Iron hydroxide oxide yellow

Carcinogenicity

Description of key information

Long term inhalation, oral and dermal carcinogenicity studies are not available on iron hydroxide oxide (FeOOH) nano material. Seven different types of iron oxides were examined for carcinogenic properties after intratracheal instillation and intraperitoneal injection tests in rats, which represent particularly sensitive methods for local carcinogenic effects of particles/fibres. The total doses lay in the range of maximum tolerance.

The JECFA (1980) evaluation reported that iron oxide (unspecified compound) in the diet at levels up to 10 g/kg did not result in adverse effects in dogs and cats (no further details reported). These unpublished studies were more fully described in the JECFA evaluation report on iron (1983). In an unpublished study from Carnation Co. (1967), ten dogs were fed on diets containing iron oxide colourant from 1 to 9 years at about 570 mg/lb (equivalent to 1.25 g/kg diet, 0.312 mg/kg bw/day19). Daily consumption was estimated at 428 mg/dog. Two Labradors, fed for 1 year, had loose faeces; otherwise, no adverse effects were observed. In a study from Ralston Purina Cat Care Center (1968), no adverse effects were reported in cats maintained on diets containing 1 900 mg/kg diet (475 mg/kg bw/day) of iron from iron oxide (equivalent to 0.27 % iron oxide) for periods of 2–9 years (EFSA, 2015).

 

The carcinogenicity of ferric chloride (FeCl3), a compound that is used as a food additive, a haemostatic or treatment for hypochromic anaemia, was examined in F344 rats of both sexes. It was dissolved in distilled water at levels of 0, 0.25 or 0.5%, and groups of 50 male and 50 female rats were given one of these solutions ad lib. as their drinking water for up to 2 yr. The mean body weights of the treated rats were lower than control group values for both males and females. A variety of tumours developed in all groups, including the control group, but all these neoplasms were histologically similar to those known to occur spontaneously in this strain of rats, and no statistically significant increase in the incidence of any tumour was found in the treated groups of either sex. Thus, it is concluded that under the conditions of this experiment, ferric chloride exerts no carcinogenic potential in F344 rats (Sato et al, 1992).

 

Overall, given that the soluble iron trichloride has been shown to be negative in a carcinogenicity assay, since red iron oxides in contrast are of negligible bioavailability, the carcinogenicity hazard for red iron oxide is deemed to be similarly negligible.

Key value for chemical safety assessment

Carcinogenicity: via oral route

Endpoint conclusion

Endpoint conclusion:

no study available

Carcinogenicity: via inhalation route

Link to relevant study records

Reference

Endpoint:

carcinogenicity, other

Type of information:

read-across from supporting substance (structural analogue or surrogate)

Adequacy of study:

key study

Reliability:

2 (reliable with restrictions)

Rationale for reliability incl. deficiencies:

other: as reported in source record

Justification for type of information:

see attachment "Endpoint-specific read-across justification for the iron oxide category" in section 13.

Reason / purpose for cross-reference:

read-across source

Reason / purpose for cross-reference:

read-across source

Executive summary:

Steinhoff 1991, it

SPF-bred Sprague-Dawley rats 8 weeks of age were used as experimental animals. The animals A dose of 1x10 mg/kg bw every 14 days was initially established for intratracheal instillation. The size of the individual dose could be doubled after 13 treatments, and doubled again following 6 further treatments. The surviving animals were sacrificed after 798 study days. Each test and control group was made up of 50 male and 50 female rats. Rats appropriately treated with physiological saline solution, and untreated animals were used as controls. All tumors and tumor-suspect organs and tissues, together with the organs of the following list were preserved for histological examination: adrenals, brain, epididymis, esophagus, eyes, femur, heart, intestines, kidneys, larynx, liver, lung, mammary gland, mesentery, nasopharynx, omentum, ovaries, pancreas, pituitary, prostate, slivary glands, seminal vesicles, skeletal muscle, skin, spinal cord with marrow, spleen, sternum, stomach, submaxillary gland, with lymph nodes, testes, thymus, thyroids, tongue, trachea, urinary bladder and uterus.

