Sodium N-(2-carboxyethyl)-N-(2-ethylhexyl)-β-alaninate

Basic toxicokinetics

Administrative data

Endpoint:

basic toxicokinetics

Type of information:

calculation (if not (Q)SAR)

Remarks:

Migrated phrase: estimated by calculation

Adequacy of study:

key study

Reliability:

2 (reliable with restrictions)

Rationale for reliability incl. deficiencies:

other: Assessment based on public literature. Full assessment included as part of read-across justifications for reproduction and long-term toxicity . Attached in Section 13.

Cross-reference

Reason / purpose for cross-reference:

reference to same study

Data source

Reference

Reference Type:

other company data

Title:

Unnamed

Year:

2015

Report date:

2015

Materials and methods

Objective of study:

metabolism

Test guideline

Qualifier:

no guideline followed

Principles of method if other than guideline:

Examination of published metabilc pathways for amino acids and primary amines

GLP compliance:

no

Test material

Test material information

Constituent 1

Reference substance name:

Range of alklyamine alaninates

IUPAC Name:

Range of alklyamine alaninates

Results and discussion

Any other information on results incl. tables

Review of chemistry and potential metabolic processes

The metabolism and degradation of branched and linear amines and (imino)propionates are well evaluated. However, no primary research has been found relating to the registered substance itself, and the proposed first stage of metabolic breakdown to the aliphatic amine and propionate is based on similar substance. A review of amino acids indicates that the iminopropionate will quicklymetabolise. This metabolism will release energy into cells and the nitrogen will play a part in protein synthesis or excreted as urea; this process is also referred to as ‘catabolism’, with removal of propanoate from the nitrogen, yielding ammonium ions that are then excreted as urea.   

 

A review by CIR review suggests an alternative metabolic route for lauryldipropionate based on dealklyation of the fatty amine; although this is likely to be important for the amine metabolism, oxidative or catabolic processes on the carboxylates are likely to be faster.

 

Mechanisms for metabolic degradation of alkyl propionates in general can be explored by checking the rate and degree of biodegradation. In addition, it is necessary to confirm if there is any impact on rates of metabolism between linear and branched amines to confirm validity of read-across to linear amines.  Biodegradation is a good indicator that metabolism will occur in eukaryotic cells under aerobic conditions.

 

Assessment based on ready-biodegradation

A ready biodegradation study on the substance attained 90% degradation over 20 days. This is based on CO₂evolution compared to the theoretical oxygen demand and is within experimental error to indicate completemineralisation, with no possible organic residue. Other substances such as the coco-iminodipropionate tested and reported in the EPA review [Analogue substance 1] andEthyl N-acetyl-N-butyl-β-alaninate, as well as primary amines, all show a high level of biodegration

 

Assessment based on toxicity findings

Following repeated oral administration, adaptive changes were seen in the liver. Liver hypertrophy was reported in males and females at the mid- and high doses as well as renal histopathology in males [ref 1]. There was no direct evidence of liver toxicity, and the hypertrophy was considered an adaptive effect and non-adverse. Together with dose-related weight gain of the liver, this is a strong indicator of metabolic processes taking place.

 

Proposed mechanism for metabolic degradation

The metabolism needs to be reviewed in various stages to assess which intermediates may form. The most likely is catabolic action on the amino acid releasing propionate and primary amine. However, the carboxylate / carboxcylic acid will itself readily metabolise through oxidative processes, but either way, a first stage metabolite is considered to be the primary amine.  

 

To assess this mechanism, the first step involves the amino acid based on iminodipropionic acid [ref metabolite 2]; this amino acid has been widely investigated and is important in metabolic processes and is itself a metabolite of more complex amino acids and proteins. There is little primary data on the further metabolism of iminodipropionic acid, but data has been found that it is readily biodegradable [ref 6]. General mechanisms for amino acids suggest catabolic degradation to propanoate (metabolite 3). Amino propionate is also found in nature as part of amino acid / protein metabolic pathways.

 

Propionates are metabolites of amino acids naturally found in foods and in the digestive system and are anessentialpart of metabolic processes involving Vitamin B₁₂. The ultimate pathway is well established and is part of the glucaneogenesis process; research has been performed to demonstrate metabolism in liver [ref 8]. This research shows rapid update of propionate into liver hepatocytes withulitisationin sugar metabolism.

 

2-ethylhexylamine is itself readily biodegradable (up to 80% over 28 days), but no primary data has been found regarding routes of metabolism. References are made in an OECD SIDS review [ref 4] covering a range of branched and un-branched aliphatic alklyamines in the range of C1 – C13. These have been grouped together in having similar biological properties.

 

The SIDS report concludes that the aliphatic amines metabolise readily in animals by oxidation with formation of CO₂as an ultimate metabolite. The fate of the nitrogen is not discussed, but amines and amino acids are essential in metabolic processes and building blocks.

 

The report also notes that the C10-C13 primary amines may be absorbed through the skin up to chain length of about six carbon.

 

The EPA review [ref 1] makes an alternative proposal for metabolic degradation with oxidation of the nitrogen and formation of iminodipropionic acid and primary alcohol. Although this process is likely to occur, it is considered to be a minor route in biological systems with enzyme enhanced catabolic activity on the nitrogen, resulting in propionic acid and primary amine.

 

Either route will ultimately lead to complete degradation with excretion (urea) or assimilation (proteins) of nitrogen and formation of carbon dioxide.

 

In conclusion, there is good evidence that the Registered substance, sodium N-(2-carboxyethyl)-N-(2-ethylhexyl)-β-alaninate, will be readily absorbed on ingestion and metabolised quickly to amino acids, amines and ultimately oxidised to carbon dioxide and nitrogen compounds. 

Applicant's summary and conclusion

Conclusions:

Interpretation of results (migrated information): no bioaccumulation potential based on study results
In conclusion, there is good evidence that the Registered substance, sodium N-(2-carboxyethyl)-N-(2-ethylhexyl)-β-alaninate, will be readily absorbed on ingestion and metabolised quickly to amino acids, amines and ultimately oxidised to carbon dioxide and nitrogen compounds.

Executive summary:

In conclusion, there is good evidence that the Registered substance, sodium N-(2-carboxyethyl)-N-(2-ethylhexyl)-β-alaninate, will be readily absorbed on ingestion and metabolised quickly to amino acids, amines and ultimately oxidised to carbon dioxide and nitrogen compounds.