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Toxicological information

Acute Toxicity: oral

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Administrative data

Endpoint:
acute toxicity: oral
Type of information:
experimental study
Adequacy of study:
key study
Reliability:
2 (reliable with restrictions)
Rationale for reliability incl. deficiencies:
other: Basic data given: comparable to guidelines/standards with acceptable restrictions; many extra endpoints examined; published in a peer reviewed scientific journal

Data source

Reference
Reference Type:
publication
Title:
The acute oral toxicity of reduced iron.
Author:
Boyd EM, Shanas MN
Year:
1963
Bibliographic source:
Canad Med Ass J July 27, 1963, vol. 89, 171-175

Materials and methods

Test guideline
Qualifier:
equivalent or similar to guideline
Guideline:
OECD Guideline 401 (Acute Oral Toxicity)
GLP compliance:
not specified
Remarks:
study performed many years before the GLP principles were established
Test type:
standard acute method
Limit test:
no

Test material

Constituent 1
Reference substance name:
hydrogen reduced iron powder
IUPAC Name:
hydrogen reduced iron powder
Details on test material:
- Name of test material (as cited in study report): reduced iron
- Substance type: pure active substance
- Physical state: solid
- Analytical purity: probably 100%
- The test material is described as to pass "freely through a No. 100 sieve"; such a sieve has openings of 150 micrometer; the particles are thus smaller than 150 micrometer.
- Reduced iron is elemental iron, available as an amorhous powder, free of crystals. It is prepared through reduction of iron oxide by hydrogen.

Test animals

Species:
rat
Strain:
Wistar
Sex:
male
Details on test animals or test system and environmental conditions:
TEST ANIMALS
- Source: animal quarters of the Department of Pharamcology, Queen´s University, Kingston, Ontario, Canada
- Age at study initiation: young
- Weight at study initiation: 221 ± 28 (mean ± S.D.)
- Fasting period before study: 16 hours (overnight)
- Housing: metabolism cages, one rat per cage
- Diet: ad libitum
- Water: ad libitum


ENVIRONMENTAL CONDITIONS

- Air changes (per hr): no data
- Photoperiod (hrs dark / hrs light): no data


Administration / exposure

Route of administration:
oral: gavage
Vehicle:
water
Details on oral exposure:
VEHICLE
- Amount of vehicle (if gavage): 75 ml/kg bw volume of the iron suspension in water, except for the 2 highest doses where it was 100 ml/kg bw

MAXIMUM DOSE VOLUME APPLIED: 100 ml/kg bw


CLASS METHOD (if applicable)
- Rationale for the selection of the starting dose: a series of pilot tests were performed
Doses:
0, 60, 65, 70, 80, 90, 100, 110, 120, 140, 170, 200 g/kg bw
No. of animals per sex per dose:
10 to 24 (also for the controls)
Control animals:
yes
Details on study design:
Pilot test performed in order to determine the appropriate dose range, with 100 g/kg administered dose. The animals were sacrified at intervals and clinical examinations and autopsies were performed.
Autopsies were performed upon 13 rats (death at 22 to 45 hours), 3 (death at 89 to 142 hours), survivors at 2 and 4 weeks after administration, and control groups.
Statistics:
linear regression
least squares method

Results and discussion

Preliminary study:
no
Effect levels
Sex:
male
Dose descriptor:
LD50
Effect level:
98.6 other: g/kg bw
Remarks on result:
other: ±26.7 S.E.
Mortality:
9% at 60 g/kg bw
70% at 140 g/kg bw
100% at the two top doses
Clinical signs:
Inactivity and depression of the animals within a few minutes after administration. Hypersensitivity to sudden stimuli at 24 hours followed by a period of hyposensitivity. Anorexia, oligodipsia, oliguria, alkalosis, diarrhea, loss of body weight, hypothermia were observed. Respiratory failure was the immediate cause of death.
Body weight:
Loss of body weight due to decreased food intake and to diarrhea.
Gross pathology:
- Iron and gas in gastrointestinal tract of deaths at 24 to 48 h.
- Death after 48 h: shrunken and collapsed gastrointestinal tract with remaining iron in hard lumps.
- Enlarged adrenal glands; reduced liver and thymus.
- Most organ weights reduced due to treatment, with the exception of the adrenals.
- In animals dying relatively late, organs were found to be edematous; dry weights were even more reduced than wet weights.
Other findings:
Histopathology:
- Capillary and vein congestion in gastrointestinal tract, kidneys, liver, lungs, spleen, adrenals and thymus gland.
- Minor capillary congestion in heart and brain.
- Red pulp of spleen contracted and packed with erythrocytes.
- Congested areas in the adrenals and thymus.
- Shrunken hepatic cells.
- Pulmonary congestion and venous thrombosis after early death; in addition pulmonary perivascular edema after later death.

Applicant's summary and conclusion

Interpretation of results:
practically nontoxic
Remarks:
Migrated information Criteria used for interpretation of results: EU
Conclusions:
The LD50 ± S.E. estimated was 98.6 ± 26.7 g/kg bw, which is much higher than 2 g/kg bw, maximum LD50 that still leads to classification (Category IV, EU). Therefore, reduced iron could be considered as practically non-toxic based on the LD50.
Executive summary:

In an acute oral toxicity study, groups of young, male, albino rats of a Wistar strain were given a single oral dose of reduced iron (a form of powdered, elemental iron) in distilled water rat doses of   0, 60, 65, 70, 80, 90, 100, 110, 120, 140, 170 and 200  g/kg bw. Food was withdrawn for 16 hours (overnight) before administration of iron.The oral LD50was found to be 98.6 ± 26.7 g/kg bw. Reduced iron is of very low toxicity based on the LD50 in males. Death occurred at a mean ± S.D. of 62 ± 35 hours and its immediate cause was respiratory failure. Clinical signs were as follows: hypersensitivity and hyposensitivity periods, anorexia, oligodipsia, oliguria, alkalosis, diarrhoea, loss of body weight and hypothermia. Most of the symptoms were not dose-dependent. Autopsy revealed loss of weight in the majority of the organs, caused either by dehydration at early death or by edema when death was delayed. The main histopathologic signs were congestion of capillaries and veins in gastrointestinal tract, kidneys, liver, lungs, spleen, adrenals and thymus gland, heart and brain.