Registration Dossier

Administrative data

Endpoint:
basic toxicokinetics, other
Type of information:
other: Expert statement
Adequacy of study:
key study
Reliability:
1 (reliable without restriction)
Rationale for reliability incl. deficiencies:
other: Expert statement, no study available

Data source

Reference
Reference Type:
other: Expert Statement
Title:
Unnamed
Year:
2018
Report date:
2018

Materials and methods

Principles of method if other than guideline:
Expert statement
GLP compliance:
no

Test material

Constituent 1
Chemical structure
Reference substance name:
Reaction mass of isomers of disodium amino-(3-carboxylatopropanamido)hexanoate and trisodium 2,6-bis(3-carboxylatopropanamido)hexanoate
EC Number:
947-940-6
Cas Number:
1917323-94-4
Molecular formula:
C14H21N2Na3O8 and C10H16N2Na2O5
IUPAC Name:
Reaction mass of isomers of disodium amino-(3-carboxylatopropanamido)hexanoate and trisodium 2,6-bis(3-carboxylatopropanamido)hexanoate
Test material form:
liquid
Remarks:
highly viscous, semi-solid mass

Results and discussion

Toxicokinetic / pharmacokinetic studies

Details on absorption:
Absorption is a property of a substance to diffuse across biological membranes. Generally, oral absorption is favored for molecular weights below 500 g/mol and log Pow values between -1 and 4. In the GI tract absorption of small water-soluble molecules (molecular weight up to around 200 g/mol) occurs through aqueous pores or carriage of such molecules across membranes with the bulk passage of water.
From the physicochemical properties of Reaction mass of isomers of disodium amino-(3-carboxylatopropanamido)hexanoate and trisodium 2,6-bis(3-carboxylatopropanamido)hexanoate is can be assumed that the bioavailability of the substance will be low. Furthermore, Reaction mass of isomers of disodium amino-(3-carboxylatopropanamido)hexanoate and trisodium 2,6-bis(3-carboxylatopropanamido)hexanoate dissociates in aqueous solution. It is generally assumed that ionized substances do not readily diffuse across biological membranes. This assumption is supported by the results of an acute oral toxicity study with the test item where no clinical signs and no mortality were observed indicating low systemic bioavailability.

Absorption via the respiratory route also depends on physico-chemical properties like vapor pressure, log Pow and water solubility. In general, highly volatile substances are those with a vapor pressure greater than 25 kPa or boiling point below 50 °C. Substances with log Pow values between -1 and 4 are favored for absorption directly across the respiratory tract epithelium by passive diffusion. Due to its low vapor pressure of 1.24E-5 Pa at 20 °C and 1.78E-5 Pa at 25 °C Reaction mass of isomers of disodium amino-(3-carboxylatopropanamido)hexanoate and trisodium 2,6-bis(3-carboxylatopropanamido)hexanoate is unlikely to be available as a vapor to a large extent and exposure and uptake via inhalation is considered as negligible.

In general, dermal absorption is favored by small molecular weights and high water solubility of the substance. Log Pow values between 1 and 4 favor dermal absorption, particularly if water solubility is high. However, if water solubility is high and the log Pow value below 0 the substance may be too hydrophilic to cross the lipid rich stratum corneum and dermal uptake will be low. Therefore, for Reaction mass of isomers of disodium amino-(3-carboxylatopropanamido)hexanoate and trisodium 2,6-bis(3-carboxylatopropanamido)hexanoate low dermal absorption is predicted because of its high water solubility and an estimated log Pow value of -3.25. In skin irritation and eye irritation studies with the structural analogues substance Reaction mass of calcium 2,6-bis(3-carboxylatopropanamido)hexanoate and isomers of calcium amino-(3-carboxylatopropanamido)hexanoate neither systemic nor local skin findings were reported and no skin sensitizing potential was shown indicating that dermal uptake is low. As the basic structure of the analogous substance is the same as of the target substance similar toxic behavior can be assumed.
Details on distribution in tissues:
In general, the smaller the molecule the broader is its distribution. Small water-soluble molecules and ions will diffuse through aqueous channels and pores in the membranes. After being absorbed into the body, Reaction mass of isomers of disodium amino-(3-carboxylatopropanamido)hexanoate and trisodium 2,6-bis(3-carboxylatopropanamido)hexanoate is expected to distribute through-out the body water. Due to its low log Pow the test item is unlikely to bioaccumulate in tissue, and there are no other physicochemical properties indicating bio-accumulating properties.
Details on excretion:
In general, urinary excretion is favored by low molecular weight (below 300 g/mol in the rat) good water solubility, and ionization of the molecule. In rats for organic cations with a molecular weight above 300 it is likely to be excreted via bile and in the faeces.
Therefore, Reaction mass of isomers of disodium amino-(3-carboxylatopropanamido)hexanoate and trisodium 2,6-bis(3-carboxylatopropanamido)hexanoate is expected to be excreted partially via urine but also via faeces.

Metabolite characterisation studies

Details on metabolites:
Reaction mass of isomers of disodium amino-(3-carboxylatopropanamido)hexanoate and trisodium 2,6-bis(3-carboxylatopropanamido)hexanoate dissociates in aqueous solution to render anions and cations. Sodium ions are essential constituents of the human body. The anions produced are expected to be metabolized further. From the Ames test no remarkable differences in regard to genotoxicity and cytotoxicity in the presence or absence of metabolic S9 Mix could be detected, which might indicate that no metabolic activation of the substance occurs in vitro and probably also in vivo.

Applicant's summary and conclusion