA) concentration were mildly decreased in group 6 (high dose recovery) after a two week recovery period. All values were within the normal range and the changes were considered not treatment related and to be due to interindividual variability.
During necropsy, no substance-related findings were observed. No effects were seen on organ weights or the organ weight to bodyweight ratio. During histopathological examination, no substance-related findings were observed in the examined organs of males of the control and high dose group.
Applicant's summary and conclusion
- Conclusions:
- Synthetic Amorphous Silica did not cause any substance-related effects in doses of up to 1000 mg/kg bodyweight after oral exposure for 28 days in male Wistar (WU) rats. Therefore, the highest dose tested (1000 mg/kg BW) was determined as the NOAEL in this study.
- Executive summary:
The objective of this study was to evaluate the possible toxicity of Synthetic Amorphous Silica (NM-200) after oral administration (gavage) in rats for 28 days and an additional 14-day recovery period.
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