Succinic acid

Carcinogenicity

Description of key information

Monosodium succinate had neither toxic nor carcinogenic activity in F344 rats when it was given continuously at levels of 1 or 2 % in the drinking water for 2 years. 

Key value for chemical safety assessment

Carcinogenicity: via oral route

Link to relevant study records

Reference

Endpoint:

carcinogenicity: oral

Type of information:

migrated information: read-across from supporting substance (structural analogue or surrogate)

Adequacy of study:

key study

Reliability:

2 (reliable with restrictions)

Rationale for reliability incl. deficiencies:

other: Study published in a peer-reviewed journal, Read across

Qualifier:

equivalent or similar to guideline

Guideline:

OECD Guideline 451 (Carcinogenicity Studies)

Deviations:

not specified

Remarks:

publication, no report; therefore some data probably existent, but not available

GLP compliance:

not specified

Species:

rat

Strain:

Fischer 344

Sex:

male/female

Details on test animals or test system and environmental conditions:

TEST ANIMALS
- Source: Charles River Japan, Inc. (Kanagawa, Japan)
- Status: SPF
- Age at study initiation: 6 weeks
- Weight at study initiation: between 100 and 200 g, not reported (only growth curves available)
- Fasting period before study: none reported
- Diet: basal diet (CRF-1), Oriental Yeast Inc., Tokyo, Japan), ad lib. Checked for contaminants (pesticides, benzopyrene, aflatoxin, N-nitroso compounds: negative. A small amount (mean amount 3 ppm) of N-nitrosodimethylamine was detected
- Water: distilled water (test substance dissolved in distilled water as drinking water)
- Acclimation period:one week

ENVIRONMENTAL CONDITIONS
- Temperature (°C):24 +- 1 °C
- Humidity (%): 55 +- 5 %
- Air changes (per hr): not reported
- Photoperiod (hrs dark / hrs light): not reported

Route of administration:

oral: drinking water

Vehicle:

water

Remarks:

distilled water

Details on exposure:

PREPARATION OF DOSING SOLUTIONS:
- Test substance dissolved in distilled water (vehicle), used as drinking water
- Preparation: prepared freshly three times a week

VEHICLE
- Concentration in vehicle: 0, 1 and 2 %
- Justification for choice of vehicle: based on the results of a sub-chronic study (see reference "RA, WoE. Maekawa 1990. Repeated dose toxicity rat").

Analytical verification of doses or concentrations:

not specified

Duration of treatment / exposure:

104 weeks

Frequency of treatment:

Daily/continuously, because administered via drinking water ad lib.

Post exposure period:

9 weeks

Remarks:

Doses / Concentrations:
0, 1 an d2 % in drinking water
Basis:
nominal in water

No. of animals per sex per dose:

50

Control animals:

yes, concurrent vehicle

Details on study design:

- Dose selection rationale: based on the results of a sub-chronic study:

Positive control:

Not appropriate

Observations and examinations performed and frequency:

ANIMAL OBSERVATIONS, MORTALITY: Yes
- Cage side/detailed clinical: not stated
- Time schedule: once daily

BODY WEIGHT: Yes
- Time schedule for examinations: once a week for the first 13 weeks and then once every 4 weeks.

WATER CONSUMPTION AND COMPOUND INTAKE (if drinking water study): Yes
- Time schedule for examinations: three times a week

OPHTHALMOSCOPIC EXAMINATION: No data

HAEMATOLOGY: No

CLINICAL CHEMISTRY: No

Sacrifice and pathology:

NECROPSY, HISTOPATHOLOGY:
- All animals which died during the study, all animals killed as moribund and all animals surviving until the end of the experiment.
- Complete macroscopic and microscopic examination for the presence of non-neoplastic and neoplastic lesions.
- Fixation of organs: 10 % buffered formalin, staining with haematoxylin/eosin.

Statistics:

Fisher's exact probability test and/or Chi square test
Age-adjusted statistical tests recommended by Peto et al.

