Registration Dossier

Toxicological information

Carcinogenicity

Currently viewing:

Administrative data

Description of key information

A series of experimental studies aimed at the observation of carcinogenic effects of iron oxides in the respiratory tract gave basically negative results. The study of Nettesheim showed that life long exposure to 40 mg/m^3 (6 h/d, 5 d/week) of Fe2O3d in hamsters did not result in carcinogenicity, while signs of fibrosis were observed. The absence of carcinogenicity in the experimental studies is confirmed by a series of epidemiological studies. The available data has made the MAK Commission, IARC and ACGIH to conclude that iron oxides are not carcinogenic. The submitter further refers to the read-across statement attached to the overall summary of Chapter 7.

Key value for chemical safety assessment

Additional information

See the read-across statement attached to the overall summary of Chapter 7

Animal data

A series of experimental studies on the possible carcinogenic effects of iron oxides after inhalation, intratracheal instillation or injection are summarized in the present section of this IUCLID file. No oral or dermal studies were identified in the literature.

Inhalation of ferric oxide (Fe2O3) caused no cancer in the lungs of exposed hamsters (40 mg/m3) via (exposed 6h/day, 5 d/week, during life span) (Nettesheim et al., 1975).

No carcinogenic effects could be demonstrated for the iron oxides FeO, Fe2O3, Fe3O4 and FeO(OH) after intraperitoneal injection (200 mg/kg bw, 3 times at interval of 3 weeks, for 790-914 days) or intratracheal installation (10 mg/kg bw every 14 days) in rats (Steinhoff et al., 1991).

Fifteen intratracheal instillations (once per week) of feric oxide (Fe2O3) particles at a dose of 30 mg/kg bw in hamsters, did not lead to any formation of tumours in the upper and lower respiratory tract (Feron et al., 1972; summarized under the endpoint 7.5.3 Acute toxicity inhalation).

Marshall et al., (1987; summarized under the endpoint 7.5.3 Acute toxicity inhalation) investigated the effects on the cell proliferation and morphology of the respiratory epithelium in rats, after repeated intralaryngeal instillations (weekly for 5, 10 or 15 weeks) of Fe2O3 (dose: 30 mg/kg bw) in saline. The instillations of Fe2O3 increased cell proliferation in the bronchioles after 5 instillations. After 10 and 15 instillations proliferation was back to control levels, suggesting that the respiratory epithelium adapted to the injury induced. Proliferative responses were not found in the trachea.

Harries et al., (1971) observed cell hyperplasia in the trachea of Syrian hamsters after instillations (single and multiple, 42 mg/kg bw) of Fe2O3 particles. However, these effects were reversible.

The results of Campbell et al. (1940) show that dusting with “brown iron(III) oxide” (Fe2O3.H2O) at rather undefined, but assumed to be high exposure rates of “0.5 g dust per 8 -10 animals/day” for approximately 830 days, trebles the incidence of primary lung tumours in mice living 10 months or longer compared to controls. A definitive increase in malignancy was observed. However, the reliability of these findings is uncertain and they definetely do not allow iron oxide to be regarded as a carcinogen. The effect may very well be regarded as secondary, due to lung overload by PSPs (poorly soluble particles).

The result of carcinogenicity bioassays with iron(III) oxide investigated in rats by subcutaneous injection gave a borderline positive result (Maltoni et al., 1991). However, the information provided lacks sufficient detail for the evaluation and this result should thus not be used to draw conclusions on the carcinogenicity of iron oxide. Moreover, the relevance of the exposure route (subcutaneous injection) employed for the insoluble iron oxide particles is questionable in the present context.

Human data

Whatever the results of the experimental studies, in this case, they are overruled by the epidemiological studies. The assessment of cancer risk due to pure exposure to iron oxide is difficult, since most industrial activities, which may give rise to iron oxide exposure do generate mixed exposures containing several different chemicals and dusts, or radiation. While excess risks of lung cancers have been reported in epidemiological studies of iron ore miners, foundry workers, steel workers and welders, industrial settings where exposure to iron oxides were involved, the majority of the studies were not able (or did not intend) to separate iron oxide exposure from other exposures to known or suspected carcinogens often present at the same settings or same workplaces. 

Four epidemiological studies of good quality have been conducted, which either tried to separate iron oxide exposure from other exposures (Moulin et al. 2000 and Bourgkard et al. 2009 in the iron and steel industry) or which have been conducted under circumstances, in which only low levels of exposure to other agents were present (Axelson et al. 1979 among workers exposed to iron oxide during production of sulfuric acid from pyrite and Lawler et al. 1985 among iron-ore miners). These studies specifically addressing the affect of iron oxide on lung cancer did not show any risk of lung cancer associated with exposure to iron oxides.

Institutions like the German MAK commission (1984), IARC (1987) or ACGIH (2006) have reviewed the available information regarding the carcinogenicity of iron oxides and found iron oxide not to be a carcinogen.

Conclusion

Based on these results it is concluded that respiratory exposure to iron oxides does not present a cancer risk.

Justification for classification or non-classification

No classification required.