Sodium chloride

Repeated dose toxicity: oral

Administrative data

Endpoint:

chronic toxicity: oral

Type of information:

other: publication

Adequacy of study:

key study

Study period:

1986

Reliability:

2 (reliable with restrictions)

Rationale for reliability incl. deficiencies:

other: The publication contains sufficient information to permit a meaningful evaluation of study results

Cross-reference

Cross-reference 1

Reason / purpose for cross-reference:

reference to same study

Cross-reference 2

Reason / purpose for cross-reference:

reference to other study

Data source

Reference

Reference Type:

publication

Title:

Chronic Toxicity Test of KCl and NaCl in F344/Slc rats

Author:

Imai et al

Year:

1986

Bibliographic source:

J. Nara Med. Ass. (1986); 37: 115-127

Materials and methods

Test guideline

Qualifier:

equivalent or similar to guideline

Guideline:

OECD Guideline 453 (Combined Chronic Toxicity / Carcinogenicity Studies)

Principles of method if other than guideline:

not applicable

GLP compliance:

not specified

Test material

Test material information

Constituent 1

Reference substance name:

Sodium chloride

EC Number:

231-598-3

EC Name:

Sodium chloride

Cas Number:

7647-14-5

Molecular formula:

ClNa

IUPAC Name:

sodium chloride

Constituent 2

Reference substance name:

23-598-3

IUPAC Name:

23-598-3

Details on test material:

- Name of test material (as cited in study report): Sodium chloride
- Physical state: white crstalline granules
- Analytical purity: not specified in the publication
- Impurities (identity and concentrations): not specified in the publication
- Composition of test material, percentage of components: not specified in the publication
- Purity test date: not specified in the publication
- Lot/batch No.: not specified in the publication
- Expiration date of the lot/batch: not specified in the publication
- Stability under test conditions: not specified in the publication
- Storage condition of test material: not specified in the publication
- Other: Sourced from (Hayashi Junyaku Kogyo Co.)

Test animals

Species:

rat

Strain:

Fischer 344

Sex:

male

Details on test animals or test system and environmental conditions:

TEST ANIMALS
- Source: Shizuka Experimental Cooperative
- Age at study initiation: 4 weeks on receipt of animals
- Weight at study initiation: not specified in the publication
- Fasting period before study: not specified in the publication
- Housing: 2 rats/cage
- Diet (e.g. ad libitum): ad libitum
- Water (e.g. ad libitum): ad libitum
- Acclimation period: 1 week

ENVIRONMENTAL CONDITIONS
- Temperature (°C): 23 ± 2°C
- Humidity (%): 40%
- Air changes (per hr): not specified in the publication
- Photoperiod (hrs dark / hrs light): not specified in the publication

Administration / exposure

Route of administration:

oral: feed

Vehicle:

unchanged (no vehicle)

Details on oral exposure:

DIET PREPARATION
- Rate of preparation of diet (frequency): not specified in the publication
- Mixing appropriate amounts with (Type of food): not specified in the publication
- Storage temperature of food: not specified in the publication
- The administration was performed by mixing with the feed. MF powdered feed (oriental Kobo Co.) was used as the basal diet and appropriate amounts of either sodium chloride were added to the basal diet.

Analytical verification of doses or concentrations:

no

Details on analytical verification of doses or concentrations:

not applicable

Duration of treatment / exposure:

2 years

Frequency of treatment:

daily

Doses / concentrations

Remarks:

Doses / Concentrations:
0.25% KCl, 1% KCl, 4% KCl, 4% NaCl and 2% KCl+2% NaCl
Basis:
nominal in diet

No. of animals per sex per dose:

50 rats/group

Control animals:

yes, plain diet

Details on study design:

- Dose selection rationale: not specified in the publication
- Rationale for animal assignment: not specified in the publication

Positive control:

not applicable

Examinations

Observations and examinations performed and frequency:

CAGE SIDE OBSERVATIONS: Yes
- Time schedule: daily

DETAILED CLINICAL OBSERVATIONS: No data

BODY WEIGHT: Yes
- Time schedule for examinations: not specified in the publication

FOOD CONSUMPTION: Yes
- Time schedule for examinations: not specified in the publication

HAEMATOLOGY: Yes
- Time schedule for collection of blood: at termination
- Anaesthetic used for blood collection: No data
- Animals fasted: data
- How many animals: all surviving animals
- Parameters examined: Red blood and white blood cell counts, hemoglobin, hematocrit, MCV, MCH, MCHC and platelets

CLINICAL CHEMISTRY: Yes
- Time schedule for collection of blood: at termination
- Animals fasted: No data
- How many animals: all surviving animals
- Parameters examined: GOT, GPT, ALP, LDH, CH-E, Na, K, Ca, NU, Clu, TP and Glu

URINALYSIS: Yes
- Time schedule for collection of urine: at termination
- Metabolism cages used for collection of urine: No data
- Animals fasted: No data
- Parameters examined: protein, glucose, ketone, bilirubin, urobilinogen, pH, occult blood and specific gravity

NEUROBEHAVIOURAL EXAMINATION: No

Sacrifice and pathology:

GROSS PATHOLOGY: Yes
HISTOPATHOLOGY: Yes

Other examinations:

Blood pressure measurements were performed 3 times, at 1 year, 1.5 year and 2 years.

Statistics:

Standard descriptive statistics were used.

Results and discussion

Results of examinations

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):

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

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, treatment-related

Description (incidence and severity):

Among non-tumorous lesions, nephrotic lesion was predominant in all groups, especially in the 4% NaCl group along with increased gastritis and ulcerative lesions of the stomach.

Histopathological findings: neoplastic:

no effects observed

Details on results:

At the end of the 2-year experimental period, the survival rates were 64%, 58%, 84%, 60%, 52% and 48% in 0.25% KCl, 1% KCl, 4% KCl, 4% NaCl, 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 KCl and 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.

Effect levels

Dose descriptor:

LOEL

Effect level:

4 other: per cent in the diet

Based on:

test mat.

Sex:

male

Basis for effect level:

other: Although not specified, the LOEL of sodium chloride was < 4% to rats, when administered over a period of two years and was based on overall effects noted during the study. (The calculated LOEL of sodium chloride is approximately 2533 mg/kg/day)

Target system / organ toxicity

Critical effects observed:

not specified

Any other information on results incl. tables

none

Applicant's summary and conclusion

Conclusions:

Based on the results of the study, NaCl was not considered carcinogenic when administered thorugh the diet to F344/Slc rats for a period of two years.

Executive summary:

Chronic toxicity tests of KCl and NaCl were carried out in male F344/Slc rats for two years. Each group consisted of 50 rats and each group was fed with 0.25% KCl, 1% KCl, 4% KCl, 4% NaCl, 2% KCl+2% NaCl.

At the end of the 2-year experimental period, the survival rates were 64%, 58%, 84%, 60%, 52% and 48% in 0.25% KCl, 1% KCl, 4% KCl, 4% NaCl, 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 KCl and NaCl. Among non-tumorous lesions, nephrotic lesion was predominant in all groups, especially in the 4% NaCl group, along with an increased incidence of gastritis and ulcerative lesions of the stomach. 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.