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Description of key information

There are no experimental toxicokinetic data available for L-asparagine, thus, the toxicokinetic behaviour of the test item was evaluated according to ECHA endpoint specific guidance Chapter 7c based on its physico-chemical properties. A detailed description is given below.

Key value for chemical safety assessment

Bioaccumulation potential:
no bioaccumulation potential
Absorption rate - oral (%):
50
Absorption rate - dermal (%):
50
Absorption rate - inhalation (%):
100

Additional information

Data from in vitro or in vivo studies, which were designed to identify the toxicokinetic properties of L-asparagine, are not available. But there are published results substantiating the assumed toxicokinetic behaviour which is in line with the physico-chemical properties of L-asparagine

 

Parameter

Value used for CSR

Molecular Weight

132.12 g/mol

Melting Point

234-235°C decomposition

Boiling Point

n.a. (decomposition)

Density

1.543 g/cm3

Vapour Pressure

2.26 E-005 Pa

Partition coefficient n-octanol/water (log Kow)

-4.99

Water solubility

22.1 g/L

CMC

0.009 g/L (at 25°C)

pKa1

2.02

pKa2

8.80

Particle size

awaiting granulometry tests results

 

Oral absorption

L-asparagine has a molecular weight of less than 500 g/mol and a log Kow of -4.99 which is in general a prerequisite for absorption. Due to its structure L-asparagine possesses two pKa values therefore it will be present in its unionized form in stomach (pH 2) as well as in the small intestine (pH 8) which is also favourable for absorption. L-asparagine is a ubiquitous occurring component in proteins and polypeptides. Furthermore, L-asparagine is a substrate for the intermediary metabolism. It is either formed by L-aspartic acid and glutamine or hydrolysed to L-aspartic acid but mainly L-asparagine is incorporated into proteins (Krotkov et al. 1953, O´Connor et al. 1994). It was reported that only 14 % of ingested L-asparagine is exhaled as CO2and that about 45% of it is recovered in the remaining carcass. The overall recovery from the main tissues in rats was nearly 100%, for this reason it can be considered that the absorption rate for L-asparagine is 50 % for both animals and humans with respect to ECHA endpoint specific guidance Chapter 7c.

 

Respiratory absorption

L-asparagine is a solid at room temperature and decomposes at 235°C together with a low vapor pressure of 2.26 E-005 Pa substance evaporation and uptake by inhalation is unlikely. However, the uptake after direct inhalation of substance dust particles and aerosols is possible because L-asparagine is marketed and used in a granular form,but considered very unlikely because the median particle size was determined to be D50 = 251.2 µm which is above the critical size for particles to be inhaled (i.e. 100 µm). Nevertheless, after uptake L-asparagine it will be readily absorbed due to its physicochemical properties, i.e. its high water solubility (22.1 g/L) or its low log Kow and is therefore unlikely to be coughed or sneezed out of the body. It will be taken up and possibly immediately be metabolised or incorporated into proteins and therefore be indistinguishable from asparagine taken up from other sources (i.e. diet). A deposition into lymphoid tissues is also rather unlikely.

Because L-asparagine is produced and marketed in granular form accidental exposure to dusts cannot be excluded. Thus, for precautionary reasons the estimated absorption of L-asparagine via the respiratory tract is 100%.

 

 

Dermal absorption

Due to its low molecular weight, its low log Kow and its high water solubility, L-asparagine may be dermally absorbed. Based on the pKa values of which one is 2.02 and the other is 8.80 L-asparagine is supposed to be partially ionized, but due to its small size (MW 132.12 g/mol) it is presumably absorbed. However, since L-asparagine is handled in its solid form, it is not expected to be dermally absorbed. Thus, because uptake of L-asparagine by dermal route is not expected but can also not be excluded and because dermal absorption is not expected to exceed oral uptake a value of 50% absorption after dermal exposure should be assumed. However, lower values for dermal absorption cannot be considered due to lack of data.

