Potassium (S)-lactate

Endpoint summary

Description of key information

No data on repeated dose toxicity are available for the target substance potassium-S-lactate itself. Thus, available data from the structurally related substances L-lactide, calcium lactate and potassium chloride were used to assess in a read-across approach the specific toxicity of potassium-S-lactate. In sub-chronic and chronic repeated dose toxicity studies no adverse effects were observed attributable to lactate or potassium. The obtained NOAEL of 1820 mg/kg bw/day from a chronic repeated dose toxicity in rats can be re-calculated on a molar basis to 3130 mg/kg bw/day for the target substance potassium-S-lactate.

Key value for chemical safety assessment

Repeated dose toxicity: via oral route - systemic effects

Link to relevant study records

Reference

Reference 1

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 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:

effects observed, treatment-related

Description (incidence and severity):

Emesis once in each of two female dogs (one in the 0 mg/kg and one in the 100 mg/kg group during week 9). Bloody diarrhoea was seen once during week 6 in one female dog of the 100 mg/kg group. No other clinical signs were observed.

Mortality:

no mortality observed

Description (incidence):

All dogs survived.

Body weight and weight changes:

effects observed, non-treatment-related

Description (incidence and severity):

On day 1 of the study, the mean weight of males in the 100 mg/kg/ dose group was significantly lower than the mean weight of dogs in other dose groups. This was due to the fact that one dog previously assigned to the 100 mg/kg/day dose group was found at the baseline bleed to have an abnormal alanine aminotransferase (ALT) value and had to be replaced with a dog of lower body weight. However, the data indicate that male dogs in this dose group gained weight at a rate comparable to controls and that, although the terminal body weights of males in the 100 mg/kg/dose group remained depressed relative to controls, the difference between the two groups was smaller than on day 1. Therefore, administration of lactide had no significant effect (p < 0.01) on body weights of dogs of either sex.

Food consumption and compound intake (if feeding study):

effects observed, non-treatment-related

Description (incidence and severity):

Administration of lactide had no significant effect (p < 0.01) on food consumption for dogs of either sex. Although a dose-related increase in food consumption for both sexes of dogs was seen during week 2, this increase was attributed to adaptation of the dogs to the irritating effect of the lactide on the gastrointestinal tract rather than to a direct effect of the lactide itself. No other dose-related differences in food consumption were observed at any other time during the 13-week study.

Food efficiency:

not specified

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

not specified

Ophthalmological findings:

not specified

Haematological findings:

no effects observed

Clinical biochemistry findings:

no effects observed

Urinalysis findings:

no effects observed

Behaviour (functional findings):

not examined

Immunological findings:

not examined

Organ weight findings including organ / body weight ratios:

no effects observed

Gross pathological findings:

effects observed, treatment-related

Description (incidence and severity):

Stomach foci in one male/female from the 100 mg/kg , and one female from the 4mg/kg dose group. See also Table 1 in "Any other information on results incl. tables".

Neuropathological findings:

not specified

Histopathological findings: non-neoplastic:

effects observed, treatment-related

Description (incidence and severity):

Moderately severe ulceration of the stomach mucosa seen in one female dog of the high dose group.

Histopathological findings: neoplastic:

no effects observed

Other effects:

not examined

Details on results:

The primary toxic effect of lactide in dogs under the experimental conditions employed was irritation of the alimentary tract. The gross and histopathologic lesions observed confirmed the irritant effect of the Lactide on the gastrointestinal tract. There was no evidence of kidney toxicity in any of the dogs in the 13-week study. Based on these results, the primary toxic effect of lactide after subchronic oral dosing in dogs was irritation of the gastrointestinal tract. It is significant to note that irritation was the only toxicologic effect seen in dogs in the subchronic study, and that there was no evidence of other systemic toxicity at any dose after 13 week of dosing.

Dose descriptor:

NOAEL

Remarks:

(systemic)

Effect level:

100 mg/kg bw/day (actual dose received)

Based on:

test mat.

Sex:

male/female

Basis for effect level:

other: no adverse effects observed

Dose descriptor:

LOAEL

Remarks:

(local)

Effect level:

100 mg/kg bw/day (actual dose received)

Based on:

test mat.

Sex:

male/female

Basis for effect level:

other: gastrointestinal irritation

Dose descriptor:

NOAEL

Remarks:

(local)

Effect level:

20 mg/kg bw/day (actual dose received)

Based on:

test mat.

Sex:

male/female

Basis for effect level:

other: no adverse effects observed

Critical effects observed:

not specified

 Table 1: Incidence of gross lesions in dogs treated for 13 weeks with oral doses of lactide

Dose group		0 mg/kg	4 mg/kg	20 mg/kg	100 mg/kg
Males
Stomach focus		0	0	0	1
Females
Stomach focus		0	1	0	1

Incidence= number of dogs in a given dose group with a given lesion. n=4 for all dose groups

Conclusions:

Lactide acts primarily, if not only, as an irritant after oral administration. The 13-week NOAEL is 100 mg/kg bw/d.

