Hematite (Fe2O3)

Developmental toxicity / teratogenicity

Administrative data

Endpoint:

developmental toxicity

Type of information:

experimental study

Adequacy of study:

key study

Study period:

No data

Reliability:

1 (reliable without restriction)

Rationale for reliability incl. deficiencies:

other: 1d The study was well documented and meets generally accepted scientific principles, and conducted in compliance with GLP.

Data source

Reference

Reference Type:

study report

Title:

Unnamed

Year:

2002

Report date:

2002

Materials and methods

Test guideline

Qualifier:

according to guideline

Guideline:

other: OECD 422

Deviations:

no

GLP compliance:

yes

Limit test:

no

Test material

Test material information

Constituent 1

Reference substance name:

iron(2+);sulfate;heptahydrate

Cas Number:

7782-63-0

Molecular formula:

FeH14O11S

IUPAC Name:

iron(2+);sulfate;heptahydrate

Constituent 2

Reference substance name:

Iron (II) sulfate heptahydrate

IUPAC Name:

Iron (II) sulfate heptahydrate

Details on test material:

- Name of test material (as cited in study report): Iron (II) sulfate heptahydrate
- Physical state: blue-green crystalline powder
- Analytical purity: 91.1% (Lot No. 010628) and 90.6% (Lot No. 010903)
- Impurities (identity and concentrations): Mg 0.3%, Mn 0.19%, Zn 75 ppm (Lot No. 010628) and Mg 0.28%, Mn 0.16%, Zn 84 ppm (Lot No. 010903)
- Storage condition of test material: room temperature under argon
- Stability under test conditions: The stability of test concentrations was confirmed for 6 hours in the dark at room temperature.

Test animals

Species:

rat

Strain:

Sprague-Dawley

Details on test animals or test system and environmental conditions:

TEST ANIMALS
- Source: Charles River Laboratories Japan, Inc., Yokohama, Japan
- Age at study initiation: 10 weeks
- Weight at study initiation: male: 341 -383 g; female: 222 -255 g
- Housing: stainless steel cage
- Diet (ad libitum): CRF-1 from Oriental Yeast Co., Ltd.
- Water (ad libitum): tap water
- Acclimation period: 12 days

ENVIRONMENTAL CONDITIONS
- Temperature (°C): 20 - 26
- Humidity (%): 40 - 70
- Air changes (per hr): 12
- Photoperiod (hrs dark / hrs light): 12 / 12

Administration / exposure

Route of administration:

oral: gavage

Vehicle:

water

Details on exposure:

PREPARATION OF DOSING SOLUTIONS: Test substance was prepared with water for injection purposes. Gavage solutions were prepared freshly each time and used within 6 hours.

Analytical verification of doses or concentrations:

yes

Details on analytical verification of doses or concentrations:

The concentrations were measured in samples used for males at the first teatment and at the end of administration.

Details on mating procedure:

- M/F ratio per cage: 1/1
- Length of cohabitation: up to 14 days
- Proof of pregnancy: vaginal plug / sperm in vaginal smear referred to as day 0 of pregnancy

Duration of treatment / exposure:

Males: Total of 49 days beginning 14 days before mating.
Females: Total of 42-47 days beginning 14 days before mating.

Frequency of treatment:

Once daily

Duration of test:

49 days

No. of animals per sex per dose:

12

Control animals:

yes, concurrent vehicle

Details on study design:

- Dose selection rationale: Doses selected for the main studies were based on gross pathology findings observed in the 14-days preliminary studies (Study No. 100520P).

Examinations

Maternal examinations:

Observation performed and frequency: General condition was observed twice a day (before and after treatment). 

Male body weights were  measured twice a week. Female body weights were measured twice a week  during the pre-mating and mating period and on days 0, 7, 14 and 21 of gestation and days 0 and 4 of lactation. 

Food consumption was determined twice a week during the pre- and post-mating period in males, and twice a week during the pre-mating period and on days 2, 9, 16 and 21 of gestation and day 4 of lactation in females. 

