Disodium succinate

Endpoint summary

Description of key information

Repeated dose toxicity: Oral

The NOAEL  was considered to be 2500 mg/kg/day) when Sprague Dawley male rats were treated with test substance.

Repeated dose toxicity: Inhalation

Disodium succinate has a particle size distribution of 53-150 micron, so the potential for the generation of inhalable vapours is very low. Also the normal conditions of use of this substance will not result in aerosols, particles or droplets of an inhalable size, so exposure to humans via the inhalatory route will be highly unlikely and therefore this end point for repeated dose toxicity by inhalation route is considered for waiver.

Repeated dose toxicity: Dermal

The acute toxicity value for Disodum succinate (150-90-3) (as provided in section 7.2.3) is >2000 mg/kg body weight. Also, given the use of the chemical; repeated exposure by the dermal route is unlikely since the use of gloves is common practice in industries. Thus, it is expected that 2 Disodum succinate shall not exhibit 28 day repeated dose toxicity by the dermal route. In addition, there is no data available that suggests that Disodum succinate shall exhibit repeated dose toxicity by the dermal route. Hence this end point was considered for waiver.

Key value for chemical safety assessment

Repeated dose toxicity: via oral route - systemic effects

Link to relevant study records

Reference

Endpoint:

sub-chronic toxicity: oral

Type of information:

experimental study

Adequacy of study:

key study

Reliability:

2 (reliable with restrictions)

Rationale for reliability incl. deficiencies:

data from handbook or collection of data

Justification for type of information:

Data is from peer reviewed journal

Qualifier:

according to guideline

Guideline:

other: Refer below principle

Principles of method if other than guideline:

Subacute oral toxicity study was performed for the test chemical using rats.

GLP compliance:

not specified

Species:

rat

Strain:

Sprague-Dawley

Details on species / strain selection:

No data

Sex:

male

Details on test animals or test system and environmental conditions:

- Age at study initiation: weanling rats
- Weight at study initiation: 32-38 g
- Fasting period before study: No data available
- Housing: housed individually in metal cages with raised wire screens
- Diet (e.g. ad libitum): Basal diet ad libitum
- Water (e.g. ad libitum): Water ad libitum
- Acclimation period: No data available

ENVIRONMENTAL CONDITIONS
- Temperature (°C): Regulated
- Humidity (%):No data available
- Air changes (per hr): No data available
- Photoperiod (hrs dark / hrs light): No data available

IN-LIFE DATES: From: To: No data available

Route of administration:

oral: feed

Details on route of administration:

No data

Vehicle:

other: Basal diet

Details on oral exposure:

PREPARATION OF DOSING SOLUTIONS: Dose was prepared by adding 5 or 10% (5000 or 10000 mg/Kg) of Sodium succinate to the basal diet at the expense of an equivalent amount of glucose.

DIET PREPARATION
- Rate of preparation of diet (frequency): No data available
- Mixing appropriate amounts with (Type of food): Basal diet
- Storage temperature of food: No data available

VEHICLE
- Justification for use and choice of vehicle (if other than water): Basal diet
- Concentration in vehicle: 0, 5 and 10 % (0, 5000 or 10000 mg/Kg)
- Amount of vehicle (if gavage): No data available
- Lot/batch no. (if required): No data available
- Purity: No data available

Analytical verification of doses or concentrations:

not specified

Details on analytical verification of doses or concentrations:

No data

Duration of treatment / exposure:

7 weeks

Frequency of treatment:

Daily

Remarks:

Doses / Concentrations:
0, 5 and 10 % (0, 2500 and 5000 mg/kg/day)

No. of animals per sex per dose:

Total: 30
0 % : 10 male
5 % : 10 male
10 % : 10 male

Control animals:

yes, concurrent vehicle

Details on study design:

- Dose selection rationale: No data available
- Rationale for animal assignment (if not random): Animal were assignment to group on the basis of mean body weight and a similar weight distribution in each group (RGB design).
- Rationale for selecting of satellite groups: No data available
- Post-exposure recovery period in satellite groups: No data available
- Section schedule rationale (if not random): No data available

Positive control:

No data

Observations and examinations performed and frequency:

CAGE SIDE OBSERVATIONS: Yes
Time schedule: Daily
- Cage side observations checked in table [No.?] were included: Mortality was observed.

