hydronium;iron(3+);hexahydroxide;disulfate

Carcinogenicity

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

Link to relevant study records

Reference

Endpoint:

carcinogenicity: oral

Type of information:

read-across based on grouping of substances (category approach)

Adequacy of study:

key study

Study period:

No data

Reliability:

2 (reliable with restrictions)

Rationale for reliability incl. deficiencies:

other: 2a The study appears to have been conducted according to an appropriate OECD test guideline but full details are not available and the GLP status of the study is not known.

Justification for type of information:

The Reporting Format for the Chemical Category According to ECHA (2008) Guidance R.6.2.6.2 can be found in the Endpoint Summary of Toxicokinetics, metabolism and distribution.

Reason / purpose for cross-reference:

read-across: supporting information

Qualifier:

equivalent or similar to guideline

Guideline:

OECD Guideline 451 (Carcinogenicity Studies)

Deviations:

yes

Remarks:

Limited reporting of methods and results in publication. Only two doses that were quite low, and no haematological examinations.

GLP compliance:

not specified

Species:

rat

Strain:

Fischer 344

Sex:

male/female

Details on test animals or test system and environmental conditions:

TEST ANIMALS
- Source: Charles River Japan Inc
- Age at study initiation: Six weeks
- Weight at study initiation: No data
- Fasting period before study: No data
- Housing: Three to four males or five females in plastic cages.
- Diet (e.g. ad libitum): Ad libitum
- Water (e.g. ad libitum): Ad libitum
- Acclimation period: One week


ENVIRONMENTAL CONDITIONS
- Temperature (°C): 24± 1
- Humidity (%): 55±5
- Air changes (per hr): No data
- Photoperiod (hrs dark / hrs light): No data


IN-LIFE DATES: No data

Route of administration:

oral: drinking water

Vehicle:

water

Details on exposure:

PREPARATION OF DOSING SOLUTIONS: Ferric chloride was dissolved in distilled water to give concentrations of 0.25 and 0.5% (w/v).

Analytical verification of doses or concentrations:

no

Duration of treatment / exposure:

Two years

Frequency of treatment:

Continuous

Post exposure period:

Eight weeks

Remarks:

Doses / Concentrations:
0, 0.25% or 0.5%, equivalent to mean daily doses of 170 and 320 mg/kg for males and of 188 and 336 mg/kg for females.
Basis:
nominal in water

No. of animals per sex per dose:

50

Control animals:

other: drinking water only

Details on study design:

- Dose selection rationale: Based on a 13-week dose range-finding study.
- Rationale for animal assignment (if not random): Random
- Rationale for selecting satellite groups: To investigate the reversibility of any adverse effects observed.
- Post-exposure recovery period in satellite groups: Eight weeks
- Section schedule rationale (if not random): No data

Observations and examinations performed and frequency:

CAGE SIDE OBSERVATIONS: Yes
- Time schedule: Daily

DETAILED CLINICAL OBSERVATIONS: No data

BODY WEIGHT: Yes
- Time schedule for examinations: Weekly

FOOD CONSUMPTION AND COMPOUND INTAKE (if feeding study):
- Food consumption for each animal determined and mean daily diet consumption calculated as g food/kg body weight/day: No

FOOD EFFICIENCY:
- Body weight gain in kg/food consumption in kg per unit time X 100 calculated as time-weighted averages from the consumption and body weight gain data: No

WATER CONSUMPTION AND COMPOUND INTAKE (if drinking water study): Yes
- Time schedule for examinations: Continuous

OPHTHALMOSCOPIC EXAMINATION: No

HAEMATOLOGY: No data

CLINICAL CHEMISTRY: No data

URINALYSIS: No data

NEUROBEHAVIOURAL EXAMINATION: No

Sacrifice and pathology:

GROSS PATHOLOGY: Yes
HISTOPATHOLOGY: Yes

Statistics:

Body weight and the daily water intake data were analysed statistically using Student's t-test. The survival times were analysed using the generalised Wilcoxon test. The incidences of tumours were analysed statistically by Fisher's exact probability test.

