(R)-lactic acid

Endpoint summary

Description of key information

There are no reliable studies available for the assessment of the repeated dose toxicity endpoint with the target substance D-(-)-lactic acid. Therefore, available data from an oral sub-chronic repeated dose toxicity study conducted with a suitable read-across partner, calcium lactate, was used to assess the specific target organ toxicity of the target substance. Based on the results, no classification for specific target organ toxicity is warranted for target substance.

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

Key value for chemical safety assessment

Repeated dose toxicity: via oral route - systemic effects

Link to relevant study records

Reference

Endpoint:

sub-chronic toxicity: oral

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

Clinical signs:

no effects observed

Mortality:

no mortality observed

Body weight and weight changes:

no effects observed

Details on results:

All observed effects could be attributed to calcium overload/imbalance. No lactate toxicity was observed.

Dose descriptor:

NOAEL

Effect level:

50 000 mg/L drinking water

Based on:

test mat.

Sex:

male/female

Basis for effect level:

body weight and weight gain

Critical effects observed:

no

Conclusions:

In conclusion, 5% calcium lactate in drinking water or diet does not result in adverse effects attributable to lactate.

Executive summary:

In a subchronic toxicity study (similar to OECD 408), Calcium lactate was administered to Fischer 344/DuCrj rats.

In Experiment I, Calcium lactate was mixed at 5, 2.5, 1.25, 0.6, and 0.3 % in the drinking water and the rats were given this solution ad libitum for 13 weeks. As a result, the inhibition of body weight gain in the 5 % group fell within 10 % of that in the control group. Some examination values showed variations in the hematological and hematobiochemical studies, but no controversial findings were obtained in the pathohistological search. Since the highest solubility of Calcium lactate is 5%, experiments II and III were carried out by giving blended diet in order to study the toxicity at higher doses. In experiment II, Calcium lactate was mixed at concentrations of 30, 20, 10, and 5 % in the B-blend powder diet and then the rats were given this diet ad libitum for 20 weeks. In experiment III, the rats were given the CRF-1 or the B-blend powder diet ad libitum for 8 weeks. As a result, in experiment II, nephrocalcinosis was observed in all the groups including the control group. The degree of the lesion was in reverse correlation with the administered concentrations of calcium and the lesion was seen more intensely in female rats. In experiment III, nephrocalcinosis resulting from the administration of the B-blend diet was already observed in the 4th week. Nephrocalcinosis as observed in experiments II and III was attributable to the small Ca/P value in the B-blend diet.

From the above results, the optimal dose for a long-term toxicity/carcinogenicity study has been determined to be 5 and 2.5 % based on the values obtained from experiment I.

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 conclusion

Endpoint conclusion:

no adverse effect observed

Repeated dose toxicity: inhalation - systemic effects

Endpoint conclusion

Endpoint conclusion:

no study available

Repeated dose toxicity: inhalation - local effects

Endpoint conclusion

Endpoint conclusion:

no study available

Repeated dose toxicity: dermal - systemic effects

Link to relevant study records

Reference

Endpoint:

sub-chronic toxicity: dermal

Type of information:

other: review publication

Adequacy of study:

supporting study

Reliability:

4 (not assignable)

Rationale for reliability incl. deficiencies:

secondary literature

Principles of method if other than guideline:

The dermal toxicity of a face cream containing 0.25% of 85% aq. Lactic Acid was evaluated using two groups of 15 female Sprague-Dawley rats (Avon Products, Inc., 1995b). The test group received daily applications of 886 mg/kg applied 5 days/week for 13 weeks to a shaved dorsal area of the back; the control group was untreated (The dose was determined by applying a factor of 100 x to the average daily human use determined using 1 g/day.) Animals were observed daily, and blood and urine samples were collected during weeks 7 and 13 from randomly selected animals.

Specific details on test material used for the study:

- Purity: 85%

Species:

rat

Strain:

Sprague-Dawley

Sex:

female

Type of coverage:

not specified

Vehicle:

other: cosmetic cream

Details on exposure:

The test group received daily applications of 886 mg/kg bw applied 5 days/week for 13 weeks to a shaved dorsal area of the back. The control group was untreated.

Analytical verification of doses or concentrations:

not specified

Duration of treatment / exposure:

13 weeks

Frequency of treatment:

daily, 5 days/week

Dose / conc.:

886 mg/kg bw/day (nominal)

Remarks:

dose group

Dose / conc.:

0 mg/kg bw/day (nominal)

Remarks:

untreated control group

No. of animals per sex per dose:

15 (female only)

Control animals:

yes, concurrent no treatment

Details on study design:

Animals were observed daily, and blood and urine samples were collected during weeks 7 and 13 from randomly selected animals.