For 6 males and females per group, urinalysis was carried out before final administration. 

Blood samples were collected from the abdominal aorta on next day of the last  administration and hematological  and blood chemical examinations were carried out. 

Ovaries and uterine content:

The ovaries and uterine content was examined after termination: Yes
Examinations included:
- Gravid uterus weight: Yes
- Number of corpora lutea: Yes
- Number of implantations: Yes
- Number of early resorptions: No
- Number of late resorptions: No

Fetal examinations:

- External examinations: Yes:
- Soft tissue examinations: No data
- Skeletal examinations: No data
- Head examinations: No data

Statistics:

Bartlett´s test, Dunnett´s test and ?2 test

Indices:

copulation index, fertility index, gestation index, delivery index, implantation index, live birth index and viability index

Results and discussion

Results: maternal animals

Maternal developmental toxicity

Details on maternal toxic effects:

Maternal toxic effects:yes

Details on maternal toxic effects:
See section 7.5.1, for details of parental toxicity.

Effect levels (maternal animals)

1

Dose descriptor:

NOAEL

Remarks:

maternal toxicity

Effect level:

100 mg/kg bw/day (actual dose received)

Based on:

test mat. (total fraction)

Remarks:

FeSO4.7H2O

Basis for effect level:

clinical biochemistry

2

Key result

Dose descriptor:

NOAEL

Remarks:

developmental toxicity

Effect level:

>= 1 000 mg/kg bw/day (actual dose received)

Based on:

test mat. (total fraction)

Remarks:

FeSO4.7H2O

Basis for effect level:

other: Recalculated value from the FeSO4.7H2O level

Remarks on result:

not determinable due to absence of adverse toxic effects

3

Dose descriptor:

NOAEL

Remarks:

maternal toxicity

Effect level:

20 mg/kg bw/day (actual dose received)

Based on:

element (total fraction)

Remarks:

Fe

Basis for effect level:

other: Recalculated value from the FeSO4.7H2O level

4

Key result

Dose descriptor:

NOAEL

Remarks:

developmental toxicity

Effect level:

>= 200 mg/kg bw/day

Based on:

element (total fraction)

Remarks:

Fe

Basis for effect level:

other: Recalculated value from the FeSO4.7H2O level

Remarks on result:

not determinable due to absence of adverse toxic effects

Results (fetuses)

Details on embryotoxic / teratogenic effects:

Embryotoxic / teratogenic effects:no effects

Effect levels (fetuses)

1

Key result

Dose descriptor:

NOAEL

Effect level:

>= 1 000 mg/kg bw/day (actual dose received)

Based on:

test mat. (total fraction)

Remarks:

FeSO4.7H2O

Sex:

male/female

Remarks on result:

not determinable due to absence of adverse toxic effects

2

Key result

Dose descriptor:

NOAEL

Effect level:

>= 200 mg/kg bw/day (actual dose received)

Based on:

element (total fraction)

Remarks:

Fe

Sex:

male/female

Basis for effect level:

other: Recalculated value from the FeSO4.7H2O level

Fetal abnormalities

Abnormalities:

not specified

Overall developmental toxicity

Developmental effects observed:

not specified

Applicant's summary and conclusion

Conclusions:

In a well conducted OECD 422 study conducted to GLP (reliability score 1), the NOAEL for developmental toxicity was at least 1000 mg/kg bw/day iron sulphate heptahydrate (equivalent to 200 mg/kg bw/day iron) in rats. The NOAEL for parental toxicity was 100 mg/kg bw/day (equivalent to 20 mg/kg bw/day iron).

Executive summary:

In a well conducted OECD 422 study conducted to GLP (reliability score 1), the NOAEL for developmental toxicity was at least 1000 mg/kg bw/day iron sulphate heptahydrate (equivalent to 200 mg/kg bw/day iron) in rats. The NOAEL for parental toxicity was 100 mg/kg bw/day (equivalent to 20 mg/kg bw/day iron).