Mill scale (ferrous metal)

Basic toxicokinetics

Administrative data

Endpoint:

basic toxicokinetics in vivo

Type of information:

migrated information: read-across from supporting substance (structural analogue or surrogate)

Adequacy of study:

weight of evidence

Reliability:

2 (reliable with restrictions)

Rationale for reliability incl. deficiencies:

other: see 'Remark'

Remarks:

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-reference

Cross-reference 1

Reason / purpose for cross-reference:

reference to same study

Cross-reference 2

Reason / purpose for cross-reference:

reference to other study

Data source

Reference

Reference Type:

publication

Title:

Uptake of iron oxide aerosols by mouse airway epithelium

Author:

Watson AY, and Brain JD

Year:

1979

Bibliographic source:

Laboratory Investigation, 40: 450-459

Materials and methods

Objective of study:

other: iron uptake by the airway epithelium

Test guideline

Qualifier:

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

Remarks:

Study performed before the adoption of GLP principles

Test material

Test material information

Constituent 1

Reference substance name:

Diiron trioxide

EC Number:

215-168-2

EC Name:

Diiron trioxide

Cas Number:

1309-37-1

Molecular formula:

Fe2O3

IUPAC Name:

diiron trioxide

Constituent 2

Reference substance name:

Iron(III)oxide

IUPAC Name:

Iron(III)oxide

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

Radiolabelling:

no

Test animals

Species:

mouse

Strain:

CD-1

Sex:

male

Administration / exposure

Route of administration:

inhalation: aerosol

Vehicle:

unchanged (no vehicle)

Duration and frequency of treatment / exposure:

3 h, single exposure

Doses / concentrations

Remarks:

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

Type:

distribution

Toxicokinetic / pharmacokinetic studies

Details on absorption:

No

Details on distribution in tissues:

See below “any other information on materials and methods"

Details on excretion:

No

Metabolite characterisation studies

Metabolites identified:

yes

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.

DISTRIBUTION

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

Conclusions:

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.