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Toxicological information

Toxicity to reproduction

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Administrative data

Endpoint:
screening for reproductive / developmental toxicity
Type of information:
experimental study
Adequacy of study:
key study
Study period:
2002
Reliability:
2 (reliable with restrictions)
Rationale for reliability incl. deficiencies:
guideline study with acceptable restrictions
Justification for type of information:
Succinic acid is one of the suspected degradation products and can be used as an indicator of possible effects from metabolites. The data shows that this possible metabolite is not considered to be mutagenic.

Data source

Reference
Reference Type:
review article or handbook
Title:
Unnamed
Year:
2003
Report Date:
2002

Materials and methods

Test guideline
Qualifier:
according to
Guideline:
OECD Guideline 422 (Combined Repeated Dose Toxicity Study with the Reproduction / Developmental Toxicity Screening Test)
GLP compliance:
yes

Test material

Reference
Name:
Unnamed
Type:
Constituent
Test material form:
solid: crystalline
Specific details on test material used for the study:
Test substance: disodium succinate hexahydrate (CAS No. 6106-21-4),Nippon Shokubai Co., Ltd., Purity 99.9%, Lot No. 9P01B

Test animals

Species:
rat
Strain:
Crj: CD(SD)
Sex:
male/female

Administration / exposure

Route of administration:
oral: gavage
Vehicle:
not specified
Duration of treatment / exposure:
Males; for 52 daysFemales; from 14 days before mating to day 4 of lactation
Frequency of treatment:
Once daily
Doses / concentrationsopen allclose all
Dose / conc.:
0 mg/kg bw/day
Dose / conc.:
100 mg/kg bw/day
Dose / conc.:
300 mg/kg bw/day
Dose / conc.:
1 000 mg/kg bw/day
No. of animals per sex per dose:
No. of animals/group: males 12, females 12
Control animals:
yes, concurrent vehicle

Examinations

Parental animals: Observations and examinations:
Clinical observations
Litter observations:
Yes

Results and discussion

Results: P0 (first parental generation)

General toxicity (P0)

Clinical signs:
no effects observed
Mortality:
no mortality observed
Body weight and weight changes:
no effects observed

Reproductive function / performance (P0)

Reproductive function: oestrous cycle:
no effects observed

Details on results (P0)

Copulation and fertility: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.Parturition and lactation: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)
Remarks on result:
not determinable due to absence of adverse toxic effects

Target system / organ toxicity (P0)

Critical effects observed:
no

Results: F1 generation

General toxicity (F1)

Clinical signs:
effects observed, non-treatment-related
Description (incidence and severity):
In the external examination in neonates, anophthalmia and polydactyly were observed in 1 animal each in the 300 mg/kg group.
Body weight and weight changes:
effects observed, non-treatment-related
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.

Details on results (F1)

In the necropsy on day 4 of lactation, red patches on the plantar were observed in 15 males and 13 females in the 100 mg/kg group, and the number of occurrences significantly increased in both males and females compared with the control group. However, this finding occurred in litters in 2 broods in both males and females. In addition, dilation of the ureter was observed in 3, 4 and 3 males and 5, 1 and 2 females in the 100, 300 and 1000 mg/kg groups, respectively, and the number of occurrences significantly increased in the male 100 mg/kg group. However, dilation of the ureter in the female 100 mg/kg group was observed in litters in 4 of 5 animals. Other findings included thymic remnant in the neck in 3, 1, 2 and 3 male animals in the control, 100, 300 and 1000 mg/kg groups and in 1, 2 and 2 female animals in the control, 100 and 300 mg/kg groups, nodes in the liver in 1 animal each in the male and female 1000 mg/kg groups, white patches in the liver in 1 animal in the male 100 mg/kg group, pyelectasia in 3 animals each in the male 100, 300 and 1000 mg/kg groups and in 2 and 1 animal in the female 300 and 1000 mg/kg groups, anophthalmia in 1 animal in the female 300 mg/kg group, cysts in the hindlimbs in 1 animal in the female 100 mg/kg group and polydactyly in 1 animal in the female 300 mg/kg group.

Effect levels (F1)

Dose descriptor:
NOAEL
Generation:
F1
Effect level:
>= 1 000 mg/kg bw/day (nominal)
Based on:
test mat.
Sex:
not specified
Remarks on result:
not determinable due to absence of adverse toxic effects

Target system / organ toxicity (F1)

Critical effects observed:
no

Overall reproductive toxicity

Reproductive effects observed:
no

Applicant's summary and conclusion

Conclusions:
There is no evidence that disodium succinate has reproductive/developmental toxicity in rats. The NOAEL for reproduction/developmental toxicity wasconsidered to be 1000 mg/kg bw/day as disodium succinate hexahydrate (600 mg/kg bw/day as disodium succinate.
Executive summary:

In a combined repeated dose toxicity study with the reproduction/developmental toxicity screening test [OECD TG 422], Crj: CD (SD) IGS rats were given disodium succinate hexahydrate by gavage at 0, 100, 300, or 1,000 mg/kg bw/day. Males were dosed for 52 days from day 14 before mating and females were dosed from day 14 before mating to day 4 of lactation throughout the mating and pregnancy period. The study showed that the reproduction/developmental parameters, i.e., mating, pregnancy, delivery, lactation, and viability and body weight of pups, were not affected by disodium succinate hexahydrate at up to 1,000 mg/kg bw/day. The NOAEL of disodium succinate hexahydrate for reproduction/developmental toxicity was considered to be 1,000 mg (highest dose tested, equivalent to 600 mg of disodium succinate)/kg bw/day in rats.