DETAILED CLINICAL OBSERVATIONS: No data available
- Time schedule: No data available

BODY WEIGHT: Yes
- Time schedule for examinations: Weekly intervals

FOOD CONSUMPTION AND COMPOUND INTAKE (if feeding study): Yes
- Food consumption for each animal determined and mean daily diet consumption calculated as g food/kg body weight/day: Yes

- Compound intake calculated as time-weighted averages from the consumption and body weight gain data: No data available

FOOD EFFICIENCY: No data available
- 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 available

WATER CONSUMPTION AND COMPOUND INTAKE (if drinking water study): No data No data available
- Time schedule for examinations: No data available

OPHTHALMOSCOPIC EXAMINATION: No data No data available
- Time schedule for examinations: No data available
- Dose groups that were examined: No data available

HAEMATOLOGY: No data No data available
- Time schedule for collection of blood: No data available
- Anaesthetic used for blood collection: Yes (identity) / No / No data No data available
- Animals fasted: Yes / No / No data No data available
- How many animals: No data available
- Parameters checked in table [No.?] were examined. No data available

CLINICAL CHEMISTRY: No data No data available
- Time schedule for collection of blood: No data available
- Animals fasted: Yes / No / No data No data available
- How many animals: No data available
- Parameters checked in table [No.?] were examined. No data available

URINALYSIS: No data No data available
- Time schedule for collection of urine: No data available
- Metabolism cages used for collection of urine: Yes / No / No data No data available
- Animals fasted: Yes / No / No data No data available
- Parameters checked in table [No.?] were examined. No data available

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

Sacrifice and pathology:

No data available

Other examinations:

No data available

Statistics:

No data available

Clinical signs:

not specified

Description (incidence and severity):

Clinical signs: No data available

Mortality:

no mortality observed

Description (incidence):

No effect were observed on survival of treated rats as compared to control.

Body weight and weight changes:

effects observed, treatment-related

Description (incidence and severity):

Slight decrease in weight gain was observed in 5 and 10 % treated rat as compared to control.

Food consumption and compound intake (if feeding study):

no effects observed

Description (incidence and severity):

No effect was observed on food consumption of treated rat as compared to control.

Food efficiency:

not specified

Water consumption and compound intake (if drinking water study):

not specified

Ophthalmological findings:

not specified

Haematological findings:

not specified

Clinical biochemistry findings:

not specified

Urinalysis findings:

not specified

Behaviour (functional findings):

not specified

Organ weight findings including organ / body weight ratios:

not specified

Gross pathological findings:

not specified

Neuropathological findings:

not specified

Histopathological findings: non-neoplastic:

not specified

Histopathological findings: neoplastic:

not specified

Other effects:

not specified

Details on results:

Although addition of 5 or 10% sodium succinate led to a slight decrease in weight gain it had no effect on survival time of the treated animals

Dose descriptor:

NOAEL

Effect level:

2 500 mg/kg bw/day (actual dose received)

Based on:

test mat.

Sex:

male

Basis for effect level:

other: Slight decrease in body weight gain was observed

Remarks on result:

other: No toxic effects were observed

Critical effects observed:

not specified

Conclusions:

The NOAEL was considered to be 2500 mg/kg/day) when Sprague Dawley male rats were treated with test substance.

Executive summary:

Subacute oral toxicity study was performed for the test chemical using weanling male Sprague Dawley rats deficient in biotin. The test chemical was mixed with feed at dose level of 0, 5 or 10% (0, 2500 or 5000 mg/Kg). The animals were fed the diet containing the test chemical for 7 weeks. Body weights were recorded at about weekly intervals. The animals were observed for Survival time. Slight decrease in weight gain was observed in 5 and 10 % treated rat as compared to control it had no effect on survival time of the treated rats. Based on the observations made, the NOAEL for test chemical was considered to be 2500 mg/Kg/day.

Endpoint conclusion

Endpoint conclusion:

no adverse effect observed

Dose descriptor:

NOAEL

2 500 mg/kg bw/day

Study duration:

subacute

Species:

rat

Quality of whole database:

Data is from peer reviewed publication

Repeated dose toxicity: inhalation - systemic effects

Link to relevant study records

Reference

Endpoint:

repeated dose toxicity: inhalation

Data waiving:

other justification

Justification for data waiving:

other:

Critical effects observed:

not specified

Endpoint conclusion

Endpoint conclusion:

no study available

Quality of whole database:

Waiver

Repeated dose toxicity: inhalation - local effects

Endpoint conclusion

Endpoint conclusion:

no study available

Repeated dose toxicity: dermal - systemic effects

Link to relevant study records

Reference

Endpoint:

repeated dose toxicity: dermal, other

Data waiving:

other justification

Justification for data waiving:

other:

Critical effects observed:

not specified

Endpoint conclusion

Endpoint conclusion:

no study available

Quality of whole database:

Waiver

Repeated dose toxicity: dermal - local effects

Endpoint conclusion

Endpoint conclusion:

no study available

Additional information

Data available for the target chemical was reviewed to determine the toxic nature of Disodum succinate (150-90-3). The studies are as mentioned below:

 

