Triiron tetraoxide

Exposure related observations in humans: other data

Administrative data

Endpoint:

exposure-related observations in humans: other data

Type of information:

other: review of the scientific literature

Adequacy of study:

weight of evidence

Reliability:

2 (reliable with restrictions)

Rationale for reliability incl. deficiencies:

other: review (literature evaluation)

Cross-reference

Reason / purpose for cross-reference:

reference to same study

Data source

Reference

Reference Type:

review article or handbook

Title:

Unnamed

Year:

2010

Materials and methods

Type of study / information:

literature evaluation of human studies on siderosis and pulmonary fibrosis and evaluation of animal studies on effects of iron and iron oxides

Endpoint addressed:

repeated dose toxicity: inhalation

Test guideline

Qualifier:

no guideline followed

Principles of method if other than guideline:

This paper evaluates the scientific literature on the effects of prolonged inhalation of iron or iron compounds

GLP compliance:

no

Test material

Test material information

Constituent 1

Reference substance name:

Iron oxide(s)

IUPAC Name:

Iron oxide(s)

Details on test material:

test material not specified

Method

Details on study design:

This paper evaluates the scientific literature on the effects of prolonged inhalation of iron or iron compounds and, specifically, any association between these exposures and the development of siderosis or pulmonary fibrosis. It considers whether these two conditions require iron and iron compounds to be classified as causing specific target organ toxicity (STOT) – repeated exposure under the CLP regulation criteria.

Exposure assessment:

not specified

Results and discussion

Results:

It is difficult to find groups of workers who are exposed to pure iron powder or fumes. The only such group of workers appears to be silver polishers who are exposed to pure ferric oxide. They have been shown to accumulate iron in their lungs without serious consequences (Barrie and Harding 1947). The lack of data since this paper shows the extreme rarity of consequences from the prolonged inhalation of pure iron and iron compounds. All other papers and reviews of these conditions discuss the consequences of prolonged high exposures to welding fumes, a complex mixture of iron and other metal particles and a variety of gases derived from the process. Pulmonary fibrosis, or scarring of the lung, is a not uncommon condition and can be caused by a variety of disease processes. Historically, a major cause was tuberculosis. The term “siderosis” was introduced by Zenker, in 1866 describing two cases who worked with powered iron oxide and which showed iron pigmentation of the lung as well as tuberculous fibrosis. This led Zenker to the conclusion that iron oxide could cause fibrosis of the lungs.
This view changed significantly in the first half of the 20th century starting with the investigation among electric arc welders by Doig in 1936, who suggested that the iron oxide particles inhaled from the welding fume might be opaque to X-rays and produce the picture without the presence of pulmonary fibrosis, or congestion. Based on the results of further studies among, and case reports from, different occupational groups like welders, silver finishers or steel grinders, with assumed high exposure to iron oxides and low exposure to crystalline silica (e.g. Enzer 1938, Fawcit 1943, McLaughlin 1945, Prendergrass 1945, Buckell 1946, Barrie 1947, Sander 1947, Harding 1948, Hamlin 1950), McLaughlin (1951) stated “It is evident that Zenker’s original conception of siderosis as being a fibrosis is no longer valid, because it has been shown conclusively that inorganic iron and iron oxide will not cause fibrosis.” This view of McLaughlin is the one most generally accepted today (ACGIH 2006). Prolonged inhalation of high levels of metallic iron or iron compounds (e.g., 10-700 mg/m3) (ACGIH 2006) may cause pulmonary siderosis, a benign non-specific pneumoconiosis. It is detectable as radiographic changes (opacities) in the lung. On chest radiographs, diffuse, small rounded opacities, usually of low profusion and without the presence of complicated lesions or progressive fibrosis, are observed (Antonini 2003). These changes are not associated with any symptoms or physical impairment of lung function. Following removal from exposure, radiographic abnormalities may improve (Doig 1948; DFG 1984; Kelleher 2000). Other studies have shown that a significant number of welders develop pulmonary siderosis (Attfield 1978) but that pulmonary function in welders is within normal limits (Kleinfeld 1969). Similar results have been shown in other industries (Jones 1972, Teculescu 1974).
Cases of pulmonary fibrosis observed among iron oxide exposed populations has been ascribed to associated fibrogenic dust components such as crystalline silica, often also present in the work environment of foundries, haematite mining, welding etc (Brooks 1981). There are reports on cases of pulmonary fibrosis among welders with or without siderosis and with no documented exposure to crystalline silica (Charr 1955, 1956, Guidotti 1978, Funahashi 1988, Lasfargues 1991; Roesler 1996; Buerke 2002; McCormick 2008). A review by Billings in 1993 proposed that pulmonary siderosis may lead both to symptomatic and functional changes but also noted that a number of constituents of welding fume could, along with iron, contribute to the observed pulmonary changes. This latter aspect also has been expressed for example by Guidotti (1978) who drew the distinction between arc welders siderosis, as result of the exposure to iron oxides alone, and arc welders pneumoconiosis as the health effects of inhaling dust with heterogeneous composition during welding. Buerke (2002), in a case series of welders with interstitial pulmonary fibrosis, specifically refers to the complex composition of welding fumes and gases containing different types of hazardous substances that are able to initiate obstructive respiratory tract and other symptoms. Analysis of deposits found in welders’ lungs show them to consist of a mixture of welding fume constituents, not solely iron. By recognizing that more than 100 agents are known to cause interstitial lung disease and that background population rates on the prevalence of the disease are not known, the authors suggest that case reports or case series can only provide limited evidence for a causal relationship. In an overall review of the available evidence, however, they conclude that “inhalation of high concentrations of welding fumes under poor working conditions over many years may cause IPF [interstitial pulmonary fibrosis] with significant clinical and functional implications in some welders” (Buerke 2002). In Germany, pulmonary fibrosis due to extreme exposure over many years to welding fume and welding gases (“siderofibrosis“) is listed as an occupational disease - BK No. 4115 - since July 2009. The scientific reasoning of the Medical Expert Advisory Committee at the German Ministry for Work and Social Matters was published in September 2006 (BMAS 2006); this clearly differentiates between siderofibrosis and classical siderosis. Siderofibrosis is described as a consequence of prolonged inhalation of high levels of welding fumes – a complex mixture of iron and other metal particles and a variety of welding gases. A prominent feature of the case history of siderofibrosis is shortage of breath during exertion which may progress and the physician may detect dorsobasal crepitation on auscultation.
According to this document siderosis does not generally lead to a measurable reduction in lung function or to subjective impairment and therefore is not listed as an occupational disease (BMAS 2006).

