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Toxicological information

Repeated dose toxicity: inhalation

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Administrative data

Endpoint:
short-term repeated dose toxicity: inhalation
Type of information:
migrated information: read-across based on grouping of substances (category approach)
Adequacy of study:
key study
Reliability:
1 (reliable without restriction)
Rationale for reliability incl. deficiencies:
other: Guideline study - very well documented, study was performed with Fe3O4 as a representative for the iron oxide group - see Category approach for Fe2O3, Fe3O4, FeOOH, (Fe,Mn)2O3, (Fe,Mn)3O4, ZnFe2O4

Data source

Reference
Reference Type:
study report
Title:
Unnamed
Year:
2006
Report Date:
2006

Materials and methods

Test guideline
Qualifier:
according to
Guideline:
OECD Guideline 412 (Subacute Inhalation Toxicity: 28-Day Study)
Principles of method if other than guideline:
Wistar rats (30 male rats per group) were exposed in a subacute 4-week inhalation study to four different concentrations of aerosolized Magnetite powder (Ferroxide Slack 88P, abbreviated also as 'iron oxide black' throughout the report).
Exposure was 6-hours/day on five days/week for four consecutive weeks. The rats were exposed to mean actual concentrations (i.e., breathing zone concentrations) of 10.1±1.4, 19.7±3.3, 45.6±6.8, and 95.8±17.6 mg/m3 air, 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 1.5 µm, the geometric standard deviation (GSD) was ~2.
During a 6 month postexposure period subgroups of rats (ten per sacrifice) were serially sacrificed 1, 8, and 24 weeks after the 4 week exposure period.
GLP compliance:
yes

Test material

Reference
Name:
Unnamed
Type:
Constituent
Test material form:
solid: particulate/powder
Remarks:
migrated information: powder

Test animals

Species:
rat
Strain:
Wistar
Sex:
male

Administration / exposure

Route of administration:
inhalation
Type of inhalation exposure:
nose only
Vehicle:
other: unchanged (no vehicle)
Remarks on MMAD:
MMAD / GSD: MMAD = 1.5 µm; GSD ~2
Analytical verification of doses or concentrations:
yes
Duration of treatment / exposure:
4 weeks
Frequency of treatment:
6 hours/day 5 days/week
Doses / concentrations
Remarks:
Doses / Concentrations:
10.1, 19.7, 45.6, 95.8 mg/m³
Basis:
analytical conc.
No. of animals per sex per dose:
30
Control animals:
yes

Results and discussion

Effect levels

Dose descriptor:
NOAEL
Remarks:
Toxicity
Effect level:
10.1 mg/m³ air
Based on:
test mat. (dissolved fraction)
Sex:
male
Basis for effect level:
other: See remarks
Remarks on result:
not determinable due to absence of adverse toxic effects

Target system / organ toxicity

Critical effects observed:
not specified

Any other information on results incl. tables

The evaluation of the lungs of rats exposed to four different concentrations of 
magnetite revealed findings clearly consistent with a  poor soluble particle 
effect after 4-weeks exposure period followed by a  6-month postexposure period. 
Conclusive evidence of bioavailable iron  particles that were translocated to extrapulmonary organs to any  appreciable extent was not observed. 
Extrapulmonary effects causally  linked to the exposure of magnetite were not 
found at any exposure  concentration and time point. At the end of the 6-month 
postexposure  period, the findings causally linked to the exposure to iron oxide
(e.g.  broncho-alveolar hypercellularity, septal thickening) showed a decrease  
in incidence and/or severity and occured essentially only at 95.8 mg/m³,  a 
concentration shown to be high enough to cause a self-sustained type of  
inflammation due to a substantially delayed clearance of particles (t1/2  = 165 days) as a result of lung overload. Thus, the results of this study  support the view that the NOAEL of magnetite is 10.1 mg/m³ with  borderline effects at 19.7 mg/m³, a concentration considered to be at the  transition of lung overloading.

Applicant's summary and conclusion

Conclusions:
NOAEL (no-observed adverse effect level) of Magnetite is 10.1 mg/m³ with borderline effects at 19.7 mg/m³.
Executive summary:
The evaluation of the lungs of rats exposed to four different concentrations of magnetite revealed findings clearly consistent with a poor soluble particle effect after 4-weeks exposure period followed by a 6-month postexposure period. Conclusive evidence of bioavailable iron particles that were translocated to extrapulmonary organs to any appreciable extent was not observed. Extrapulmonary effects causally linked to the exposure of magnetite were not found at any exposure concentration and time point. Thus, the results of this study support the view that the NOAEL of magnetite is 10.1 mg/m³ with borderline effects at 19.7 mg/m³, a concentration considered to be at the transition of lung overloading.