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Administrative data

Description of key information

Tartaric acid and its salts do not have significant (sub)chronic toxicity.

Key value for chemical safety assessment

Repeated dose toxicity: via oral route - systemic effects

Link to relevant study records
Reference
Endpoint:
chronic toxicity: oral
Type of information:
experimental study
Adequacy of study:
weight of evidence
Reliability:
2 (reliable with restrictions)
Rationale for reliability incl. deficiencies:
other: The study has been assessed for the use in a category approach. According to the methodology and to the extent of available details, the study has been judged as reliable with restrictions.
Qualifier:
equivalent or similar to guideline
Guideline:
OECD Guideline 453 (Combined Chronic Toxicity / Carcinogenicity Studies)
Principles of method if other than guideline:
Chronic administration of substance by oral route to in vivo animals to evaluate repeated dose toxicity
GLP compliance:
no
Limit test:
no
Species:
rat
Strain:
other: CFY rats, a hysterectomy-derived strain of Sprague-Dawley
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
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
Remarks:
Doses / Concentrations:
0, 25600, 42240, 60160 or 76800 ppm (equivalent to a tartaric acid dietary level of 0, 20000, 33000, 47000 or 60000 ppm, respectively)
Basis:
nominal in diet
No. of animals per sex per dose:
Five groups each containing 35 male and 35 female rats, with equai numbers of animals of comparable bodyweight in each group
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.
Positive control:
no positive control
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
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
Immunological findings:
not specified
Organ weight findings including organ / body weight ratios:
no effects observed
Gross pathological findings:
no effects observed
Neuropathological findings:
not specified
Description (incidence and severity):
Only the weight of the brain has been evaluated.
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.
Key result
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
Key result
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:
food consumption and compound intake
Key result
Critical effects observed:
not specified

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   male 0.89 - female 1.19   male 0.71 - female 0.93    
 42240  33000  male 1.62 - female 2.05   male 1.22 - female 1.60    
 60160  47000  male 2.20 - female 3.10   male 1.84 - female 2.36    
 76800  60000  male 3.10 - female 4.10   male 2.46 - female 3.20    
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.

Endpoint conclusion
Endpoint conclusion:
no adverse effect observed
Dose descriptor:
NOAEL
2 460 mg/kg bw/day
Study duration:
chronic
Species:
rat
Quality of whole database:
Database does not contain data obtained by means of tests in accordance with standard testing guidelines; however, it is constituted by many data which are consistent about the absence of significant toxicity of tartaric acid and its salts following repeated administration.

Repeated dose toxicity: inhalation - systemic effects

Endpoint conclusion
Endpoint conclusion:
no study available

Repeated dose toxicity: inhalation - local effects

Endpoint conclusion
Endpoint conclusion:
no study available

Repeated dose toxicity: dermal - systemic effects

Endpoint conclusion
Endpoint conclusion:
no study available

Repeated dose toxicity: dermal - local effects

Endpoint conclusion
Endpoint conclusion:
no study available

Additional information

The repeated dose toxicity of tartaric acid and its salt was assessed by oral route. According to Hunter et al. (1977), monosodium L(+) tartrate, given to rats in their diet for a total period of two years at dose levels of 25600, 42240, 60160 and 76800 ppm (equivalent to a tartaric acid dietary level of 20000, 33000, 47000 or 60000 ppm, respectively), did not cause adverse clinical effects. Moreover, the investigation of the animals' eyes, blood and urine did not reveal any reaction to treatment. In the same manner, no changes related to treatment were seen in the macroscopic pathology or in organ weights of the rats killed after 104 weeks. The histological examination of the tissues did not show any evidence of toxicity or tumour induction that could be attributed to treatment with monosodium L(+) tartrate.

Other studies showed adverse effects on renal function following repeated administration of tartaric acid or disodium tartrate. However, these effects were exclusively observed at very high doses and, therefore, they were judged as non-significant.

Overall, it is believed that the tartaric acid and its salts possess similar profiles of systemic toxicity, therefore, the assessment of this endpoint may be jointly performed using all available data for these substances. In conclusion, these substances do not deemed to be toxic following repeated administration.


Justification for selection of repeated dose toxicity via oral route - systemic effects endpoint:
The study selected is exhaustively documented, it allows to evaluate the reliability of the test.

Justification for classification or non-classification

According to Directive 67/548/EEC and to Regulation (EC) n. 1272/2008, the study results indicate that the substances should not be classified for the specific target organ toxicity - repeated exposure because data are judged as "conclusive but not sufficient for classification".