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Please be aware that this old REACH registration data factsheet is no longer maintained; it remains frozen as of 19th May 2023.

The new ECHA CHEM database has been released by ECHA, and it now contains all REACH registration data. There are more details on the transition of ECHA's published data to ECHA CHEM here.

Diss Factsheets

Administrative data

Endpoint:
basic toxicokinetics
Type of information:
other: Toxikokinetic assessment
Adequacy of study:
key study
Study period:
April 2012
Reliability:
2 (reliable with restrictions)
Rationale for reliability incl. deficiencies:
other: Toxicokinetic assessment

Data source

Reference
Reference Type:
other company data
Title:
Unnamed
Year:
2012

Materials and methods

Objective of study:
toxicokinetics
Test guideline
Qualifier:
no guideline available
Principles of method if other than guideline:
Toxicokinetic assessment, based on
- Guidance on information requirements and chemical safety assessment Chapter R.7c: Endpoint specific guidance
- ECB EU Technical Guidance Document on Risk Assessment, 2003
GLP compliance:
no

Test material

Constituent 1
Chemical structure
Reference substance name:
Arginine
EC Number:
200-811-1
EC Name:
Arginine
Cas Number:
74-79-3
Molecular formula:
C6H14N4O2
IUPAC Name:
arginine

Results and discussion

Main ADME results
Type:
absorption
Results:
Oral route: 100%. Dermal route: 10 %. Inhalation route: 100 %

Any other information on results incl. tables

L-arginine is a natural occurring amino acid and a natural constituent of peptides and proteins. Its content in most proteins is ca. 3 – 6 % and high in the proteins of the peanut (ca. 11 %) (Belitz et al, 2007). Free L-arginine occurs in many plants by i.a. serving as a reservoir for nitrogen in seedlings. L-arginine belongs to the group of amino acids with charged side chains. It is semi-essential in humans; its supply via food seems to be essential with certain metabolic conditions. Biosynthesis does not produce sufficient L-arginine, and some must be consumed through diet. Individuals who have poor nutrition or certain physical conditions may be advised to increase their intake of foods containing L-arginine (e.g. Vasdev and Gill, 2008).

 

L-arginine is synthesized from citrulline by the sequential action of cytosolic enzymes. In terms of energy, this is costly, as the synthesis of each molecule of argininosuccinate requires hydrolysis of adenosine triphosphate (ATP) to adenosine monophosphate (AMP), i.e., two ATP equivalents. Taking an excess of L-arginine essentially gives more energy by saving ATPs that can be used elsewhere. Citrulline can be derived from multiple sources:

 

·        from arginine via nitric oxide synthase (NOS)

·        from ornithine via catabolism of proline or glutamine/glutamate

·        from asymmetric dimethylarginine (ADMA) via DDAH

 

The pathways linking arginine, glutamine, and proline are bidirectional. Thus, the net utilization or production of these amino acids is highly dependent on cell type and developmental stage (Lehninger et al, 2000).

 

 

Adsorption

L-arginine is absorbed from the gastrointestinal tract. Ingested dietary protein is denatured in the stomach due to low pH. Denaturing and unfolding of the protein makes the chain susceptible to proteolysis. Up to 15% of dietary protein may be cleaved to peptides and amino acids by pepsins in the stomach. 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-arginine is absorbed from ileum and distal jejeunum. After its absorption by the brush-border membrane, L-arginine is extensively catabolized by enterocytes (Reyees et al, 1994).

 

 

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-arginine 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 L-arginine concentrations in normal subjects are reported to be ca. 80 µM/L + 20 mM/L with plasma samples collected from healthy volunteers after an overnight fast; Cynober 2002). As with most nutrients, plasma concentration of L-arginine is subject to homeostasis, which is subject to certain limitations for L-arginine (Tangphao et al, 1999); renal clearance is significant and occurs after infusion of high doses, when plasma L-arginine concentrations exceed the renal threshold. Homeostatic control of the concentration of L-arginine in serum was shown for several species (ewes, pigs) of common breeder animals as well as rats (Wu et al., 2007). L-arginine was administered as L-arginine-HCl in this study.

