Sodium lactate

Carcinogenicity

Description of key information

There is no toxicological data available for the assessment of carcinogenic effects of the target substance Sodium lactate itself. Sodium lactate fully dissociates into sodium ions (Na⁺) and lactate in aqueous and/or physiological conditions. Therefore, the information requirements concerning the carcinogenic effects of Sodium lactate will be addressed based on a read-across approach with information for sodium ions and lactate. For more details on the read-across justification, please refer to IUCLID section 13.

Based on the physiological role of both sodium and lactate and the available information from read-across partners, Sodium 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.

Reason / purpose for cross-reference:

read-across source

Sex:

male

Clinical signs:

no effects observed

Dermal irritation (if dermal study):

not examined

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):

not examined

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

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. With regard to blood pressure, the level of the 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:

NOAEL

Effect level:

1 913 mg/kg bw/day (actual dose received)

Based on:

test mat.

Sex:

male

Basis for effect level:

other: no carcinogenic effects were recorded which were related to the treatment

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:

no

Conclusions:

In conclusion, in a chronic toxicity/carcinogenicity feeding study conducted similar to OECD 453 no carcinogenic effects were observed which could be related to the Sodium chloride treatment via the diet.

Executive summary:

In a chronic toxicity/carcinogenecity study conducted similar to OECD 453, 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.

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.

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

Clinical signs:

no effects observed

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 parameters.

Clinical biochemistry findings:

no effects observed

Description (incidence and severity):

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

Endocrine findings:

not examined

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. The type of lesion observed in the kidney of female rats in the 5% group was histologically different from the so-called nephrocalcinosis, which is characterized by an intraluminal deposition of calcium observed mainly in the cortico-medullary region. The pathogenesis of this lesion is unclear and might depend on the increase in the urinary calcium level; this parameter was not determined in this study.

Histopathological findings: neoplastic:

effects observed, non-treatment-related

Description (incidence and severity):

Tumours were found in many organs and/or tissues in all groups including the controls. In males from all groups, tumours of the testis were the most frequent, followed by those of the adrenal gland, thyroid gland, pituitary gland, haematopoietic organs, mammary gland, lung and pancreas. In females, the commonest tumours were those of the uterus, pituitary gland, haematopoietic organs, mammary gland, thyroid gland, adrenal gland and pancreas. Tumours were also detected in other organs/tissues from rats of all groups, but at lower incidences. Histologically, all the tumours observed in this experiment were similar to those known to occur spontaneously in F344 rats, as reported in previous studies (Goodman et al.,1979; Maekawa et al.,1983; Maita et al.,1987; Solleveld et al.,1984). 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; Pete et al., 1980). 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.

Other effects:

not specified

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

Lactate intakes:

In the present study, high doses of calcium were administered continiously and the daily calcium lactate intakes of males and females in the 5% group were 860 mg and 570 mg/rat, respectively.

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 long-term toxicity, 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 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

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, Sodium lactate does not warrant classification for carcinogenicity in accordance with CLP Regulation 1272/2008.

Additional information

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

In a chronic toxicity study (Imai et al., 1986), Sodium chloride was administered to 50 male F344 rats/dose at dose levels of 0 and 4% (corresponding to 0 and 1913 mg/kg bw/day (recalculated to 3668 mg/kg bw/day Sodium lactate) via the diet for 2 years. At the doses tested, there were no treatment-related effects in mortality, clinical signs, body weight, food consumption, hematology, 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 and an increased liver weight. In addition, there was no treatment related increase in tumor incidence when compared to controls.

In a second 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, hematology, 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 tumor incidence when compared to controls.

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

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