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Toxicological information

Carcinogenicity

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Administrative data

Description of key information

- carcinogenicity: 
• FeCl3: no classification, negative for carcinogenicity (one study; key study: Santo 1992b, comparable to OECD TG 451)
• Fe2(SO4)3: no classification, no studies available, accordingly read across is used from FeCl3
• FeCl2: no classification, no data available on any endpoint, read across from FeCl3
• FeSO4: no classification, no data available on any endpoint, read across from FeCl3
• FeClSO4: no classification, no studies available, accordingly read across is used from FeCl3

Key value for chemical safety assessment

Carcinogenicity: via oral route

Endpoint conclusion
Endpoint conclusion:
no adverse effect observed
Dose descriptor:
NOAEL
Study duration:
chronic
Species:
rat
Quality of whole database:
One reliable key and two not-assignable supporting studies.

Carcinogenicity: via inhalation route

Endpoint conclusion
Endpoint conclusion:
no study available

Carcinogenicity: via dermal route

Endpoint conclusion
Endpoint conclusion:
no study available

Additional information

This endpoint is covered by the category approach for soluble iron salts (please see the section Toxicokinetics, metabolism and distribution for the category justification/report format).

- carcinogenicity:

 • animal data:

 - FeCl3 is deemed negative for carcinogenicity (one study; key study: Sato 1992b), conducted using a study protocol similar to OECD 451 (no information on GLP status), ferric chloride was dissolved in distilled water at concentrations of 0.25 and 0.5%, and the solutions were given ad libitum, to F344 rats (50/sex/dose) as their drinking water for up to two years. Control animals received untreated drinking water. The mean body weights of the treated rats were lower than control group values for males and females. A variety of tumours developed in all groups, including the controls, but all of these neoplasms were histologically similar to those of those known to occur spontaneously in this strain of rat. There was no statistically significant increase in the incidence of any tumour found in the treated animals compared with the controls. Therefore it was concluded that ferric chloride did not exert any carcinogenic potential in F344 rats. Accordingly FeCl3 is not classifiable for carcinogenicity.

 - For Fe2(SO4)3 no studies are available for this endpoint. Accordingly a read across is applied from FeCl3 and Fe2(SO4)3 is deemed not carcinogenic.

- For FeCl2: no studies are available for this endpoint. Accordingly a read across is applied from FeCl3 and FeCl2 is deemed not carcinogenic.

 - For FeSO4 no studies are available for this endpoint. Accordingly a read across is applied from FeCl3 and FeSO4 is deemed not carcinogenic.

  - For FeClSO4 no studies are available for this endpoint. Accordingly a read across is applied from FeCl3 and FeClSO4 is deemed not carcinogenic.

 • human data:

 - For oral iron intake mainly via diet or via iron supplementation 5 studies are available touching carcinogenicity issues. Ullen 1997 (reliability 2) conducted a population based case control study on the relationship between dietary and supplemental iron intake and cancer risk (colorectal cancer). The study was carried out to investigate whether increased iron intake is associated with the development of colorectal cancer. An initial indication of a positive association between supplementary iron intake and colorectal cancer risk was reversed when supplementary iron intake in the 5 years prior to cancer diagnosis was subtracted. So iron supplementation is rather protective when regarding the risk of colorectal cancer.

Freng 1998 carried out a dietary socio-medical case-control and survival study with the focus the influence of social dietary and environmental factors on the incidence of malignant epithelial tumours in the upper digestive tract at the Department of Otorhinolaryngology at Ulleval University hospital. 84 patients and 89 controls were included. The study found an increased incidence of tumours with low values for haemoglobin, iron folic acid, magnesium and albumin, and with high values for ferritin, vitamin B12 and thiocyanate. It is concluded that low serum iron increases the risk of this type or tumour. Again iron supplementation is rather protective when regarding the risk of epithelial tumours in the upper digestive tract.

A study to potential risk factors on the incidence malignant epithelial tumours adenocarcinomas of the oesophagus and gastric cardia was prepared by Zhang 1997. An increased risk of adenocarcinomas of the oesophagus and gastric cardia was found to be associated with hypertension, age, male gender, and Caucasian race, tobacco smoking. Iron deficiency was significantly associated with increased risk of both adenocarcinomas of the oesophagus and gastric cardia and adenocarcinomas of the distal stomach. Again iron supplementation is rather protective when regarding the risk for malignant epithelial tumours adenocarcinomas of the oesophagus and gastric cardia.

In a summary report by the Scientific Panel on Dietetic Products, Nutrition and Allergies of EFSA (2004) on the tolerable upper intake level of iron the adsorption of iron and its toxicity has been analysed. It was concluded that the evidence that suggests that luminal exposure to excessive iron plays a role in the development of colon carcinoma is limited and unconvincing. Few data are available for other cancers, and the evidence is unconvincing. Epidemiological associations between high iron intake and/or stores and increased risk of chronic diseases such as cardiovascular disease, type II diabetes and cancer of the gastrointestinal tract are not considered to provide convincing evidence of a causal relationship between iron intake or stores and such chronic diseases.

Boffetta 2004 conducted a large human – epidemiological study where workers involved in the manufacture of titanium dioxide were analysed for the risk for mortality from lung cancer. These workers frequently also come into contact with copperas (iron II sulphate). It was found that mortality from lung cancer did not increase with duration of employment or estimated cumulative exposure to TiO2 dust. So it was concluded that also concomitant exposure to copperas was without effect on the standardized mortality ratios.

 

 • summary:

Only one reliable carcinogenicity study in animals is available for FeCl3. It clearly shows that FeCl3 is not carcinogenic. Based on the category approach this result is used for read across to all other members of this category. This conclusion is validated by five human studies where the effect of oral exposure (4 studies) and inhalation exposure (Boffetta 2004) to iron species was analysed. In the case of the oral studies, iron supplementation is rather protective when regarding the risk of epithelial tumours in the upper digestive tract. In the inhalation study no negative effect of iron exposure on the risk of mortality from lung cancer. Taken together human and animal data are in agreement that iron is not carcinogenic and accordingly no classification is necessary for the iron salts of this category.


Justification for selection of carcinogenicity via oral route endpoint:
Only one reliable with restrictions study.

Justification for classification or non-classification

Based on the above stated assessment of the carcinogenic potential all members of this iron salt category are deemed non-carcinogenic and accordingly do not need to be classified according to Council Directive 2001 59 EC (28th ATP of Directive 67 548 EEC) and according to CLP (5th ATP of Regulation (EC) No 1272/2008 of the European Parliament and of the Council) as implementation of UN-GHS in the EU.