Clinical signs:

no effects observed

Mortality:

no mortality observed

Body weight and weight changes:

effects observed, treatment-related

Food consumption and compound intake (if feeding study):

not examined

Food efficiency:

not examined

Water consumption and compound intake (if drinking water study):

effects observed, treatment-related

Ophthalmological findings:

not examined

Haematological findings:

not specified

Clinical biochemistry findings:

not specified

Urinalysis findings:

not specified

Behaviour (functional findings):

not examined

Organ weight findings including organ / body weight ratios:

not specified

Gross pathological findings:

no effects observed

Histopathological findings: non-neoplastic:

no effects observed

Histopathological findings: neoplastic:

no effects observed

Details on results:

CLINICAL SIGNS AND MORTALITY: No clinical signs of toxicity were reported. The cumulative mortality at termination in males of the 0.5% group was significantly decreased compared with the controls (see Table 1).

BODY WEIGHT AND WEIGHT GAIN: The mean body weights of the treated males and females were significantly lower than those of the control groups (see Table 1).

WATER CONSUMPTION AND COMPOUND INTAKE (if drinking water study): The mean daily water intake of the treated groups were significantly lower than those of the controls (see Table 1).

GROSS PATHOLOGY: No findings reported.

HISTOPATHOLOGY: NON-NEOPLASTIC: Age-related non-neoplastic lesions, such as chronic nephropathy and testicular atrophy, were observed in all groups. There were no specific lesions considered to be attributable to ferric chloride treatment. 

HISTOPATHOLOGY: NEOPLASTIC: There were no statistically significant differences in the overall tumour incidence between control and treated groups of either sex. All tumours observed in this study were similar to those that are known occur spontaneously in this strain of rats. 

Relevance of carcinogenic effects / potential:

No carcinogenic activity was evident in F344 rats administered ferric chloride at concentrations of 0.25 or 0.5% in drinking water for up to two years.

Dose descriptor:

NOAEL

Effect level:

> 0.5 other: %

Sex:

male/female

Basis for effect level:

other: Approximately equivalent to 320 mg/kg bw/day for males and 336 mg/kg bw/day for females.

Remarks on result:

other: Effect type: carcinogenicity (migrated information)

Table 1. Final body weight, intake of drinking water and test substance, and survival times.

		Average daily intake
Group	Final body weight (mean± SD)	Drinking water (g/kg bw)	Test substance (mg/kg bw)	Final survival (%)	Mean survival time and range
Males
Control	458.4 ± 40	95.8	0	62	107.0 (69 -112)
0.25%	431.0 ± 35*	67.4*	169.7	54	104.5 (60 -112)
0.5%	430.6 ± 24*	63.2*	319.7	82*	109.3 (64 -112)
Females
Control	317.6 ± 33	105.0	0	72	106.5 (50 -112)
0.25%	287.3 ± 29*	73.6*	187.9	56	106.9 (73 -112)
0.5%	271.1 ± 24*	67.2*	336.0	62	105.6 (49 -112)

*Significantly different from control value at P<0.05

Conclusions:

In a two year carcinogenicity study (reliability score 2) conducted using a study protocol similar to OECD 451 (no information on GLP status), there was no evidence that ferric chloride has carcinogenic properties in rats.

Executive summary:

In a two year carcinogenicity study (reliability score 2) 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.

Endpoint conclusion

Endpoint conclusion:

no adverse effect observed

Dose descriptor:

NOAEL

Study duration:

chronic

Species:

rat

Quality of whole database:

One reliable study with analogue material.

Carcinogenicity: via inhalation route

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 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.

Additional information

This endpoint is covered by the category approach for dissociating, inorganic and non-toxic iron compounds (please see the section on 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 study (with restrictions).