Potassium (S)-lactate

Carcinogenicity

Description of key information

There is no toxicological data available for the assessment of carcinogenic effects of the target substance potassium-S-lactate itself. Potassium-S-lactate fully dissociates into potassium ions (K⁺) and lactate in aqueous and/or physiological conditions. Therefore, the information requirements concerning the carcinogenic effects of potassium-S-lactate will be addressed based on a read-across approach with information for potassium ions and lactic acid.

For more details on the read-across justification, please refer to IUCLID section 13.

Based on the physiological role of both potassium and lactate and the available information from read-across partners which is described in more detail in the section "Additional information", potassium-S-lactate is considered not to exert any carcinogenic effects.

Key value for chemical safety assessment

Carcinogenicity: via oral route

Link to relevant study records

Reference

Reference 1

Endpoint:

carcinogenicity: 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.

Clinical signs:

no effects observed

Dermal irritation (if dermal study):

not examined

Mortality:

mortality observed, non-treatment-related

Description (incidence):

No treatment related effect on mortality was observed. At the end of the 2 year experimental period, the survival rates were 64% in the 110 mg/kg bw/day, 58% in the 450 mg/kg bw/day, 84% in the 1820 mg/kg bw/day, and 48% in the 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 specified

Haematological findings:

no effects observed

Clinical biochemistry findings:

no effects observed

Urinalysis findings:

no effects observed

Behaviour (functional findings):

not specified

Immunological findings:

not examined

Organ weight findings including organ / body weight ratios:

no effects observed

Gross pathological findings:

no effects observed

Neuropathological findings:

not examined

Histopathological findings: non-neoplastic:

effects observed, treatment-related

Description (incidence and severity):

Nephrotic lesions were predominant in all groups. Chronic gastritis and ulcer were found more in the experimental groups than in the control group.

Histopathological findings: neoplastic:

no effects observed

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.

Details on results:

Chronic toxicity tests of KCl and NaCl were carried out in male F344/Slc rats for two years. At the end of the 2-year experimental period, the survival rates were 64%, 58%, 81% and 48% in 0.25% KCl, 1% KCl, 4% KCl and control groups. Pathological non-tumorous and tumorous lesions did not indicate a toxic or carcinogenic effect of KCl and NaCl. Among non-tumorous lesions, nephrotic lesions were predominant in all groups. 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 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 this study were thought to be spontaneous in origin.

Relevance of carcinogenic effects / potential:

The incidence and type of tumor in exprimental and control groups were comparable to those of spontaneous tumors in F344/Slc rats. Therefore, the tumors observed in this study were thought to be spontaneous in origin.

Key result

Dose descriptor:

NOAEL

Effect level:

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 conclusion, in a chronic toxicity/carcinogenicity feeding study conducted similar to OECD 453 neither toxic nor carcinogenic effects were observed which could be related to the potassium chloride treatment via the diet. Therefore, the NOAEL is considered to be 1820 mg/kg bw/day.

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 incidence and type of tumor in exprimental and control groups were comparable to those of spontaneous tumors in F344/Slc rats. Therefore, the tumors observed in this study were thought to be spontaneous in origin. In addition, no adverse toxic effects were observed.

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 chronic/carcinogenicity study in the rat is acceptable with deviations compared to the guideline requirements for a chronic/ carcinogenicity study (OPPTS 870.4300; OECD 453) in rodents, because only one sex of the species was used for investigations.

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:

carcinogenicity: 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

No. of animals per sex per dose:

50

Control animals:

yes, plain diet

Clinical signs:

no effects observed

Description (incidence and severity):

There were no treatment-related abnormalities in condition or behaviour.

Dermal irritation (if dermal study):

not examined

Mortality:

no mortality observed

Description (incidence):

In the chronic studies mortality rate was not affected by treatment with KCl.

Body weight and weight changes:

effects observed, treatment-related

Description (incidence and severity):

In the 30-month study, mean body weights were decreased in males and females of the 3% KCl group. The overall differences with the controls were between 4 and 10%.

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 groups (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:

not examined

Urinalysis findings:

effects observed, non-treatment-related

Description (incidence and severity):

Urinary pH was not influenced by the feeding of 3% KCl except for a decrease in the first week of the study only. The volume of the urine collected during 24 h (food and water available), was generally increased in rats fed 3% KCl.
In females, this finding was no longer apparent in the later stages of the study, which may have been due to the high values obtained in the control group. The urinary density did not show consistent differences but tended to be decreased in males of these groups. Potassium excretion was consistently increased in males and females fed 3% KCl. Urinary sodium excretion tended to be relatively high at various occasions in rats fed 3% KCl., which may be ascribed to the natriuretic effect of high potassium intake (Tannen, 1983), but the figures showed large variation. There were no consistent differences ib 24 h excretion of sulphate, gamma glutamyl transferase or hydroxyproline among the groups.
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 at most sampling points.
Brownish discoloration of the urine and haematuria of the urinary sediment were occasionally increased in rats fed KCl, but there were no consistent or dose-related differences in incidence or severity of hematuria among these groups.

