Disodium succinate

Toxicity to reproduction

Administrative data

Endpoint:

one-generation reproductive toxicity

Type of information:

experimental study

Adequacy of study:

weight of evidence

Reliability:

2 (reliable with restrictions)

Rationale for reliability incl. deficiencies:

data from handbook or collection of data

Justification for type of information:

Data from secondary source

Data source

Reference

Reference 1

Reference Type:

other: j -check

Title:

Reproductive toxicity study of Disodium succinate hexahydrate

Author:

National Institute Of Technology and Evaluation

Year:

2018

Bibliographic source:

Japan Chemical Collaborative Knowledge Database, 2018

Reference 2

Reference Type:

secondary source

Title:

SIDS Initial Assessment Report For Disodium succinate hexahydrate

Author:

OECD SIDS

Year:

2003

Bibliographic source:

SIDS Initial Assessment Report For SIAM 16, 2003

Materials and methods

Test guideline

Qualifier:

equivalent or similar to guideline

Guideline:

OECD Guideline 422 (Combined Repeated Dose Toxicity Study with the Reproduction / Developmental Toxicity Screening Test)

Principles of method if other than guideline:

Reproductive toxicity evaluation of test chemical administered by gavage.

GLP compliance:

not specified

Limit test:

no

Justification for study design:

No data available

Test material

Test material information

Constituent 1

Reference substance name:

Disodium succinate hexahydrate

EC Number:

612-073-1

Cas Number:

6106-21-4

Molecular formula:

C4H6O4.6H2O.2Na

IUPAC Name:

Disodium succinate hexahydrate

Details on test material:

- Name of test material: Disodium succinate hexahydrate
- Molecular formula: C4H6O4.6H2O.2Na
- Molecular weight: 270.1404 g/mol
- Substance type: Organic
- Physical state: No data

Test animals

Species:

rat

Strain:

Crj: CD(SD)

Details on species / strain selection:

No data available

Sex:

male/female

Details on test animals or test system and environmental conditions:

No data available

Administration / exposure

Route of administration:

oral: gavage

Vehicle:

water

Remarks:

Water for injection

Details on exposure:

Details on exposure
PREPARATION OF DOSING SOLUTIONS:
Test materials dissolved in Water for injection
DIET PREPARATION
- Rate of preparation of diet (frequency):No data available
- Mixing appropriate amounts with (Type of food )
- Storage temperature of food: No data available
VEHICLE
- Justification for use and choice of vehicle (if other than water): Test material dissolved in Water for injection
- Concentration in vehicle: 0 (vehicle), 100, 300, 1000 mg/kg
- Amount of vehicle (if gavage):
- Lot/batch no. (if required): No data available
- Purity: No data available

Details on mating procedure:

No data available

Analytical verification of doses or concentrations:

not specified

Duration of treatment / exposure:

Males, 52 days
Females, from 14 days before mating to day 4 of lactation

Frequency of treatment:

Once daily

Details on study schedule:

No data available

Doses / concentrations

Remarks:

0 (vehicle), 100, 300, 1000 mg/kg

No. of animals per sex per dose:

Total:96
0 mg/kg bw/day:12 male and 12 female
100mg/kg bw/day:12 male and 12 female
300mg/kg bw/day:12 male and 12 female
1000 mg/kg bw/day:12 male and 12 female

Control animals:

yes, concurrent vehicle

Details on study design:

No data available

Positive control:

No data available

Examinations

Parental animals: Observations and examinations:

Parental animals observation and examinations
CAGE SIDE OBSERVATIONS: yes

DETAILED CLINICAL OBSERVATIONS:

Time schedule:

BODY WEIGHT: Yes
Time schedule for examinations:
FOOD CONSUMPTION AND COMPOUND INTAKE (if feeding study):.
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: Yes / No / No data: No data available


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

Oestrous cyclicity (parental animals):

yes

Sperm parameters (parental animals):

No data available

Litter observations:

STANDARDISATION OF LITTERS
- Performed on day 4 postpartum: [yes/no]
- If yes, maximum of [...] pups/litter ([...]/sex/litter as nearly as possible); excess pups were killed and discarded.

PARAMETERS EXAMINED
The following parameters were examined in [F1] offspring:
number and sex of pups, stillbirths, live births, postnatal mortality, presence of gross anomalies, weight gain, physical or behavioural abnormalities, were observed.
GROSS EXAMINATION OF DEAD PUPS: no
[no / yes, for external and internal abnormalities; possible cause of death was/was not determined for pups born or found dead.]

ASSESSMENT OF DEVELOPMENTAL NEUROTOXICITY:No

ASSESSMENT OF DEVELOPMENTAL IMMUNOTOXICITY:No

Postmortem examinations (parental animals):

Postmortem examinations (Parent Animal)
SACRIFICE:
Male animals: yes on 53 days
Female animals: yes on day 5 of lactation
All surviving animals [describe when, e.g. after the last litter of each generation was weaned :

GROSS NECROPSY: yes
HISTOPATHOLOGY / ORGAN WEIGHTS

Postmortem examinations (offspring):

SACRIFICE
- The F1 offspring were sacrificed at [5] days of age.
- These animals were subjected to postmortem examinations (macroscopic and/or microscopic examination) as follows:

GROSS NECROPSY
- Gross necropsy consisted of [external examinations ]

HISTOPATHOLOGY / ORGAN WEIGTHS : No
The tissues indicated in Table [#] were prepared for microscopic examination and weighed, respectively.

