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Basic toxicokinetics

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Administrative data

Endpoint:
basic toxicokinetics in vivo
Type of information:
experimental study
Adequacy of study:
key study
Reliability:
2 (reliable with restrictions)
Rationale for reliability incl. deficiencies:
other: It is an acceptable, well-documented publication which meets basic scientific principles. It is published in a peer-reviewed scientific journal.
Cross-referenceopen allclose all
Reason / purpose for cross-reference:
reference to same study
Reason / purpose for cross-reference:
reference to other study

Data source

Reference
Reference Type:
publication
Title:
Acute toxicity of carbonyl iron and sodium iron EDTA compared with ferrous sulfate in young rats.
Author:
Whittaker P, Ali SF, Imam SZ and Dunkel VC.
Year:
2002
Bibliographic source:
Regulatory Toxicology and Pharmacology, 36: 280-286

Materials and methods

Objective of study:
absorption
distribution
Test guideline
Qualifier:
no guideline followed
Principles of method if other than guideline:
The acute oral toxicity of carbonyl iron was examined in male rats at doses of 40 and 50 g/kg bw. In addition, a time-response study was performed of serum and liver non-haem Fe in rats after oral administration of 30 g/kg bw of carbonyl iron. These results represent pertinent information for the endpoint toxicokinetics. Together with carbonyl iron, FeSO4 and NaFeEDTA were investigated.
GLP compliance:
not specified
Remarks:
It is not customary to refer to GLP compliance in publications

Test material

Constituent 1
Reference substance name:
carbonyl iron
IUPAC Name:
carbonyl iron
Details on test material:
Name of test material (as cited in study report): carbonyl iron
- Physical state: solid (particles with an average size of 5 to 6 µm, almost perfect spheres)
- Analytical purity: very high, normally from 97 to more than 99.5%; the authors of the publication state thar carbonyl iron is "extremely pure".
- The authors of the publication state: "Carbonyl iron is made by treating iron with carbon monoxide (CO) under heat and pressure. The resulting iron pentacarbonyl (Fe[CO]5) is then decomposed under controlled conditions and yields CO and iron powder...".
Radiolabelling:
no

Test animals

Species:
rat
Strain:
Sprague-Dawley
Sex:
male
Details on test animals or test system and environmental conditions:
TEST ANIMALS
- Source: National Center for Toxicological Research (NCTR)
- Age at study initiation: "young"
- Housing: polycarbonate cages
- Diet: ad libitum
- Water: ad libitum


ENVIRONMENTAL CONDITIONS
- Temperature (°C): controlled
- Photoperiod (hrs dark / hrs light): controlled

Administration / exposure

Route of administration:
oral: gavage
Vehicle:
not specified
Details on exposure:
carbonyl Fe was administered in 2 ml volume of vehicle
Duration and frequency of treatment / exposure:
single gavage treatments
Doses / concentrations
Remarks:
Doses / Concentrations:
30, 40 and 50 g/kg bw
No. of animals per sex per dose / concentration:
38 (time-response study, treated with 30 g/kg bw), 8 (acute toxicity study, treated with 40 and 50 g/kg bw), 12 control animals (time-reponse study), and 8 control animals (acute toxicity study).
Control animals:
yes
Positive control reference chemical:
In a strict sense, there was no positive control. However, carbonyl iron was investigated concurrently with FeSO4 and NaFeEDTA. In particular the first compound can be regarded as a positive control if the absorption of iron is concerned. The iron in the salt does not have to be converted to an ionic form to allow absorption. This conversion is a prerequisite for the absorption of the iron in carbonyl iron.
Details on study design:
- Dose selection rationale: the doses used were based on the LD50 levels reported in the literature.
-The serum Fe concentrations were measured with an electrochemical technique (Ferrochem II analyzer; ESA, Inc., Bedford, MA). Serum samples were analyzed in duplicate according to the method of Skinke (1987).
-Nonheme Fe was determined with the bathophenanthroline reaction.
Details on dosing and sampling:
A time-response study was performed for serum and liver nonheme Fe in rats after oral administration of 30 g/kg bw of carbonyl Fe. Serum and liver samples were taken at half hour intervals for 3-4 hours after treatment. Additionally, samples were collected at 24 h and one at 48 h. The 40 and 50 g/kg bw doses were used for the acute toxicity test, and determination of serum Fe and liver nonheme Fe levels.
Statistics:
Analysis of variance and Scheffe multiple comparison method, values expressed as means with their standard errors.

