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Description of key information

No data on repeated dose toxicity are available for the target substance Sodium (S)-lactate itself. Thus, available data from the structurally related substances Calcium lactate and Sodium chloride were used to assess in a read-across approach the specific target organ toxicity of Sodium (S)-lactate. Based on the results, no classification for specific target organ toxicity is warranted in accordance with CLP Regulation 1272/2008.

Key value for chemical safety assessment

Repeated dose toxicity: via oral route - systemic effects

Link to relevant study records

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Endpoint:
short-term repeated dose toxicity: oral
Type of information:
read-across from supporting substance (structural analogue or surrogate)
Adequacy of study:
supporting study
Justification for type of information:
For justification of read-across please refer to the read-across report attached to IUCLID section 13.
Reason / purpose for cross-reference:
read-across source
Sex:
male/female
Vehicle:
unchanged (no vehicle)
Clinical signs:
no effects observed
Description (incidence and severity):
None of the 40 rats used in this study died. No adverse clinical signs of toxicity were reported.
Mortality:
no mortality observed
Description (incidence):
None of the 40 rats used in this study died.
Body weight and weight changes:
effects observed, treatment-related
Description (incidence and severity):
When the body weight data were examined separately by sex, each group of male rats was found to have gained statistically significantly less weight than did the male controls (+92.6 g, +161.6 g, +217.6 g, and +236.8 for the 32, 8, 2, and 0% added salt groups). For females the weight gain was +70.6 g, +97.4 g, +95.0 g and 112.0 g 32, 8, 2, and 0% added salt groups.
Food consumption and compound intake (if feeding study):
not examined
Description (incidence and severity):
Whe
Food efficiency:
not examined
Water consumption and compound intake (if drinking water study):
not specified
Ophthalmological findings:
not specified
Haematological findings:
not specified
Clinical biochemistry findings:
not specified
Endocrine findings:
not examined
Urinalysis findings:
not specified
Behaviour (functional findings):
not specified
Immunological findings:
not examined
Organ weight findings including organ / body weight ratios:
no effects observed
Description (incidence and severity):
The mean liver weights of the high dose group (combined) were statistically lower than the controls. The mean kidney weights of the high dose group were significantly higher in comparison to the control. Nevertheless, no pathological changes were seen by during histopathological examination.
Gross pathological findings:
no effects observed
Neuropathological findings:
not examined
Histopathological findings: non-neoplastic:
no effects observed
Description (incidence and severity):
The mean liver weights of the high dose group (combined) were statistically lower than the controls. The mean kidney weights of the high dose group were significantly higher in comparion to the control. Nevertheless, no pathological changes were seen by during histopathological examination.
Histopathological findings: neoplastic:
not specified
Other effects:
not examined
Dose descriptor:
NOAEL
Effect level:
1 330 mg/kg diet
Based on:
test mat.
Sex:
male/female
Basis for effect level:
body weight and weight gain
Critical effects observed:
not specified

Please refer to study results as attached.

Conclusions:
In a sub-chronic repeated dose toxicity study the NOAEL for Sodium chloride was established to be < 1330 mg/kg/day.
Executive summary:

In a sub-chronic repeated dose toxicity study, a group of 5 males and 5 female Wistar rats were fed with diets for 91 days, which contained additionally 32, 8, 2 and 0% Sodium chloride in excess of the 2% already present as a normal constituent of basic FRL-2C rat diet.

None of animals died during the study. At the end of 91 days of doses, the rats were weighed and sacrificed. Portions of kidney, liver, and lung were taken for histopathological examination. Livers and kidneys were weighed and the mean organ weight, expressed as percentage of the body weight, calculated.

When the body weight data were examined separately by sex, each group of male rats was found to have gained statistically significantly less weight than did the male controls (+92.6 g, +161.6 g, +217.6 g, and +236.8 for the 32, 8, 2, and 0% added salt groups). For females the weight gain was +70.6 g, +97.4 g, +95.0 g and 112.0 g for the 32, 8, 2, and 0% added salt groups. The mean liver weights of the high dose group (combined) were statistically lower than the controls. The mean kidney weights of the high dose group were significantly higher in comparison to the control. Nevertheless, no pathological changes were seen during histopathological examination.

