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Acute Toxicity: inhalation

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acute toxicity: inhalation
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 summarie 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:
Pneumotoxicity and pulmonary clearance of different welding fumes after intratracheal instillation in the rat.
Antonini JM, Murthy GGK, Rogers RA, Albert R, Uldrich GD, Brain JD.
Bibliographic source:
Toxicology and applied pharmacology, 140: 188-199.
Report date:

Materials and methods

Test guideline
no guideline followed
Principles of method if other than guideline:
The study shows the effects of different welding fumes, which were instilled intratracheally, on parameters of lung toxicity. Iron(III)oxide is used as a negative control as it is considered as a relatively inert dust, and crystalline silica as a positive control. Only one dose was tested.
GLP compliance:
not specified
It is not customary to refer to GLP compliance in publications.
Test type:
other: intratracheal instillation
Limit test:

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:
iron(III) oxide
iron(III) oxide
Details on test material:
Name of test material (as cited in study report): iron oxide (γ- Fe2O3)
- Molecular formula (if other than submission substance): γ- Fe2O3
- Physical state: solid;particles of about 0.1-0.2 µm in diameter
- Other: magnetic iron particles (γ- Fe2O3) were produced by the combustion of Fe pentacarbonyl (Fe(CO)5) vapors as described by Vlberg and Brain (1979). The Fe(CO)5 is carried as a vapor to 650°C furnace, where air is added to provide oxygen for the formation of γ- Fe2O3. The reducing property of the H2 carrier gas is necessary to prevent oxidation of the Fe before it reaches the furnace, otherwise nonmagnetic hematite will result. The particles produced are crystalline in shape and measure about 0.1-0.2 µm in diameter. The final aerosol is produced from the rapid agglomeration of these individual units immediately after their formation in the furnace. The effluent is diluted with air and cooled to achieve the desired concentration and temperature.

Test animals

other: CD/VAF

Administration / exposure

Route of administration:
other: intratracheal instillation
Type of inhalation exposure:
other: intratracheal instillation
other: 150 µl of 0.9% sterile saline/100 g bw
Analytical verification of test atmosphere concentrations:
non relevant; intratracheal instillations
Dose: 10 mg/kg bw particles instilled
No. of animals per sex per dose:
Control animals:
other: Solvent control: saline; negative control: iron(III) oxide was used as a negative control because it is considered as a relatively inert dust; positive control: pneumotoxic crystalline silica,

Results and discussion

Effect levels
Dose descriptor:
Effect level:
> 104 mg/m³ air
Based on:
test mat.
Remarks on result:
other: see details for this calculation below

Any other information on results incl. tables

Table 2a: Bronchoalveolar Lavage Cell Profiles (total number 10^6).

Time point





1 day

Iron(III) oxide

3.8± 1

6.6± 0.7#

0.3± 0.1#

Solvent control

5.1± 1

0.3± 0.1


Positive control

5.7± 0.5

13.4± 1.8*

0.6± 0.2#

7 days

Iron(III) oxide

5.5± 0.8

1.6± 0.6#

1.3± 0.3#

Solvent control

4.7± 0.6



Positive control

7.2± 0.4

10.3± 0.6*

0.7± 0.1

14 days

Iron(III) oxide

4.1± 0.3

1± 0.6

0.2± 0.1

Solvent control

4.8± 0.2



Positive control

6.8± 1.1

20.4± 1.4*

1.6± 0.2*

35 days

Iron(III) oxide

3.3± 0.5

0.2± 0.1


Solvent control

3.7± 0.2

0.2± 0.1


Positive control

8.7± 0.7*

41.4± 5.2*

2.8± 0.5*

Values are means± SE, n=4

# significantly greater than saline control group (p<0.05); * significantly greater than all other groups

Results are presented in Table 2, Fig. 1, 2, 3 & 4 (see attachment below).

Iron(III) oxide

- Significant elevations were observed in the number of neutrophils and lymphocytes on days 1 and 7 postinstillation, in comparison to the solvent control.

- Albumine levels appearedincreased at the 1 day postinstillation measurement, while at the 14th day, there was no difference anymore in response in comparison to saline control group.

- LDH activity was significantly increased at day 1 postinstillation, whilst it diminished by 7 days and reached the same levels of control group by 14 days.

- None of the two cytokines was detected in the BAL fluid.

- Accumulation of the particles at some areas in the lungs was apparent at both (day 14 and 35) histopathological examinations, usually present inside the macrophages. At 35 day postinstillation lung changes from the Fe oxide were minimal. Macrophages containing oxide particle were observed in the terminal bronchioles and alveolar ducts.

Applicant's summary and conclusion

Interpretation of results:
other: In rats Fe2O3 behaves like an inert, non-toxic dust when instilled intratracheally at 10 mg/kg bw.
In rats Fe2O3 behaves like an inert, non-toxic dust when instilled intratracheally at 10 mg/kg bw. No real evidence of pulmonary injury after exposure to the oxide particles was detected. The observed inflammatory responses were clearly associated with the particle clearance. After 14 days the lungs of the rats appeared fully recovered.
Executive summary:

In an acute inhalation toxicity study groups of young adult male CD/VAF rats were exposed by intratracheal instillation to welding fumes. Iron(III) oxide was chosen as a negative control since it was considered by the investigators as a relatively inert dust and crystalline silica as a positive control. Iron(III) oxide particles were suspended in saline (one dose used, 1 mg suspended in 150 µl of 0.9% sterile saline/100 g bw). Animals then were observed for 14 days. No real evidence of pulmonary injury after exposure to the oxide particles occured. The observed inflammatory responses were clearly associated with particle clearance. Histopathology revealed that by 14 days the lungs of the rats appeared normal. Fe2O3 was indeed found to behave like an inert, non-toxic dust when instilled intratracheally at this dose level.An LC50 value for Fe2O3 was estimated by the conversion of the instilled dose to a concentration in air that was inhaled for 4 h by the rats; this resulted in a value > 104 mg/m3.