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Toxicological information

Basic toxicokinetics

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Administrative data

Endpoint:
basic toxicokinetics in vivo
Type of information:
experimental study
Adequacy of study:
key study
Study period:
2-Generation-Reproduction-Study
Reliability:
1 (reliable without restriction)
Rationale for reliability incl. deficiencies:
test procedure in accordance with national standard methods

Data source

Reference
Reference Type:
study report
Title:
Unnamed
Year:
2018
Report Date:
2018

Materials and methods

Objective of study:
distribution
Test guideline
Qualifier:
no guideline available
Principles of method if other than guideline:
Histopathology, immunohistochemistry, EDX analysis
GLP compliance:
yes (incl. certificate)
Remarks:
certified by Swiss Federal Office of Public Health, consumer product protection directorate, notification authority for chemicals, CH-3003 Bern, Switzerland

Test material

Reference
Name:
Unnamed
Type:
Constituent
Test material form:
solid: nanoform, no surface treatment
Details on test material:
Precipitated, CAS-No.: 112926-00-8, Surface area / BET [m2/g]: 160
Specific details on test material used for the study:
NM-200 synthetic amorphous silica
Radiolabelling:
no

Test animals

Species:
rat
Strain:
Wistar
Sex:
male/female
Details on test animals and environmental conditions:
histopathology, immunechemistry and EDX analysis of animals from TNO Triskelion study V9127 (oral two-generation reproduction study)

Administration / exposure

Route of administration:
oral: unspecified
Doses / concentrationsopen allclose all
Dose / conc.:
0 mg/kg bw/day
Remarks:
control
Dose / conc.:
1 000 mg/kg bw/day
Remarks:
liver and jejunum, colon, EDX
Dose / conc.:
100 mg/kg bw/day
Remarks:
jejunum, colon, EDX
Dose / conc.:
300 mg/kg bw/day
Remarks:
jejunum, colon, EDX
No. of animals per sex per dose:
Liver: 10 males and 10 females for 0 mg/kg bw/d (control) and 1000 mg/kg bw/d (highest dose)
Jejunum, colon: 5 females for 0 mg/kg bw/d (control), 100, 300 and 1000 mg/kg bw/d
EDX analyis: 2 females for 0 mg/kg bw/d (control) and 1000 mg/kg bw/d (highest dose)
Positive control:
no
Details on study design:
Allocation liver: rats from P-generation (10 males and 10 females respectively, 0 mg/kg bw/d = control, 1000 mg/kg bw/d = highest dose): Liver samples were embedded in paraffin, cut at an approx. thickness of 2-4 µm and stained with hematoxylin and eosin or Sirius Red and collagen I, II and III by immunehistochemistry reaction
Allocation jejunum, colon: rats from F1-generation (5 females respectively, 0 mg/kg bw/d = control, 100, 300, 1000 mg/kg bw/d): epoxy resin embedded materials submitted from TNO: Immunohistochemistry: CD11, CD40,CD69, CD86, IL-1 beta, IL6 for immune reaction, image analysis for the lenght of jejunal villi
other available organs (liver, kidney cortex and medulla, spleen, brain great 1 and 2, brain small, urinary bladder, oesophagus, duodenum, jejunum, ileum, caecum, stomach cardia, fundus and pylorus, blood): 2 female rats from F1-generation (2 from control group, 2 from 1000 mg/kg bw/d): material submitted was embedded in epoxy resin, placed on aluminium grid, evaluated by scanning electron microscopy and energy dispersive X-ray (EDX) analysis (accelaration voltage 20kV, variable pressure), suspicious spots were evaluated at magnifications of x200 and x400
Statistics:
Image analysis on liver samples for immunehistochemistry: 3 spots with Glisson`s triade were photographed by a camera connected with Olympus CellSense System. The relative area was measured and summarized on EXCEL sheets. The results were calculated by GraphPad Prism 7. Descriptive statistics and t-test were applied.
For jejunum and colon histoimmunechemistry a semi-quantative evaluation was applied. The lenth of 5 villi (if technical possible) was measured and the results summarized on EXEL sheets. Then the results were calculated by GraphPad Prism 7. Descriptive statistics and t-test were applied.
EDX: semi-quantative analysis

Results and discussion

Preliminary studies:
two-generation-reproduction study
Main ADME results
Type:
distribution
Results:
No treatment related findings in liver, jejunum and colon; in terated animals tiny silicon particles found in increased incidence in the oesophagus and gastrointestinal tract.

Toxicokinetic / pharmacokinetic studies

Details on distribution in tissues:
In all animals tiny silicon particles (interpreted as Feldspar, Albit) were observed located free on the surface and hence are deemed to be dust particles. In treated animals such particles were found at increased incidence in the oesophagus and gastrointestinal tract, but not in other organs.
Transfer into organs
Key result
Transfer type:
secretion via gastric mucosa
Observation:
no transfer detectable

Metabolite characterisation studies

Metabolites identified:
not specified
Remarks:
tiny spots of Na, Al and Si, interpreted as Feldspar (Albit)

Applicant's summary and conclusion

Conclusions:
Synthetic amorphous silica is not systemically distributed from the gastrointestinal tract.