Behaviour (functional findings):

no effects observed

Immunological findings:

not examined

Organ weight findings including organ / body weight ratios:

no effects observed

Description (incidence and severity):

Relative kidney weight tended to be increased at several stages. However, these findings were not consitent or dose-related.

Gross pathological findings:

no effects observed

Description (incidence and severity):

Macroscopic examination at necropsy after 30 months did not reveal significant differences among the treatment groups and the controls, apart from macroscopic lesions in the urinary bladder in rats fed KCl.

Neuropathological findings:

not examined

Histopathological findings: non-neoplastic:

effects observed, treatment-related

Description (incidence and severity):

Most histopathological changes observed 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 observed:
Dose-related increases in the incidence of zona glomerulosa hypertrophy occurred in all treatment groups in both sexes at the end of the 30-month study. The zona glomerulosa was distinctly wider than in controls; the cells in this area were enlarged and showed a finely vacuolar cytoplasm.
A number of rats receiving KCl showed oncocytic tubules after 18 months but, because after 30 months this finding was also noted in control animals, differences were no longer apparent at this stage.
The oncocytic tubules were characterised by tubules lined with, often hypertrophic, epithelial cells containing eosinophilic granular cytoplasm (oncocytes). The oncocytic tubules often showed a cystically dilated lumen with epithelial cells protruding into the lumen.
The overall incidence of nephrosis was comparable among the groups throughout the studies. Nephrosis or ‘chronic progressive nephrosis’ is a
common lesion in ageing male Wistar rats, and is characterised by loss of a progressive number of nephrons due to glomerularsclerosis and subsequent protein
leakage.

Histopathological findings: neoplastic:

effects observed, treatment-related

Description (incidence and severity):

The incidences of simple epithelial hyperplasia (1/9 males, 1/3 females) and of papillary/nodular hyperplasia (0/2 males and females) of the urinary bladder were slightly increased in the 3% KCl group.
Apart from these observations, there were no treatment-related changes in any specific tumour type among the groups. The total number of rats with tumours or the total incidence of tumours was not affected by the treatment.

Other effects:

no effects observed

Relevance of carcinogenic effects / potential:

In summary, apart from the effects on the urinary bladder, treatment with KCl did neither affect type, incidence and multiplicity of tumours, nor time of tumour appearance and the ratio of benign-malignant tumours. It may be concluded that most of the observed changes can be regarded as physiological adaptations to KCl feeding.

Key result

Dose descriptor:

NOAEL

Effect level:

1 454 mg/kg bw/day (actual dose received)

Based on:

test mat.

Sex:

male

Basis for effect level:

other: No adverse effects observed

Key result

Dose descriptor:

NOAEL

Effect level:

1 685 mg/kg bw/day (actual dose received)

Based on:

test mat.

Sex:

female

Basis for effect level:

other: No adverse effects observed

Key result

Critical effects observed:

no

Conclusions:

In conclusion, in a chronic toxicity study, rats were orally exposed to 3% potassium chloride (corresponding to 1454 mg/kg bw/day for males and 1685 mg/kg bw/day for females) via the diet. Besides lesions concerning the urinary bladder, potassium chloride did not affect tumor incidence. It was concluded, that most of the observed changes can be regarded as physiological adaptations. Based on the results from this study, potassium chloride can be considered to be non-carcinogenic.

Executive summary:

In a chronic toxicity study, potassium chloride (≥ 99.5% purity) was administered to 50 Wistar rats/sex/dose at concentrations of 0 and 3% (corresponding to 1454 mg/kg bw/day for males and 1685 mg/kg bw/day for females) via the diet for 30 months.

At the doses tested, there were no compound related effects in mortality, clinical signs, food consumption, hematology, clinical chemistry organ weights or gross pathology. There was a slight decrease in body weight gain in males and females treated with KCl compared to controls. Increases in the incidence of zona glomerulosa hypertrophy occurred in the treatment groups in both sexes.

