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Description of key information

No skin sensitisation study with ammonium hydrogen citrate is available, thus the skin sensitisation potential will be addressed with existing data on the individual moieties ammonium and citrica acid/citrates.

Key value for chemical safety assessment

Skin sensitisation

Endpoint conclusion
Additional information:

Substance specific information on acute oral toxicty are not available for diammonium hydrogen citrate. Hence, a read-across concept was developed:

Read-across - diammonium hydrogen citrate:

The target substancediammonium hydrogen citrate(CAS # 221-146-3, EC # 221-146-3) is a mono-constituent substance that consists of two monovalent ammonium cation and a divalent hydrogencitrate anion, designated as inorganic salt (IUPAC 2005). Upon dissolution,diammonium hydrogen citrateliberates ammonium cations and (depending on pH) citrate anions, which represent the sub-categories. In the following, “citrate anions” represents the anions citrate, hydrogencitrate and dihydrogencitrate as well as citric acid.Citrate, hydrogencitrate, dihydrogencitrate and citric acid are considered as common anion based on theequilibrium between those anions in aqueous solutions under physiological/environmental conditions depending on pH value which is clearly described in published literature and summarised in the following equations:

Diammonium hydrogen citrate consists of two ammonium [NH4]+ ions and one hydrogen citrate ion [C6H6O7]2-. Based on the solubility of diammonium hydrogen citrate in water (1,000 g/L at 20°C), a complete dissociation of diammonium hydrogen citrate, resulting in ammonium (NH4+) and (hydrogen) citrate, may be assumed.

 

Depending on solution pH, citrate anions exist as citrate, hydrogencitrate, dihydrogencitrate and citric acid  species in aqueous solutions under physiologically/environmentally relevant conditions as summarised in the following equations:

 

C6H8O7+ H2O <->(C6H7O7)- + H3O+                       [pka1: 3.13; citric acid             <->dihydrogencitrate]

(C6H7O7)- + H2O <-> H3O++(C6H6O7)2-                 [pKa2: 4.76;dihydrogencitrate <-> hydrogencitrate]

(C6H6O7)2-+ H2O <->(C6H5O7)3-+H3O+                [pKa3:6.40; hydrogencitrate    <->citrate]

Ammonium cations are formed by an acid-base reaction of e.g. H2O (or other, stronger aids) and NH3as follows:

NH4++ OH-<->NH3+ H2O                                        [pka:9.25; ammonium            <-> ammonia] 

NH4+and NH3coexist in aqueous solution in adynamic pH-dependent equilibrium. Under basic conditions (pH >10), ammonia (NH3) redominates whereas theammoniumion (NH4+) is the dominant species in weakly basic to neutral (environmental) conditions. With decreasing pH, the ammonium cation becomes the only species. A Hägg-graph representing the described equilibrium in solution is provided in Section 13 (Read-across assessment report) using the above given pka[1]value at 25°C

[1]Weast, R.C. (ed.) (1974) CRC Handbook of Chemistry and Physics, 55th ed. CRC Press.

Since the target substance and the source substance release the (eco-)toxicological relevant units under environmental/physiological relevant conditions, the overall ecotoxicity/toxicity of the dissociated diammonium hydrogen citrate can be interpolated by assessing the (eco-)toxicity of the individual moieties. The category hypothesis, i.e. release of the common (eco-)toxicological units, applies to the target substance and the source substances.Thus, the category consists of ammonium salts for which the (eco-)toxicity is either governed by the ammonium cation (sub-category 1) or the citric acid anion (sub-category 2).

Skin sensitisation ammonium:

Ammonia/ammonium is an important source of nitrogen for mammals and plants due to its use in thesynthesis of amino acids, DNA, RNA and proteins. It is produced endogenously in all mammalian species. 

 

Ammonium ion is endogenously produced in the human digestive tract, much of it arising from the bacterial degradation of nitrogenous compounds from ingested food. About 4,200 mg/day are produced, greater than 70% of which is synthesized or liberated within the colon and its fecal contents. The total amount absorbed is about 4,150 mg/day, or 99% of the amount produced (Summerskill and Wolpert 1970); absorption after oral loading of NH4 + is similarly complete (Fürst et al. 1969). Evidence fromCastell and Moore (1971) and Mossberg and Ross (1967) suggests that absorption of NH4 + increases as the pH of the contents of the lumen increases, and that the ammonium ion is actively transported at the lower pH levels (pH 5 was lowest detected absorption). Ammonium ion absorbed from the gastrointestinal tract travels via the hepatic portal vein directly to the liver, where in healthy individuals, most of it is converted to urea and glutamine. Human and animal data show that little of it reaches the systemic circulation as ammonia or ammonium compounds, but that it is a normal constituent of plasma at low levels (Brown et al. 1957; Pitts 1971; Salvatore et al. 1963; Summerskill and Wolpert 1970). Analysis of plasma drawn from 10 healthy young male subjects yielded endogenously derived NH4+ concentrations ranging from 30 to 55μg NH3/100 mL, with a mean of 39μg/100 mL (Brown et al. 1957).

