Registration Dossier

Diss Factsheets

Administrative data

Link to relevant study record(s)

Referenceopen allclose all

Endpoint:
basic toxicokinetics, other
Type of information:
read-across from supporting substance (structural analogue or surrogate)
Adequacy of study:
key study
Justification for type of information:
For details and justification of read-across please refer to the read-across report attached to IUCLID section 13.
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 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 mM/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, in contrast to previously held belief, 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 mM/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.

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

Endpoint:
dermal absorption in vitro / ex vivo
Type of information:
read-across from supporting substance (structural analogue or surrogate)
Adequacy of study:
key study
Justification for type of information:
For details and justification of read-across please refer to the read-across report attached to IUCLID section 13.
Reason / purpose for cross-reference:
read-across source
GLP compliance:
no
Radiolabelling:
yes
Signs and symptoms of toxicity:
not examined
Dermal irritation:
not examined
Absorption in different matrices:
Absorption in stratum corneum, epidermis, dermis, and receptor fluid was determined.
Time point:
6 h
Dose:
2 µL
Parameter:
percentage
Absorption:
ca. 16 %
Remarks on result:
other:
Remarks:
Worst case conditions: low dose, o/w emulsion; Stratum Corneum
Time point:
6 h
Dose:
2 µL
Parameter:
percentage
Absorption:
ca. 2 %
Remarks on result:
other:
Remarks:
Worst case conditions: low dose, o/w emulsion; Epidermis
Time point:
6 h
Dose:
2 µL
Parameter:
percentage
Absorption:
ca. 4 %
Remarks on result:
other:
Remarks:
Worst case conditions: low dose, o/w emulsion; Dermis
Time point:
6 h
Dose:
2 µL
Parameter:
percentage
Absorption:
ca. 0.5 %
Remarks on result:
other:
Remarks:
Worst case conditions: low dose, w/o emulsion; Receptor fluid
Conclusions:
Skin absorption of lactic acid can be substantial, with up to 25% being present in skin after prolonged exposure to low doses of high concentration formulations. This is expected and often wanted as lactic acid is a well known humectant (skin moisturizer) in cosmetic applications. The dermal uptake of lactic acid leading to systemic exposure is much lower; even under worst case conditions, the transdermal uptake is less than 1% of the applied dose.
Executive summary:

The efficacy of lactic acid-containing products is linked to their ability to deliver it to specific skin strata. The penetration of L(+)- lactic acid to different skin layers of porcine skin from various emulsions was measured in vitro using flow-through diffusion cells. The effects of pH, propylene glycol, product structure, and mode of application on percutaneous absorption of lactic acid were investigated. The absorption of lactic acid from oil-in-water (o/w) emulsions was measured at pH 3.8 and 7.0. The effect of propylene glycol (5 %) as a penetration enhancer for lactic acid was also investigated from an o/w emulsion. The emulsion was applied either as a finite-dose 2-µl topical film or as a 75-µL "infinite" dose occluded patch on a 0.64 cm² skin disc. A key finding was that the effects of changes in product compositions such as vehicle pH and propylene glycol on percutaneous absorption of lactic acid depended on the application mode. Increasing the aqueous phase acidity in an oil-in-water emulsion enhanced lactic acid delivery in the finite dose but not in the infinite-dose application. Finite-dose films were significantly more efficient than infinite dose for lactic acid delivery to tissue compartments. The penetration enhancer propylene glycol was more efficacious at the infinite-dose application. However, it also significantly enhanced lactic acid delivery to viable epidermis in the finite-dose application. Finally, the effect of emulsion phase structure on lactic acid uptake was investigated by comparing delivery from oil-in-water (o/w), water-in-oil (w/o), and water-in-oil-in water (w/o/w) multiple emulsions with identical compositions. The total tissue delivery of lactic acid from the three emulsions was in the order of o/w > w/o/w > w/o.

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

Description of key information

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. As such the biokinetics, metabolism and distribution of lactic acid have to be considered in the context of its normal biochemistry; exogenous lactic acid will be indistinguishable from endogenous lactic acid and will follow the same biochemical pathways as endogenous lactic acid, at least up to a certain systemic level.

The biochemistry of lactic acid has been reviewed and summarized in Sterenborg, 2007.

Dermal absorption of lactic acid is not a toxicologically relevant pathway, since lactic acid is a natural constituent of the human dermis and epidermis. Lactic acid is frequently used as a humectant in leave-on skin cosmetics, where its main mode of action is through its sequestration in the stratum corneum, where it will aid in attracting water into the SC and holding it there. The cosmetics-oriented skin penetration studies clearly support the notion that lactic acid does not penetrate the skin, but is sequestered in the SC, and even there only up to ca 16% of the applied amount

Key value for chemical safety assessment

Additional information