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Toxicological information

Repeated dose toxicity: oral

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Administrative data

Endpoint:
sub-chronic toxicity: oral
Type of information:
experimental study
Adequacy of study:
key study
Study period:
1978
Reliability:
2 (reliable with restrictions)
Rationale for reliability incl. deficiencies:
other: Study without detailed documentation.

Data source

Reference
Reference Type:
study report
Title:
Unnamed
Year:
1978

Materials and methods

Test guideline
Qualifier:
equivalent or similar to
Guideline:
OECD Guideline 408 (Repeated Dose 90-Day Oral Toxicity in Rodents)
Deviations:
yes
Remarks:
-Data on concentration verification and stability of test solution, levels of hematocrit, urea, and creatinine not provided. Histopathology not conducted on aorta, trachea, lymph nodes, spinal cord, parathyroid, oesophagus, and skin. No individual data.
GLP compliance:
no
Remarks:
Study pre-dates GLP requirements.
Limit test:
no

Test material

Reference
Name:
Unnamed
Type:
Constituent
Details on test material:
- Name of test material (as cited in study report): Glucono delta lactone
- Physical state: Solid (White crystalline powder)
- Analytical purity: The substance conformed with the specifications of Japan's Specifications and Standards for Food Additives (99.0%).
- Lot/batch No.: Not reported
- Expiration date of the lot/batch: Not reported
- Stability under test conditions: Not reported
- Storage condition of test material: Not reported

Test animals

Species:
rat
Strain:
other: JCL:SD
Sex:
male/female
Details on test animals and environmental conditions:
TEST ANIMALS
- Source: Not reported
- Age at study initiation: 6 weeks
- Weight at study initiation: 100 to 200 g
- Fasting period before study: Not reported
- Housing: One rat per cage
- Diet (e.g. ad libitum): Solid feed, ad libitum
- Water (e.g. ad libitum): Given water ad libitum by the equipment for supplying water automatically.
- Acclimation period: Not reported


ENVIRONMENTAL CONDITIONS
- Temperature (°C): 21 to 23
- Humidity (%): 70 to 75
- Air changes (per hr): Not reported
- Photoperiod (hrs dark / hrs light): Not reported

Administration / exposure

Route of administration:
oral: gavage
Vehicle:
other: Distilled water
Details on oral exposure:
PREPARATION OF DOSING SOLUTIONS: Not reported


VEHICLE
- Justification for use and choice of vehicle (if other than water): Distilled water was used.
- Concentration in vehicle: See Table 1
- Amount of vehicle (if gavage): See Table 1
- Lot/batch no. (if required): Not reported
- Purity: Not reported
Analytical verification of doses or concentrations:
not specified
Details on analytical verification of doses or concentrations:
No data
Duration of treatment / exposure:
6 months
Frequency of treatment:
daily
Doses / concentrations
Remarks:
Doses / Concentrations:
250, 500, 1000, 2000, and 4000 mg/kg body weight
Basis:
actual ingested
No. of animals per sex per dose:
10 animals/sex/dose
Control animals:
yes, concurrent vehicle
Details on study design:
- Dose selection rationale: Not reported
- Rationale for animal assignment (if not random): Not reported
- Section schedule rationale (if not random): Not reported
Positive control:
Positive control was not included in the study.

Examinations

Observations and examinations performed and frequency:
CAGE SIDE OBSERVATIONS: Yes
- Time schedule: Twice (one hour and 24 hours after dosing)


DETAILED CLINICAL OBSERVATIONS: No data


BODY WEIGHT: Yes
- Time schedule for examinations: Once or twice per week


FOOD CONSUMPTION AND COMPOUND INTAKE (if feeding study): Weekly food consumption was monitored and reported.
- Food consumption for each animal determined and mean daily diet consumption calculated as g food/kg body weight/day: No data
- Compound intake calculated as time-weighted averages from the consumption and body weight gain data: No data


FOOD EFFICIENCY:
- Body weight gain in kg/food consumption in kg per unit time X 100 calculated as time-weighted averages from the consumption and body weight gain data: No data


WATER CONSUMPTION AND COMPOUND INTAKE (if drinking water study): No data


OPHTHALMOSCOPIC EXAMINATION: No data


HAEMATOLOGY: Yes
- Time schedule for collection of blood: At the end of the treatment period.
- Anaesthetic used for blood collection: No data
- Animals fasted: No data
- How many animals: No data
- Parameters checked in Attached File 1 (Table 4) were examined.


CLINICAL CHEMISTRY: Yes
- Time schedule for collection of blood: At the end of the treatment period.
- Animals fasted: No data
- How many animals: No data
- Parameters checked in Attached File 1 (Table 5) were examined.


URINALYSIS: Yes
- Time schedule for collection of urine: At 1, 3, and 6 months.
- Metabolism cages used for collection of urine: No data
- Animals fasted: No data
- Parameters checked in Attached File 1 (Tables 3-a and 3-b) were examined.


