Registration Dossier

Administrative data

Endpoint:
sub-chronic toxicity: oral
Type of information:
migrated information: read-across from supporting substance (structural analogue or surrogate)
Adequacy of study:
key study
Reliability:
2 (reliable with restrictions)
Rationale for reliability incl. deficiencies:
other: Study published in a peer-reviewed journal, Read across

Data source

Reference
Reference Type:
publication
Title:
Unnamed
Year:
1990
Report date:
1990

Materials and methods

Test guideline
Qualifier:
equivalent or similar to guideline
Guideline:
OECD Guideline 408 (Repeated Dose 90-Day Oral Toxicity Study in Rodents)
Deviations:
not specified
Remarks:
. Study details are missing, but obviously performed in accordance with guideline.
GLP compliance:
not specified
Limit test:
no

Test material

Constituent 1
Reference substance name:
Monosodium succinate
IUPAC Name:
Monosodium succinate
Constituent 2
Reference substance name:
Sodium hydrogen succinate
EC Number:
220-871-2
EC Name:
Sodium hydrogen succinate
Cas Number:
2922-54-5
IUPAC Name:
sodium hydrogen succinate
Details on test material:
- Name of test material (as cited in study report): Monosodium succinate
- Analytical purity: 100.2 % (99.7-100.7 %)
- Producer: Mitsubishi Kasei Food Co. (Tokyo, Japan)
- Provider: Japan Food Additives Association (Tokyo, Japan)
- Stability under test conditions: The stability of a 2 % aqueous solution of the test substance was ascertained for at least one week at room temperature.

Test animals

Species:
rat
Strain:
Fischer 344
Sex:
male/female
Details on test animals or test system and environmental conditions:
TEST ANIMALS
- Source: Charles River Japan, Inc. (Kanagawa, Japan)
- Status: SPF
- Age at study initiation: 6 weeks
- Weight at study initiation: between 100 and 200 g, not reported (only growth curves available)
- Fasting period before study: none reported
- Diet: basal diet (CRF-1), Oriental Yeast Inc., Tokyo, Japan), ad lib.
- Water: distilled water (test substance dissolved in distilled water as drinking water)
- Acclimation period: one week

ENVIRONMENTAL CONDITIONS
- Temperature (°C): not reported
- Humidity (%): not reported
- Air changes (per hr): not reported
- Photoperiod (hrs dark / hrs light): not reported

Administration / exposure

Route of administration:
oral: drinking water
Vehicle:
water
Remarks:
distilled water
Details on oral exposure:
PREPARATION OF DOSING SOLUTIONS:
- Test substance dissolved in distilled water (vehicle), used as drinking water

VEHICLE
- Concentration in vehicle: 0, 0.3, 0.6, 1.25, 2.5, 5 and 10 %
- Justification for choice of vehicle: not reported
Analytical verification of doses or concentrations:
not specified
Duration of treatment / exposure:
13 weeks
Frequency of treatment:
daily / continuously (access to test substance solutions in drinking water ad lib.)
Doses / concentrations
Remarks:
Doses / Concentrations:
0, 0.3, 0.6, 1.25, 2.5, 5, 10 %
Basis:
nominal in water
No. of animals per sex per dose:
10
Control animals:
yes, concurrent vehicle
Details on study design:
Dose selection rationale: to find appropriate doses for a subsequent long-term toxicity/carcinogenicity study
Positive control:
Not appropriate

Examinations

Observations and examinations performed and frequency:
ANIMAL OBSERVATIONS: Yes
- Cage side/detailed clinical: not stated
- Time schedule: once daily

BODY WEIGHT: Yes
- Time schedule for examinations: every other week

WATER CONSUMPTION AND COMPOUND INTAKE (if drinking water study): Yes
- Time schedule for examinations: not reported

OPHTHALMOSCOPIC EXAMINATION: No data

HAEMATOLOGY: Yes
- Time schedule for collection of blood: at necropsy
- Animals fasted: No data
- How many animals: survivors

CLINICAL CHEMISTRY: Yes
- Time schedule for collection of blood: at necropsy
- Animals fasted: No data
- How many animals: survivors