Apart from macroscopic lesions and a slight increase in epithelial and papillary hyperplasia of the urinary bladder, potassium chloride did neither affect type, incidence and multiplicity of tumours, nor time of tumour appearance and the ratio benign-malignant tumours when compared to controls. It was concluded that most of the observed changes can be regarded as physiological adaptations. Based on the results from this study, potassium chloride can be considered to be non-carcinogenic and the NOAEL is 1454 mg/kg bw/day for males and 1685 mg/kg bw/day for females (recalculated to 2501 and 2898 mg/kg bw/day potassium-S-lactate).

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:

carcinogenicity: 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 report attached in section 13 of IUCLID.

Reason / purpose for cross-reference:

read-across source

Clinical signs:

not specified

Dermal irritation (if dermal study):

not examined

Mortality:

mortality observed, non-treatment-related

Description (incidence):

In females, the mortality rate in the 5% group was slightly higher than those in the other two groups.

Body weight and weight changes:

effects observed, treatment-related

Description (incidence and severity):

Compared with the controls, a 13% decrease in body-weight gain was observed in male and female rats of the high-dose group. The toxicological relevance was not further discussed.

Food consumption and compound intake (if feeding study):

not examined

Food efficiency:

not examined

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

no effects observed

Description (incidence and severity):

Throughout the administration period, daily water consumption was almost constant in all groups of both sexes.

Ophthalmological findings:

not examined

Haematological findings:

no effects observed

Description (incidence and severity):

No specific dose-related changes were observed in any of the haematological and biochemical parameters.

Clinical biochemistry findings:

no effects observed

Description (incidence and severity):

No specific dose-related changes were observed in any of the haematological and biochemical parameters.

Urinalysis findings:

not examined

Behaviour (functional findings):

not specified

Immunological findings:

not examined

Organ weight findings including organ / body weight ratios:

effects observed, non-treatment-related

Description (incidence and severity):

Females in the 5% group exhibited slightly but significantly higher kidney weights compared with controls. Histologically, however, there was no difference in the severity of chronic nephropathy between different groups.
A significant dose-dependent increase was observed in the relative brain weights of both male and female rats, although no histological change was detected which may result from the decrease in body weight gains.

Gross pathological findings:

effects observed, non-treatment-related

Description (incidence and severity):

A number of non-neoplastic lesions (e.g. myocardial fibrosis, bile-duct proliferation, hepatic microgranulomas and chronic nephropathy) were observed in all groups, with no difference in their incidences and/or degrees.

Neuropathological findings:

not examined

Histopathological findings: non-neoplastic:

no effects observed

Description (incidence and severity):

A slight increase in calcium deposition in the papilla compared to controls was observed in females of the 5% dose group. This type of lesion was histologically different from nephrocalcinosis and might depend on the increase in urinary calcium levels.
It is known that these lesions occur spontaneously in old F344 rats (Goodman et al., (1979): "Neoplastic and nonneoplastic lesions in aging F344 rats.", Toxicology and Applied Pharmacology 48, 237-248.). The data show that no clear toxic lesions specifically caused by long-term administration of calcium lactate, except for the slight calcium deposition in the renal papilla, were detected in any organ.

Histopathological findings: neoplastic:

no effects observed

Description (incidence and severity):

Tumor incidences were 100% in all the male groups. In females, they were 80-86%, and there was no significant difference in the incidences between different groups.Histologically, all the tumours observed in this experiment were similar to those known to occur spontaneously in F344 rats, as reported in previous studies.
Male rats in the 5% group, showed a slightly higher incidence of pheochromocytomas compared with the present controls and also with historical controls (12-28%; Maekawa et al., (1983): "Spontaneous tumors in F344/DuCrj rats." Gann 74, 365-372).
The incidence of adrenal medullary hyperplasias in the high-dose group (24%) was also higher than that in the low-dose and control groups (12% and 10%, respectively). A positive trend was observed in the occurrence of the two types of lesions (combined hyperplasias and pheochromocytomas).
For further details see section "Relevance of carcinogenic effects/potential.

Other effects:

not specified

Relevance of carcinogenic effects / potential:

None of the experimental groups showed a significant increase in the incidence of any specific tumours compared with the corresponding control value (chi-square and/or Fisher's test), and also no positive trend was noted in the occurrence of any tumour (trend analysis test; Peto et al., (1980), except for the slightly higher incidence and positive trend of pheochromocytomas and medullary hyperplasias in male rats in the 5% group. This finding is considered to be due to experimental variability and not related to treatment with calcium lactate because the incidence of pheochromocytomas observed in the present male controls was also higher than that in historical controls. Furthermore, no significant increase or positive trend in the incidences of hyperplasias/ pheochromocytomas was detected in females from all groups.
It was therefore concluded that calcium lactate had no carcinogenic activity in F344 rats when it was given continuously in the drinking-water for 2 years.