 

Distribution

As a small molecule a wide distribution can be expected. It was reported that the main occurrence of L-asparagine was detected in the whole carcass, whereas only 14.3 % were recovered in the gastro-intestinal tract and 7% of dietary administered L-asparagine was found in the liver (Breuer et al. 1966). The amount of respired L-asparagine was measured in another study but with remarkable varying results, between 14 and 36% of i.p. or s.c administered L-asparagine was respired as CO2(Krotkov et al. 1953). However, as demonstrated by the studies mentioned above, L-asparagine is mainly incorporated into proteins, i.e. metabolised in protein biosynthesis.

 

Metabolism

As a ubiquitous occurring molecule, L-asparagine in known to be readily metabolised by the intermediary metabolism. As mentioned before, it is a substrate for the synthesis of L-aspartic acid and therefore participates as a precursor in the generation of neurotransmitter (i.e. glutamate and aspartate. Furthermore, once aspartic acid is synthesised, it plays a key role in the urea cycle and is involved in transamination reactions e.g. with oxaloacetate, thereby acting as carbon source to form ATP (see also general biochemistry textbooks). The metabolism of L-asparagine is not restricted to mammalian species, also algae and bacteria are capable of using asparagine as a carbon source for energy supply (Oda et al. 1982, Alpert et al. 2009). Furthermore, it was shown that L-asparagine administered in a rat model of sepsis was able to improve muscle wasting and reduce weight loss naturally occurring with the condition of sepsis (Breuille et al. 2006). In another study it was reported that endotoxin administration inhibited gluconeogenesis rising from L-asparagine as a source (Perchellet et al. 1983). The results presented in this study indicate that L-asparagine plays a pivotal role in intermediary metabolism and its inhibition may be deleterious. 

 

Elimination

The major routes of excretion for substances from the systemic circulation are the urine and/or the faeces. Excretion by exhalation does not seem to be relevant as demonstrated by Krotkov et al.(1953).

As depicted above, L-asparagine is metabolised either by forming L-aspartic acid or by entering the tricarboxylic acid cycle in order to provide reduction equivalents for energy supply. The third elimination route is the partition in protein synthesis. Thus, asparagine is rather incorporated into proteins than renally or biliary excreted.

 

Bioaccumulation

Based on the log Kow of -4.99 the substance is unlikely to accumulate with the repeated intermittent exposure patterns normally encountered in the workplace.

 

 

 

 

 

 

 

 

 

 

 

 

References

Krotkov, G., et al. "Utilization of asparagine by rats."Archives of biochemistry and biophysics42.2 (1953): 471-472.

 

M O'Connor, Clare. "Analysis of aspartic acid and asparagine metabolism in Xenopus laevis oocytes using a simple and sensitive HPLC method."Molecular reproduction and development39.4 (1994): 392-396.

 

Breuer Jr, L. H., et al. "Dietary requirement for asparagine and its metabolism in rats."Journal of Nutrition88 (1966): 143-150.

 

Breuillé, Denis, et al. "Beneficial effect of amino acid supplementation, especially cysteine, on body nitrogen economy in septic rats."Clinical Nutrition25.4 (2006): 634-642.

 

Oda, Yuji, Yoshihisa Nakano, and Shozaburo Kitaoka. "Utilization and toxicity of exogenous amino acids in Euglena gracilis."Microbiology128.4 (1982): 853-858.

 

Alpert, Carl, et al. "Adaptation of protein expression by Escherichia coli in the gastrointestinal tract of gnotobiotic mice."Environmental microbiology11.4 (2009): 751-761.

 

Perchellet, Jean-Pierre, Elizabeth A. Conrad, and R. K. Boutwell. "Effects of amino acid treatments on 12-O-tetradecanoylphorbol-13-acetate-induced ornithine decarboxylase activity in mouse epidermis in vivo and in vitro."Journal of investigative dermatology81.6 (1983): 560-566.