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Repeated dose toxicity: oral

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Administrative data

Endpoint:
short-term repeated dose toxicity: oral
Remarks:
combined repeated dose and reproduction / developmental screening
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
Reference Type:
secondary source
Title:
Unnamed
Year:
2003

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
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
Details on oral 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.
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 were dosed daily for 52 days. Females were exposed from 14 days before mating to day 4 of lactation.
Frequency of treatment:
The frequency of treatment was once per day.
Doses / concentrationsopen allclose all
Remarks:
Doses / Concentrations:
100 mg/kg bw/day
Basis:
actual ingested
Remarks:
Doses / Concentrations:
300
Basis:
actual ingested
Remarks:
Doses / Concentrations:
1000 mg/kg bw/day
Basis:
actual ingested
No. of animals per sex per dose:
12 males and 12 females per group
Control animals:
yes, concurrent vehicle
Details on study design:
According to OECD guideline

Examinations

Observations and examinations performed and frequency:
According to OECD guideline
Sacrifice and pathology:
According to OECD guideline
Other examinations:
According to OECD guideline
Statistics:
According to OECD guideline

Results and discussion

Results of examinations

Clinical signs:
no effects observed
Mortality:
no mortality observed
Body weight and weight changes:
no effects observed
Food consumption and compound intake (if feeding study):
no effects observed
Food efficiency:
not specified
Haematological findings:
no effects observed
Clinical biochemistry findings:
no effects observed
Urinalysis findings:
effects observed, treatment-related
Description (incidence and severity):
Abnormally high levels of protein in urine at 300 and 1000 mg/kg bw
Organ weight findings including organ / body weight ratios:
no effects observed
Gross pathological findings:
no effects observed
Histopathological findings: non-neoplastic:
no effects observed
Details on results:
Information transcribed from OECD SIDS:

1) Mortality and clinical signs
No death occurred in males and females in any group throughout the treatment period.
As the changes in clinical signs, loosening of stool was observed in 1 and 4 males in the 100 and 1000 mg/kg groups and 1 female in the 1000 mg/kg group, respectively. This finding was a mild one and not accompanied by dirty hair in any group. One male in the 100mg/kg group and 1 female in the 1000 mg/kg group showed this finding in 1 day only, but 3 males except one male in the 1000 mg/kg group showed this finding in 3 to 4 days. In addition, for males, there were alopecia in 2 and 3 animals in the 300 and 1000 mg/kg groups, eschar in 1 and 2 animals in the 300 and 1000 mg/kg groups, ocular discharge in 1 animal each in the 300 and 1000 mg/kg groups, nasal discharge in 2 animals each in the 300 and 1000 mg/kg groups and salivation in 1 animal in the 1000 mg/kg group, respectively. For females, there was alopecia in 1, 2, 3 and 1 animals in the control, 100, 300 and 1000 mg/kg groups, eschar in 1 animal each in the 100 and 1000 mg/kg groups and salivation in 1 animal in the 1000 mg/kg group, respectively.

2) Body weight
There was no significant difference between the treatment groups and the control group in both males and females throughout the treatment period.

3) Food consumption
There was no significant difference between the treatment groups and the control group in both males and females throughout the treatment period.

4) Hematology
In the hematology and the blood coagulation test, there was no significant difference between the treatment groups and the control group in all test
items in both males and females.

5) Clinical chemistry
In males, sodium showed high values in the 300 and 1000 mg/kg groups compared with the control group. In addition, chloride showed high values in the 300 mg/kg group, which was a slight and insignificant change. Also, total bile acid showed low values in the 1000 mg/kg group. The values in the control group, however, scattered large, and those of most animals in the 1000 mg/kg group were within the scatter in the control group. In females, creatinine showed high values in the 300 mg/kg group, which was a change not related to the dose. In the 1000 mg/kg group, urea nitrogen showed high values.

6) Urinalysis (conducted only for males)
There was moderate occult blood in 1 of 5 animals in the 300 mg/kg group and severe one in 1 of 5 animals in the 1000 mg/kg group. The protein of 300 mg/dL or more were observed in 1 of 5 animals in the 300 mg/kg group and 2 of 5 animals in the 1000 mg/kg group. In addition, the yellow-brownish urine was observed in 2 of 5 animals in the 1000 mg/kg group, which were the changes within the normal values. Also, the abnormally high volumes of 24-hour urine were observed in 1 animal each in the 100 and 300 mg/kg groups, but there was no intergroup difference in the results of urine volume and urinary osmotic pressure in the animals excepting
these 2 animals.