Based on the results, the NOAEL is considered to be less than 1330 mg Sodium chloride/kg/day.

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

Endpoint:
chronic toxicity: oral
Type of information:
read-across from supporting substance (structural analogue or surrogate)
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
Qualifier:
equivalent or similar to guideline
Guideline:
OECD Guideline 453 (Combined Chronic Toxicity / Carcinogenicity Studies)
Clinical signs:
no effects observed
Mortality:
mortality observed, non-treatment-related
Description (incidence):
At the end of the 2 year experimental period, the survival rates were 48% in the control group, 60% in the 4% NaCl group and 52% in the 2% NaCl/KCl group.
Body weight and weight changes:
no effects observed
Food consumption and compound intake (if feeding study):
no effects observed
Food efficiency:
not examined
Water consumption and compound intake (if drinking water study):
not examined
Ophthalmological findings:
not examined
Haematological findings:
no effects observed
Clinical biochemistry findings:
no effects observed
Endocrine findings:
not examined
Urinalysis findings:
no effects observed
Behaviour (functional findings):
not examined
Immunological findings:
not examined
Organ weight findings including organ / body weight ratios:
effects observed, treatment-related
Description (incidence and severity):
In the organ weight ratios, an increase in the liver weight was seen in the 4% NaCl group
Gross pathological findings:
no effects observed
Neuropathological findings:
not examined
Histopathological findings: non-neoplastic:
effects observed, non-treatment-related
Description (incidence and severity):
Nephritis was reported in all treatment groups as well as in the control group. The level of gastritis and ulcer was higher in the treated groups compared to the control groups; 23 % in the 4% NaCl group compared to 6 % in the control group.
Histopathological findings: neoplastic:
effects observed, non-treatment-related
Description (incidence and severity):
In tumorous lesions, testicular tumor developed with a high incidence in all groups and the incidence of pheochromocytoma in the adrenals was moderately high in all the groups. However, the incidence and type of tumor in experimental and control groups were comparable to those of spontaneous tumors in F344/Slc rats. Therefore, the tumors observed in the study were considered to be spontaneous in origin.
Other effects:
not specified
Details on results:
At the end of the 2-year experimental period, the survival rates were 60, 52% and 48% in the 4% KCl, 2% KCl+2% NaCl and control groups. In regard to blood pressure, the level of 4% NaCl group was higher than that of the control group. Pathological non-tumorous and tumors lesions did not indicate a toxic or carcinogenic effect of NaCl. Among non-tumorous lesions, nephrotic lesion was predominant in all groups, especially in the 4% NaCl group.
Chronic gastritis and ulcer were found more in the experimental groups than in the control group. In tumorous lesions, testicular tumor developed with a high incidence in all groups and the incidence of pheochromocytoma in the adrenals was moderately high in all the groups. However, the incidence and type of tumor in experimental and control groups were comparable to those of spontaneous tumors in F344/Slc rats. Therefore, the tumors observed in the study were considered to be spontaneous in origin.
Dose descriptor:
LOEL
Effect level:
1 913 mg/kg bw/day (actual dose received)
Based on:
test mat.
Sex:
male
Basis for effect level:
other: At 4% NaCl in diet (recalculated to 1913 mg/kg bw/day) the liver weight was increased in comparison to the control.
Critical effects observed:
not specified
Conclusions:
In this study, a LOAEL was determined to be 1913 mg/kg bw/day (recalculated to 3668 mg/kg bw/day Sodium (S)-lactate).
Executive summary:

In a chronic study conducted similar to OECD 453, 4% w/w Sodium chloride was administered to 50 male F344/Slc rats in feed over a period of 2 years. The animals were observed for clinical signs and mortality and were examined for gross and histopathological changes at the end of the treatment period. Due to an increased liver weight in comparison to the control, the LOAEL was set to 1913 mg/kg bw/day (re-calculated to 3668 mg/kg bw/day Sodium (S)-lactate). In addition, the blood pressure level of the 4% NaCl group animals was higher than that of the control animals.

