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Exposure related observations in humans: other data

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exposure-related observations in humans: other data
Type of information:
experimental study
Adequacy of study:
supporting study
2 (reliable with restrictions)
Rationale for reliability incl. deficiencies:
other: Study was published in a peer-reviewed scientific journal.

Data source

Reference Type:
High-dose carbonyl iron for iron deficiency anemia: a randomized double blind trial.
Gordeuk VR, Brittenham GM, Hughes M, Keating LJ, Opplt JJ.
Bibliographic source:
Am J Clin Nutr 46: 1029-1034

Materials and methods

Endpoint addressed:
basic toxicokinetics
repeated dose toxicity: oral
Principles of method if other than guideline:
Human study for which no particular guideline is available. Carbonyl iron was compared with FeSO4 for the therapy of mild iron deficiency in menstruating non pregnant women.
GLP compliance:
not specified
It is not customary to refer to GLP in pubications in peer-reviewed scientific journals.

Test material

Constituent 1
Reference substance name:
carbonyl iron
carbonyl iron
Details on test material:
In the introduction of the paper it is stated: 'Carbonyl Fe, a pure form of elemental Fe used widely as a food additive (..,..), has remarkably low toxicity and much larger doses are tolerated when compared with ionized forms of Fe such as FeSO4 (..,..). Carbonyl does not refer to the composition of the Fe particles but rather to the manufacturing process in which the controlled heating of vaporized Fe pentacarbonyl leads to the deposition of uncharged elemental Fe as microscopic spheres of < 5µ in diameter (..).' No information is provided on the source or the purity of the material.


Ethical approval:
confirmed and informed consent free of coercion received
Details on study design:
Fifty volunteers were recruited from blood donors to the Northern Ohio Red Cross who met the following criteria: 1) menstruating nonpregnant women between the ages of 18 and 40 y and 2) deferral for repeat blood donation because of haematocrit < 38% (0.38 L/L).
In a randomized double-blind fashion, each volunteer was given a bottle with 63 doses of 300 mg FeSO4 (60 mg Fe^++) or 600 mg carbonyl Fe, contained in identical capsules, to be taken three times daily between meals for 3 wk. Thus, the FeSO4 was given in standard doses for therapy of Fe deficiency anaemia .
Each volunteer was questioned regarding possible sources of blood loss. A menstrual history was taken in which the menstrual flow was characterized as light, moderate, or heavy and the duration of menstruation in days was recorded.
Side effects were recorded at weeks 1 and 3 of the study on a standard form that included space to record constipation, diarrhoea, heartburn, nausea, abdominal cramps, headache, weakness, and unpleasant taste.
Blood samples were drawn at 0, 1, 3, 6, 12, and 16 wk for determination of free erythrocyte protoporphyrin (FEP), serum ferritin, serum Fe, total Fe binding capacity (TIBC), percent satuation of TIBC (transferrin saturation), and complete blood count (CBC) including hemoglobin, mean cellular volume (MCV), white blood cells (WBC), and platelets. Also monitored at these times were serum albumin, total bilirubin, alkaline phosphatase, serum glutamic oxaloacetic transaminase (SGOT), and serum glutamic pyruvic transaminase (SGPT).
At 6 wk, the volunteers were given Haemoccult slides (Smith Kline Diagnostics, Inc, Sunnyvale, CA) and asked to collect stool samples for 4 d and to return them for testing for occult blood.
Laboratory methods
Serum Fe, TIBC, and transferrin saturation were determined by the methods of the International Committee for Standardization in Haematology (ICSH). Serum ferritin was analyzed using FER-IRON immunoradiometric assay kits (Ramco Laboratories, Inc, Houston, TX). FEP was measured with a ZnP model 4000 Haematofluorometer (Environmental Sciences Associates, Inc, Bedford, MA). CBC was determined with a Coulter Counter Model S-Plus II (Coulter Electronics, Inc, Hialeah, FL).
Serum albumin, serum bilirubin, SOOT, SGPT, and alkaline phosphatase were measured by an automated method using the Parallel Analytical System (American Monitor Corporation, Indianapolis, IN).
Statistical methods
Pairwise independent sample t tests were used to comparethe initial mean values for haemoglobin, MCV, FEP, log serum ferritin, serum Fe, TIBC, and transferrin saturation between the two arms of the randomized trial. Paired t tests were used to compare these mean values before and 12 wk and 16 wk after starting carbonyl Fe and FeSO4 treatment for the two groups of anaemic volunteers. Pairwise independent sample t tests were used to compare the 12 wk and 16 wk mean values for the indices measured, the estimated amounts of Fe balance at weeks 3, 9, 12, and 16, and the haemoglobin regeneration rates between the two treatment regimens. The chi-square test was used to compare the incidence of side effects between participants in the randomized trial treated with carbonyl Fe and those treated with ferrous sulfate.
Exposure assessment:
Details on exposure:
See 'Details on study design' above. The subjects received measured doses.
From the 50 subjects, 36 were ultimately selected. 18 subjects received 63 doses of 60 mg Fe^2+ in the form of iron sulfate, 3 doses per day, 7 days per week, 3 weeks; the other 18 subjects received 63 doses of 600 carbonyl iron following the same timing of dosage.

Results and discussion

14 subjects were excluded from the initial group of 50 because they failed to meet selection criteria. The study shows that 10 times higher iron doses in the form of carbonyl iron (1.8 g/day) than iron(II)sulfate (180 mg/day) resulted only in an about 1.5 times higher iron absorption. Side effects as recorded by the subjects did not differ much. No signs of haematologic toxicity or hepatotoxicity were found over the whole study period, as measured by individual and mean values for white blood cells and platelets, and albumin, bilirubin, SGOT, SGT and alkaline phosphatase, respectively.

Any other information on results incl. tables

See attached file (Results from Gordeuk et al, 1987.pdf ).

Applicant's summary and conclusion

1.8 g of iron given as carbonyl iron per day for 3 weeks resulted in a 1.5 times greater iron absorption than 0.18 g iron in the form of iron sulfate in mildly iron deficient women. No effects were found on the usual clinical-chemical parameters of hepatotoxicity, whereas the self-recorded side effects of the two treatments did not differ much. The benefit of carbonyl iron for iron supplementation is primarily associated with its lack of toxicity.
Executive summary:

Thirty six menstruating women with mild signs of anemia were given either carbonyl iron or iron(II)sulfate. Endpoints studied were anemia, iron status, hematological effects and hepatotoxicity. Moreover, the subjects were asked to self-record side effects. It was found that 1.8 g per day of iron for 3 weeks given as carbonyl iron resulted in a 1.5 times greater iron absorption than 0.18 g iron in the form of iron sulfate. No effects were found on hepatotoxicity and hamatology, whereas the self-recorded side effects of the two treatments did not differ much. The benefit of carbonyl iron for iron supplementation is primarily associated with its lack of toxicity.

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