URINALYSIS: No data

NEUROBEHAVIOURAL EXAMINATION: No data

OTHER:
Sacrifice and pathology:
GROSS PATHOLOGY: Yes
HISTOPATHOLOGY: Yes
Statistics:
None reported

Results and discussion

Results of examinations

Clinical signs:
effects observed, treatment-related
Description (incidence and severity):
100 % mortality at 10 % test substance
Mortality:
mortality observed, treatment-related
Description (incidence):
100 % mortality at 10 % test substance
Body weight and weight changes:
effects observed, treatment-related
Description (incidence and severity):
suppression of body-weight gain at >= 2.5 % test substance
Food consumption and compound intake (if feeding study):
not examined
Food efficiency:
not examined
Water consumption and compound intake (if drinking water study):
effects observed, treatment-related
Description (incidence and severity):
small at 10 %, larger than in other groups at 5 %
Ophthalmological findings:
not specified
Haematological findings:
no effects observed
Clinical biochemistry findings:
no effects observed
Urinalysis findings:
not specified
Behaviour (functional findings):
not specified
Organ weight findings including organ / body weight ratios:
not specified
Gross pathological findings:
effects observed, treatment-related
Description (incidence and severity):
emaciation in rats that died during the study
Histopathological findings: non-neoplastic:
no effects observed
Histopathological findings: neoplastic:
no effects observed

Effect levels

open allclose all
Dose descriptor:
NOAEL
Effect level:
12 500 mg/L drinking water
Based on:
dissolved
Sex:
male/female
Basis for effect level:
other: clinical signs; mortality; body weight; haematology; clinical chemistry; gross pathology; histopathology
Dose descriptor:
LOAEL
Effect level:
25 000 mg/L drinking water
Based on:
dissolved
Sex:
male/female
Basis for effect level:
other: body weight gain (suppressed)
Dose descriptor:
NOAEL
Effect level:
860 other: mg succinic acid / kg bw /day
Based on:
other: This NOEL (mg/kg bw/d) for succinic acid was calculated from the NOEL (mg/mL/d) for Na-succinate, the average body weight, the average water consumption, both taken from Figures 1 and 2 of the publication, and also from the different molecular masses.
Sex:
male
Dose descriptor:
NOAEL
Effect level:
990 other: mg succinic acid / kg bw /day
Based on:
other: This NOEL (mg/kg bw/d) for succinic acid was calculated from the NOEL (mg/mL/d) for Na-succinate, the average body weight, the average water consumption, both taken from Figures 1 and 2 of the publication, and also from the different molecular masses.
Sex:
female

Target system / organ toxicity

Critical effects observed:
not specified

Applicant's summary and conclusion

Conclusions:
On the basis of body-weight depression, the maximum tolerated dose of monosodium succinate was determined to be about 2-2.5 % when it was given in the drinking water. The NOAEL is 12.5 mg/mL drinking water/day.
The derived NOAEL for succinic acid, assuming that monosodium succinate and succinic acid dissociate completely in low concentrations, was calculated to 860 mg/kg/d for male rats and 990 mg/kg/d for female rats.
Executive summary:

Monosodium succinate was dissolved in distilled water which was given as drinking water to groups of 10 male and 10 female rats each for a period of 13 weeks. Substance concentrations in water were 0, 0.3, 0.6, 1.25, 2.5, 5 or 10 %. The rats were observed daily for clinical signs. Body weights were determined weekly. At the end of the study period, haematological and biochemical examinations were carried out and the survivors were killed for gross and microscopic examination.

Severe suppression of body weights occurred in rats in the highest dose group, and all of these rats died during the first 4 weeks of the experiment. All of the other animals survived until the end of the study. Suppression of body weight was found in groups given >= 2.5 % of test substance in the drinking water, and this suppression was >10 % in the groups given 5 or 10 % in comparison with the controls. The volume of drinking water consumed was very small in the highest dose group. No specific and dose-related changes were observed in any parameters in the haematological and biochemical investigations.

Rats that died during the study were severely emaciated. However, in the histopathological examination no toxic lesions caused by monosodium succinate was found in any organs of these rats, although atrophy of the organs was observed. In the other groups also, there were no specific lesions.

On the basis of body-weight depression, the maximum tolerated dose of monosodium succinate was determined to be about 2 -2.5 % when it was given in the drinking water.