Iron(II) fumarate

Repeated dose toxicity: oral

Administrative data

Endpoint:

short-term repeated dose toxicity: oral

Type of information:

experimental study

Adequacy of study:

key study

Reliability:

2 (reliable with restrictions)

Rationale for reliability incl. deficiencies:

data from handbook or collection of data

Justification for type of information:

Data is from peer reviewed journal

Data source

Reference

Reference Type:

publication

Title:

Review of the animal and human studies on the test chemical

Author:

BERENBAUM et.al

Year:

1960

Bibliographic source:

Blood, 1960

Materials and methods

Test guideline

Qualifier:

according to guideline

Guideline:

other: Refer below principle

Principles of method if other than guideline:

Subacute repeated dose oral toxicity study was performed to determine the oral toxic nature of the test chemical using rats

GLP compliance:

not specified

Limit test:

no

Test material

Test material information

Constituent 1

Reference substance name:

Iron(II) fumarate

EC Number:

205-447-7

EC Name:

Iron(II) fumarate

Cas Number:

141-01-5

Molecular formula:

C4H4O4.Fe

IUPAC Name:

iron(II) fumarate

Test material form:

solid: particulate/powder

Details on test material:

- Name of test material (as cited in study report): Ferrous fumarate
- Molecular formula: C4H4O4.Fe
- Molecular weight : 169.901 g/mol
- Smiles notation : [Fe+2].[O-]C(\C=C\C(=O)[O-])=O
- InChl : 1S/C4H4O4.Fe/c5-3(6)1-2-4(7)8;/h1-2H,(H,5,6)(H,7,8);/q;+2/p-2/b2-1+;
- Substance type:Organic
- Physical state:Solid

Test animals

Species:

rat

Strain:

other: Albino rats of WAG strain

Details on species / strain selection:

No data

Sex:

male/female

Details on test animals or test system and environmental conditions:

TEST ANIMALS
- Source: No data available
- Age at study initiation: No data available
- Weight at study initiation: 40 to 100 gm
- Fasting period before study: No data available
- Housing: No data available
- Diet (e.g. ad libitum): No data available
- Water (e.g. ad libitum): No data available
- Acclimation period: No data available

ENVIRONMENTAL CONDITIONS
- Temperature (°C): No data available
- Humidity (%):No data available
- Air changes (per hr): No data available
- Photoperiod (hrs dark / hrs light): No data available

IN-LIFE DATES: From: To: No data available

Administration / exposure

Route of administration:

oral: unspecified

Details on route of administration:

No data

Vehicle:

not specified

Details on oral exposure:

PREPARATION OF DOSING SOLUTIONS: No data available

DIET PREPARATION
- Rate of preparation of diet (frequency): No data available
- Mixing appropriate amounts with (Type of food): No data available
- Storage temperature of food: No data available

VEHICLE
- Justification for use and choice of vehicle (if other than water): No data available
- Concentration in vehicle: No data available
- Amount of vehicle (if gavage): No data available
- Lot/batch no. (if required): No data available
- Purity: No data available

Analytical verification of doses or concentrations:

not specified

Details on analytical verification of doses or concentrations:

No data

Duration of treatment / exposure:

12 weeks

Frequency of treatment:

Daily excluding weekends

Doses / concentrations

Remarks:

0, 50 and 100 mg Fe/kg

No. of animals per sex per dose:

Total: 30
0 mg/Kg : 5 males and 5 females
50 mg/Kg: 5 males and 5 females
100 mg/Kg: 5 males and 5 females

Control animals:

yes, concurrent vehicle

Details on study design:

Details on study design
- Dose selection rationale: No data available
- Rationale for animal assignment (if not random): No data available
- Rationale for selecting satellite groups: No data available
- Post-exposure recovery period in satellite groups: No data available
- Section schedule rationale (if not random): No data available

Positive control:

No data

Examinations

Observations and examinations performed and frequency:

CAGE SIDE OBSERVATIONS: No data
- Time schedule: No data available
- Cage side observations checked in table [No.?] were included: No data available

DETAILED CLINICAL OBSERVATIONS: Yes
- Time schedule: No data

BODY WEIGHT: Yes
- Time schedule for examinations: At intervals

FOOD CONSUMPTION AND COMPOUND INTAKE (if feeding study): No data
- Food consumption for each animal determined and mean daily diet consumption calculated as g food/kg body weight/day: No data
- Compound intake calculated as time-weighted averages from the consumption and body weight gain data: No data

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 data

WATER CONSUMPTION AND COMPOUND INTAKE (if drinking water study): No data
- Time schedule for examinations: No data

OPHTHALMOSCOPIC EXAMINATION: No data
- Time schedule for examinations: No data
- Dose groups that were examined: No data