Repeated dose toxicity: Oral

In Combined repeated dose & carcinogenicity study F344 male rats were treated with test substance in concentration of 0 and 5% (0 and 5000 mg/kg/day) orally in diet. The treated animals were observed body weight, food and water consumption changes weekly. For urinary electrolyte analysis, samples of urine were obtained from the five rats used for labeling index evaluation in each group. For urine collection, rats were housed individually in metabolic cages without food or water for 4 h in the morning. Sodium, potassium and chloride were analyzed. Five rats received a single i.p. injection of BrdU at a dose of 50 mg/kg body wt 1 h before death. Then the urinary bladders were excised, inflated and fixed in 10% phosphate- buffered formalin and embedded in paraffin. Epithelial cells incorporating BrdU were demonstrated in histological sections by the avidin-biotin-peroxidase complex imrnunomstochemical method (20) with anb-BrdU monoclonal antibody. Numbers of labeled cells per 1000 cells were counted by light microscopy and labeling indices were expressed as percentage values. The urinary bladders of five rats from each group were inflated with 2% glutaraldehyde in 0.1 M cacodylate buffer and divided in half longitudinally. One half was processed for light microscopy and the other half for SEM. The ephhelia of 40 urinary bladders (10 rats in each group) were stripped off, suspended in 0.5 ml of 50 mM Tris (pH 7.5) containing 0.25 M sucrose, and disrupted by sonication for 30 s (Sonifer). In each group, the epithelia from two rats were pooled as one sample. The sonicated suspensions were centrifuged at 100 000 g for 30 min and the supernatant was assayed for SAT activity by measurement of the amount of acetyl moiety transferred from [l-14C]acetyl coenzyme A to spermidine. Hematuria, significantly increased urinary pH, sodium ion concentration and significantly decreased concentrations of potassium and chloride was observed in treated rat as compared to control. The concentrations of calcium and phosphorus showed no consistent pattern of differences relative to the controls. No Necrotic lesions were observed in treated rat. Simple hyperplasia was observed in treated rat. The luminal surfaces of the urinary bladder epithelial cells in rats given the sodium salts were covered with ropy or Jeafy microridges and short, uniform microvilli. The grading of cell surface alterations in rats treated with 2Na-Suc was higher. Pleomorphic microvilli were occasionally observed on the urinary bladder epithelial cell surfaces of rats treated with 2Na-Suc. Significantly increased in BrdU uptake was observed in treated rat. Increased levels of SAT in urinary bladder epithelium of treated rats were observed as compared to control. Based on the observations made, the lowest-observed-adverse-effect level (LOAEL) for test substance is considered to be 5 % (5000 mg/Kg/day) when F344 male rat treated with the test chemical  for 8 weeks.

 

Supported by other study. Subacute oral toxicity study was performed for the test chemical using weanling male Sprague Dawley rats deficient in biotin. The test chemical was mixed with feed at dose level of 0, 5 or 10% (0, 2500 or 5000 mg/Kg). The animals were fed the diet containing the test chemical for 7 weeks. Body weights were recorded at about weekly intervals. The animals were observed for Survival time. Slight decrease in weight gain was observed in 5 and 10 % treated rat as compared to control it had no effect on survival time of the treated rats. Based on the observations made, the NOAEL for test chemical was considered to be 5000 mg/Kg/day.

 

 

Repeated dose toxicity: Inhalation

Disodium succinate has a particle size distribution of 53-150 micron, so the potential for the generation of inhalable vapours is very low. Also the normal conditions of use of this substance will not result in aerosols, particles or droplets of an inhalable size, so exposure to humans via the inhalatory route will be highly unlikely and therefore this end point for repeated dose toxicity by inhalation route is considered for waiver.

Repeated dose toxicity: Dermal

The acute toxicity value for Disodum succinate (150-90-3) (as provided in section 7.2.3) is >2000 mg/kg body weight. Also, given the use of the chemical; repeated exposure by the dermal route is unlikely since the use of gloves is common practice in industries. Thus, it is expected that 2 Disodum succinate shall not exhibit 28 day repeated dose toxicity by the dermal route. In addition, there is no data available that suggests that Disodum succinate shall exhibit repeated dose toxicity by the dermal route. Hence this end point was considered for waiver.

 

Disodium succinate is considered to be toxic at high doses as high as 5000 mg/Kg. However, the estimated daily per capita intake on the basis of "Maximised Survey-derived Daily Intake” (MSDI) appraoch ( EFSA Journal 2011; 9(7):2164) is 1500 µg/person/day. Based on these considerations and from the data available from the read across chemical, Disodium succinate is considered to be safe at low dose levels of use.

Justification for classification or non-classification

Disodium succinate is considered to be toxic at high doses as high as 5000 mg/Kg. However, the estimated daily per capita intake on the basis of "Maximised Survey-derived Daily Intake” (MSDI) appraoch ( EFSA Journal 2011; 9(7):2164) is 1500 µg/person/day. Based on these considerations and from the data available from the read across chemical, Disodium succinate is considered to be safe at low dose levels of use.