Reaction products of sodium glucoheptonate with manganese sulfate and sodium hydroxide

Basic toxicokinetics

Administrative data

Endpoint:

basic toxicokinetics in vivo

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 MnGHA was performed, taking into account the chemical structure, the available physico-chemical-data and the available toxicity data.

Data source

Reference

Reference Type:

other: Toxicokinetic statement

Title:

Unnamed

Year:

2017

Report date:

2017

Materials and methods

Objective of study:

absorption

distribution

excretion

metabolism

Test guideline

Test guideline 1

Qualifier:

according to guideline

Guideline:

OECD Series on Testing and Assessment No. 29 (23-Jul-2001): Guidance document on transformation/dissolution of metals and metal compounds in aqueous media

Deviations:

no

Test guideline 2

Qualifier:

according to guideline

Guideline:

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

Deviations:

no

Principles of method if other than guideline:

An assessment of toxicological behaviour of MnGHA is based on its physico-chemical properties and on the results of available toxicity data data.

GLP compliance:

no

Test material

Test material information

Constituent 1

Reference substance name:

Reaction products of sodium glucoheptonate with manganese sulfate and sodium hydroxide

EC Number:

946-400-7

Molecular formula:

Not specified (UVCB substance).Molecular formula of the main substance:C14H30O22SMn2

IUPAC Name:

Reaction products of sodium glucoheptonate with manganese sulfate and sodium hydroxide

Results and discussion

Main ADME results

Main ADME results 1

Type:

absorption

Results:

GI absorption of 100 % and 3-5 % for the chelating agent GHA and free manganese, respectively, are considered. Dermal absorption is very low and absorption via inhalation is confined to the amount deposited in upper airways which can be swallowed.

Main ADME results 2

Type:

distribution

Results:

Distribution of dissociation products absorbed from the gastrointestinal tract is expected to be extensive throughout the body. However, no wide distribution is expected in case of dermal or inhalation exposure.

Main ADME results 3

Type:

excretion

Results:

The released free GHA and manganese are expected to be excreted mainly via the urine or faeces, respectively. Small amounts of manganese can be excreted via the urine. Biliary excretion was also observed for glucoheptonate.

Main ADME results 4

Type:

metabolism

Results:

Glucoheptonate is involved into intermediary carbohydrate metabolism. Mn may undergo changes in oxidation state within the body: from Mn (II) to Mn (III), but the formation of complexes with biomolecules is also possible:bile salts, proteins, nucleotids.

Applicant's summary and conclusion

Conclusions:

The substance will be limted absorbed following inhalation exposure due to its very low vapour pressure (12.75 x 10E-5 Pa) and microgranulated form. Dermal absorption is considered to be negligible. In case of oral route of exposure the substance will dissociate under acidic conditions releasing free GHA and manganese, which are expected be readily absorbed, wide distributed and not extensively metabolised in the body. Excretion will be primarily via the faeces and via the urine, in case of manganese and glucoheptonate, respectively.
No bioaccumulation potential is expected.

Executive summary:

Manganese 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 for the complex whereby only limited absorption (5 %) is determined for manganese. Concerning absorption after exposure via inhalation, as the chemical has a low vapour pressure, is highly hydrophilic, has a negative LogPow, and has 11.47 % 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. Manganese 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 manganese and glucoheptonate moieties. 10 % absorption is therefore considered for dermal route of exposure. The glucoheptonate moieties or as complex with manganese are expected to be distributed predominantly to kidneys and organs with higher expression of glucose transporters. Manganese is distributed predominantly to brain, liver, pancreas, and kidney. The substance does not indicate a significant potential for accumulation. Manganese 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 manganese is maintained constant at the physiologically required levels of manganese in the various tissues at low and high dietary manganese intakes. Manganese, 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. Manganese is excreted mainly via the faeces. Glucoheptonate is involved into intermediary carbohydrate metabolism and eliminated unchanged primarily via the urine and to a lesser extent via the bile.