HAEMATOLOGY: Yes
- Time schedule for collection of blood: After 12 weeks dosing
- Anaesthetic used for blood collection: No data available
- Animals fasted: No data available
- How many animals: 2 males and 2 females from each group
- Parameters checked in table [No.?] were examined: Red and total white cell count and hemoglobin concentration

CLINICAL CHEMISTRY: No data available
- Time schedule for collection of blood: No data available
- Animals fasted: No data available
- How many animals: No data available
- Parameters checked in table [No.?] were examined: No data available

URINALYSIS: No data available
- Time schedule for collection of urine: No data available
- Metabolism cages used for collection of urine: No data available
- Animals fasted: No data available
- Parameters checked in table [No.?] were examined: No data available

NEUROBEHAVIOURAL EXAMINATION: No data available
- Time schedule for examinations: No data available
- Dose groups that were examined: No data available
- Battery of functions tested: No data available
sensory activity / grip strength / motor activity / other: No data available

OTHER: No data available

Sacrifice and pathology:

GROSS PATHOLOGY: Yes, the major organs ( liver, spleen, heart, lungs, thymus, kidneys, adrenals, thyroid, testes, prostate, seminal vesicles, ovaries and uterus ) were excised, blotted dry, and weighed.

HISTOPATHOLOGY: Yes, the organs from two males and two females from each group dosed at 50 mg Fe/kg were examined histologically.

Other examinations:

No data

Statistics:

Standard deviation

Results and discussion

Results of examinations

Clinical signs:

no effects observed

Mortality:

not specified

Body weight and weight changes:

effects observed, treatment-related

Description (incidence and severity):

An increase in group mean body weight was observed after 12 weeks. At higher dose levels (100 mg/Kg), depressed growth rate in the male rats was noted but the effect was not observed in female rats. At 50 mg/Kg, the depression in growth rate produced in the male rats was not significant.

Food consumption and compound intake (if feeding study):

not specified

Food efficiency:

not specified

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

not specified

Ophthalmological findings:

not specified

Haematological findings:

no effects observed

Description (incidence and severity):

No abnormalities were found in the red and total white cell counts or hemoglobin concentration

Clinical biochemistry findings:

not specified

Urinalysis findings:

not specified

Behaviour (functional findings):

not specified

Immunological findings:

not specified

Organ weight findings including organ / body weight ratios:

no effects observed

Description (incidence and severity):

None of the organ weights in the dosed group differed significantly (P: 0.05) from those of the controls.

Gross pathological findings:

not specified

Neuropathological findings:

not specified

Histopathological findings: non-neoplastic:

no effects observed

Description (incidence and severity):

Histological examination of the organs did not reveal the abnormalities apart from slight and variable increase in the iron deposition in the tissue phagocytes.

Histopathological findings: neoplastic:

not specified

Other effects:

not specified

Effect levels

Key result

Dose descriptor:

NOAEL

Effect level:

50 mg/kg bw/day (nominal)

Based on:

test mat.

Sex:

male/female

Basis for effect level:

body weight and weight gain

gross pathology

haematology

histopathology: non-neoplastic

organ weights and organ / body weight ratios

Target system / organ toxicity

Critical effects observed:

not specified

Any other information on results incl. tables

Table: Effect of the test chemical on growth rate in rats

Dose	Control		Test group
	Male	Female	Male	Female
0	181 ± 13.6	92 ± 6.6	-	-
50	-	-	156 ± 11.7	101 ± 5.8
100	-	-	136 ± 12.8	87 ± 10.7

Applicant's summary and conclusion

Conclusions:

The No Observed Adverse Effect Level (NOAEL) for the test compound Ferrous fumarate is considered to be 50 mg/Kg using albino rats of WAG strain.

Executive summary:

Subacute repeated dose oral toxicity study was performed to determine the oral toxic nature of the test chemical using rats. The study was performed on 5 male and 5 females rats per group at dose levels of 0, 50 or 100 mg/Kg for 12 weeks. The animals were observed for changes in body weight, hematology parameters, organ weight changes were noted and histological parameters were noted. An increase in group mean body weight was observed after 12 weeks. At higher dose levels (100 mg/Kg), depressed growth rate in the male rats was noted but the effect was not observed in female rats. At 50 mg/Kg, the depression in growth rate produced in the male rats was not significant. No abnormalities were found in the red and total white cell counts or hemoglobin concentration. None of the organ weights in the dosed group differed significantly (P: 0.05) from those of the controls. Histological examination of the organs did not reveal the abnormalities apart from slight and variable increase in the iron deposition in the tissue phagocytes. Based on the observation made, the No Observed Adverse Effect Level (NOAEL) for the test chemical was considered to be 50 mg/Kg using albino rats of WAG strain.