 

A number of hormones (e.g., thyroid hormone, catecholamines, and growth hormone) may affect plasma AA levels in diseases (Cynober et al., 1987). However, in the physiologic state, their influence is probably marginal.

 

 

Metabolism

There is no storage form for amino acids in animals and human except in the biologically active protein of the cells.

 

L-arginine exhibits the same metabolic pathway as several other amino acids do. Metabolism of L-arginine is thus described by the entire pathway (Lehninger, 2010; Salway, 2004). This pathway (also known as “Ornithine and Proline Metabolism”) describes the co-metabolism of arginine, ornithine, proline, citrulline and glutamate in humans.

 

Arginine is synthesized from citrulline by the sequential action of the cytosolic enzymes argininosuccinate synthetase (ASS) and argininosuccinate lyase (ASL). Citrulline can be derived from ornithine via the catabolism of proline or glutamine/glutamate. Many of the reactions required to generate proline and glutamate from ornithine are located in the mitochondria. Proline is biosynthetically derived from glutamate and its immediate precursor, 1-pyrroline-5-carboxylate. The pathways linking arginine, glutamine, and proline are bidirectional. Thus, the net utilization or production of these amino acids is highly dependent on cell type and developmental stage.

 

On a whole-body basis, synthesis of arginine occurs principally via the intestinal–renal axis, wherein epithelial cells of the small intestine, which produce citrulline primarily from glutamine and glutamate, collaborate with the proximal tubule cells of the kidney, which extract citrulline from the circulation and convert it to arginine, which is returned to the circulation. Consequently, impairment of small bowel or renal function can reduce endogenous arginine synthesis, thereby increasing the dietary requirement.

 

Both proline and arginine are proteinogenic amino acids and are incorporated into proteins by prolyl-tRNA and arginyl-tRNA, which are synthesized by their respective tRNA synthetases. Arginine can also serve as a precursor for the synthesis of creatine and phopshocreatine through the intermediate guanidoacetic acid. A key component of the arginine/proline metabolic pathway is ornithine. In epithelial cells of the small intestine, ornithine is used primarily to synthesize citrulline and arginine, in liver cells surrounding the portal vein, ornithine functions primarily as an intermediate of the urea cycle, in liver cells surrounding the central vein, ornithine is used to synthesize glutamate and glutamine while in many peripheral tissues, ornithine is used for the synthesis of glutamate and proline.

 

 

Excretion

Body losses of amino acids are minimal because amino acids filtered by the kidneys are actively reabsorbed. This refers to normal doses of L-arginine, too. Also cutaneous losses and losses via exhalation are negligible. Since there is no long term storage for amino acids in mammals, excess amino acids are degraded, mainly in the liver. Metabolism of amino acids involves removal of the amino group which is converted to urea and excreted in the urine. After removal of the amino group the rest of the acid is utilised as energy source or in anabolism of other endogenous substances.

 

The following data on the fate of L-arginine after intake in high doses are from Tangphao et al. (1999). A pharmacokinetic study carried out in healthy subjects shows a biphasic elimination pattern after both oral and intravenous L-arginine administration, and concentrations of L-arginine have not returned to baseline after 8 h of sampling. Moreover, plasma concentration data obtained from the control study over 8 h with a normal diet clearly show that there is a substantial variation in plasma concentrations of L-arginine. The variation in the daytime concentrations was taken into account in the analysis of these data in order to better estimate values for clearance and bioavailability following oral and intravenous exogenous L-arginine administration.

Renal clearance is significant and occurs after infusion of high doses, when plasma l-arginine concentrations exceed the renal threshold.

Excess L-arginine intake in animals is also associated with increased urinary excretion of the amino acid as the renal tubular reabsorption of L-arginine in the distal loop of Henle exhibits a transport maximum. L-arginine is excreted via renal cleareance.

 

Intestinal absorption rates of amino acids were found to be > 50 % for most amino acids (Adibi et al, 1967) whereby the absorption rate of individual amino acids may increase depending of the administered concentration.These findings were made with amino acid concentrations far below the saturation plateau of the transport system. The absorption rate expressed as g/h of amino acids from different dietary proteins is high (Bilsborough and Mann, 2006) and indicates absorption rates > 50 % for individual amino acids. An oral absorption rate of 100 % is more realistic than a rate of 50 %.

