Reaction products of sodium glucoheptonate with iron sulfate and ammonium hydroxide

Basic toxicokinetics

Administrative data

Endpoint:

basic toxicokinetics, other

Remarks:

expert satement

Type of information:

other: expert statement

Adequacy of study:

key study

Study period:

2017

Reliability:

2 (reliable with restrictions)

Rationale for reliability incl. deficiencies:

other: An extended assessment of the toxicokinetic behaviour of iron glucoheptonate was performed, taking into account the chemical structure, the available physico-chemical-data and the available toxicity data of the structural analogues.

Data source

Reference

Reference Type:

other: Expert statement

Title:

Toxicokinetic assessment of FeGHA

Author:

Chemservice S.A.

Year:

2017

Report date:

2017

Materials and methods

Objective of study:

absorption

distribution

excretion

metabolism

Test guideline

Qualifier:

according to guideline

Guideline:

other: TGD, Part I, Annex IV, 2003; ECHA guidance R7c., 2012

Principles of method if other than guideline:

Physical chemical properties of iron glucoheptonate were integrated with the published toxicological data and data on ADME parameters of the structurally related substance iron gluconate to create a prediction of its toxicokinetic behaviour. Additionally, well investigated ADME data on iron from different sources (food, medications and other inorganic and organic compounds) have been taken into account, because the systemic toxicity of iron glucoheptonate is considered to be driven by released iron from the iron glucoheptonate complex.

Test material

Test material information

Constituent 1

Reference substance name:

Reaction products of sodium glucoheptonate with iron sulfate and ammonium hydroxide

EC Number:

946-072-5

Molecular formula:

Not specified (UVCB substance). Molecular formula of the main substance: C7FeH10NaO8

IUPAC Name:

Reaction products of sodium glucoheptonate with iron sulfate and ammonium hydroxide

Test material form:

solid: granular

Remarks:

brown microgranulated

Radiolabelling:

no

Results and discussion

Main ADME results

Main ADME results 1

Type:

absorption

Results:

Due the MW of 300.8 g/mol and Log Pow -10.5, it is readily absorbed via the GI tract. Low absorption potential via dermal route and inhalation is expected due to its high water solubility (>1000 g/L) and low vapour pressure (5.13 x 10E-5 Pa).

Main ADME results 2

Type:

distribution

Results:

The substance is expected to be distributed predominantly to kidneys and organs with higher expression of glucose transporters. The absorbed non-haem iron is transported via transferrin in the plasma to all body cells.

Main ADME results 3

Type:

metabolism

Results:

Iron glucoheptonate is expected to be metabolised by pathways involved into intermediary carbohydrate metabolism or eliminated unchanged via the urine and to a lesser extent via the bile.

Main ADME results 4

Type:

excretion

Results:

The majority of absorbed iron is lost in the feces. Glucoheptonate is mainly excreted via the kidneys

Toxicokinetic / pharmacokinetic studies

Details on absorption:

Iron glucoheptonate is expected to be moderately absorbed after oral exposure, based on its high water solubility and molecular weight suggestive for favoured absorption through gastrointestinal tract. As worst-case, 100 % oral absorption is considered appropriate. Concerning absorption after exposure via inhalation, as the chemical has a low vapour pressure, is highly hydrophilic, has a negative LogPow, and has 12 % of particles less than 100 µm, it is clear, that the substance is poorly available for inhalation and will not be absorbed significantly via lungs. However, an absorption by aspiration cannot be fully ruled out. Therefore, 100% inhalation absorption is considered. Iron glucoheptonate is not expected to be absorbed following dermal exposure into the stratum corneum and into the epidermis, due to its very high water solubility. 10 % absorption is considered.

Details on distribution in tissues:

Since iron dissociates from the glucoheptonate moiety before absorption, their distribution and accumulative potential can follow more or less independent ways.
The absorbed non-haem iron becomes available for binding onto transferrin, and is then transported via transferrin in the plasma to all body cells. Entering cells, iron may be incorporated into functional compounds, stored as ferritin or hemosiderin, or used to regulate future cellular iron metabolism. While all cells are capable of storing iron, the cells of the liver, spleen, and bone marrow are the primary iron storage sites in humans. Almost two-thirds of iron in the body is found in haemoglobin present in circulating erythrocytes. Glucoheptonate is expected to be distributed predominantly to kidneys and organs with higher expression of glucose transporters. The substance does not indicate a significant potential for accumulation.

Details on excretion:

At normal physiological conditions, only a small quantity of iron is lost each day. Body iron is therefore highly conserved and is regulated by absorption. The majority of absorbed iron is lost in the feces. Glucoheptonate is mainly excreted via the kidneys.

Metabolite characterisation studies

Details on metabolites:

Metabolism of glucoheptonate in mammalian tissues is described in several publications dealing with investigations of substrate specificity of a various number of aldonic acids and its isomeric analogues lactones. The enzyme 6-phosphogluconolactonase (catalysing the second step of pentose phosphate pathway (PPP)) was shown to possess a broad substrate specificity hydrolysing gluconolactone moieties including glucoheptonate. The enzyme is present in almost all mammalian tissues including humans. Further investigations revealed that glucoheptonate moiety undergoes a series of biochemical transformations similar to those of PPP.

Applicant's summary and conclusion

Executive summary:

Iron glucoheptonate is expected to be moderately absorbed after oral exposure, based on its high water solubility and molecular weight suggestive for favoured absorption through gastrointestinal tract. As worst-case, 100 % oral absorption is considered appropriate. Concerning absorption after exposure via inhalation, as the chemical has a low vapour pressure, is highly hydrophilic, has a negative LogPow, and has 12 % of particles less than 100 µm, it is clear, that the substance is poorly available for inhalation and will not be absorbed significantly via lungs. However, an absorption by aspiration cannot be fully ruled out. Therefore, 100% inhalation absorption is considered. Iron glucoheptonate is not expected to be absorbed following dermal exposure into the stratum corneum and into the epidermis, due to its very high water solubility. 10 % absorption is considered. The substance is expected to be distributed predominantly to kidneys and organs with higher expression of glucose transporters. The substance does not indicate a significant potential for accumulation. Iron glucoheptonate is expected to be metabolised by pathways involved into intermediary carbohydrate metabolism or eliminated unchanged via the urine and to a lesser extent via the bile.