Executive summary:

In a subchronic toxicity study Lactide (18:1 mixture of l-lactide and m-lactide) was administered to 4 beagle dogs/sex/dose by capsule at dose levels of 4, 20, 100 mg/kg bw/day for 13 weeks.

The only apparent toxic effect at 100 mg/kg/day was gastrointestinal irritation. Therefore, the local LOAEL is 100 mg/kg/d. No systemic effects were reported at 100 mg/kg/d. Thus, the systemic NOAEL for orally administered Lactide under the conditions in this study was considered to be 100 mg/kg/day.

This subchronic study in the dog is acceptable and satisfies the principle requirement for a subchronic oral study similar to OECD 409 in dogs.

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.

Reference 2

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

Sex:

male

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 64 % in 110 mg/kg bw, 58 % in 450 mg/kg bw, 84 % in 1820 mg/kg bw, and 48 % in control groups.

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

Urinalysis findings:

no effects observed

Behaviour (functional findings):

not examined

Immunological findings:

not specified

Organ weight findings including organ / body weight ratios:

no effects observed

Gross pathological findings:

no effects observed

Neuropathological findings:

not specified

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; 18 % in the 110 and 450 mg/kg bw/day groups and 30 % in the 1820 mg/kg bw/day 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:

The NOAEL from this study is set at 1820 mg/kg bw/day since nephritis was reported in all treatment groups as well as in the control group. The gastritis is considered a local effect, and is not used for deriving a NOAEL value.

Key result

Dose descriptor:

NOAEL

Effect level:

ca. 1 820 mg/kg bw/day (nominal)

Based on:

test mat.

Sex:

male

Basis for effect level:

other: No test-item related adverse effects were observed

Critical effects observed:

no

Conclusions:

In this study an unbounded NOAEL (rats) for KCl was determined at 1820 mg/kg bw/d.

Executive summary:

In a chronic study conducted similar to OECD 453, potassium 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. The NOAEL was set 1820 mg/kg bw/day (re-calculated to 3130 mg/kg bw potassium-S-lactate) since nephritis was reported in all treatment groups as well as in the control group. The weakness of this study relates to the fact that the results are not given in sufficient detail, and that the mortality in the control group is very high. In addition, the possible effect of KCl on kidneys cannot be evaluated because of limited reporting and the fact that all animals, including controls, had nephrotic lesions.

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.

Reference 3

Endpoint:

sub-chronic 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

Clinical signs:

no effects observed

Mortality:

no mortality observed

Body weight and weight changes:

no effects observed

Food consumption and compound intake (if feeding study):

not specified

Food efficiency:

not specified

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

not specified

Ophthalmological findings:

not specified

Haematological findings:

not specified

Clinical biochemistry findings:

not specified

Urinalysis findings:

not specified

Behaviour (functional findings):

not specified

Immunological findings:

not specified

Organ weight findings including organ / body weight ratios:

not specified

Gross pathological findings:

not specified

Neuropathological findings:

not specified

Histopathological findings: non-neoplastic:

not specified

Histopathological findings: neoplastic:

not specified

Other effects:

not specified

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

Sex:

male/female

Critical effects observed:

not specified

Conclusions:

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 justification of read-across please refer to the read-across report attached to IUCLID section 13.

Reference 4

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

Duration of treatment / exposure:

13 weeks

Clinical signs:

no effects observed

Description (incidence and severity):

There were no treatment-related abnormalities in condition or behaviour in any of the studies.

Mortality:

no mortality observed

Description (incidence):

None of the rats died during the 13-week study.

Body weight and weight changes:

no effects observed

Description (incidence and severity):

KCl treatment showed no effect on body weight.

Food consumption and compound intake (if feeding study):

no effects observed

Description (incidence and severity):

There were no consistent differences in food intake among the groups.

Food efficiency:

not examined

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

effects observed, treatment-related

Description (incidence and severity):

Water intake was increased in the 3% KCl group (ca. 40 and 25% for males and females, respectively).

Ophthalmological findings:

not examined

Haematological findings:

no effects observed

Description (incidence and severity):

There were no consistent or treatment-related effects on red blood cell variables, clotting potential or total and differential white blood cell counts in any of the groups.

Clinical biochemistry findings:

effects observed, treatment-related

Description (incidence and severity):

Potassium levels in plasma were increased in males and females fed 3% KCl, although the differences with the controls was only statistically significant for male rats. No changes in plasma chloride levels were observed with 3% KCl.

Urinalysis findings:

effects observed, treatment-related

Description (incidence and severity):

The volume of the urine collected during 24 h (food and water available), was generally increased in rats fed 3% KCl.
Potassium excretion was consistently increased in males and females fed 3% KCl, while phosphate excretion was significantly increased in males only. The renal concentration test (no food and water available prior to and during urine sampling) showed a slightly increased volume associated with a decreased density of the urine in males fed 3% KCl.
Brownish discoloration of the urine and haematuria, as detected with urinary test strips and by microscopic examination of the urinary sediment were occasionally increased in rats fed KHCO3, NH4Cl or KCl, but there were no consistent or dose-related differences in incidence or severity of hematuria among these groups.
Urinary pH was not influenced by the feeding of 3% KCl except for a decrease in the first week of the study only. With the KCl diet, no consistent changes were observed in net acid excretion

Behaviour (functional findings):

no effects observed

Description (incidence and severity):

There were no treatment-related abnormalities in condition or behaviour in any of the studies.