NEUROBEHAVIOURAL EXAMINATION: No data
- Time schedule for examinations: No data
- Dose groups that were examined: No data
- Battery of functions tested: sensory activity / grip strength / motor activity / other: No data

Sacrifice and pathology:
GROSS PATHOLOGY: Yes
HISTOPATHOLOGY: Yes (See Attached File 2, Tables 8-a, 8-b, and 8-c)
Other examinations:
Organ weights: Yes (see Attached File 1, Tables 6 and 7)
Statistics:
By Student's t-test or Cochram-Cox test

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 specified
Water consumption and compound intake (if drinking water study):
not specified
Ophthalmological findings:
not specified
Haematological findings:
no effects observed
Clinical biochemistry findings:
effects observed, treatment-related
Urinalysis findings:
no effects observed
Behaviour (functional findings):
not specified
Organ weight findings including organ / body weight ratios:
no effects observed
Gross pathological findings:
not specified
Histopathological findings: non-neoplastic:
effects observed, treatment-related
Histopathological findings: neoplastic:
not specified
Details on results:
CLINICAL SIGNS AND MORTALITY: No deaths or signs of clinical abnormality were observed in any of groups.


BODY WEIGHT AND WEIGHT GAIN: See Attached File 1 Figures 1-a and 1-b. All animals gained body weight and no significant differences in mean body weights were observed between the treated and control groups for males and females.


FOOD CONSUMPTION AND COMPOUND INTAKE (if feeding study): See Attached File 1 Table 2. No dose-dependent compound-related effects on food consumption was observed.


FOOD EFFICIENCY: No data


WATER CONSUMPTION AND COMPOUND INTAKE (if drinking water study): No data


OPHTHALMOSCOPIC EXAMINATION: No data


HAEMATOLOGY: See Attached File 1 Table 4. Significant changes observed were sporadic, not dose-dependent, and occurred in one sex only, and therefore, were considered not-compound related. These changes included increased neutrophil levels in females dosed with 4000 mg/kg body weight/day and decreased monocyte levels in males dosed with 4000 mg/kg body weight/day. No other statistically significant changes were observed between treated and control groups.


CLINICAL CHEMISTRY: See Attached File 1 Table 5. Significant changes in males included increased albumin levels and decreased total cholesterol levels in the 1000, 2000, and 4000 mg/kg body weight/day groups. Significantly decreased blood urea nitrogen levels were also observed in males dosed at 4000 mg/kg body weight/day. All changes in males appeared to be dose-dependent. In females, significant changes observed were sporadic and not dose-dependent. These changes included increased blood urea nitrogen levels in the 250 mg/kg body weight/day group, decreased alanine aminotransferase activity levels in the 1000 mg/kg body weight/day group, decreased calcium levels in the 4000 mg/kg body weight/day group, and increased alkaline phosphatase activity levels in the 4000 mg/kg body weight/day group. No other dose-dependent statistically significant changes were observed between treated and control groups.

URINALYSIS: See Attached File 1 Tables 3-a and 3-b. No dose-dependent statistically significant changes were observed between treated and control groups.


NEUROBEHAVIOUR: No data


ORGAN WEIGHTS: See Attached File 1 Tables 6 and 7. Significant changes observed were sporadic, not dose-dependent, and occurred in one sex only, and therefore, were considered not compound related. In males, these changes included decreased absolute thymus weight in the 4000 mg/kg body weight/day group, decreased relative thymus weight in the 1000 mg/kg body weight/day group, and decreased relative thyroid and testes weights in the 250 mg/kg body weight/day group. In females, changes included increased absolute heart weight in the 1000 mg/kg body weight/day group, increased relative spleen weight in the 4000 mg/kg body weight/day group, and increased relative kidney weights in the 2000 mg/kg body weight/day group. No other statistically significant changes were observed between treated and control groups.


GROSS PATHOLOGY: No data


HISTOPATHOLOGY: NON-NEOPLASTIC: Dose-dependent increase in frequency and severity of hypertrophy of stratified squamous epithetlium in the stomach; observed in all groups dosed with glucono-delta-lactone. In 3 male rats and 1 female rat at 4000 mg/kg body weight/day and 1 female rat at 500 mg/kg body weight/day, inflammatory cellular infiltration under mucous membrane was observed. But their degree was not severe. It was considered that this lesion occurred by stimulus of glucono-delta-lactone.


HISTOPATHOLOGY: NEOPLASTIC (if applicable): No data


HISTORICAL CONTROL DATA (if applicable): No data


OTHER FINDINGS: No data

Effect levels

Dose descriptor:
other: NOAEL not reported
Basis for effect level:
other: NOAEL was not reported by authors
Remarks on result:
not measured/tested
Remarks:
Effect level not specified (migrated information)

Target system / organ toxicity

Critical effects observed:
not specified

Applicant's summary and conclusion

Executive summary:

The authors of this study reported that compound-related effects were observed in the stomach of rats and consisted of thickening of the stratified squamous epithelieum at the anterior stomach, which is perceived to pertain to the rat forestomach. The area particularly affected was the transitional area continuous with the pyloric stomach, which is consistent with a description of the limiting ridge. The effect was observed in all dose groups and was reported with dose-dependency in frequency and severity, and therefore, a NOAEL for glucono delta lactone could not be determined based on the results of this study. However, given that the forestomach and limiting ridge are structures unique to the rodent, the effects observed in the stomach of rats in this study are not relevant to humans. It should be noted that the results reported herein were taken from a partial English translation of a study report written in Japanese.