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Basic toxicokinetics

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basic toxicokinetics in vivo
Type of information:
migrated information: read-across from supporting substance (structural analogue or surrogate)
Adequacy of study:
weight of evidence
2 (reliable with restrictions)
Rationale for reliability incl. deficiencies:
other: see 'Remark'
Mill scale is mainly and primarily composed of high-purity iron oxides (on average above 65%, i.e. FeO, Fe2O3, Fe3O4). Besides, other metal oxides and spinels, elements, and trace compounds such as oil residues <1% for all the uses except for batteries and Melting charge for which <3% can be found in the mill scale. More information on the justification of read across can be found in the attached document in the endpoint summaries of section 7.
Cross-referenceopen allclose all
Reason / purpose for cross-reference:
reference to same study
Reason / purpose for cross-reference:
reference to other study

Data source

Reference Type:
Uptake of iron oxide aerosols by mouse airway epithelium
Watson AY, and Brain JD
Bibliographic source:
Laboratory Investigation, 40: 450-459

Materials and methods

Objective of study:
other: iron uptake by the airway epithelium
Test guideline
no guideline followed
Principles of method if other than guideline:
Mice were exposed to an aerosol of iron oxide for 3 hours. Participation of the tracheal and bronchial epithelium in the uptake of iron oxide was investigated immediately following the exposure and at 1 day, 4 days and 7 days post exposure. Two or three animals were sacrificed at each time point for a total of 10 experimental animals. The main objective of the publication was to describe the uptake and transport of submicrometer insoluble particles by the airway epithelium. Iron oxide (Fe203) was selected due to its non-toxic properties.
GLP compliance:
not specified
Study performed before the adoption of GLP principles

Test material

Constituent 1
Chemical structure
Reference substance name:
Diiron trioxide
EC Number:
EC Name:
Diiron trioxide
Cas Number:
Molecular formula:
diiron trioxide
Constituent 2
Reference substance name:
Details on test material:
-Name of test material (as cited in study report): iron oxide
-Other: nano spherical iron oxide particles (approx 0.005 µm in diameter); self made material

Test animals


Administration / exposure

Route of administration:
inhalation: aerosol
unchanged (no vehicle)
Duration and frequency of treatment / exposure:
3 h, single exposure
Doses / concentrations
Doses / Concentrations:
300 mg/m3
No. of animals per sex per dose / concentration:
One dose used, 10 animals tested (plus 2 controls)
Control animals:
yes, sham-exposed

Results and discussion

Preliminary studies:
No data
Main ADME results

Toxicokinetic / pharmacokinetic studies

Details on absorption:
Details on distribution in tissues:
See below “any other information on materials and methods"
Details on excretion:

Metabolite characterisation studies

Metabolites identified:
Details on metabolites:
Ferritin and hemosiderin

Any other information on results incl. tables

Perl’s positive material was detected in the airway epithelial cells and in the connective tissue with light microscopy, but the form of Fe could not be identifies this way.


Qualitative:Some Fe-oxide particles were detected on the surface if the airway epithelium immediately and after 1 day of exposure, but at 4 days. Particles were observed on the mucous layer, on cell surfaces and between cilia. Electron dense pinocytic material was detected in the apical cytoplasm, of some cells, but Fe oxide was not observed in large phagocytic vesicles. The authors suggest its dissolution in the lumen and uptake from the cell, but this speculation could not be verified. The pinocytic vesicles appeared o migrate from the apical surface to the Golgi complex and the endoplasmic reticulum. Intracellular ferritin and hemosiderin were detected immediately after the 3h exposure to the Fe oxide and at all later time points.

No Fe oxide was detected in the connective tissue and between epithelial cells.


Quantitative: hemosiderin appears in conditions of Fe excess, and thus, it was quantified and scored (by electron microscopy) in the sections of the trachea and bronchus, as an indicator of iron uptake by the cells. The results can be seen in Table 1 (attachment below). Each cell section with one or more hemosiderin granules was scored as positive. The percentage of hemosiderin containing cell sections increased significantly over time. Hemosiderin levels were observed also in control animals (killed immediately after exposure), but at significantly lower levels.

Applicant's summary and conclusion

Interpretation of results (migrated information): other:
Iron oxide nanoparticles are pinocytised by the epithelial cells of the airways and subsequently give rise to the formation of ferritin and hemosiderin. Quantification of hemosiderin reveals thats that Fe storage increases with time, after exposure to the Fe2O3. The study provides some evidence of dissolution of the Fe oxide after entering the cells. However, the very small particle size has to be taken into account.
Executive summary:

Male CD-1 mice were exposed to an aerosol of Fe2O3 at 300 mg/m3 for 3 hours. Uptake by the tracheal and the bronchial epithelium was examined following the exposure and at 1 day, 4days and 7 days post exposure. Two or three animals were sacrificed at each time point for a total of 10experimental animals. The findings reveal that iron oxide particles were probably pinocytised by the epithelial cells of the airways and subsequently lead to increase of ferritin and hemosiderin. Quantification of hemosidering reveals that’s the Fe storage increases with time, after exposure to the Fe2O3.


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