Any other information on results incl. tables

ANIMAL STUDIES ON EFFECTS OF IRON AND IRON OXIDES

A number of authors studied the effects of inhalation and instillation of iron oxide particles in experimental animals. An Inhalation study reported a transient inflammatory response of Syrian hamsters when exposed to 274 mg iron oxide/m3 for 3 hours but failed to demonstrate any fibrogenic potential (Kavet 1978). Similar results were found in instillation studies. Instillation of 3 mg iron oxide particles in Syrian hamsters leads to a mild inflammatory response characterized by transient influx of alveolar macrophages (Keenan 1989). However, Das et al. found no evidence for irreversible changes in the lungs of guinea pigs even after repeated instillations of large amounts of iron oxide up to 50 mg per dose (Das 1983). Naeslund found no evidence of fibrosis produced in lung tissue of rabbits and guinea pigs after intratracheal injection or inhalation of iron oxide mixed with less than 5% silica (Naeslund 1940). The effects of inhalation of welding fume in experimental animals have also been studied. Inhalation and installation studies have demonstrated dose-dependent increases in inflammatory cytokines in bronchio-alveolar washings; these cytokines including tumour necrosis factor and Interleukin -1 beta (Antonini et al 1996, 1997). Hicks et al (1984) found fibrotic changes in the rat lung after single intra-tracheal installation of high doses of welding fumes (10 and 50 mg per rat).

Applicant's summary and conclusion

Conclusions:

Our review using a weight of evidence approach to this human and animal literature leads us to conclude that:
• The prolonged inhalation of high concentrations of pure iron and iron compounds can produce a benign pneumoconiosis without impairment of lung morphology, function or symptoms;
• Pulmonary siderosis secondary to the inhalation of complex mixtures containing iron or iron compounds, such as welding fumes, is a benign pneumoconiosis without impairment of lung function or symptoms;
• Pulmonary fibrosis (“siderofibrosis”) and loss of lung function may occur after the pronged inhalation of high level of welding fumes ;
• The lung changes of siderosis may regress on cessation of exposure.
We conclude that the conditions occurring after prolonged inhalation of high levels of iron or iron compounds do not meet the criteria for classification.

Executive summary:

This paper evaluates the scientific literature on the effects of prolonged inhalation of iron or iron compounds and, specifically, any association between these exposures and the development of siderosis or pulmonary fibrosis. It considers whether these two conditions require iron and iron compounds to be classified as causing specific target organ toxicity (STOT) – repeated exposure under the CLP regulation criteria. The only group of workers exposed to pure iron or iron oxides appear to be silver polishers who are exposed to pure ferric oxide. They have been shown to accumulate iron in their lungs without health consequences. The animal data on inhalation and instillation of iron oxide also demonstrates that iron does not produce lung fibrosis. Most publications and reviews of these conditions discuss the consequences of prolonged high exposures to mixed dust or to welding fumes, a complex mixture of iron and other metal particles and a variety of gases derived from the process. Prolonged inhalation of high levels of these mixed dusts and fumes may cause siderosis (a benign pneumoconiosis) but also may cause pulmonary fibrosis, sometimes called siderofibrosis, which may lead to restriction in lung capacity. It is not known specifically which components of the complex mix of gases and fumes are responsible for the development of fibrosis. Using a weight of evidence approach to this human and animal literature we conclude that the prolonged inhalation of pure iron and iron compounds may produce a benign pneumoconiosis without impairment of lung morphology, function or symptoms. Therefore the conditions occurring after the prolonged inhalation high levels of iron or iron compounds as placed on the market do not meet the criteria for classification under either REACH or CLP.