Iron trinitrate

Carcinogenicity

Description of key information

An oral carcinogenicity study is available for the read-across substance iron chloride.

Key value for chemical safety assessment

Carcinogenicity: via oral route

Link to relevant study records

Reference

Endpoint:

carcinogenicity: oral

Type of information:

migrated 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: 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.

Qualifier:

equivalent or similar to guideline

Guideline:

OECD Guideline 451 (Carcinogenicity Studies)

Deviations:

yes

Remarks:

Limited reporting of methods and results in publication

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%
Basis:
nominal in water

Remarks:

Doses / Concentrations:
Equivalent to mean daily doses of 170 and 320 mg/kg for males and of 188 and 336 mg/kg for females.
Basis:
actual ingested

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.

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: %

Based on:

test mat.

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)

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

320 mg/kg bw/day

Study duration:

chronic

Species:

rat

Quality of whole database:

A guideline-comparable published study is available for the read-across substance iron chloride.

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

Available data for the read-across substance do not indicate carcinogenicity. No classification for carcinogenicity is therefore proposed.

Additional information

In a good quality carcinogenicity study iron trichloride was administered to F344 rats in their drinking water for 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 iron trichloride did not exert any carcinogenic potential in F344 rats. The NOAEL was >0.5% (equivalent to 219.7 and 336 mg/kg bw/day in males and females, respectively and to 76 and 116 mgFe/kg bw/day in males and females, respectively).

Justification for selection of carcinogenicity via oral route endpoint:
Only one study available