Registration Dossier

Diss Factsheets

Toxicological information

Repeated dose toxicity: oral

Currently viewing:

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-referenceopen allclose all
Reason / purpose for cross-reference:
reference to same study
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

Constituent 1
Chemical structure
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.

Categories Display