Key result

Dose descriptor:

NOAEC

Effect level:

50 000 ppm (nominal)

Based on:

test mat.

Sex:

male/female

Basis for effect level:

other: no calcium lactate-related carcinogenic activity observed

Key result

Critical effects observed:

no

Conclusions:

It was concluded that calcium lactate had neither toxic nor carcinogenic activity in F344 rats when it was given continuously in the drinking-water for 2 years.

Executive summary:

In a carcinogenicity study Calcium lactate (>97% purity) was administered ad libitum to 50 F344 rats per sex per dose in drinking-water at levels of 0, 2.5 or 5 % for two years. Calcium lactate is the calcium salt of lactic acid, which is a major and essential species in mammalian primary metabolism and a ubiquitous ingredient in all kinds of food.

No clear toxic lesion was specifically caused by long-term administration of Calcium lactate. No significant dose-related increase in the incidences of tumours in any organ or tissue was found. The results indicate that calcium lactate had neither toxic nor carcinogenic activity in F344 rats.

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 (see IUCLID section 13).

Endpoint conclusion

Endpoint conclusion:

no adverse effect observed

Carcinogenicity: via inhalation route

Endpoint conclusion

Endpoint conclusion:

no study available

Carcinogenicity: via dermal route

Endpoint conclusion

Endpoint conclusion:

no study available

Justification for classification or non-classification

Based on the available data, potassium-S-lactate does not warrant classification for carcinogenicity in accordance with CLP regulation 1272/2008.

Additional information

No data is available for the target substance potassium-S-lactate. Dissociation of potassium-S-lactate takes place immediately, resulting in formation of potassium (K+) and lactate ions. Thus, any ingestion of potassium-S-lactate by living organisms, most notably humans, will inevitably result in systemic exposure to the dissociation products and the toxicology of potassium-S-lactate can be understood accordingly. In line with the read-across approach, data from the suitable read-across partners potassium chloride and calcium lactate was used.

In a chronic toxicity study (Imai et al., 1986), potassium chloride was administered to 50 male F344 rats/dose at dose levels of 0, 0.25, 1 and 4% (corresponding to 0, 110, 450 and 1820 mg/kg bw/day) via the diet for 2 years.

At the doses tested, there were no treatment-related effects in mortality, clinical signs, body weight, food consumption, haematology, clinical chemistry, urinalysis, organ weights or gross and histologic pathology, besides chronic gastritis and ulcer which were found more in the experimental groups than in the control group. In addition, there was no treatment related increase in tumour incidence when compared to controls. Based on the results, the NOAEL can be considered 1820 mg/kg bw/day (re-calculated to 3130 mg/kg bw potassium-S-lactate).

In addition, potassium chloride was administered in another chronic toxicity study (Lina et al., 2004) to 50 Wistar rats/sex/dose a nominal concentration of 0 and 3% (corresponding to 1454 mg/kg bw/day for males and 1685 mg/kg bw/day for females) via the diet for 30 months.

There were no compound related effects in mortality, clinical signs, food consumption, haematology, clinical chemistry organ weights or gross pathology. There was a slight decrease in body weight gain in males and females treated with KCl compared to controls. Increases in the incidence of zona glomerulosa hypertrophy occurred in the treatment groups in both sexes.

Apart from macroscopic lesions and a slight increase in epithelial and papillary hyperplasia of the urinary bladder, potassium chloride did neither affect type, incidence and multiplicity of tumours, nor time of tumour appearance and the ratio benign-malignant tumours when compared to controls. It was concluded that most of the observed changes can be regarded as physiological adaptations.

Based on the results, the NOAEL can be considered to be at least 1454 mg/kg bw/day (re-calculated to 2501 mg/kg bw potassium-S-lactate).

 

In a third chronic toxicity study (Maekawa et al., 1991), calcium lactate was administered to F344 rats at concentrations of 0, 2.5 and 5% via drinking water for 104 weeks.

At the concentration tested, there were no compound related effects in mortality, clinical signs, haematology, clinical chemistry or gross and histologic pathology. There was a decrease in body weight gain in the male and female high dose group compared to controls and a slight increase in kidney weights in females of the high dose group without histological correlate. In addition, there was no treatment related increase in tumour incidence when compared to controls.

Overall, the studies performed with the read-across partners for potassium-S-lactate (potassium chloride and calcium lactate) do not suggest any substance-related carcinogenic potential.

Based on the available data, the target substance potassium-S-lactate is not considered to be carcinogenic.