reaction mass of disodium;3-[2-(2-carboxylatoethylamino)-ethylamino]propanoate and sodium 3-[(2-aminoethyl)amino]propanoate

Endpoint summary

Description of key information

Based on physico-chemical properties, oral and partially dermal absorption and distribution through-out the body is expected.These assumptions are supported by the results of single and repeated-dose toxicity studies in vivo. Absorption via the inhalation route is, due to physico-chemical properties of the solid 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 predominantly excreted via urine and to a lower extent via faeces.

Key value for chemical safety assessment

Bioaccumulation potential:

no bioaccumulation potential

Additional information

The reaction mass of disodium;3-[2-(2-carboxylatoethylamino)-ethylamino]propanoate and sodium 3-[(2-aminoethyl)amino]propanoate is a solid and the main component has a molecular weight of 154.1 g/mol. The substance is miscible with water in a concentration range of ≥ 61 g/100 g < 71 g/100 g at 23°C. The log P_ow is estimated from the solubilities in n-octanol and in water to be <-4.7 at 25°C and the vapor pressure is calculated to be 1.57E-7 Pa at 25°C. The boiling point is calculated to be 479.62°C.

 

Absorption

Oral

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 P_ow 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. As the substance shows a good water solubility, is highly hydrophilic (log P_ow<-4.7) and a small molecule, it can be considered as likely that the substance becomes bioavailable following the oral route.

Oral uptake was confirmed by results of the acute oral and repeated dose reproductive/developmental oral toxicity studies where, clinical signs and kidney damage up to mortality were observed indicating systemic bioavailability.

Inhalation

Absorption via the respiratory route also depends on physico-chemical properties like vapor pressure, log P_ow 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 P_ow 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 1.57E-7 Pa at 25°C the substance is unlikely to be available as a vapor and exposure and uptake via inhalation is considered as negligible.

Dermal

In general, dermal absorption is favored by small molecular weights and high water solubility of the substance. Log P_ow values between 1 and 4 favor dermal absorption, particularly if water solubility is high. However, if water solubility is above 10 g/L and the log P_ow value below 0 the substance may be too hydrophilic to cross the lipid rich stratum corneum and dermal uptake will be low. Therefore, for the substance low dermal absorption is predicted because of its high water solubility and an estimated log P_ow value of < -4.7.

In line with this prediction, no mortality, no signs of systemic toxicity nor local skin effects were observed in an acute dermal toxicity study performed with the substance.

Distribution

In general, the smaller the molecule the broader is its distribution. Small water-soluble molecules will diffuse through aqueous channels and pores in the membranes. After being absorbed into the body, the substance is expected to distribute through-out the body water. Due to its low log P_ow the test item is unlikely to bioaccumulate in tissue,and there are no other physicochemical properties indicating bio-accumulating properties. A passage over the placental barrier is not expected since in the developmental toxicity study no teratogen or specific embryotoxic effects were reported up to the limit dose of 1000 mg/kg bw/day.

 

Metabolism

QSAR Toolbox was used to predict possible metabolites of the substance. Besides Sodium [Na+] and N-(2-Aminoethyl)-β-alanine further metabolites, which are oxidized at various positions of the molecules were predicted using the rat liver metabolic simulator of QSAR Toolbox (see table 1).

Thein vitrorat liver metabolic simulator of QSAR toolbox was used to predict these further metabolites. It represents an electronically designed set of 509 structurally generalized, hierarchically arranged biotransformation reactions, which are characteristic for the metabolism forin vitroexperimental systems such as rodent (mostly rat) liver microsomes and S9 fraction. The principal applicability of this simulator is associated with the reproduction as well as the prediction of the metabolic activation reactions and pathways of xenobiotic chemicals. Each transformation in the simulator consists of source and product structural fragments, and inhibiting “masks”. A probability of occurrence is ascribed to each principal transformation, which determines its hierarchy in the transformation list. A training set of xenobiotic chemicals of a wide structural diversity, with experimentally observed metabolic reactions and pathways has been built, using published data on their metabolism in rodent liver microsomes and S9 fraction. The organic compounds in the training set belong to different classes of industrial chemicals. The data on their metabolism are collected mostly from research publications and are associated with the commonly observed in vitro liver metabolic reactions of chemicals with different structures. The molecular transformations set consists partly of 25 - 30 abiotic and, also, a few enzyme-controlled reactions believed to occur at a very high rate as compared to the duration of the tests, and the highest priority is assigned to these reactions. This subset of reactions includes also transformations of highly-reactive functional groups and intermediates. On the whole, the simulator contains also 450 – 470 enzymatic phase I and 15 – 20 enzymatic phase II transformations.

 

Table 1: Predicted metabolites using QSAR Toolbox

 

[O-H].[Na+]	N-(2-Aminoethyl)-β-alanine   NCCNCCC(O)=O
OC(=O)CCNCC(O)=O	OC(=O)CCNCC=O

 

Excretion

In general, urinary excretion in favored by low molecular weight (below 300 g/mol in the rat) and good water solubility. Therefore, the substance is expected to be excreted mostly via urine. This assumption is supported by the observation that the kidneys as predominant excretion organ were affected after repeated oral application showing papillary necrosis.