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Toxicological information

Toxicity to reproduction

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Administrative data

Endpoint:
one-generation reproductive toxicity
Remarks:
based on test type (migrated information)
Type of information:
migrated information: read-across from supporting substance (structural analogue or surrogate)
Adequacy of study:
key study
Study period:
2002
Reliability:
1 (reliable without restriction)
Rationale for reliability incl. deficiencies:
other: RSS reported in published OECD SIDS for disodium succinate and assigned Klimish 1 rating. Abundant data in RSS seems to support K1 rating.

Data source

Reference
Title:
Unnamed
Year:
2003

Materials and methods

Test guideline
Qualifier:
equivalent or similar to
Guideline:
OECD Guideline 422 (Combined Repeated Dose Toxicity Study with the Reproduction / Developmental Toxicity Screening Test)
Deviations:
no
GLP compliance:
yes
Limit test:
no

Test material

Reference
Name:
Unnamed
Type:
Constituent
Details on test material:
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
Details on test animals and environmental conditions:
Not described in source RSS but presumably according to OECD guidance.

Administration / exposure

Route of administration:
oral: gavage
Vehicle:
water
Details on exposure:
Males were dosed daily for 52 days. Females were exposed from 14 days before mating to day 4 of lactation.
The frequency of treatment was once per day.
Details on mating procedure:
Not stated in source RSS but likely as study done under GLP and OECD guidance stated as followed.
Analytical verification of doses or concentrations:
not specified
Details on analytical verification of doses or concentrations:
Not stated in source RSS but likely as study done under GLP and OECD guidance stated as followed.
Duration of treatment / exposure:
Males: 52 days
Females: Females were exposed from 14 days before mating to day 4 of lactation
Frequency of treatment:
Once daily
Doses / concentrationsopen allclose all
Remarks:
Doses / Concentrations:
100 mg/kg bw/day
Basis:
actual ingested
hexahydrate salt
Remarks:
Doses / Concentrations:
300 mg/kg bw/day
Basis:
actual ingested
hexahydrate salt
Remarks:
Doses / Concentrations:
1000
Basis:
actual ingested
hexahydrate salt
No. of animals per sex per dose:
12 males and 12 females per group

Results and discussion

Results: P0 (first parental generation)

General toxicity (P0)

Clinical signs:
no effects observed
Body weight and weight changes:
no effects observed
Food consumption and compound intake (if feeding study):
no effects observed
Organ weight findings including organ / body weight ratios:
no effects observed
Histopathological findings: non-neoplastic:
no effects observed
Other effects:
no effects observed

Reproductive function / performance (P0)

Reproductive function: oestrous cycle:
no effects observed
Reproductive function: sperm measures:
no effects observed
Reproductive performance:
no effects observed

Effect levels (P0)

open allclose all
Dose descriptor:
NOAEL
Effect level:
> 1 000 mg/kg bw/day (nominal)
Based on:
test mat.
Sex:
male/female
Basis for effect level:
other: Referred to disodium succinate hexahydrate
Dose descriptor:
NOAEL
Effect level:
> 600 mg/kg bw/day (nominal)
Based on:
act. ingr.
Sex:
male/female
Basis for effect level:
other: Expressed as anhydrous disodium succinate

Target system / organ toxicity (P0)

Critical effects observed:
not specified

Results: P1 (second parental generation)

General toxicity (P1)

Clinical signs:
no effects observed

Details on results (P1)

No single or two generation reproductive toxicity studies have been identified applicable to
Potassium Sodium Tartrate or any sodium or potassium salt of tartaric acid. Toxicokinetic information indicates
rapid metabolism and elimination of tartaric acid and of its salts and available information corresponding to an
oral chronic toxicity test performed in rat with monosodium tartrate do not indicate any abnormalities in testes or
ovaries after a 2-year study (see report in section 7.5.1.). In addition its low toxicity and absence of indication of
reproductive effects after a long history of dietary exposure of humans to tartrates do no warrant the performance
of a specific reproductive toxicity study

Results: F1 generation

General toxicity (F1)

Clinical signs:
no effects observed
Mortality / viability:
no mortality observed
Body weight and weight changes:
no effects observed
Description (incidence and severity):
Non dose related low body weight in lactation period in some animals
Sexual maturation:
not specified
Organ weight findings including organ / body weight ratios:
not examined
Gross pathological findings:
no effects observed
Histopathological findings:
not examined

Details on results (F1)

No single or two generation reproductive toxicity studies have been identified applicable to
Potassium Sodium Tartrate or any sodium or potassium salt of tartaric acid. Toxicokinetic information indicates
rapid metabolism and elimination of tartaric acid and of its salts and available information corresponding to an
oral chronic toxicity test performed in rat with monosodium tartrate do not indicate any abnormalities in testes or
ovaries after a 2-year study (see report in section 7.5.1.). In addition its low toxicity and absence of indication of
reproductive effects after a long history of dietary exposure of humans to tartrates do no warrant the performance
of a specific reproductive toxicity study

Effect levels (F1)

Remarks on result:
not determinable due to absence of adverse toxic effects
Remarks:
The results obtained upon surrogate substance disodium succinate hexahydrate in OECD combined repeated dose and developmental toxicity screening test indicate that up to 1000 mg/ kg bw/day there are no significant effects upon the parental animals’s ability to reproduce or upon the health and viability of their offspring (as determined up to the 4th day of lactation).

Overall reproductive toxicity

Reproductive effects observed:
not specified

Any other information on results incl. tables

 

1) 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.

 

2) 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.

 

3) Morphology, body weight and necroptic findings of neonates

In the external examination in neonates, anophthalmia and polydactyly were observed in 1 animal each in the 300 mg/kg group. Body weight during lactation period was significantly low on days 0 and 4 of lactation in males and dayfemales in the 100 mg/kg group and on day

4 inmales in the 300 mg/kg group, which was the change not associated

with the dose. In the necropsy of dead offspring during the lactation period, pyelectasia

was observed in 1 animal in the 100 mg/kg group. 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.

 

Applicant's summary and conclusion

Conclusions:
The results obtained upon surrogate substance disodium succinate hexahydrate in OECD combined repeated dose and developmenmental toxicity screening test indicate that up to 1000 mg/ kg bw/day there are no significant effects upon the parental animals ability to reproduce or upon the health and viability of their offspring (as determined up to the 4th day of lactation).
Executive summary:

The results obtained upon surrogate substance disodium succinate hexahydrate in OECD combined repeated dose and developmenmental toxicity screening test indicate that up to 1000 mg/ kg bw/day there are no significant effects upon the parental animals ability to reproduce or upon the health and viability of their offspring (as determined up to the 4th day of lactation).

These results are considered relevant towards the assessment of the reproductive toxicity of Potassium Sodium Tartrate, as both are structurally very similar C4 dicarboxillic acids. These results support further teratology studies performed with tartaric acid.

In a weight of evidence aproach it is considered unnecesary to propose a specific 1 or 2 generation reproductive toxicity test on the reference substance Potassium Sodium Tartrate.