No relevant effect on survival or body weight gain.

Substance related effects only in the lungs (foreign body

deposit, metaplasia).

Lung tumors in 0-4/100 animals in the test groups and 0/100

in the control group

Steinhoff 1991, ip

Number of animals: 50 m + 50 f per group Two groups of controls were treated with saline or left untreated. Total dose : 600 mg/kg Parameters: Histopathology of adrenals, brain, epididymides, esophagus, eyes, femur, heart, intestines, kidneys, larynx, liver, lung, mammary gland, mesentery, nasopharynx, omentum, ovaries, pancreas, pituitary, prostate, salivary glands, seminal vesicles, skeletal muscle, skin, spinal cord, spleen, sternum, stomach, submaxillary gland, lymph nodes, testes, thymus, thyroid, tongue, trachea, bladder, uterus.

Local tumors in 8-15/100 animals in the test group and 8/120 or 7/100 in  the control group

Endpoint conclusion

Endpoint conclusion:

no study available

Carcinogenicity: via dermal route

Endpoint conclusion

Endpoint conclusion:

no study available

Justification for classification or non-classification

Based on the available data (see discussion) a classification is not justified.

Additional information

In the key studies seven different types of iron oxides were examined for carcinogenic properties after intratracheal instillation and intraperitoneal injection tests in rats, which represent particularly sensitive methods for local carcinogenic effects of particles/fibres. The total doses lay in the range of maximum tolerance. No carcinogenic effect was observed. Overall, based on a weight-of-evidence consideration there is no evidence of a carcinogenic potential of iron oxides from animal data. From epidemiological studies there is no evidence for carcinogenicity after exposure to zinc or its compounds through relevant routes of exposure. No valid studies are available for Mn3O4. There are no epidemiological data showing that excess manganese will cause cancer in human beings. Based on the physico-chemical properties, the negative genotoxicity data as well as the lack of specific long term local effects in the most valid studies with intraperitoneal (i.p.) administration there is no evidence of any specific toxicity. This is confirmed by the result of the subchronic inhalation study with Fe3O4 that revealed findings consistent with a 'poorly soluble particle' and no specific toxicity. No analytical or toxicological evidence existed that free, biosoluble iron was liberated from the inhaled particle dust to any appreciable extent. Also no evidence of extrapulmonary toxicity existed. Haematology, clinical pathology and urinalysis were unobtrusive and no specific clinical signs were observed during the study.

A human study is available with the objective to study the possible association between iron oxide exposures and lung cancer risk among workers employed in a French carbon steel-producing factory. A historical cohort was set up of all workers ever employed for at least one year between 1959 and 1997. The cohort was followed up for mortality from January 1968 to December 1998. Causes of death were ascertained from death certificates. Job histories in the factory and smoking habits were available. Occupational exposures were assessed by a factory-specific job-exposure matrix (JEM) developed by a panel of 8 experts and validated with atmospheric measurements. Standardized Mortality Ratios (SMRs) were computed using local death rates (external references). Poisson regressions were used to estimate the Relative Risks (RRs) for occupational exposures (internal references), adjusted on potential confounding factors (Bourgkard et al., 2008).

The cohort comprised 16,742 males and 959 females. Among males, the observed mortality was lower than expected for lung cancer when compared to the local population (233 deaths, SMR 0.89, 95%CI 0.78-1.01) and higher than expected when compared to the French population (SMR 1.30, 95%CI 1.15-1.48). No lung cancer excess was observed for exposure to iron oxides (RR 0.80, 95%CI 0.55-1.17) and no dose-response relationship was found with intensity, duration of exposure, and cumulative index. A significant bladder cancer excess was observed among workers exposed to oil mist, increasing significantly with intensity, duration of exposure, and cumulative index. The authors concluded: “This study did not detect any relationship between exposure to iron oxides and lung cancer mortality” (Bourgkard et al., 2008).