(3R,6R)-3,6-dimethyl-1,4-dioxane-2,5-dione

Endpoint summary

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. This is independent from stereochemistry. 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).