Triiron tetraoxide

Repeated dose toxicity: inhalation

Administrative data

Endpoint:

sub-chronic toxicity: inhalation

Type of information:

experimental study

Adequacy of study:

key study

Reliability:

1 (reliable without restriction)

Rationale for reliability incl. deficiencies:

other: Guideline study - very well documented

Data source

Reference

Reference Type:

study report

Title:

Unnamed

Year:

2006

Report date:

2006

Materials and methods

Test guideline

Qualifier:

according to guideline

Guideline:

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

GLP compliance:

yes

Test material

Test material information

Constituent 1

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 oxide

Test material form:

solid: pressed powder

Test animals

Species:

rat

Strain:

Wistar

Sex:

male/female

Administration / exposure

Route of administration:

inhalation

Type of inhalation exposure:

nose only

Vehicle:

other: unchanged (no vehicle)

Remarks on MMAD:

MMAD / GSD: MMAD was 1.3 µm, GDS ~2

Analytical verification of doses or concentrations:

yes

Duration of treatment / exposure:

13 weeks

Frequency of treatment:

6 hours/day 5 days/week

Doses / concentrations

Remarks:

Doses / Concentrations:
4.7, 16.6, 52.1 mg/m³
Basis:
analytical conc.

No. of animals per sex per dose:

20

Control animals:

yes

Results and discussion

Effect levels

Dose descriptor:

NOAEL

Effect level:

4.7 mg/m³ air

Sex:

male/female

Basis for effect level:

other: see "Remarks"

Target system / organ toxicity

Critical effects observed:

not specified

Any other information on results incl. tables

Rats exposed subchronically to three different concentrations of Fe304 revealed findings clearly consistent with and typical for a 'poorly soluble particle'effect. Congruent with previous studies addressing the retention kinetics of inhaled Fe304 particles, neither analytical nor toxicological evidence existed that free, biosoluble iron was liberated from the inhaled dust to any appreciable extent. Also in this study no evidence of extrapulmonary toxicity existed. With regard to indicesconsidered to be adverse, viz. increased counts of cells and especially PMNs in BAL, elevated LDH as marker of cytotoxicity, and B-NAG as marker of increased lysosomal activities 4.7 mg/m3 constitute an exposure level without evidence ofadversity. These findings match those observed by histopathology. Thus, the results of this study support the view that the NOAEL (no-observed adverse effect level) of Fe304 is 4.7 mg/m3. As far as mild and borderline changes were observed they are considered to be associated with the exposure to PSPs rather than adversity. The effects found at higher exposure concentrations appear to be consistent of a particleoverload related inflammatory response. Comparison of findings of this study with published evidence from subchronic rat inhalation with titanium dioxide show that effects are clearly attributable to the particle per se rather than Fe304 or biosoluble iron.

Applicant's summary and conclusion

Executive summary:

Protocol: Wistar rats (20 male and 20 female rats per group) were exposed in a subchronic 13-week inhalation study to three different concentrations of aerosolized Fe304 (Magnetite) dry powder (also abbreviated as Iron Oxide 'Black' throughout the report).

Exposure was 6-hours/day on five days/week for at least 13 consecutive weeks.

The rats were exposed to mean actual concentrations (i.e., breathing zone concentrations) of 4.7±0.6, 16.6±3.0, and 52.1 ±6.4 mg/m3, respectively. The control group was exposed under similar conditions to conditioned, dry air. The mode of exposure was dynamic directed-flow nose-only. Throughout the groups, the solid aerosol was highly respirable to rats, i.e., the mean mass median aerodynamic diameter (MMAD) was 1.3 µm, the geometric standard deviation (GSD) was ~2. Result: In summary, rats exposed subchronically to three different concentrations of Fe304 revealed findings clearly consistent with and typical for a 'poorly soluble particle'effect. Congruent with previous studies addressing the retention kinetics of inhaled Fe304 particles, neither analytical nor toxicological evidence existed that free, biosoluble iron was liberated from the inhaled dust to any appreciable extent. Also in this study no evidence of extrapulmonary toxicity existed. With regard to indices considered to be adverse, viz. increased counts of cells and especially PMNs in BAL, elevated LDH as marker of cytotoxicity, and B-NAG as marker of increased lysosomal activities 4.7 mg/m3 constitute an exposure level without evidence of adversity. These findings match those observed by histopathology. Thus, the results of this study support the view that the NOAEL (no-observed adverse effect level) of Fe304 is 4.7 mg/m3. As far as mild and borderline changes were observed they are considered to be associated with the exposure to PSPs rather than adversity. The effects found at higher exposure concentrations appear to be consistent of a particle overload related inflammatory response. Comparison of findings of this study with published evidence from subchronic rat inhalation with titanium dioxide show thateffects are clearly attributable to the particle per se rather than Fe304 or biosoluble iron.