Registration Dossier

Diss Factsheets

Administrative data

Link to relevant study record(s)

Referenceopen allclose all

Endpoint:
basic toxicokinetics, other
Type of information:
experimental study
Adequacy of study:
weight of evidence
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
Type:
metabolism
Toxicokinetic parameters:
half-life 1st: 3 hr in aqueous medium at room temperature.
Toxicokinetic parameters:
half-life 1st: 0.4 hr in a 0.1 N HCI solution at 37 °C
Conclusions:
Lactide has a half-life of 3.0 h in an aqueous medium at room temperature. In addition, any lactide remaining unhydrolysed at the time of ingestion will be subject to rapid hydrolysis in the stomach. Lactide has a half-life of 0.4 hr in a 0.1 N HCI solution at 37 °C.
Executive summary:

In a toxicokinetic study, 100 or 1000 ppm solution of L-lactide was prepared by diluting a 1% solution of lactide in acetonitrile with distilled water or 8% ethanol at the appropriate temperature. Samples were aged at the respective temperatures, removed at various times and analysed directly by gas chromatography (GC). Lactide has a half-life of 3.0 h in an aqueous medium at room temperature. In addition, any lactide remaining unhydrolysed at the time of ingestion will be subject to rapid hydrolysis in the stomach. Lactide has a half-life of 0.4 hr in a 0.1 N HCI solution at 37 °C.

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:
basic toxicokinetics, other
Type of information:
other: Expert statement based on peer-reviewed literature
Adequacy of study:
weight of evidence
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 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, 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 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.

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:
basic toxicokinetics, other
Type of information:
other: review statement
Adequacy of study:
weight of evidence
Reliability:
4 (not assignable)
Rationale for reliability incl. deficiencies:
other: Based on literature data, in-house study results, and general chemistry argumentations. Evaluation was performed on LL-lactide. However, abiotic hydrolysis is independent from stereochemistry hence the findings are likewise applicable to DD-lactide.
Objective of study:
toxicokinetics
Qualifier:
no guideline followed
GLP compliance:
no
Type:
metabolism
Results:
hydrolytic half life of lactide in strongly acid environments, such as gastric fluid, and at physiological temperature, is in the order of 45 minutes to 1 hour
Conclusions:
Lactide is rapidly hydrolysed, both under neutral and acidic (gastric) conditions. Any systemic exposure to lactide is in fact exposure to lactic acid. Lactide toxicology, with the exception of acute local effects (skin and eye irritation) can be understood in terms of lactic acid toxicology.
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.
GLP compliance:
no
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: 6 h
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: 6 h
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.

Endpoint:
dermal absorption, other
Type of information:
calculation (if not (Q)SAR)
Adequacy of study:
supporting study
Reliability:
4 (not assignable)
Rationale for reliability incl. deficiencies:
other: Model calculation
Justification for type of information:
mathematical dermal uptake model
Principles of method if other than guideline:
Dermal absorption model based on physicochemical properties.
Conclusions:
Lactide is taken up through the skin. Dermal penetration is estimated to be ca 30.5% for a 1 hour exposure. All lactide entering the systemic compartment is expected to be converted to lactic acid.
Executive summary:

A mathematical model was used to simulate the uptake of a chemical substance through the skin into a central sink compartment. In this model, the skin is described as a two-compartment layer, consisting of a stratum corneum (SC) and a viable epidermis (VE).

If we assume that during handling of lactide in a professional environment, while wearing suitable clothing and other relevant protective equipment, the only dermal exposure of an operator is to the

backs of the hands, and that that exposure amounts to the presence of 1 g on the hands for a period of 1 hour daily, after which the hands are washed, the model outlined above predicts the

following:

During the 1 hour exposure period, 30.5% of the lactide enters the stratum corneum, the rest of the material present on the skin is washed off after the exposure period. Of those 30.5% penetrated, ca. 72% is ‘removed’ through hydrolysis during the time required to traverse the stratum corneum and viable epidermis, so that only 28% of the amount that entered the stratum corneum (or 8.5% of the amount to which the hands were exposed in the first place) enters the body as lactide. Once inside the body, the remaining amount of lactide will continue to disappear through hydrolysis. It is thus clear that after dermal administration, lactide is rapidly converted into lactic acid and its oligomers; the dermal toxicity of lactide can therefore be understood in terms of the dermal toxicity of lactic acid.

Description of key information

Lactides rapidly hydrolyse to lactoyl lactic acid and subsequently to lactic acid in aqueous media. 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 lactide can be understood in terms of the dermal toxicity of lactic acid. 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

Bioaccumulation potential:
no bioaccumulation potential

Additional information

Lactides rapidly hydrolyse to lactoyl lactic acid and subsequently to lactic acid in aqueous media. 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.

Hydrolysis of lactide

The hydrolysis rate of lactide in aqueous environments at pH 2 was determined in-house, to simulate the fate of lactide in gastric fluids. The results obtained in the PURAC study are in excellent agreement with the results presented by Conn et al. (1995), and it can be concluded that the hydrolytic half life of lactide in strongly acid environments, such as gastric fluid, and at physiological temperature, is in the order of 45 minutes to 1 hour. (half-life of 0.4 hr in a 0.1 N HCI solution at 37 °C according to Conn, 1995).

The average residence time of stomach contents is in the order of hours. As such, a significant fraction of orally administered lactide will leave the stomach, and enter the small intestine, substantially as hydrolysis products, initially lactoyl lactide, and ultimately lactic acid and its equilibrium oligomers. Since the intestines also present an aqueous environment, hydrolysis will not stop after passage through the stomach, but will proceed, only slightly more slowly (average half life ca 1.5 hours). In addition, lactide is subject to microbial degradation. Thus, it can be concluded that after oral administration, lactide is rapidly converted into lactic acid and its oligomers; the systemic toxicity of lactide can therefore be understood in terms of the systemic toxicity of lactic acid.

From the Purac in house study (Verhaar 2010), it can furthermore be concluded that the hydrolysis product of lactide is lactoyl lactic acid. Lactoyl lactic acid is a major species in the spontaneous equilibrium that gets established when lactic acid in dissolved in water, and is therefore part of any normal aqueous solution of lactic acid, including the lactic acid solutions used for toxicological and ecotoxicological testing. In fact, a solution of lactoyl lactic acid in water will itself establish an equilibrium in which lactic acid, lactoyl lactic acid, and longer oligomers are present. As such, lactoyl lactic acid falls fully under the (toxicological) definition of lactic acid.

Dermal fate of lactide

Dermally applied lactide is susceptible to hydrolysis in the sweat layer that is always present on the skin as well as in epidermal, dermal and transdermal compartments. At low concentrations, dermal toxicity of lactide can therefore be understood in terms of the dermal toxicity of lactic acid.

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. 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. However, the dermal uptake of lactic acid leading to systemic exposure is only a small fraction (Sah 1998).