L-(+)-2,5-diaminopentanoic acid

Endpoint summary

Key value for chemical safety assessment

Bioaccumulation potential:

no bioaccumulation potential

Absorption rate - oral (%):

100

Absorption rate - dermal (%):

10

Absorption rate - inhalation (%):

100

Additional information

Toxicokinetic Statement on the Substance L-(+)-2,5-diaminopentanoic acid (Orn-HCl, ORH) EC 221-678-6 for the Purpose of REACH Registration, IUCLID Section 7.1

 

Usually L-(+)-2,5-diaminopentanoic acid (Orn-HCl) as such is not a natural constituent of the biochemical pathways in living cells.

 

Under physiological conditions L-(+)-2,5-diaminopentanoic acid is present as L-ornithine in organisms. Thus the toxicokinetic statement primarily refers to L-ornithine.

 

A non-essential and nonprotein amino acid, L-ornithine is critical for the production of the body's proteins, enzymes and muscle tissue. L-Ornithine plays a central role in the urea cycle and is important for the disposal of excess nitrogen (ammonia). L-Ornithine is the starting point for the synthesis of many polyamines such as putrescine and spermine. L-Ornithine supplements are claimed to enhance the release of growth hormone and to burn excess body fat. L-Ornithineis necessary for proper immune function and good liver function.

 

L-Ornithine is a naturally occurring amino acid found in meat, fish, dairy and eggs. L-Ornithine is one of the key reactants in the urea cycle that is responsible for 80% of the nitrogen excretion in the body. L-Ornithine enhances liver function and helps detoxify harmful substances.

 

 

Adsorption

 

Ingested L-(+)-2,5-diaminopentanoic acid is transformed to L-ornithine, the latter is measured in blood samples (Demura et al., 2011).

 

Ingested diet containing L-ornithine is denatured in the stomach due to low pH. L-ornithine is emerging either by denaturation or released as a free component. In the duodenum and small intestine digestion continues through hydrolytic enzymes (e.g. trypsin, chymotrypsins, elastase, carboxypeptidase). The resultant mixture of peptides and amino acids is then transported into the mucosal cells by specific carrier systems for amino acids and for di- and tripeptides.

 

The products of digestion are rapidly absorbed. Like other amino acids L-ornithine is absorbed from ileum and distal jejunum.

 

A major source of L-ornithine is the urea circle. Urea synthesis takes place in the liver. Among the essential reactions in this process is hydrolysis of the amino acid L-arginine by the enzyme arginase to yield urea and L-ornithine (Lehninger, et al, 2000). Following to this reaction L-ornithine is present in the blood system.

L-(+)-2,5-diaminopentanoic acid is of low volatility due to a very low vapour pressure (1.1065726E-7 hPa). From this and from the particle size it is not expected that L-(+)-2,5-diaminopentanoic acid reaches the nasopharyncheal region or subsequently the tracheobronchial or pulmonary region in significant amounts.

 

However, being a very hydrophilic substance with a molecular mass of only 132.161, any L-(+)-2,5-diaminopentanoic acid reaching the lungs might be absorbed through aqueous pores (ECHA, 2014). For risk assessment purposes, although it is unlikely that L-(+)-2,5-diaminopentanoic acid will be available to a high extent after inhalation via the lungs due to the low vapour pressure and high MMAD, the inhalation absorption of L-(+)-2,5-diaminopentanoic acid is set at 100%.

 

Setting the dermal absorption rate of 10 % considers derivations in ECHA (2014). Initially, basic physico-chemical information should be considered, i.e. molecular mass and lipophilicity (log P). Following, a default value of 100% skin absorption is generally used unless molecular mass is above 500 and log P is outside the range [-1, 4], in which case a value of 10% skin absorption is chosen (de Heer et al, 1999). The lower limit of 10% was chosen, because there is evidence in the literature that substances with molecular weight and/or log P values at these extremes can to a limited extent cross the skin.

 

 

Distribution

Absorbed peptides are further hydrolysed resulting in free amino acids which are secreted into the portal blood by specific carrier systems in the mucosal cell. Alternatively, they are metabolised within the cell itself. Absorbed amino acids pass into the liver where a portion of the amino acids are used. The remainder pass through into the systemic circulation and are utilised by the peripheral tissue. L-Ornithine is actively transported across the intestine from mucosa to serosal surface. The mechanism of absorption is that of the ion gradient. All L-amino acids are absorbed by Na+dependant, carrier mediated process. This transport is energy dependant by ATP. (All data from: Lehninger et al, 2000; Chatterjea and Shinde, 2012.)

