Registration Dossier

Diss Factsheets

Toxicological information

Repeated dose toxicity: inhalation

Currently viewing:

Administrative data

Endpoint:
sub-chronic toxicity: inhalation
Type of information:
migrated information: read-across from supporting substance (structural analogue or surrogate)
Adequacy of study:
key study
Reliability:
1 (reliable without restriction)
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 summarie of section 7.
Cross-reference
Reason / purpose for cross-reference:
reference to other study

Data source

Reference
Title:
Unnamed
Year:
2006
Report date:
2006

Materials and methods

Test guidelineopen allclose all
Qualifier:
according to guideline
Guideline:
OECD Guideline 413 (Subchronic Inhalation Toxicity: 90-Day Study)
Qualifier:
equivalent or similar to guideline
Guideline:
EPA OPPTS 870.3465 (90-Day Inhalation Toxicity)
Qualifier:
equivalent or similar to guideline
Guideline:
other: EC Directive 67/302/EEC
GLP compliance:
yes
Limit test:
no

Test material

Constituent 1
Reference substance name:
Iron(II,III) oxide
IUPAC Name:
Iron(II,III) oxide
Constituent 2
Chemical structure
Reference substance name:
Triiron tetraoxide
EC Number:
215-277-5
EC Name:
Triiron tetraoxide
Cas Number:
1317-61-9
Molecular formula:
Fe3O4
IUPAC Name:
iron(II) diiron(III) oxide
Constituent 3
Reference substance name:
triion tetraoxide
IUPAC Name:
triion tetraoxide
Details on test material:
- Name of test material (as cited in study report): iron oxide 'black' or magnetite (ferroxide black 88P; purchased by ROCKWOOD ITALIA)
- Molecular formula (if other than submission substance): Fe3O4
- Physical state: solid; powder
- Analytical purity/impurities:
PURITY DATA
mg/kg Batch Specification
Arsenic (As) <1 Max. 3
Barium (Ba) 6 Max. 50
Cadmium (Cd) <1 Max. 5
Chromium (Cr) 36 Max. 100
Mercury (Hg) <0.1 Max. 1
Nickel (Ni) 42 Max. 50
Lead (Pb) <3 Max. 10
Copper (Cu) 11 Max. 50
Zinc (Zn) 75 Max. 100
Fe content (%) 69.5 Min. 68

- Purity test date: 25/02/2004
- Lot/batch No.: 846
- Storage condition of test material: room temperature
- Other
specific surface area: 10.5 m2/g (BET, DIN 66131, 90% He, 10% N2)
EINECS: 215-277-5
Appearance: powder with characterisitic colour

Test animals

Species:
rat
Strain:
Wistar
Sex:
male/female

Administration / exposure

Route of administration:
inhalation: aerosol
Type of inhalation exposure:
nose only
Remarks:
dynamic air-flow
Vehicle:
air
Remarks:
conditioned dry air
Remarks on MMAD:
MMAD / GSD: 1.3 µm/ ~ 2
Analytical verification of doses or concentrations:
yes
Duration of treatment / exposure:
6h per day; 5 days/week; 10 animals/group/sex were exposed for 13 consecutive weeks; 10 animal/group/ sex were exposed for 14-15 consecutive weeks
Frequency of treatment:
5 days/week
Doses / concentrations
Remarks:
Doses / Concentrations:
0 (conditioned dry air), 4.7 ±0.6, 16.6 ±3 and 52.1 ±6.4 mg/m3 (target concentrations: 5, 15 and 50 mg/m3)
Basis:
analytical conc.
No. of animals per sex per dose:
20
Control animals:
yes, concurrent vehicle

Results and discussion

Effect levels

Dose descriptor:
NOAEC
Effect level:
4.7 mg/m³ air (analytical)
Based on:
test mat.
Sex:
male/female
Basis for effect level:
other: adverse effects observed in BAL fluid (PMNs, protein levels) and relative lung weights

Target system / organ toxicity

Critical effects observed:
not specified

Any other information on results incl. tables

Table 1: Summary of subchronic inhalation toxicity of Fe3O4dry powder.

N Group/sex

Target concentration (mg/m3)

Toxicological result

Onset and duration of signs

Onset and duration of mortality

1/m

0

0/0/20 

-

-

2/m

5

0/0/20

-

-

3/m

15

0/0/20 

-

-

4/m

50

0/0/20 

-

-

1/f

0

 0/0/20

-

-

2/f

5

 0/0/20

-

-

3/f

15

0/0/20 

-

-

4/f

50

0/0/20 

-

-

N= group assignment, m=males, f= females.Values given in the ‘Toxicological Results’ column are:1st= No of deaths,2nd= No of animals with signs after cessation of exposure and3rd= No of animals exposed.

The table below presents the findings from clinical sings and observations. No mortality was found. The clinical results did not occur in any consistent concentration or time-related manner.

Table 2: Signs and observations.

Group 1/m

Palpable mass flank, eschar formation skin

Group 2/m

Nose: red encrustations

Group 3/m

No findings

Group 4/m

Nose: red encrustations

Group 1/f

Nose: red encrustations

Group 2/f

No findings

Group 3/f

No findings

Group 4/f

Nose: red encrustations, discharge from eyes, eyelids reddened, alopecia, eyelids swollen

Applicant's summary and conclusion

Conclusions:
These results were clearly consistent with what would be expected for a poorly soluble particle, indicating their clearance in the lungs, via efficient phagocytosis by the alveolar macrophages and/or movement into the lymphatic system.
Executive summary:

In a subchronic inhalation toxicity study Fe3O4 aerosols were administered to Wistar rats(20 male and 20 female per group)by the dynamic directed-flow nose-only thechnique; actual mean concentrations were 0, 4.7 ±0.6, 16.6 ±3 and 52.1 ±6.4 mg/m3 air; the animals were exposed for 6 h/day, 5 days/week over a period of 13 weeks.Ten rats/group were necropsied 1 -2 weeks later (exposure continued). Particles hada MMAD of 1.3 µm and GSD ~2. The exposure was not associated with any specific clinical signs and consistent changes in body weights. Hematology, clinical pathology and urinanalysis were unobtrusive. TheNOAEC was 4.7 mg/m3, based on the findings from BAL analysis and histopathology. Mild and borderline changes were considered to be associated with the exposure to poorly soluble particles rather than specific toxicity of the tested particles. The effects found at higher concentrations appear to be consistent with a particle-overload related inflammatory response.