Reaction products of sodium glucoheptonate with zinc sulfate and sodium hydroxide

Basic toxicokinetics

Administrative data

Endpoint:

basic toxicokinetics, other

Remarks:

expert satement

Type of information:

other: expert satement

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 zinc 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 ZnGHA

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

Test material

Test material information

Constituent 1

Reference substance name:

Reaction products of sodium glucoheptonate with zinc sulfate and sodium hydroxide

EC Number:

946-329-1

Molecular formula:

Not specified (UVCB substance).Molecular formula of the main substance:C14H30O22SZn2

IUPAC Name:

Reaction products of sodium glucoheptonate with zinc sulfate and sodium hydroxide

Test material form:

solid: granular

Remarks:

microgranulated

Radiolabelling:

no

Results and discussion

Main ADME results

Main ADME results 1

Type:

absorption

Results:

Due to the MW of 619.2 g/mol and logPow -16.9, it is readily absorbed via the GI tract. Low absorption potential via dermal route and inhalation is expected due to its high water solubility (500-550 g/L) and low vapour pressure (1.55 x 10E-4 Pa).

Main ADME results 2

Type:

distribution

Results:

Zinc, if released from glucoheptonate, is distributed to all organs and tissues and will be bound with organic ligands rather than existing free in solution as a cation

Main ADME results 3

Type:

metabolism

Results:

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.

Main ADME results 4

Type:

excretion

Results:

Glucoheptonate is mainly excreted via the kidneys. About 70-80% of the ingested amount of zinc is excreted via faeces (5 to 10 mg/day depending upon the dietary zinc concentration).

Toxicokinetic / pharmacokinetic studies

Details on absorption:

Zinc 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 13.9 % 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. Zinc 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 and considering low absorption potential of zinc and glucoheptonate moieties. 10 % absorption is therefore considered for dermal route of exposure.

Details on distribution in tissues:

Glucoheptonate moieties, are 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. Zinc, if released from glucoheptonate, is distributed to all organs and tissues and will be bound with organic ligands rather than existing free in solution as a cation

Details on excretion:

Glucoheptonate is involved into intermediary carbohydrate metabolism and eliminated unchanged primarily via the urine and to a lesser extent via the bile. About 70-80% of the ingested amount of zinc is excreted via faeces (5 to 10 mg/day depending upon the dietary zinc concentration).

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:

Zinc 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 13.9 % 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. Zinc 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 and considering low absorption potential of zinc and glucoheptonate moieties. 10 % absorption is therefore considered for dermal route of exposure. Glucoheptonate moieties, are 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. Zinc homeostasis is regulated in mammals by gastrointestinal absorption, excretion via faeces and via the urine as well as by the release from tissues. The total body zinc is maintained constant at the physiologically required levels of zinc in the various tissues at low and high dietary zinc intakes. Zinc, if released from glucoheptonate, is distributed to all organs and tissues and will be bound with organic ligands rather than existing free in solution as a cation. Glucoheptonate is involved into intermediary carbohydrate metabolism and eliminated unchanged primarily via the urine and to a lesser extent via the bile.