Results and discussion

Preliminary studies:
not applicable
Main ADME results
Type:
other: absorption & distribution

Toxicokinetic / pharmacokinetic studies

Details on absorption:
No mortality was observed. The results obtained regarding the serum levels of Fe are shown in Table 1 (below).The time-response after administration of the 30 g/kg bw is depicted in Fig.3 (see attachment): Fe levels peaked at 0.5 h (787 µg/l) and then gradually decreased up to 4 h. Measurements at 24 and 48 h indicate that the serum Fe level remained constant.
Details on distribution in tissues:
Liver non-haem iron levels peaked at 1.5 h and then fluctuated between 56 and 90 µg/g over the 48h period ( Fig.3, see attachment), after administration of the 30 g/kg bw of carbonyl Fe. Liver non-haem iron levels were increased significantly after administration of 40 and 50 g/kg bw of carbonyl Fe in comparison to the controls
Details on excretion:
not examined
Toxicokinetic parametersopen allclose all
Test no.:
#1
Toxicokinetic parameters:
Tmax: 0.5 h (Fe levels in blood serum after administration of 30 mg/kg bw of carbonyl Fe)
Test no.:
#1
Toxicokinetic parameters:
Cmax: 787 µg/l (Fe levels in blood serum after administration of 30 mg/kg bw of carbonyl Fe)
Test no.:
#1
Toxicokinetic parameters:
Tmax: 1.5 h (non-haem Fe in the liver, after administration of 30 mg/kg bw of carbonyl Fe)
Test no.:
#1
Toxicokinetic parameters:
Cmax: 165 µg/l (non-haem Fe in the liver, after administration of 30 mg/kg bw of carbonyl Fe); estimated from the figure provided

Metabolite characterisation studies

Metabolites identified:
not measured
Details on metabolites:
not examined

Any other information on results incl. tables

Table 1: Response of experimental animals to the two doses of carbonyl Fe.

 

n (deaths)

Dose (g/kg bw)

Body weight

Liver weight

Liver nonheme Fe (µg/g)

Total liver nonhem Fe (µg)

Serum Fe (µg/dl)

Control

8 (0)

0

121± 4

5.87± 0,23*,°

42.9± 3.7*

252± 23*

229± 11*,°

Carbonyl Fe

8 (0)

40

89± 3

3.89±0.18*

448± 50~

1687± 130°,~

406± 30°

8 (0)

50

92± 5

4.32± 0.45*

407± 58°,~

1582± 97°,~

358± 28*,°

Values are means ± SEM for surviving animals. Means for a variable not sharing a common symbol (*,°,~) are significantly different (p<0,05) as determined by the Scheffe multiple comparison method, which was applied only if significant differences were determined to exist by ANOVA.

Serum Fe levels showed a slight increase after administration of 40 and 50 g/kg bw of carbonyl Fe to the rats, in comparison to the controls. On the contrary, liver noneheme Fe levels ( µg/g liver weight) increased significantly in comparison to the controls, which indicates that iron is stored in the liver (Table 1).

The results regarding the effects of FeSO4 and NaFeEDTA are shown in Table 2 (see attachment).

Applicant's summary and conclusion

Conclusions:
Interpretation of results (migrated information): other: Iron overload due to consumption of carbonyl Fe, may result in its accumulation in the liver; however, large Fe particles are not expected to be solubilized, and hence, become systemically available.
The study allows for the comparison of the systemic bioavailability of iron after oral treatment with carbonyl iron, FeSO4 and NaFeEDTA. The lack of acute toxicity observed for carbonyl iron in comparison to the two other compounds could be the result of its toxicokinetic behaviour.
Executive summary:

A time-response study was performed of serum and liver nonheme Fe in rats after oral administration of 30 g/kg bw of carbonyl iron. In addition, the acute oral toxicity of carbonyl iron was examined in male rats at doses of 40 and 50 g/kg bw. Together with carbonyl iron, FeSO4 and NaFeEDTA were investigated (tested in different doses). Fe levels peaked at 0.5 h (787 µg/l) and then gradually decreased up to 4 h. Measurements at 24 and 48 h indicate that the serum Fe level remained constant. Liver nonheme Fe levels(µg/g liver weight) increased significantly in comparison to the controls, which indicates that iron was stored in the liver.

What follows is the original abstract of the publication.

According to the American Association of Poison Control Centers, exposures to excessive doses of iron supplements still occur in children less than 6 years of age. Since 1998, there has been one death among U.S. children in this age group. Exposures, including adverse events, to iron supplements and iron-containing vitamins for the years 1999 and 2000 were 23 215 and 24 249, respectively. To reduce the potential seriousness of such exposures, carbonyl Fe has been suggested as a possible replacement for ferrous sulfate (FeSO4). Carbonyl Fe is a unique form of elemental iron because of its small particle size. It is highly bioavailable when used to correct iron deficiency anemia. There is also current interest in using sodium (III) EDTA for food fortification. In this study both NaFeEDTA and carbonyl Fe were compared with FeSO4, the most common form of Fe for dietary supplements, to obtain information relevant to the acute toxicological profile in young rats. With FeSO4 and NaFeEDTA, total liver nonheme Fe increased with increasing dose, but the response was approximately 50% lower with NaFeEDTA compared with FeSO4. Serum Fe peaked at at approximately 0.5 to 1 h for both FeSO4 and carbonyl Fe, while NaFeEDTA was elevated up to 4 h. FeSO4 had an LD50 of 1.1 g Fe/kg and was approximately 45 times more toxic than carbonyl Fe, which had an LD50 greater than50 g Fe/kg. NaFeEDTA had an LD50 of 1.3 g Fe/kg and, compared with FeSO4, had approximately the same level of toxicity.

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