Propanoic acid, 2-hydroxy-, ammonium salt (1:1), (2S)-

Endpoint summary

Link to relevant study record(s)

Reference

Reference 1

Endpoint:

basic toxicokinetics

Type of information:

read-across from supporting substance (structural analogue or surrogate)

Adequacy of study:

supporting study

Justification for type of information:

For details and justification of read-across please refer to the report attached in section 13 of IUCLID.

Reason / purpose for cross-reference:

read-across source

The role of lactic acid in metabolism has kept researchers occupied for a long time. For many years, lactic acid was considered a dead-end waste product of the glycolysis, the conversion of glucose into pyruvate (producing a relatively small amount of ATP), in the absence of oxygen. Recently, the role of lactic acid in metabolism was reconsidered, and L-lactate is considered as a functional metabolite and mammalian fuel. It was observed that lactate can be transferred from its site of production (cytosol) to neighbouring cells and other organs, as well as intracellularly, where its oxidation or continued metabolism can occur. This "lactate shuttle" results in the distribution of lactic acid to other cells, where it is directly oxidised, re-converted back to pyruvate or glucose, allowing the process of glycolysis to restart and ATP provision maintained.

Conclusions:

In body fluids, dissociation of ammonium-(S)-lactate takes place immediately, resulting in the formation of ammonium (NH4+) and L(+)-lactic acid. The metabolism of lactic acid is well understood. In the evaluation of the use of lactic acid as the active substance in biocidal products, the natural occurrence of lactic acid in human food and the human body, as well as the role of the compound in human metabolism and physiology should be taken into account. This means that, when the risk for its use in biocidal products is assessed, the natural exposure to lactic acid in food and via endogenous sources, as well as exposure via the use of lactic acid as a food additive should be considered.
In the present report it is concluded that lactic acid can no longer be considered as a “dead-end” waste product of human metabolism, but should instead be seen to play an important role in cellular, regional, and whole body metabolism. Lactic acid has been detected in blood, several other body fluids and tissues. Concentrations of lactic acid increase significantly during intense exercise. At rest, blood concentrations have been reported of 1-1.5 mMol/L (90.1-135.12 mg/L), which can increase up to 10 mMol/L (900.8 mg/L) during exercise.
External human exposure to lactic acid can occur via its natural presence in food, for example in fruit, vegetables, sour milk products, and fermented products such as sauerkraut, yogurt and beer. Based on the available information on concentrations of lactic acid in some of these products, an estimate of the daily consumption of lactic acid due to its natural presence in food was made using the ‘FAO/WHO standard European diet’. A (minimum) daily intake of 1.175 g/person/day was calculated using the available information. Another source of external exposure is its use as food additive; as such it is authorized in Europe (E270) and the United States (generally recognized as safe = GRAS). A daily intake of 1.65-2.76 g/person/day was estimated using the “Per Capita times 10” method, based on the amount of lactic acid put onto the market (EU and USA) as a food additive by Purac. Based on the high levels of lactic acid in the human body and in human food, and its use as food additive, the evaluation of the human health effects of lactic acid should first and for all be based on a comparison of this background exposure and the potential contribution of lactic acid in biocidal products to these levels. Therefore, a risk assessment should not be based on the comparison with effects of exposure, but on the comparison with the total daily intake of lactic acid via food, both naturally and as food additive, which was estimated to be 2.8 g/person/day. When the application of Purac’s products will not result in a systemic exposure that contributes substantially to the total systemic exposure, many of the standard human toxicological studies dealing with systemic effects are deemed superfluous.

Executive summary:

The natural occurrence of lactic acid in human food and the human body, as well as the role of the compound in human metabolism and physiology is of primary importance in the understanding of the metabolism and toxicology of lactic acid. This means that, in risk assessment, the natural exposure to lactic acid in food and via endogenous sources, as well as exposure via the use of lactic acid as a food additive should be considered.

In the present report it is concluded that lactic acid, unlike believed previously, can no longer be considered as a “dead-end” waste product of human metabolism, but should instead be seen to play an important role in cellular, regional, and whole body metabolism. Lactic acid has been detected in blood, several other body fluids and tissues. Concentrations of lactic acid increase significantly during intense exercise. At rest, blood concentrations have been reported of 1–1.5 mMol/L (90.1–135.12 mg/L), which can increase up to 10 mMol/L (900.8 mg/L) during exercise.

External human exposure to lactic acid can occur via its natural presence in food, for example in fruit, vegetables, sour milk products, and fermented products such as sauerkraut, yoghurt and beer. Based on the available information on concentrations of lactic acid in some of these products, an estimate of the daily consumption of lactic acid due to its natural presence in food was made using the ‘FAO/WHO standard European diet’. A (minimum) daily intake of 1.175 g/person/day was calculated using the available information.

