Mill scale (ferrous metal)

Repeated dose toxicity: inhalation

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 guideline

Test guideline 1

Qualifier:

according to guideline

Guideline:

OECD Guideline 413 (Subchronic Inhalation Toxicity: 90-Day Study)

Test guideline 2

Qualifier:

equivalent or similar to guideline

Guideline:

EPA OPPTS 870.3465 (90-Day Inhalation Toxicity)

Test guideline 3

Qualifier:

equivalent or similar to guideline

Guideline:

other: EC Directive 67/302/EEC

GLP compliance:

yes

Limit test:

no

Test material

Test material information

Constituent 1

Reference substance name:

Iron(II,III) oxide

IUPAC Name:

Iron(II,III) oxide

Constituent 2

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/m^3)	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:1^st= No of deaths,2^nd= No of animals with signs after cessation of exposure and3^rd= 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.