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

Endpoint:
sub-chronic toxicity: oral
Type of information:
read-across from supporting substance (structural analogue or surrogate)
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
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

Endpoint conclusion
Endpoint conclusion:
no study available

Repeated dose toxicity: dermal - local effects

Endpoint conclusion
Endpoint conclusion:
no study available

Additional information

There are no reliable studies available for the assessment of the repeated dose toxicity endpoint with the target substance Sodium (S)-lactate itself, but available data from oral repeated dose toxicity studies conducted with the pentahydrate of Calcium lactate and from repeated dose toxicity conducted with Sodium chloride were used to assess the specific target organ toxicity of the target substance.

In a 13-week sub-chronic oral toxicity study conducted similar to OECD TG 408, Calcium lactate in drinking water was administered to Fischer 344/DuCrj rats. In this study, 5% calcium lactate in drinking water does not result in adverse effects.

By using the default values of water intake and body weights of Fischer 344 rats established by US EPA, 1988: Recommendations for and Documentation of Biological Values for Use in Risk Assessment, EPA/600/6-87/008, the 5% dose can be estimated to be equivalent to 7777 mg/kg bw/day for males and 8468 mg/kg bw for females. 

In addition, the long-term toxicity, carcinogenicity of Calcium lactate was examined in F344 rats. Calcium lactate was given ad libitum in the drinking-water at levels of 0, 2.5 or 5% to groups of 50 male and 50 female rats for two years. No clear toxic lesion was specifically caused by long-term administration of Calcium lactate. No significant dose-related increase was found in the incidences of tumors in any organ or tissue. The results indicated that Calcium lactate had neither toxic nor carcinogenic activity in F344 rats (see IUCLID section 7.7). Supportive information was derived from two repeated dose toxicity studies conducted with Sodium chloride.

 

Historically, Sodium chloride (as a major ingredient in edible salt) has been commonly used in cooking and as a condiment and food preservative. Sodium chloride is categorized under GRAS (Generally Recognized as Safe) by the FDA (U.S. Food and Drug Administration) and the average daily levels of sodium intake for adults range from 2 to 5 grams. A technical report by WHO and the Food and Agriculture Organization (FAO) recommended the consumption of less than 5 grams Sodium chloride (or 2 grams sodium) per day as a population nutrient intake goal, while ensuring that the salt is iodized (WHO, 2003). More recently, the EFSA published a scientific opinion in 2019 [doi: 10 .2903/j.efsa.2019.5778] on dietary reference values for sodium and a sodium intake of 2.0 g/day was considered as safe and is an adequate intake for the general EU population of adults. Furthermore, sodium is an essential constituent of the body of all animals and is the dominant cation in the extracellular fluid (ECF) of the body. The functions of sodium lie in its participation in the control of the volume and systemic distribution of total body water; enabling the cellular uptake of solutes; and the generation via interactions with potassium of transmembrane electrochemical potentials.

Based on available studies, sodium chloride is not classified for any repeated dose effects. The LOAEL from a chronic repeated dose toxicity study in rats was set to 1913 mg/kg bw/day (recalculated to 3668 mg/kg bw/day Sodium (S)-lactate) due to an increase in liver weight in comparison to the control. In a second repeated dose toxicity study, Wistar rats were fed with diets for 91 days, which contained additionally 32, 8, 2 and 0% Sodium chloride. The NOAEL was established to be less than 1330 mg Sodium chloride/kg/day (recalculated to 2540 mg Sodium (S)-lactate/kg/day).

Justification for classification or non-classification

Based on the available data, classification of Sodium (S)-lactate is not warranted according to CLP Regulation 1272/2008.