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

Endpoint summary

Key value for chemical safety assessment

Effects on fertility

Description of key information

No reproductive toxicity data is available for the target substance D-lactide. Due to the rapid hydrolysis of lactide into lactoyl lactic acid and subsequently lactic acid, under acid and neutral conditions, the toxicology of lactides can be understood in terms of the toxicology of lactic acid.

Lactic acid is not only a natural molecule found in all higher animals and many microorganisms but also a ubiquitous ingredient used in various kinds of food. Therefore, it is not possible to lower external exposure levels below the minimum required levels for human physiological functions. Nevertheless, given the understanding of lactic acid production under human physiological conditions, there is no reproductive/developmental toxicity concern of lactic acid.

Lactic acid is a natural metabolite found in humans and animals as it can be endogenously produced from metabolic pathways such as glycogen breakdown, glycolysis and amino acid metabolism. Normal human blood contains 8–17 mg lactic acid/100 mL plasma, and the concentration of lactate in normal human skin is three times or more of that in the blood due to glycolytic enzymes, which actively convert glucose to lactic acid in the epidermis. Furthermore, lactic acid bacteria, which produce lactic acid as one of their major fermented products, are abundantly found in humans, including breast milk and vaginal cavity, and are considered as probiotic bacteria. Infants can be exposed to lactic acid bacilli during breastfeeding. Lactic acid bacteria are known to be beneficial in preserving healthy vaginal functions such as maintenance of acidic vaginal pH and the prevention of infections.

In accordance with Section 1 of REACH Annex XI, a reproductive/developmental toxicity study does not need to be conducted. Given the existing data and taking a weight-of-evidence approach, there is no reproductive/developmental toxicity concern of D-lactide.

Link to relevant study records

Reference

Reference 1

Endpoint:

screening for reproductive / developmental toxicity

Data waiving:

study scientifically not necessary / other information available

Justification for data waiving:

other:

Reproductive effects observed:

not specified

Reference 2

Endpoint:

extended one-generation reproductive toxicity - basic test design (Cohorts 1A, and 1B without extension)

Data waiving:

study scientifically not necessary / other information available

Justification for data waiving:

other:

Effect on fertility: via oral route

Endpoint conclusion:

no study available

Effect on fertility: via inhalation route

Endpoint conclusion:

no study available

Effect on fertility: via dermal route

Endpoint conclusion:

no study available

Additional information

No reproductive toxicity data is available for the target substance D-lactide. Due to the rapid hydrolysis of lactide into lactoyl lactic acid and subsequently lactic acid, under acid and neutral conditions, the toxicology of lactides can be understood in terms of the toxicology of lactic acid.

Lactic acid is a natural metabolite found in humans and animals as it is endogenously produced from metabolic pathways such as glycogen breakdown, glycolysis and amino acid metabolism. Normal human blood contains 8-17 mg lactic acid/100 mL plasma, and the concentration of lactate in normal human skin is three times or more of that in the blood due to glycolytic enzymes, which actively convert glucose to lactic acid in the epidermis. Lactic acid has been detected in blood but also in several other body fluids and tissues. Concentrations of lactic acid increase significantly during intense exercise. At rest, blood concentrations of 1-1.5 mmol/L (90.1-135.12 mg/L) have been reported, 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 placed on the market (EU and USA) as a food additive by the registrant (please refer to IUCLID section 7.1.1, Sterenborg 2007 for detailed information and references). Due to its role as a common and natural food ingredient, and ubiquitous metabolic product/substrate in mammals with proven low toxicity, it can safely be concluded that lactic acid does not contribute to any systemic effects. Lactic acid is a major and essential species in mammalian primary metabolism, and a ubiquitous ingredient in all kinds of food. There is no way of lowering exposure below minimum required levels or normal (or even abnormal) internal levels. Furthermore, lactobacilli, which produce lactic acid as their major fermentation product, are abundantly found in humans, including breast milk and vaginal cavity, and are considered as probiotic bacteria. Infants can be exposed to lactobacilli during breastfeeding. Lactobacilli are known to be beneficial in preserving healthy vaginal functions such as maintenance of acidic vaginal pH and the prevention of infections. These observations are common textbook knowledge hence can be considered as adequately and reliably documented, fulfilling the criteria of REACH Annex XI, section 1.1. Supporting evidence that lactic acid has no potential to induce any reproductive/developmental toxicity is derived from a sub-chronic and chronic repeated dose toxicity study conducted with calcium lactate. No adverse effects on reproductive organs were described. Calcium lactate is a suitable read-across partner as the substance either dissociate or hydrolyses, thereby liberating lactic acid/lactate. In summary, reproductive/developmental toxicity is not a relevant endpoint for such a substance since there is no way of lowering exposure below minimum required levels or normal (or even abnormal) internal levels. Thus, in accordance with REACH annex XI, section 1.1 it is scientifically not justified to conduct reproductive toxicity study in rats with the target substance D-lactide.

Effects on developmental toxicity

Description of key information

No developmental toxicity data is available for the target substance D-lactide. Due to the rapid hydrolysis of lactide into lactoyl lactic acid and subsequently lactic acid, under acid and neutral conditions, the toxicology of lactides can be understood in terms of the toxicology of lactic acid.

Lactic acid is a major and essential species in mammalian primary metabolism, and a ubiquitous ingredient in all kinds of food. Developmental toxicity is not a relevant endpoint for such a substance since there is no way of lowering exposure below minimum required levels or normal (or even abnormal) internal levels. In accordance with section 1.1 of REACH Annex XI, reproductive/developmental toxicity studies do not need to be conducted as scientifically not justified.

Link to relevant study records

Reference

Reference 1

Endpoint:

developmental toxicity

Data waiving:

study scientifically not necessary / other information available

Justification for data waiving:

other:

Species:

rabbit

Abnormalities:

not specified

Developmental effects observed:

not specified

Reference 2

Endpoint:

developmental toxicity

Data waiving:

study scientifically not necessary / other information available

Justification for data waiving:

other:

Species:

rat

Effect on developmental toxicity: via oral route

Endpoint conclusion:

no study available

Effect on developmental toxicity: via inhalation route

Endpoint conclusion:

no study available

Effect on developmental toxicity: via dermal route

Endpoint conclusion:

no study available

Additional information

Lactide is known to be unstable in aqueous solution and breaks down quickly to form the acidic compound lactoyl lactic acid (the open-ring lactic acid dimer), and subsequently to lactic acid. Lactic acid is a ubiquitous and essential molecule of life, found in all higher animals, and many micro-organisms. It is also found in many food items. As local and route specific effects are not relevant for this endpoint, submitting a reprotox study is not relevant.

Justification for classification or non-classification

In accordance with section 1 of REACH Annex XI, reproductive/developmental toxicity studies do not need to be conducted as scientifically not justified. Given the existing data and taking a weight-of-evidence approach, there is no reproductive/developmental toxicity concern of D-lactide. Therefore, no classification for developmental/reproductive toxicity is warranted for D-lactide.