Another source of external exposure is its use as food additive; as such it is authorized in Europe (E270) and the United States (generally recognized as safe = GRAS). A daily intake of 1.65–2.76 g/person/day was estimated using the “Per Capita times 10” method, based on the amount of lactic acid put onto the market (EU and USA) as a food additive.

Based on the high levels of lactic acid in the human body and in human food, and its use as food additive, the evaluation of the human health effects of lactic acid should first and for all be based on a comparison of this background exposure and the potential contribution of lactic acid in biocidal products to these levels. Therefore, a risk assessment should not be based on the comparison with effects of exposure, but on the comparison with the total daily intake of lactic acid via food, both naturally and as food additive, which was estimated to be 2.8 g/person/day.

This information is used in a read-across approach in the assessment of the target substance. For justification of read-across please refer to the read-across report attached to IUCLID section 13.

Reference 2

Endpoint:

basic toxicokinetics, other

Type of information:

read-across from supporting substance (structural analogue or surrogate)

Adequacy of study:

supporting study

Justification for type of information:

For justification of read-across please refer to the read-across report attached to IUCLID section 13.

Reason / purpose for cross-reference:

read-across source

Conclusions:

In aqueous environments, such as the body the ammonium sulphate is completely dissociated into the ammonium and the sulfate ions. At physiological pH in aqueous media, the ammonium ion is in equilibrium with un-ionized ammonia. The ammonium ion serves a major role in the maintenance of the acid-base balance. In the normal pH range of blood, the NH4 +/NH3 is about 100 (WHO, 1986). An ammonium ion via the equilibrium with ammonia is readily taken up. Some evidence exists also for an active transport of the ammonium ion from the intestinal tract. It was shown that ammonia transport by the human colon still occurred when the luminal pH was reduced to 5, where non-ionized ammonia would be virtually absent (WHO, 1986). Absorbed ammonium is transported to the liver and metabolized to urea and excreted via the kidneys. Minor amounts of nitrogen are incorporated in the physiological N-pool (WHO, 1986).

Executive summary:

In the review publication OECD SIDS, 2004 the following was published for Toxicokinetics, Metabolism and Distribution:

In aqueous environments, such as the body the ammonium sulphate is completely dissociated into the ammonium and the sulfate ions. At physiological pH in aqueous media, the ammonium ion is in equilibrium with un-ionized ammonia. The ammonium ion serves a major role in the maintenance of the acid-base balance. In the normal pH range of blood, the NH4 +/NH3 is about 100 (WHO, 1986). An ammonium ion via the equilibrium with ammonia is readily taken up. Some evidence exists also for an active transport of the ammonium ion from the intestinal tract. It was shown that ammonia transport by the human colon still occurred when the luminal pH was reduced to 5, where non-ionized ammonia would be virtually absent (WHO, 1986). Absorbed ammonium is transported to the liver and metabolized to urea and excreted via the kidneys. Minor amounts of nitrogen are incorporated in the physiological N-pool (WHO, 1986)

This information is used in a read-across approach in the assessment of the target substance. For justification of read-across please refer to the read-across report attached to IUCLID section 13.

Description of key information

In body fluids, dissociation of ammonium-(S)-lactate takes place immediately, resulting in the formation of ammonium (NH4+) and L(+)-lactic acid.

Lactic acid is a ubiquitous and essential biological molecule in humans and other mammals, but also in most if not all vertebrate and invertebrate animals, as well as in many micro-organisms. Therefore, the biokinetics, metabolism and distribution of lactic acid have to be considered in the context of its normal biochemistry; lactic acid is of minor toxicological concern as it functions as a ubiquitous and integral element of mammalian metabolism.

The ammonium ion plays a major role in maintaining the acid-base balance. In the normal pH range of blood, the NH4 +/NH3 ration is about 100 (WHO, 1986). An ammonium ion via the equilibrium with ammonia is readily taken up. Some evidence exists also for active transport of the ammonium ion from the intestinal tract. It was shown that ammonia transport by the human colon still occurred when the luminal pH was reduced to 5, where non-ionized ammonia would be virtually absent (WHO, 1986). Absorbed ammonium is transported to the liver and metabolised to urea and excreted via the kidneys. Minor amounts of nitrogen are incorporated in the physiological N-pool (WHO, 1986).

Based on a log Kow of -3.84 (see IUCLID section 4.7), bioaccumulation of the target substance ammonium-S-lactate is not expected.

Key value for chemical safety assessment

Bioaccumulation potential:

no bioaccumulation potential