Reaction mass of calcium 2,6-bis(3-carboxylatopropanamido)hexanoate and isomers of calcium amino-(3-carboxylatopropanamido)hexanoate

Endpoint summary

Link to relevant study record(s)

Reference

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

Principles of method if other than guideline:

Expert statement

GLP compliance:

no

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 calcium 2,6-bis(3-carboxylatopropanamido)hexanoate and isomers of calcium amino-(3-carboxylatopropanamido)hexanoate is can be assumed that the bioavailability of the substance will be low. Furthermore, Reaction mass of calcium 2,6-bis(3-carboxylatopropanamido)hexanoate and isomers of calcium amino-(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 and repeated dose 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 2.1E-7 Pa at 20 °C and 3.73E-7 Pa at 25 °C Reaction mass of calcium 2,6-bis(3-carboxylatopropanamido)hexanoate and isomers of calcium amino-(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 calcium 2,6-bis(3-carboxylatopropanamido)hexanoate and isomers of calcium amino-(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 neither systemic nor local skin findings were reported and no skin sensitizing potential was shown indicating that dermal uptake is low.

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 calcium 2,6-bis(3-carboxylatopropanamido)hexanoate and isomers of calcium amino-(3-carboxylatopropanamido)hexanoate is expected to distribute through-out the body water. Due to its very 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 in 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 calcium 2,6-bis(3-carboxylatopropanamido)hexanoate and isomers of calcium amino-(3-carboxylatopropanamido)hexanoate is expected to be excreted partially via urine but also via faeces.

Details on metabolites:

Reaction mass of calcium 2,6-bis(3-carboxylatopropanamido)hexanoate and isomers of calcium amino-(3-carboxylatopropanamido)hexanoate dissociates in aqueous solution to render anions and cations. Calcium ions are essential constituents of the human body. The anions produced are expected to be metabolized further. From the in vitro genotoxicity studies 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.

Description of key information

Based on physico-chemical properties, oral and dermal absorption is expected to be low. These assumptions are supported by the results of acute and repeated dose toxicity studies in vivo. Absorption via the inhalation route is, due to physico-chemical properties of the test item, not expected. Bioaccumulation of the substance is not expected after continuous exposure. The test substance and/or its metabolites are expected to be excreted via urine and faeces.

Key value for chemical safety assessment

Bioaccumulation potential:

no bioaccumulation potential

Additional information

Reaction mass of calcium 2,6-bis(3-carboxylatopropanamido)hexanoate and isomers of calcium amino-(3-carboxylatopropanamido)hexanoate is a highly viscous semi-solid brown mass with a molecular weight range of 284.33-403.43 g/mol. The test item has a water solubility of 93.39 g/L (of one component) and 10 g/L (the other component). The log Pow is estimated for one component to be -3.25 and the vapour pressure is 2.1E-7 Pa at 20°C and 3.73E-7 Pa at 25°C. The substance shows apour point of 39°C. No boiling point was observed up to 375°C. The test item decomposes above a temperature of 109°C at 1013 hPa.

 

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 andlog 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 calcium 2,6-bis(3-carboxylatopropanamido)hexanoate and isomers of calcium amino-(3-carboxylatopropanamido)hexanoate is can be assumed that the bioavailability of the substance will be low. Furthermore, Reaction mass of calcium 2,6-bis(3-carboxylatopropanamido)hexanoate and isomers of calcium amino-(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 and repeated dose 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 2.1E-7 Pa at 20°C and 3.73E-7 Pa at 25 °C. Reaction mass of calcium 2,6-bis(3-carboxylatopropanamido)hexanoate and isomers of calcium amino-(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 calcium 2,6-bis(3-carboxylatopropanamido)hexanoate and isomers of calcium amino-(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 neither systemic nor local skin findings were reported and no skin sensitizing potential was shownindicating that dermal uptake is low.

 

Distribution

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 calcium 2,6-bis(3-carboxylatopropanamido)hexanoate and isomers of calcium amino-(3-carboxylatopropanamido)hexanoate is expected to distribute through-out the body water. Due to its very low log Pow the test item is unlikely to bioaccumulate in tissue,and there are no other physicochemical properties indicating bio-accumulating properties.

 

Metabolism

Reaction mass of calcium 2,6-bis(3-carboxylatopropanamido)hexanoate and isomers of calcium amino-(3-carboxylatopropanamido)hexanoate dissociates in aqueous solution to render anions and cations. Calcium ions are essential constituents of the human body. The anions produced are expected to be metabolized further. From the in vitro genotoxicity studies 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.

 

Excretion

In general, urinary excretion in 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 calcium 2,6-bis(3-carboxylatopropanamido)hexanoate and isomers of calcium amino-(3-carboxylatopropanamido)hexanoate is expected to be excreted partially via urine but also via faeces.