Statistics:

No data available

Reproductive indices:

Yes

Offspring viability indices:

yes

Results and discussion

Results: P0 (first parental generation)

General toxicity (P0)

Clinical signs:

no effects observed

Description (incidence and severity):

No treatment-related clinical signs were observed

Dermal irritation (if dermal study):

not specified

Mortality:

no mortality observed

Description (incidence):

No deaths were observed in any treatment group in either sex

Body weight and weight changes:

not specified

Food consumption and compound intake (if feeding study):

not specified

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

Immunological findings:

not specified

Organ weight findings including organ / body weight ratios:

not specified

Histopathological findings: non-neoplastic:

not specified

Histopathological findings: neoplastic:

not specified

Other effects:

not specified

Reproductive function / performance (P0)

Reproductive function: oestrous cycle:

no effects observed

Description (incidence and severity):

No adverse effects were observed in terms of the estrus cycle.In the observation of estrous cycle, there was no intergroup difference in the mean estrous cycle. The abnormal estrous cycle was observed in 1 animal each in the 100 and 1000 mg/kg groups. There was no intergroup difference in the incidence of abnormal estrous cycle.

Reproductive function: sperm measures:

not specified

Reproductive performance:

no effects observed

Description (incidence and severity):

Copulation and conception were all established, and both the copulation index and the fertility index were 100% in all groups.The gestation period was significantly shortened in the 100 and 1000 mg/kg groups compared with the control group. There was no abnormality in the conditions of parturition, and the numbers of corpora lutea, implantation sites, delivered offspring and live delivered offspring showed almost the same values. There were no intergroup differences in the delivery index, implantation index, parturition index, live birth index, sex ratio and viability index of neonates on day 4 of lactation

Effect levels (P0)

Dose descriptor:

NOAEL

Effect level:

1 000 mg/kg bw/day (nominal)

Based on:

test mat.

Sex:

male/female

Basis for effect level:

clinical signs

mortality

reproductive function (oestrous cycle)

reproductive performance

Remarks on result:

other: No effects on reproductive performance

Target system / organ toxicity (P0)

Critical effects observed:

not specified

System:

other: not specified

Organ:

not specified

Treatment related:

not specified

Dose response relationship:

not specified

Relevant for humans:

not specified

Results: F1 generation

General toxicity (F1)

Clinical signs:

no effects observed

Description (incidence and severity):

No treatment-related clinical signs were observed

Dermal irritation (if dermal study):

not specified

Mortality / viability:

no mortality observed

Body weight and weight changes:

no effects observed

Description (incidence and severity):

Body weight during lactation period was significantly low on days 0 and 4 of lactation in males and day 4 in females in the 100 mg/kg group and on day 4 in males in the 300 mg/kg group, which was the change not associated with the dose.

Food consumption and compound intake (if feeding study):

not specified

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

Sexual maturation:

no effects observed

Organ weight findings including organ / body weight ratios:

not specified

Gross pathological findings:

no effects observed

Description (incidence and severity):

No abnormal findings related to the test substance were noted on external examination,

Histopathological findings:

not specified

Other effects:

not specified

Developmental neurotoxicity (F1)

Behaviour (functional findings):

not specified

Developmental immunotoxicity (F1)

Developmental immunotoxicity:

not specified

Effect levels (F1)

Dose descriptor:

NOAEL

Generation:

F1

Effect level:

1 000 mg/kg bw/day (nominal)

Based on:

test mat.

Sex:

not specified

Basis for effect level:

viability

sexual maturation

clinical signs

mortality

body weight and weight gain

gross pathology

Remarks on result:

other: overall no effects on developmental parameters

Target system / organ toxicity (F1)

Critical effects observed:

not specified

System:

other: not specified

Organ:

not specified

Treatment related:

not specified

Dose response relationship:

not specified

Relevant for humans:

not specified

Overall reproductive toxicity

Reproductive effects observed:

not specified

Treatment related:

not specified

Relation to other toxic effects:

not specified

Dose response relationship:

not specified

Relevant for humans:

not specified

Applicant's summary and conclusion

Conclusions:

No Observed Adverse Effect Level (NOAEL) for maternal and foetal toxicity was considered to be 1000mg/kg/day. When male and female Crj: CD(SD) rats treated with test chemical orally.

Executive summary:

The one generation reproductive toxicity study of test chemical was performed in male and femaleCrj: CD(SD) rats. The test material was dissolved in Water for injection and administered in dose concentration 0 (vehicle), 100, 300, 1000 mg/kg to Males for 52 days and Females from 14 days before mating to day 4 of lactation. Each dose group contain 12 male and 12 female. All the animals were observed for clinical signs and body weight changes. Males were scarified on day 53 while females were killed on day 5 of lactation.

No treatment-related clinical signs were observed in parents as well as offspring.No deaths were observed in any treatment group in either sex. Copulation and conception were all established, and both the copulation index and the fertility index were 100% in all groups. In the observation of estrous cycle, there was no intergroup difference in the mean estrous cycle. The abnormal estrous cycle was observed in 1 animal each in the 100 and 1000 mg/kg groups. There was no intergroup difference in the incidence of abnormal estrous cycle. The gestation period was significantly shortened in the 100 and 1000 mg/kg groups compared with the control group. There was no abnormality in the conditions of parturition, and the numbers of corpora lutea, implantation sites, delivered offspring and live delivered offspring showed almost the same values. There were no intergroup differences in the delivery index, implantation index, parturition index, live birth index, sex ratio and viability index of neonates on day 4 of lactation. Body weight during lactation period was significantly low on days 0 and 4 of lactation in males and day 4 in females in the 100 mg/kg group and on day 4 in males in the 300 mg/kg group, which was the change not associated with the dose.No abnormal findings related to the test substance were noted on external examination. HenceNo Observed Adverse Effect Level (NOAEL) for maternal and foetal toxicity was considered to be 1000mg/kg/day.When male and female  Crj: CD(SD) rats treated with test chemical orally.