Dipotassium tartrate

Repeated dose toxicity: oral

Administrative data

Endpoint:

chronic toxicity: 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: Well documented report equivalent or similar to OECD guidelines

Data source

Reference

Reference Type:

publication

Title:

Monosodium L(+)-tartrate toxicity in two year dietary feeding to rats

Author:

Hunter B, Batham P, Heywood R, Street AE % Prentice DE

Year:

1977

Bibliographic source:

Toxicology, 8: 263-274

Materials and methods

Test guideline

Qualifier:

equivalent or similar to guideline

Guideline:

OECD Guideline 453 (Combined Chronic Toxicity / Carcinogenicity Studies)

GLP compliance:

no

Limit test:

no

Test material

Test material information

Constituent 1

Reference substance name:

Sodium hydrogen tartrate

EC Number:

208-400-9

EC Name:

Sodium hydrogen tartrate

Cas Number:

526-94-3

Molecular formula:

C4H6O6.Na

IUPAC Name:

sodium hydrogen tartrate

Details on test material:

no data
- Name of test material (as cited in study report): monosodium L(+)-tartrate

Test animals

Species:

rat

Strain:

other: CFY, a hysterectomy-derived strain of SD origin

Sex:

male/female

Details on test animals or test system and environmental conditions:

TEST ANIMALS
- Source: Anglia Laboratory Animals, Huntingdon, England
- Age at study initiation: 28±1 days
- Housing: the rats were housed five to a cage in suspended cages with wire meshfloors. The cages for each group were dispersed in batteries in such a way that possible environmental infliuences arising from their spatial distribution were equilibrated, as far as possible, for all treatments.
- Diet (e.g. ad libitum): ad libitum
- Water (e.g. ad libitum): ad libitum
- Acclimation period: 6 days

ENVIRONMENTAL CONDITIONS
- Temperature (°C): 21±2
- Humidity (%): 50±5
- Photoperiod (hrs dark / hrs light): 12h dark / 12 h light per 24 h

Administration / exposure

Route of administration:

oral: feed

Vehicle:

not specified

Details on oral exposure:

DIET PREPARATION
- Rate of preparation of diet (frequency): weekly
- Mixing appropriate amounts with (Type of food): a commercial diet

Analytical verification of doses or concentrations:

yes

Details on analytical verification of doses or concentrations:

periodic analyses confirmed the levels of monosodium L(+)-tartrate were in tolerable agreement with the nominal level

Duration of treatment / exposure:

104 weeks

Frequency of treatment:

daily

Doses / concentrations

Remarks:

Doses / Concentrations:
25600, 42240, 60160 or 76800 ppm
Basis:
nominal in diet

No. of animals per sex per dose:

35 M & 35 F per dose

Control animals:

yes, plain diet

Details on study design:

- Dose selection rationale: the intake from a half-liter bottle of wine could be equivalent to about 50 mg/kg bodyweight for a 70 kg adult. As other items of the diet contribute further amounts of tartaric acid it was considered desirable to further evaluate the safety of tartaric acid dietary levels which could give an added margin of safety over the possible human intake level.

Examinations

Observations and examinations performed and frequency:

CAGE SIDE OBSERVATIONS: Yes
- Time schedule: daily

BODY WEIGHT: Yes
- Time schedule for examinations: weekly

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

OPHTHALMOSCOPIC EXAMINATION: Yes
- Time schedule for examinations: during weeks 4, 8, 12, 24, 52, 77 and 103 of the study
- Dose groups that were examined: control and 76800 ppm groups

HAEMATOLOGY: Yes
- Time schedule for collection of blood: during weeks 4, 8, 12, 24, 52, 77 and 103 of the study.
- Anaesthetic used for blood collection: Yes
- How many animals: 10 M and 10 F of control and 76800 ppm groups

CLINICAL CHEMISTRY: Yes
- Time schedule for collection of blood: during weeks 4, 8, 12, 24, 52, 77 and 103 of the study.
- How many animals: 10 M and 10 F of control and 76800 ppm groups

URINALYSIS: Yes
- Time schedule for collection of urine: during weeks 4, 8, 12, 24, 52, 77 and 103 of the study.
- Metabolism cages used for collection of urine: No data
- Animals fasted: No data

Sacrifice and pathology:

GROSS PATHOLOGY: Yes
HISTOPATHOLOGY: Yes

Statistics:

Student's t-test

Results and discussion

Results of examinations

Clinical signs:

effects observed, treatment-related

Mortality:

mortality observed, treatment-related

Body weight and weight changes:

effects observed, treatment-related

Food consumption and compound intake (if feeding study):

effects observed, treatment-related

Food efficiency:

not examined

Water consumption and compound intake (if drinking water study):

not specified

Ophthalmological findings:

no effects observed

Haematological findings:

no effects observed

Clinical biochemistry findings:

no effects observed

Urinalysis findings:

no effects observed

Behaviour (functional findings):

not examined

Organ weight findings including organ / body weight ratios:

no effects observed

Gross pathological findings:

no effects observed

Histopathological findings: non-neoplastic:

no effects observed

Histopathological findings: neoplastic:

no effects observed

Details on results:

CLINICAL SIGNS AND MORTALITY: Dead from the groups receiving 42240, 60160, 76800 ppm was significantly less than in the control group, during the final six months.

BODY WEIGHT AND WEIGHT GAIN: Bodyweight gain of rats treated with 42240, 60160 and 76800 ppm remained depressed whereas that of 25600 ppm group was similar to that of the controls.

FOOD CONSUMPTION AND COMPOUND INTAKE (if feeding study): Rats receiving 42240, 60160 and 76800 ppm consistently ate less food than did the controls and the remainder of the study was approx 4-13 % lower than that of the controls. The weekly intake of monosodium L(+)-tartrate and the equivalent intake of L(+)-tartaric acid was calculated at weekly intervals from the group mean bodyweight and food intake data see Table 1.

OPHTHALMOSCOPIC EXAMINATION: no evidence of treatment-related ocular change.

HAEMATOLOGY: no evidence of treatment-related ocular change.

CLINICAL CHEMISTRY: no evidence of treatment-related ocular change.

URINALYSIS: no evidence of treatment-related ocular change.

ORGAN WEIGHTS: there were no differences between the organ weight values recorded for controls and rats fed monosodium L(+)-tartrate that could be ascribed to treatment.

GROSS PATHOLOGY: no changes were considered to be related to treatment. Differences that attained a level of significance were considered to be due to the intergroup disparity in bodyweight or to have arisen by chance.

HISTOPATHOLOGY: NON-NEOPLASTIC: no morphological change in any tissue examined that was considered to be related to treatment.. The pathology recorded among treated rats was similar to that recorded for controls rats.

HISTOPATHOLOGY: NEOPLASTIC (if applicable): the tumor incidence recorded for treated rats was similar to that recorded for controls and did not deviate from the known spontaneous tumor profile of the CFY rat.

Effect levels

1

Dose descriptor:

NOAEL

Remarks:

L(+)-tartaric acid

Effect level:

ca. 2 460 mg/kg bw/day (actual dose received)

Based on:

test mat.

Sex:

male

Basis for effect level:

body weight and weight gain

2

Dose descriptor:

NOAEL

Remarks:

L(+)-tartaric acid

Effect level:

ca. 3 200 mg/kg bw/day (actual dose received)

Based on:

test mat.

Sex:

female

Basis for effect level:

body weight and weight gain

Target system / organ toxicity

Critical effects observed:

not specified

Any other information on results incl. tables

 Table 1. Calculated intake of monosodium L(+)-tartrate and L(+)-tartaric acid in two-year feeding study

Monosodium L(+)-tartrate dietary level (ppm)	Equivalent L(+)-tartaric acid level (ppm)	Intake of monosodium L(+)-tartrate (g/kg/day)			Intake of L(+)-tartaric acid (g/kg/day)
25600	20000	0.89		1.19	0.71	0.93
42240	33000	1.62		2.05	1.22	1.60
60160	47000	2.20		3.03	1.84	2.36
76800	60000	3.10		4.10	2.46	3.20
		Male		Female	Male	Female

Applicant's summary and conclusion

Conclusions:

No evidence of an adverse effect on any other parameters examined and in particular no treatment-related histological changes were seen.

Executive summary:

Monosodium L(+)-tartrate was fed to rats in their diet for a total of two years at levels of 25600, 42240, 60160 and 76800 ppm. There were no adverse clinical signs and the investigation of the animals' eyes, blood and urine did not reveal any reaction to treatment, nor were changes related to treatment seen in the macroscopic pathology or organ weights of rats killed after 104 weeks. Histological examination of the tissues did not show evidence of toxicity or tumour induction that could be attributed to treatment with monosodium L(+)-tartrate. Only the survival of rats receiving 42240, 60160 or 76800 ppm was superior to that of the controls and probably correlated with the lower food intake of these groups and the resultant reduced bodyweight gain.