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Description of key information

A subacute inhalation toxicity study for Fe3O4, Fe2O3 and FeOOH and a subchronic inhalation study for Fe3O4 are available. Additional a short-term (5-day) inhalation study with two different grades of nanomaterials was conducted. Rats were exposed to 10 and 30 mg/m³ of smaller nano-sized Fe2O3 and 30 mg/m³ of larger nano-sized Fe2O3. 
For oral and dermal toxicity no reliable repeated dose toxicity studies are available for the iron oxide group. As the members of the iron oxide group are inert particles no toxicological effects are expected and the conduction of such studies seems not necessary.

Key value for chemical safety assessment

Repeated dose toxicity: via oral route - systemic effects

Endpoint conclusion
Endpoint conclusion:
no study available

Repeated dose toxicity: inhalation - systemic effects

Endpoint conclusion
Endpoint conclusion:
no adverse effect observed
Study duration:
subchronic
Quality of whole database:
GLP guideline study according OECD #413 (Subchronic Inhalation Toxicity: 90-Day)

Repeated dose toxicity: inhalation - local effects

Endpoint conclusion
Endpoint conclusion:
no adverse effect observed
Dose descriptor:
NOAEC
4.7 mg/m³
Study duration:
subchronic
Species:
rat
Quality of whole database:
GLP guideline study according OECD #413 (Subchronic Inhalation Toxicity: 90-Day)

Repeated dose toxicity: dermal - systemic effects

Endpoint conclusion
Endpoint conclusion:
no study available

Repeated dose toxicity: dermal - local effects

Endpoint conclusion
Endpoint conclusion:
no study available

Additional information

In a subacute inhalation toxicity study, 48 male rats per group were exposed to three different aerosolized iron oxide powders (Fe2O3, Fe3O4 and FeOOH). Exposure was 6-hours/day on five days/week for two consecutive weeks. The rats were exposed to mean actual concentrations of 185.6 mg/m³ Fe3O4, 210.2 mg/m³ Fe2O3 and 195.7 mg/m³ FeOOH (Pauluhn, 2005). The repeated exposure to the aerosolized iron oxides was not associated with any specific clinical signs, changes in body temperature or body weights. Histopathological evaluation of rat lungs exposed to the different iron oxides revealed findings consistent with a 'poorly soluble particle' effect after the 2-week exposure period, including the 3-month postexposure period. Conclusive evidence of bioavailable iron or iron particles that were translocated to extrapulmonary organs was not observed (Pauluhn, 2005). This supports the conclusion, that Fe3O4 can serve as a surrogate for FeOOH and Fe2O3.

For Fe3O4 valid subacute and subchronic inhalation studies are available (Pauluhn, 2006a; Pauluhn, 2006b). In the subacute inhalation toxicity study 30 male rats were exposed to 10.1, 19.4, 45.6 and 95.8 mg/m³ Fe3O4 for 6 hours/day, 5 days/week for 4 weeks and serially sacrificed 1, 8, 24 weeks after the 4 weeks exposure period. Clinical signs were recorded daily before and after exposure or once per week during the postexposure period. At each serial sacrifice, inflammatory endpoints were determined in bronchoalveolar lavage (BAL). Rats were subjected to gross pathological examination and histopathology (nasal passages, trachea, lung, liver, spleen, kidneys, testes and thymus). The repeated 4-week exposure to the aerosolized dry powder was not associated with specific clinical signs or consistent changes in body weights. Changes in organ weights occurred and consisted of increased lung and lung-associated lymph nodes (LALN) weight at 45.6 mg/m³ and above. Histopathological evaluation of rat lungs exposed to Fe3O4 revealed finding consistent with a poorly soluble particle effect. Conclusive evidence of bioavailable iron or iron particles that were translocated to extrapulmonary organs to any appreciable extent was not found. Extrapulmonary effects causally linked to the exposure of Fe3O4 were not found at any exposure concentration and time point (Pauluhn, 2006b). In the subchronic inhalation toxicity study in rats (20 male and 20 female rats per group) the animals were exposed 6 hours/day, 5 days/week for 13 weeks to 4.7, 16.6 and 52.1 mg/m³ Fe3O4. During the study, the body weights were determined twice weekly and clinical signs were recorded daily before and after exposure. At sacrifice, inflammatory endpoints were determined in BAL. Histopathology focused on the entire respiratory tract (nasal passages, trachea, lung, lung associated lymph nodes) and included all extrapulmonary organs as suggested by OECD 413. At sacrifice biological specimens were collected for hematology, clinical pathology and urinalysis (Pauluhn, 2006a). The repeated exposure of rats during a study period of 13 weeks was not associated with any specific clinical signs. Hematology, clinical pathology and urinalysis were unobtrusive. Neither analytical nor toxicological evidence existed that free, biosoluble iron was liberated from the inhaled dust to any appreciable extent. However, the neutrophils in male rats and some biochemical markers were elevated at 4.7 mg/m³ and above (Pauluhn, 2006a). The NOAECs for Fe3O4 are 10.1 mg/m³ for the subacute exposure and 4.7 mg/m³ for subchronic exposure in rats (Pauluhn, 2006a; Pauluhn, 2006b).

