Iron(II) fumarate

Endpoint summary

Description of key information

Repeated Dose toxicity- Oral

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.

 

Repeated dose toxicity -Inhalation

A short-term toxicity study doesnot need to be conducted because exposure of humans via inhalation in production/use is not likely based on the thorough and rigorous risk assessment provided. The vapor pressure of the test chemical was estimated to be 5.347939035779555e-7 mmHg at 25 degrees C. Hence, the endpoint can be considered for waiver

Repeated dose toxicity -Dermal

A short-term toxicity study doesnot need to be conducted because exposure of humans via dermal route in production/use is not likely based on the thorough and rigorous risk assessment provided. The test chemical is used as a dietary supplement in humans. The primary route of exposure of the test chemical is oral. Hence, this endpoint can be considered for waiver.

Key value for chemical safety assessment

Toxic effect type:

dose-dependent

Repeated dose toxicity: via oral route - systemic effects

Link to relevant study records

Reference

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

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

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

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

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

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

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

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

Critical effects observed:

not specified

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

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.

Endpoint conclusion

Endpoint conclusion:

no adverse effect observed

Dose descriptor:

NOAEL

50 mg/kg bw/day

Study duration:

subacute

Experimental exposure time per week (hours/week):

168

Species:

rat

Quality of whole database:

Klimisch Rating 2

Repeated dose toxicity: inhalation - systemic effects

Link to relevant study records

Reference

Endpoint:

short-term repeated dose toxicity: inhalation

Data waiving:

exposure considerations

Justification for data waiving:

a short-term toxicity study does not need to be conducted because exposure of humans via inhalation in production and/or use is not likely as based on the provided thorough and rigorous exposure assessment

Endpoint conclusion

Endpoint conclusion:

no adverse effect observed

Quality of whole database:

waiver

Repeated dose toxicity: inhalation - local effects

Endpoint conclusion

Endpoint conclusion:

no study available

Repeated dose toxicity: dermal - systemic effects

Link to relevant study records

Reference

Endpoint:

short-term repeated dose toxicity: dermal

Data waiving:

exposure considerations

Justification for data waiving:

a short-term toxicity study does not need to be conducted because exposure of humans via the dermal route in production and/or use is not likely as based on the provided thorough and rigorous exposure assessment

Endpoint conclusion

Endpoint conclusion:

no study available

Quality of whole database:

waiver

Repeated dose toxicity: dermal - local effects

Endpoint conclusion

Endpoint conclusion:

no study available

Additional information

Repeated Dose toxicity- Oral

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.  

Repeated dose toxicity -Inhalation A short-term toxicity study doesnot need to be conducted because exposure of humans via inhalation in production/use is not likely based on the thorough and rigorous risk assessment provided. The vapor pressure of the test chemical was estimated to be 5.347939035779555e-7 mmHg at 25 degrees C. Hence, the endpoint can be considered for waiver

Repeated dose toxicity -Dermal A short-term toxicity study doesnot need to be conducted because exposure of humans via dermal route in production/use is not likely based on the thorough and rigorous risk assessment provided. The test chemical is used as a dietary supplement in humans. The primary route of exposure of the test chemical is oral. Hence, this endpoint can be considered for waiver.

Justification for classification or non-classification

The test chemical can be regarded as potentially non-toxic when exposed repeatedly via oral, dermal and inhalation route of exposure. It can be classified under the category "Not Classified" as per CLP Regulation