Immunological findings:

not examined

Organ weight findings including organ / body weight ratios:

no effects observed

Description (incidence and severity):

Relative kidney weights tended to be increased but this finding was not consistent or dose-related.
There were no consistent or treatment-related changes in the weights of the liver, spleen, ovaries, pituitary, thyroid, thymus or heart.

Gross pathological findings:

no effects observed

Description (incidence and severity):

Macroscopic examination at necropsy after 13 weeks did not reveal significant differences among the treatment groups and the controls.

Neuropathological findings:

not examined

Histopathological findings: non-neoplastic:

effects observed, non-treatment-related

Description (incidence and severity):

Most histopathological changes observed in the various studies were about equally distributed among the treatment groups and the controls and represented normal background pathology for rats of this strain and age. A number of treatment-related non-neoplastic changes was, however, observed. There was a slight increase in hypertrophies of the adrenal zona glomerulosa (2 vs. 1 for males and 3 vs. 0 in the control for females) and one case of urothelial hyerplasia in the pelvis of male rats in response to 3% KCl treatment.

Histopathological findings: neoplastic:

not examined

Other effects:

not specified

Dose descriptor:

NOAEL

Effect level:

2 427 mg/kg bw/day (actual dose received)

Based on:

test mat.

Sex:

male/female

Basis for effect level:

other: no adverse effects observed

Critical effects observed:

no

Conclusions:

In conclusion, the NOAEL of potassium chloride after oral administration of 3% over a period of 13 weeks in a repeated dose feeding study is considered to be 2427 mg/kg bw/day.

Executive summary:

In a subchronic toxicity study performed similar to OECD 408, potassium chloride (≥ 99.5% purity) was administered to 10 Wistar rats/sex and dose in the diet at a nominal dose level of 3% (actual dose received in average were 2427 mg/kg bw) for 13 weeks. There were no compound related adverse effects in mortality, clinical signs, body weight, food consumption, hematology, clinical chemistry, urinalysis, organ weights, or gross and histologic pathology.

Based on these results, the NOAEL is considered to be 2427 mg/kg bw/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 conclusion

Endpoint conclusion:

no adverse effect observed

Dose descriptor:

NOAEL

3 130 mg/kg bw/day

Study duration:

chronic

Species:

rat

Quality of whole database:

Study conducted equivalent to guideline study OECD 453

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

No data on repeated dose toxicity are available for the target substance potassium-S-lactate itself. Thus, available data from the structurally related substances L-lactide, calcium lactate and potassium chloride were used to assess in a read-across approach the specific toxicity of potassium-S-lactate. For details on the read-across rationale please refer to IUCLID section 13. In a 13-week subchronic oral toxicity study similar to OECD 408, calcium lactate in drinking water was administered to Fischer 344/DuCrj rats. In this study, 5% calcium lactate in drinking water or diet does not result in adverse effects. In a 13-week subchronic study, dogs were treated with L-lactide 4, 20, 100 mg/kg bw/day. The only apparent toxic effect at 100 mg/kg/day was gastrointestinal irritation. Therefore, the local LOAEL is 100 mg/kg bw/day. No systemic effects were reported at 100 mg/kg bw/day. Thus, the systemic NOAEL for orally administered lactide under the conditions in this study was considered to be 100 mg/kg bw/day. In a 2-week dose range finding study, dogs were treated with L-lactide at dose levels of 10, 100, 400, 1000 and 2500 mg/kg bw/day. In this study, effects in the alimentary tract were noted at 400 mg/kg bw/day, resulting in a local NOAEL of 100 mg/kg bw/day. Further, a mild to moderate renal tubular regeneration was reported in all animals of the 2500 mg/kg bw/day dose. Based on the possible renal toxicity the (systemic) LOAEL is 2500 mg/kg bw/day. The (systemic) NOAEL for orally administered lactide to dogs under the conditions of this study is 1000 mg/kg/day. in a sub-chronic toxicity study similar to OECD 408, potassium chloride was administered to male and female rats in feed over a period of 13 weeks. In this study, no adverse adverse effects were observed and the NOAEL was 2427 mg/kg bw/day (re-calculated to 4174 mg/kg bw/day of potassium-S-lactate).

In a chronic study similar to OECD 453, potassium chloride was administered to 50 male F344/Slc rats in feed over a period of 2 years. In this study, the NOAEL was set to 1820 mg/kg bw/day (re-calculated 3130 mg/kg bw/day of potassium-S-lactate), since nephritis was reported in all treatment groups as well as in the control group.

Justification for classification or non-classification

Based on the available data from suitable read-across partners, classification of potassium-S-lactate is not warranted according to the CLP Regulation 1272/2008.