7) Organ weight
In males, absolute adrenal weight showed significantly high values in the 1000 mg/kg group compared with the control group. In females, there was no significant difference in any organ determined between the treatment groups and the control group.

8) Findings at necropsy
In males, red patches in the liver were observed in 1 animal in the 300 mg/kg group, white patches/region in the liver, deverticulum in the small intestine and hypertrophy of the testis in 1 animal each in the 1000 mg/kg group and nodes of the epididymis in 2 animals in the 1000 mg/kg group. In females, adhesion of the spleen was observed in 1 animal in the control group, black patches in the glandular stomach in 2 and 1 animals in the
300 and 1000 mg/kg groups, white patches in the liver in 1 animal in the 300 mg/kg group and yellow patches, hypophysial cyst and alopecia in 1 animal each in the 1000 mg/kg group, respectively.

9) Histopathology
There was no finding indicating a significant increase in the incidence in both males and females in the treatment groups compared with the control group. In males, atrophy of the seminiferous tubule was observed in 1 animal in the 300 mg/kg group and dilation of the seminiferous tubule in 1 animal in the 1000 mg/kg group. Dilation of the seminiferous tubule was hemilaterally observed, and no abnormality was observed in the cells constituting the seminiferous epithelium. Spermatic granuloma in the epididymis was observed in 2 animals in the 1000 mg/kg group but not observed in other treatment groups.

Necrosis of the liver was observed in 1 animal in the 1000 mg/kg group. No gastric finding was observed in all groups including the control group. Lymphocytic infiltration in the prostate was observed in 4 and 1 animals in the control group and the 1000 mg/kg group, respectively.
Prostatitis was observed in 1 animal in the 1000 mg/kg group. In the animal showing prostatitis, there were the findings of pyelitis and accompanied proliferation of transitional epithelium in the kidney and the findings of lymphocytic infiltration and proliferation of transitional epithelium in the urinary bladder. Other findings were those also observed in the control group or solitary occurrence.

In females, necrosis of the mucosa in the glandular stomach were observed in 2 and 1 animals in the 300 and 1000 mg/kg groups, focal necrosis of the liver in 1 animal in the 1000 mg/kg group and necrosis of the liver in 1 animal in the 300 mg/kg group. In addition, proliferation of lymphatic tissues in the small intestine was observed in 1 and 4 animals in the control group and the 1000 mg/kg group, respectively. Other histopathological findings observed were those also observed in the control group or in a few animals only.
For the testis in the control group and the 1000 mg/kg group, the number of seminiferous epithelial cells in the seminiferous tubule in the stage VIII was determined. As a result, the numbers of spermatogonia (type A), spermiocytes in the preleptotene stage, spermiocytes in the pachytene stage, round spermatids and Sertoli's cells showed no differences compared with the control group.

Effect levels

Dose descriptor:
NOAEL
Effect level:
100 mg/kg bw/day (actual dose received)
Based on:
test mat.
Sex:
male/female
Basis for effect level:
urinalysis

Target system / organ toxicity

Critical effects observed:
not specified

Applicant's summary and conclusion

Conclusions:
A Japanese study provides useful insight into the sub-acute toxicity (52 d) and effects upon fertility of analogue disodium succinate. A NOAEL of 100 mg/kg bw/day is proposed by the Japanese ellaborators of the RSS, based upon abnormalities in urinary proten concentrations at dose lavels of 300 mg/kg bw and above. No other anomalies have been encountered which suggest other sistemic or reproductive effects.
Executive summary:

A Japanese study provides useful insight into the sub-acute toxicity (52 d) and effects upon fertility of analogue disodium succinate. A NOAEL of 100 mg/kg bw/day is proposed by the Japanese ellaborators of the RSS, based upon abnormalities in urinary proten concentrations at dose lavels of 300 mg/kg bw and above.This NOAEL is of 60 mg/ kg bw/day if expressed in terms of the anhydrous salt. No other anomalies have been encountered which suggest other sistemic or reproductive (fertility) effects. Although overall the results of this test support the absence of findings in chronic tests performed with Na and K tartrate salts, no increase in urinary protein has been reported in the studies performed with tartrate salts and thereby the lower NOAEL proposed in this study is not considered appropriate for the reference substance (Potassium Sodium Tartrate). The NOAEL from this test based on the remaining end-points (> 1000 mg/ kg bw/ day) is however within the same order or magnitude than those obtained from the chronic and subcronic tests available from tests with sodium tartrate salts.