Ammonia/ammonium is an essential mammalian metabolite for DNA, RNA, and protein synthesis and is necessary for maintaining acid-base balance. Ammonia is produced and used endogenously in all mammalian species. It has been estimated that up to 17 grams of ammonia are produced in humans daily. Of these 17 grams, approximately 4 grams are produced in the gut by intestinal bacteria, where it enters the portal circulation and is metabolized rapidly in the liver to urea. Ammonia is excreted primarily as urea and urinary ammonium compounds through the kidneys. Levels of ammonia in the blood from healthy humans range from 0.7 to 2 mg/L (ATSDR,2004).

Based on the omnipresence of endogenously produced ammonium in the human body its use in the synthesis of amino acids, DNA, RNA and proteins, skin sensitising properties or intolerance to the abundantly available essential substance can safely be excluded.

References:

ATSDR (Agency for Toxic Substances and Disease Registry), 2004. Toxicological profile for

ammonia. U.S. Department of Health and Human Services, Atlanta, Georgia, 269 pp.

Conn HO, 1972. Studies of the sources and significance of blood ammonia IV. Early ammonia peaks after ingestion of ammonium salts. Yale Journal of Biology and Medicine, 45, 543-549.

Häussinger D, 2007. Ammonia, urea production and pH regulation. In: The Textbook of Hepatology: from basic science to clinical practice, 3rd Edition. Eds Rodes J, Benhamou J-P, Blei A, Reichen J and Rizzetto M. Wiley-Blackwell, 181-192.

Summerskill WHJ, Wolpert E. 1978. Ammonia metabolism in the gut.Am J Clin Nutr 23:633-639

Fürst P, Josephson B, Maschio G, et al. 1969.Nitrogen balance after intravenous and oral administration of ammonium salts to man. J Appl Phys 26:13-22.

Mossberg SM, Ross G. 1967. Ammonia, movement in the small intestine: Preferential transport by the ileum. J Clin Invest 46(4):490-498.

Brown RH, Duda GD, Korkes S, et al. 1957. A colorimetric micromethod for determination of ammonia; the ammonia content of rat tissues and human plasma. Arch Biochem Biophys 66:301-309.

Skin sensitisation citric acid/citrates:

Citric acid has a well-established role as an intermediate metabolite in the tricarboxylic acid cycle.In human (as well as in animal and plant) physiology, citric acid is a very common intermediate in one of the central biochemical cycles, the Krebs or tricarboxylic acid cycle, which takes place in every cell. It completes the breakdown of pyruvate formed from glucose through glycolysis, thereby liberating carbon dioxide and a further four hydrogen atoms which are picked up by electron transport molecules. Thus, in man approximately 2 kg of citric acid are formed and metabolised every day. This

physiological pathway is very well developed and capable of processing very high amounts of citric acid as long as it occurs in low concentrations. Part of the circulating (mainly metabolic but also ingested) citric acid is excreted in urine, with 24-hour urine reference values between 1.5 and 3.68 mmol, corresponding to 0.29– 0.71 g citric acid excreted per person per day.

 

Based on the omnipresence of citric acid and its salts in cells of the human body, skin sensitising properties or intolerance to the abundantly available essential substance can safely be excluded. Therefore, further testing should not be considered, inter alia for reasons of animal welfare. In conclusion, conduct of a skin sensitization study on citric acid and its salts is considered to be scientifically unjustified (in accordance with regulation (EC) 1907/2006, Annex XI, Section 1.1.2, 1.1.3 and 1.2).

Skin sensitisation diammonium hydrogen citrate:

Diammonium hydrogen citrate is not expected to show signs of dermal sensitisation, since the two moieties ammonium and citric acid/citrates have not shown any skin sensitisation potential in experimental testing. Thus, diammonium hydrogen citrate is not to be classified according to regulation (EC) 1272/2008 as skin sensitising. Further testing is not required. For further information on the toxicity of the individual assessment entities, please refer to the relevant sections in the IUCLID and CSR.

Justification for classification or non-classification

Diammonium hydrogen citrate is not expected to show signs of dermal sensitisation, since the two moieties ammonium and citric acid/citrates have not shown any skin sensitisation potential in experimental testing. Thus, diammonium hydrogen citrate is not to be classified according to regulation (EC) 1272/2008 as skin sensitising.