A histopathological evaluation of rat lungs exposed to three different iron oxides revealed findings consistent with a 'poorly soluble particle' effect after the 2- week exposure period, including the 3-month postexposure period. Conclusive evidence of bioavailable iron or iron particles that were translocated to extrapulmonary organs was not observed. Extrapulmonary effects causally linked to the high-level exposure of iron oxides were not be detected at any time point. At the end of the 3-month postexposure period the findings causally linked to the high-level exposure to iron oxides (e.g. focal inflammatory infiltrates, bronchioloalveolar hypercellularity) showed a decrease in incidence and/or severity. The comparative assessment of the three different iron oxides revealed the same quality and time course of responses, i.e., marked differences of any toxicological significance between the test specimens were not observed. Nonetheless, there was a consistent trend that the rats exposed to Fe3O4 displayed minimally more pronounced changes when compared to Fe2O3 and FeOOH. This supports the conclusion that from a scientific point of view further testing of Fe2O3 and Fe3O4 does not appear to be justified and that future studies with Fe3O4 can serve as conservative proxy for Fe2O3 and FeOOH (Pauluhn, 2005).

In a short-term (5-day) inhalation study (BASF SE 2015), 8 male Wistar rats (5 animals in the main group and 3 animals in the recovery group) were exposed to 10 and 30 mg/m³ of smaller nano-sized Fe2O3 and 30 mg/m³ of larger nano-sized Fe2O3. Dust Inhalation exposure of rats to 10 and 30 mg/m³ test item 1 and 30 mg/m³ of test item 2 on 5 consecutive days did not cause any adverse effect in the respiratory tract, which was examined by broncho-alveolar lavage and histopathology. There were no changes of hematology and clinical chemistry parameters. A slightly decreased mean body weight and intermittently reduced body weight change were observed during exposure and post-exposure period of the test group with micro-sized Fe2O3. However, the deviations to the control group were not biologically relevant. Thus, under current study conditions, the NOAEC was 30 mg/m³ for both nano-sized samples. No relevant differences between the smaller nano-sized and the larger nano-sized Fe2O3 were observed.

In consideration of the results of the repeated dose inhalation studies with ZnO and the repeated dose inhalation studies in rats and monkeys with Mn3O4 it can be concluded, that the NOEC of Fe2O3, FeOOH, ZnFe2O4, (Fe,Mn)2O3, and (Fe,Mn)3O4 is in the same range as for Fe3O4, both for nano-sized and micro-sized particles (see Category approach justification, IUCLID section 7.1.1).


Justification for selection of repeated dose toxicity inhalation - systemic effects endpoint:
study with the longest application duration (subchronic) is used

Justification for selection of repeated dose toxicity inhalation - local effects endpoint:
study with the longest application duration (subchronic) is used

Justification for classification or non-classification

The members of the iron oxide group are inert particles, therefore no extrapulmonary toxicological effects are expected for repeated oral and dermal toxicity. The NOAECs for Fe3O4 are 10.1 mg/m³ for the subacute exposure and 4.7 mg/m³ for subchronic exposure in rats.

A classification is therefore not justified.