 

Plasma concentrations of L-ornithine in normal subjects are reported to be ca. 55 µM/L +/- 16 µM/L with plasma samples collected from healthy volunteers after an overnight fast (Cynober 2002). This is a higher plasma concentration than those of several proteinic amino acids.

 

 

Metabolism (Catabolism)

L-Ornithine is an amino acid produced in the urea cycle by the splitting off of urea from arginine. It is a central part of the urea cycle, which allows for the disposal of excess nitrogen. L-Ornithine is also a precursor of citrulline and arginine. In order for ornithine produced in the cytosol to be converted to citrulline, it must first cross the inner mitochondrial membrane into the mitochondrial matrix where it is carbamylated by ornithine-transcarbamylase. This transfer is mediated by the mitochondrial ornithine transporter (Lehninger eta al, 2000). Mutations in the mitochondrial ornithine transporter result in hyperammonemia, hyperornithinemia, homocitrullinuria (HHH) syndrome, a disorder of the urea cycle (Morizono et al., 2005). The pathophysiology of the disease may involve diminished ornithine transport into mitochondria, resulting in ornithine accumulation in the cytoplasm and reduced ability to clear carbamoyl phosphate andammonia loads.

 

Ammonia produced in skeletal muscle is metabolized into harmless urea via the urea cycle in hepatocytes after transportation to the liver via blood. Thus, if the response speed of the urea cycle is accentuated, fatigue may be ameliorated by a reduction of the ammonia accumulation in skeletal muscle (Demura et al., 2011).

 

 

Excretion

The concentration of L-ornithine as a component of the urea cycle is comparatively constant. Urine is the relevant route of excretion if occurring.

 

Excretion of excess ammonia is via the urea circle in which L-ornithine is one of the key components.The urea is then released into the bloodstream where it travels to the kidneys and is ultimately excreted in urine.

 

The concentration of L-ornithine was measured to be (Hortin et al., 2012)

with children: 3 to 16 micromol/dL or 30 to 160 micromol/L

with adults: 5 to 70 micromol/dL or 50 to 700 micromol/L

which is expectedly low compared to proteinic amino acids.

 

For risk assessment purposes oral absorption of L-(+)-2,5-diaminopentanoic acid is set at 100%.

 

Other routes of excretion than that following to dietary intake are not relevant (e.g. exhalation).

  

For substances with log P values <0, poor lipophilicity will limit penetration into the stratum corneum and hence dermal absorption. Values <–1 suggest that a substance is not likely to be sufficiently lipophilic to cross the stratum corneum, therefore dermal absorption is likely to be low.

 

 

 

Citations:

 

M. Chatterjea and R. Shinde (2012): Textbook of Medical Biochemistry. Jaypee Brothers Medical Publishers, New Delhi

 

L. Cynober (2002): Plasma Amino Acid Levels with a Note on Membrane Transport: Characteristics, Regulation, and Metabolic Significance. Nutrition 18 (9), 761-766

 

S. Demura, K. Morishita, T. Yamada, S. Yamaji and M. Komatsu (2011): Effect of L-ornithine hydrochloride ingestion on intermittent maximal anaerobic cycle ergometer performance and fatigue recovery after exercise. European Journal of Applied Physiology, 111(11): 2837-2843

 

ECHA (2014): Guidance on information requirements and chemical assessment Chapter R. 7c: Endpoint specific guidance.

 

G. Hortin In: C. Burtis ed. Amino Acids, Peptides, and Proteins.Tietz Textbook of Clinical Chemistry and Molecular Diagnostics. 5th ed. Philadelphia, PA: Elsevier Saunders; 2012: chap 21.

 

A. Lehninger, D. Nelson, M. Cox (2000): Principles of Biochemistry (3rd ed.), New York: W. H. Freeman

 

H. Morizono, J. Woolston, M. Colombini and M. Tuchman (2005): The use of yeast mitochondria to study the properties of wild-type and mutant human mitochondrial ornithine transporter.Mol Genet Metab.2005 Dec;86(4):431-40. Epub 2005 Oct 26.