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Administrative data

Description of key information

Three repeated-dose inhalation studies with rats have been summarized in this section of Chapter 7: a 14-day study with FeO, Fe2O3 and Fe3O4, a 28-day study with Fe3O4 and a 90-day study with Fe3O4. These studies fully cover the REACH requirements as to the repeated-dose toxicity of Fe3O4 (magnetite).   The three studies show at lower concentrations and/or exposure durations the normal clearance response, e.g., the mobilization of alveolar macrophages, without adverse effects in the respiratory tract. The higher concentrations and/or exposure durations tend to lead to the effects of particle overloading that are extensively described in literature: cytotoxicity, inflammation and cell proliferation (see for instance the reviews of Oberdörster 1995 and 2002). At 4.7 mg/m3 in the 90-day study there were slight increases of protein levels in the BAL, increased numbers of PMN and alveolar macrophages in the BAL and in the blood an increase of neutrophils (in the males). The author of the study reported these effects as borderline and to represent a normal adaptive response to the exposure to particles. He reported the 4.7 mg/m3 as a NOAEC. However, the effects observed at 4.7 mg/m3 can be regarded to be a result of a specific sensitivity of rats to particle overload and its sequela.   In addition there were two intratracheal instillation studies with Fe2O3, in which hamsters were treated up to 15 times (once a week) with 3 mg of the substance. These very high doses did not result in clear-cut adverse effects.

Key value for chemical safety assessment

Repeated dose toxicity: inhalation - systemic effects

Endpoint conclusion
Dose descriptor:
NOAEC
4.7 mg/m³
Study duration:
subchronic
Species:
rat

Additional information

• The inhalation studies using FeO, Fe2O3 and Fe3O4 adequately cover the requirements as to the endpoint repeated dose toxicity for magnetite (Fe3O4) iron oxides.

The inhalation studies on various iron oxides have been carried out at concentrations near or exceeding those at which rats suffer from particle overload and the effects associated with this phenomenon.

• The effects observed in the inhalation studies are entirely in line with particle overload caused by so-called poorly soluble particles (PSPs).

• No effects were observed that could not be explained by particle overload by PSPs. This includes extra pulmonary effects.

• The effects were thus only determined by the fact that particles of a certain size and shape were inhaled and not by the specific chemical composition of the particles; in other words, no magnetite specific effects were observed.

• Rats are highly sensitive to become overloaded by the inhalation of respirable PSPs in comparison to other experimental animals and humans, which makes the derivation of a DNEL based on these studies impossible.

 The iron oxides are poorly soluble particles (PSP) which are subject to generic threshold exposure levels (TLVs, MACs etc.) and these levels should apply rather than deriving a DNEL derived from the 90-day study.

• The instillation studies with hamsters demonstrate the low toxicity of Fe2O3 particles at very high dose levels for the respiratory organs.

• The available results indicate that individual inhalation studies with iron(II) oxide (FeO) and iron(III) oxide (Fe2O3) are not necessary because:

o Magnetite is in fact an oxide of bivalent AND trivalent iron;

o It may be assumed that the bioavailability of iron will not differ much for the three oxides (FeO, Fe2O3 and Fe3O4), which all have a very low water solubility;

o Iron(III) oxide (Fe2O3) particles shows no clear toxicity in instillation studies at very high doses, which indicates that also these particles will behave in inhalation studies as PSPs.

Nevertheless, the three oxides (FeO, Fe2O3 and Fe3O4) may differ as regards the surface activity of their particles. In view of the fact that these three oxides are all three components of rust, the results of epidemiology (Section 5.6.2 of this CSR) and the long history of human exposure to rust, it is deemed not necessary to investigate this further by means of additional inhalation studies.

See attachment for further elaboration.


Repeated dose toxicity: inhalation - systemic effects (target organ) respiratory: lung

Justification for classification or non-classification

The results of the inhalation studies clearly show the iron-oxide particles to behave as poorly soluble particles. This together with the lack of bioavailability after oral exposure and dermal exposure, signifies that no classification for repeated-dose toxicity is necessary.