Clinical signs:

no effects observed

Mortality:

no mortality observed

Body weight and weight changes:

effects observed, treatment-related

Description (incidence and severity):

suppression of body weight gain by 10 % in the high dose group compared to controls

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 examined

Clinical biochemistry findings:

not examined

Urinalysis findings:

not examined

Behaviour (functional findings):

not examined

Organ weight findings including organ / body weight ratios:

not specified

Gross pathological findings:

no effects observed

Histopathological findings: non-neoplastic:

no effects observed

Description (incidence and severity):

see also below

Histopathological findings: neoplastic:

no effects observed

Description (incidence and severity):

see also below

Details on results:

CLINICAL SIGNS AND MORTALITY:
In males, the mortality rate in the control group was slightly higher than that in the other two groups throughout the experiment. The first autopsy was at wk 57, when a male rat in the control group was killed because it became moribund as the result of leukaemia. In both sexes, there were no statistically significant differences between the control and treated groups in mean survival times (generalized Wilcoxon test).

BODY WEIGHT AND WEIGHT GAIN:
Throughout the experiment, a dose-dependent inhibitory effect of monosodium succinate on growth was apparent in both sexes. In comparison with the controls about 10% suppression of body weight was observed in male and female rats in the high-dose group.

WATER CONSUMPTION AND COMPOUND INTAKE (if drinking water study)
The daily and total monosodium succinate intakes, calculated from the daily records of drinking-water intake, were dose dependent

HISTOPATHOLOGY: NEOPLASTIC
In males, the overall tumour incidence was almost 100% in all groups. In females, it was about 77-82%. In both sexes, there were no statistically significant differences between the control and treated groups in overall tumour incidences (chi square test)
Tumours were found in many organs or tissues in all groups including the controls. In males of all groups, tumours of the testes were the most frequent, followed by those of the haematopoietic organs, thyroid, adrenals, mammary, prostate, pancreas and pituitary. Tumours of the uterus, pituitary, haematopoietic organs, mammary gland, thyroid and adrenals were the most common in females. Tumours were also detected in other organs or tissues but the incidences were very low. None of the treated groups showed a significant increase in the incidence of any tumours over that in the corresponding control group, while the incidence of endometrial stromal polyp in the females given the 2% dose was significantly lower than that in the control group.
The incidence of C-cell adenoma/carcinoma of the thyroid in the female group given 2% monosodium succinate was higher than that in the control group although marginally not significant by chi square test, and a positive trend was noted in the occurrence of this turnout by an age-adjusted statistical test recommended by Peto et al. (1980). Histologically, all tumours except prostate tumours observed in this study were similar to those that are known to occur spontaneously in this strain of rats (Goodman et al., Toxic. appl. Pharmac. 48, 237-248, 1979; Maekawa et al., Gann 74, 365-372, 1983; Solleveld et al., J. natn. Cancer Inst. 72, 929-940, 1984).
Prostate tumours were observed in all male groups including the control group, at incidences much higher than those reported by others (Goodman et al., 1979; Solleveld et al., 1984). Histologically, the prostate tumours were all intraductal adenomas/ carcinomas.

HISTOPATHOLOGY: NON-NEOPLASTIC
In addition to these tumours, many kinds of nonneoplastic lesions, such as myocardial fibrosis, bileduct proliferation and chronic nephropathy, were observed in all groups including the control group, and no other specific lesions were detected in any treated groups of either sex

Relevance of carcinogenic effects / potential:

Many different types of tumours were observed in all groups, including the controls, and the organ distribution of these tumours and their histological characteristics were similar to those of the spontaneous tumours that occur in this strain of rats (Goodman et al., Toxic. appl. Pharmac. 48, 237-248, 1979; Maekawa et al., Gann 74, 365-372, 1983; Solleveld et al., J. natn. Cancer Inst. 72, 929-940, 1984). The reason that the incidence of prostate tumours was very high in the present study is obscure. Except for thyroid C-Cell tumours in females, no positive trend was evident for any tumours in the treated groups. C-cell tumours in the thyroid have been commonly observed to develop spontaneously in this strain of rats. In the present study, all C-cell tumours observed in the females given 2% monosodium succinate were histologically adenomas; four out of the seven adenomas were microscopic. There was also no difference between the female control and treated groups in the incidence of preneoplastic change of the thyroid gland (the number of rats with C-cell hyperplasia in the female 2%, 1% and control groups was 10, 6 and 10, respectively). In addition, the incidence of C-cell tumours in the female control group was lower than that in our historical controls (7-19%; Maekawa et al., 1983). The use of information on historical controls is very important for the risk evaluation of tumour incidence data when a tumour shows a marginally significant result when compared with the concurrent control, as reported by Haseman et al. (Toxic. Path. 12, 126-135, 1984). Furthermore, no significant increase or positive trend for C-cell tumours of the thyroid was detected in males. Thus, we consider that the increase in C-cell tumours in the female high-dose group and the detection of a positive trend for this tumour in females were probably a function of experimental variability and were not related to treatment with monosodium succinate. The decreased incidence of uterine endometrial stromal polyp in the high-dose group may be attributable to the relatively high incidence of this tumour in the concurrent control group in comparison with that in historical controls.
From the above result, it was concluded that monosodium succinate had no toxic or carcinogenic activity in F344 rats when it was given continuously in the drinking-water for 2 years.

Dose descriptor:

NOAEL

Effect level:

20 000 mg/L drinking water

Based on:

dissolved

Sex:

male/female

Basis for effect level:

other: histopathology: non-neoplastic lesions, neoplastic lesions NOAEL = highest dose tested

Remarks on result:

other: Effect type: carcinogenicity (migrated information)

Dose descriptor:

NOAEL

Effect level:

10 000 mg/L drinking water

Based on:

dissolved

Sex:

male/female

Basis for effect level:

other: clinical signs; mortality; body weight; gross pathology; histopathology NOAEL = lowest dose tested

Remarks on result:

other: Effect type: toxicity (migrated information)

Dose descriptor:

LOAEL

Effect level:

20 000 mg/L drinking water

Based on:

dissolved

Sex:

male/female

Basis for effect level:

other: body weight gain (suppressed) LOAEL = highest dose tested

Remarks on result:

other: Effect type: toxicity (migrated information)

Conclusions:

From the above result, it was concluded that monosodium succinate had no carcinogenic activity in F344 rats when it was given continuously in the drinking-water for 2 years.

Executive summary:

The toxicity/carcinogenicity of monosodium succinate was examined in F344 rats. The compound was dissolved in distilled water and given ad lib. as drinking water at levels of 0, 1 or 2 % to groups of 50 male and 50 female rats.

Throughout the experiment, a dose-dependent inhibitory effect of monosodium succinate on growth was apparent in both sexes. In comparison with the controls about 10% suppression of body weight was observed in male and female rats in the high-dose group.

No toxic lesion specifically caused by long-term administration of the compound was detected. No dose-related increase was found in the incidence of tumours in any organ or tissue except for C-cell tumours of the thyroid gland of females. The incidence of these tumours in females given the 2 % dose was higher than in controls but not significantly so, and a positive trend for this tumour was noted in female.C-cell tumour is one of the most commonly observed spontaneous tumours in ageing female rats of this strain and occurs at a variable incidence. There was no difference between the female control and treated groups in the incidence of preneoplastic change of the thyroid gland. Furthermore, the incidence of C-cell tumours in the female control group was lower than that in the lab's historical controls. It is concluded that the increase in C-cell tumours in the female high-dose group and the detection of a positive trend for this tumour in females were probably a function of experimental variability and were not related to treatment.

The results indicate that monosodium succinate had neither toxic nor carcinogenic activity in F344 rats when it was given continuously at levels of 1 or 2 % in the drinking water for 2 years.

Endpoint conclusion

Endpoint conclusion:

no adverse effect observed

Justification for classification or non-classification

No carcinogenicity was detected in a long-term study with rats.

Additional information

Justifications for a read-across from data of monosodium succinate or sodium succinate to succinic acid:

The read-across from the succinate to succinic acid seems justified, as both are well water soluble and will be in the ionised form in dilute aqueous solutions, to give the same anion. The different molecular weights were considered.

Justification for selection of carcinogenicity via oral route endpoint:
No carcinogenicity was detected in a long-term study with rats.