The amounts of protein and, therefore, of amino acids consumed by humans vary over a wide range.When dietary nitrogen and essential amino acid intakes are above the requirement levels, healthy individuals appear to adapt well to highly variable dietary protein intakes, because frank signs or symptoms of amino acid excess are observed rarely, if at all, under usual dietary conditions (Bier, 2003). When considering the fact that DNELs based upon 100 % absorption rate are by factors well lower than the daily dietary intake of humans, an absorption rate of 100 % is not only realistic for the purpose of safety assessment but sufficiently safe.

For risk assessment purposes oral absorption of L-arginine is set at 100%.

 

L-arginine is of low volatility due to a very low vapour pressure (0.000000185 Pa). From this and from the particle size it is not expected that L-arginine reaches the nasopharyncheal region or subsequently the tracheobronchial or pulmonary region.

 

However, being a very hydrophilic substance with a molecular mass of only 174.2, any L-arginine reaching the lungs might be absorbed through aqueous pores (ECHA, 2008). For risk assessment purposes, although it is unlikely that L-arginine 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-arginine is set at 100%.

 

L-arginine with high water solubility (182 g/L) and the log P value very well below 0 (- 4.2) may be too hydrophilic to cross the lipid rich environment of the stratum corneum. Therefore, 10% dermal absorption of l-arginine is proposed for risk assessment purposes.

Setting the dermal absorption rate of 10 % considers derivations in ECHA (2008). Initially, basic physico-chemical information should be taken into account, 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.

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:

Adibi S.A.,Gray S.J.,Menden E. (1967). The kinetics of amino acid absorption and alteration of plasma composition of free amino acids after intestinal perfusion of amino acid mixtures. Am J Clin Nutr. 1967 Jan; 20 (1): 24-33.

Belitz H.-D., Grosch W. und Schieberle P. (2007): Lehrbuch der Lebensmittelchemie.6. Auflage. Springer-Verlag, Berlin und Heidelberg

Bier, D.M. (2003): Amino acid pharmacokinetics and safety assessment. J. Nutr. 133: 2034S-2039S.

Bilsborough, S. and Mann, N. (2006): A review of issues of dietary protein intake in humans. International Journal of Sport nutrition and Excercise Metabolism, 16, 129-152

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

 

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

 

Cynober L., Coudray-Lucas C., Ziegler F., et al. (1987): Metabolisme azote´ chez le sujet sain. Nutr Clin Metabol; 3: 87

De Heer C., Wilschut A., Stevenson H., and Hakkert B. C. Guidance document on the estimation of dermal absorption according to a tiered approach: an update.V98. 1237. 1999. Zeist, NL, TNO. 

ECHA (2008): Guidance on information requirements and chemical safety assessment Chapter R.7c: Endpoint specific guidance

 

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

 

Reyes A., Karl I., Klahr S.: Role of arginine in health and in renal disease (1994). Am J Physiol.; 267: F331–F346

 

Salway J.G. (2004): Metabolism at a glance (3rd ed.). Alden, Mass.: Blackwell Pub.

 

Tangphao O., Grossmann M., Chalon S., Hoffman B., Blaschke T.: Pharmacokinetics of intravenous and oral l-arginine in normal volunteers. Br J Clin Pharmacol. 1999 March; 47(3): 261–266.

 

Vasdev S., Gill V. (2008): The antihypertensive effect of arginine. Int J Angiol. 17(1): 7–22

 

Wu, G., Bazer, F., Cudd, T., Jobgen, W., Kim, S.W., Lassala, A., Li, P., Matis, J., Meininger, C., and Spencer, T. (2007): Pharmacokinetics and Safety of Arginine Supplementation in Animals. J. Nutr., 137, 1673S-1880S

 

Applicant's summary and conclusion

Conclusions:
Interpretation of results (migrated information): other: The absorption factors for risk assessment purposes have been set as follows: absorption oral 100%, absorption dermal 10% and absorption inhalation 100%
For risk assessment purposes:
Absorption oral: 100%,
Absorption dermal: 10%
Absorption inhalation: 100%