Choline hydrogen carbonate

Endpoint summary

Description of key information

Expert statement: Choline bicarbonate (unmetabolised) has no potential for bioaccumulation, but is incorporated in the body in form of essential molecules / metabolites, such as neurotransmitters (acetylcholine) or structural membrane phospholipids. The relevant absorption rates can be estimated by expert judgment to 50 % (oral, unmetabolized), 10 % (dermal) and 25 % (inhalation).

Key value for chemical safety assessment

Bioaccumulation potential:

no bioaccumulation potential

Absorption rate - oral (%):

50

Absorption rate - dermal (%):

10

Absorption rate - inhalation (%):

25

Additional information

In order to assess the toxicokinetic behaviour of Choline hydrogen carbonate, the available literature, toxicological and physico-chemical data were evaluated.

Choline is an important nutrient as a source of labile methyl groups, a precursor for several essential molecules for the body such as cell membrane components or neurotransmitter, and already present in diet and feed. Hence, a rather good absorption, excessive metabolism and at least partial remaining of the compound in the body can be assumed, which was proved by the available data.

Due to its ionic structure, Choline bicarbonate dissociates readily in an aqueous environment. Since the inorganic bicarbonateis a normal constituent in vertebrates, as the principal extracellular buffer in the blood and interstitial fluid is the bicarbonate buffer systemand not the relevant ion when assessing the toxicokinetic behaviour of choline hydrogen carbonate, it is scientifically justified to focus mainly on the organic cation, choline.

In general, the ionic structure, the negative logPow (approx. -3.77 to -2.25) and the high water solubility suggest a poor absorption of the cation. This is the case especially regarding dermal absorption, as it cannot pass the stratum corneum. For absorption via the respiratory epithelium, at least a slight absorption due to passive diffusion should be regarded, although the retention in the mucus is rather indicated. Since no inhalable forms of choline are normally generated, however, absorption after inhalation is very unlikely. The former would normally also apply for the gastrointestinal absorption; however, choline is absorbed from the jejunum and ileum mainly by a saturable, energy-dependent carrier mechanism in the brush-border membrane and to a lesser extent via passive diffusion. The choline intake can be limited by its metabolism by the intestinal microflora to mainly trimethylamine, which also increases when high doses of choline are applied, because the choline uptake by carriers is saturable. A similar mechanism enables choline to cross the blood-brain barrier.

After absorption, choline salts can be easily distributed throughout the body via lymphatic or portal circulation in the form of phosphatidylcholine bound to chylomicra. This form will be cleaved on-site by various, tissue-related enzymes, and choline can be absorbed by a similar transport mechanism as by the brush-border membrane of the small intestine. In many tissues, transport is mediated by low-affinity or intermediate-affinity sodium-independent transporters, whereas a high-affinity transport on the other hand is unique to the cholinergic neurons of the brain, brain stem, and spinal cord. Relevant organs to consider when assessing the distribution of choline are the liver and the kidneys:All ingested choline enters the hepatic circulation, turning the liver into a significant first point of contact for excessive metabolism for choline. Second, renal tubular transport of choline is of importance because it maintains the plasma choline concentration within relatively narrow limits by employing both net secretion and reabsorption. When choline is presented to the kidney in excess of a species-specific threshold concentration, it will be excreted via the kidneys into the urine. If the plasma concentration is below this level, choline will be reabsorbed into the kidneys and not excreted. This also applies to many other tissues:In general, most of the choline in the body is found in the form of the phospholipids phosphatidylcholine (lecithine), lysophosphatidylcholine, choline plasmalogens, and sphingomyelin-essential components of all membranes.

This is due to an extensive metabolism of choline: Under normal circumstances, the amount of free choline is only 0.5-1% per cent of the total tissue choline; excess choline is catabolized via the choline oxidation pathway.

After absorption in the intestinal mucosa, choline is phosphorylated to phosphocholine, which will be furthermore transformed to structural membrane phospholipids. Also, choline can be transformed to signalling phospholipids, such as sphingosylphosphorylcholine or the platelet-activating factor. In the kidneys and the nervous system, choline is oxidized to betaine, which can undergo further transformation / degradation steps, finally to ammonium and carbon dioxide. Choline is part of intracellular, partly overlapping or intersecting metabolism pathways due to its methyl-donating properties and can be furthermore synthesized by the body itself or gained from phosphatidylcholine present in the diet. So in summary, choline is not only extensively absorbed and metabolized to essential molecules such as neurotransmitters or cell membrane compounds when applied, it is also synthesized by the body itself, and it is essential to maintain normal body functions.

Hence, when exposed to choline in the required ranges, nearly no choline will be excreted. When it is ingested, e.g. accidentally, in higher amounts, choline will be excreted mainly via the kidneys within approx. 12 hours, either as TMA after prior metabolism by the intestinal microflora, or as choline itself, although this seems to be rather relevant after intravenous injection, or as betaine and other metabolites.

In conclusion, choline has no potential for bioaccumulation in its non-metabolized form, and the incorporation of its metabolites does not bear any potential for adverse effects but is also required to maintain the normal functionality of the body. In case of an accidental high exposure, effective metabolism and clearance mechanisms take hold.

The present expert statement covers all relevant toxicokinetic parameters to assess the behaviour of Choline bicarbonate in the body, the available information is well-investigated and sufficient to enable one to perform a proper risk assessment. The tonnage-driven data requirements under REACH are fully met and hence, no further information needs to be gathered and further studies can be omitted due to animal welfare.