Observations and examinations performed and frequency:

Animals were observed daily, and blood and urine samples were collected during weeks 7 and 13 from randomly selected animals.

Clinical signs:

no effects observed

Dermal irritation:

effects observed, treatment-related

Mortality:

no mortality observed

Body weight and weight changes:

no effects observed

Food consumption and compound intake (if feeding study):

no effects observed

Food efficiency:

no effects observed

Water consumption and compound intake (if drinking water study):

no effects observed

Ophthalmological findings:

no effects observed

Haematological findings:

effects observed, treatment-related

Clinical biochemistry findings:

no effects observed

Urinalysis findings:

no effects observed

Behaviour (functional findings):

no effects observed

Organ weight findings including organ / body weight ratios:

effects observed, treatment-related

Gross pathological findings:

no effects observed

Histopathological findings: non-neoplastic:

no effects observed

Histopathological findings: neoplastic:

no effects observed

Details on results:

All animals survived to study termination. No significant gross observations, with the exception of minimal skin irritation throughout the study, could be attributed to dosing. During week 7, the blood urea nitrogen value was significantly increased for test animals as compared to controls; no other hematological effects were seen, and urinary parameters were normal. Absolute brain weight and kidney-to-body weight ratios were statistically significantly increased for the test animals. No lesions were observed at necropsy or at microscopic examination. The investigators concluded this formulation is "safe in terms of cumulative toxicity" and that "based upon the exaggerated dose level used in this study for skin care products, dermal application is not likely to produce adverse effects under conditions of consumer use."

Dose descriptor:

LOAEL

Effect level:

886 mg/kg bw/day

Based on:

test mat.

Sex:

female

Basis for effect level:

haematology

organ weights and organ / body weight ratios

Critical effects observed:

no

No significant gross observations, with the exception of minimal skin irritation. Absolute brain weight and kidney-to-body weight ratios were increased for test animals.No lesions were observed at necropsy or at microscopic examination.

Conclusions:

Formulation (face cream containing 0.25% lactic acid) is safe in terms of cumulative toxicity. Based upon the exaggerated dose levels used in this study for skin care products, dermal application is not likely to produce adverse effects under conditions of consumer use.

Executive summary:

A sub-chronic dermal toxicity study with a face cream containing 0.25% lactic acid (equals 886 mg/kg bw/day) was conducted on female rats. All animals survived to study termination. No significant gross observations, with the exception of minimal skin irritation throughout the study, could be attributed to dosing. During week 7, the blood urea nitrogen value was significantly increased for test ammals as compared to controls; no other hematological effects were seen, and urinary parameters were normal. Absolute brain weight and kidney-to-body weight ratios were statistically significantly increased for the test animals. No lesions were observed at necropsy or at microscopic exammation. The investigators concluded this formulation is "safe in terms of cumulative toxicity" and that "based upon the exaggerated dose level used in this study for skin care products, dermal application is not likely to produce adverse effects under conditions of consumer use."

Endpoint conclusion

Endpoint conclusion:

no adverse effect observed

Repeated dose toxicity: dermal - local effects

Endpoint conclusion

Endpoint conclusion:

no study available

Additional information

High levels of exposure to calcium lactate in the diet (up to 30% in feed) did not lead to any lactate-associated effects after sub-chronic exposure; all effects observed were due to the excessive intake of calcium. It could be concluded that any deleterious effects of lactic acid are caused by the effect of lactic acid on local pH, not on any biological effect of lactate. High dermal exposure to lactate, in cosmetic creams, did not lead to any effects, with the exception of slight irritation at the highest doses.

In addition, 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 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 placed on the market (EU and USA) as a food additive by Purac. 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, lactic acid bacteria, which produce lactic acid as their major fermented product, are abundantly found in humans, including breast milk and vaginal cavity, and are considered as probiotic bacteria. Infants can be exposed to lactic acid bacteria 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.

The results obtained from a sub-chronic toxicity study (IUCLID section 7.5.1) and from a chronic toxicity study (IUCLID section 7.7) showed that there is no lactic acid specific adverse systemic effect after repeated exposure.

Altogether, given the existing data and taking a weight-of-evidence approach, there is no systemic toxicity concern of lactic acid and no classification is warranted.

Justification for classification or non-classification

Based on the available data from the read-across partner, the target substance D-(-)-lactic acid does not warrant classification for specific target organ toxicity in accordance with CLP Regulation 1272/2008.