Registration Dossier

Administrative data

Key value for chemical safety assessment

Effects on fertility

Link to relevant study records
Reference
Endpoint:
toxicity to reproduction
Remarks:
other: Chronic
Type of information:
experimental study
Adequacy of study:
supporting study
Reliability:
2 (reliable with restrictions)
Reference:
Composition 0
Qualifier:
no guideline followed
Principles of method if other than guideline:
no data
GLP compliance:
not specified
Test material information:
Composition 1
Specific details on test material used for the study:
no data
Species:
rabbit
Strain:
New Zealand White
Details on species / strain selection:
albino rabbits
Sex:
male
Details on test animals and environmental conditions:
weighing 1-3 kg
Rabbits randomly divided in groups.
The control group received Rockland Rabbit Diet.
Route of administration:
oral: feed
Vehicle:
not specified
Details on exposure:
Sodium salts of tartaric acids was incorporated into the diets of the test animals
The diets and water were provided ad libitum throughout the test period.
Details on mating procedure:
no data
Analytical verification of doses or concentrations:
not specified
Details on analytical verification of doses or concentrations:
no data
Duration of treatment / exposure:
150 days
Frequency of treatment:
no data
Details on study schedule:
no data
Dose / conc.:
7.7 other: %
Remarks:
equivalent to 5% of the organic acid.
No. of animals per sex per dose:
Sixty rabbits (male), randomly divided into 4 groups of 15 animals each.
Control animals:
other: yes
Details on study design:
The mary purpose of the study was to acquire additional information relating to the safety of sodium tartratee when fed at high dietary levels to rabbits and to investigate the effects on the rabbit's testes.
Positive control:
no data
Parental animals: Observations and examinations:
Each animal was examined daily, and food intake and body weights were recorded at weekly intervals.
- growth and survival
- blood and urine studies
- organ weights
- pathology
At the conclusion of the study (150 days), all surviving animals were sacrificed, and gross and histologic studies were carried out.
For organ weights: mean ± standard deviation, expressed as g/kg bw.
Estrous cyclicity (parental animals):
no data
Sperm parameters (parental animals):
no data
Litter observations:
no data
Postmortem examinations (parental animals):
All surviving animals were sacrificed and gross and histologic studies were carried out.
Postmortem examinations (offspring):
no data
Statistics:
no data
Reproductive indices:
no data
Offspring viability indices:
no data
Clinical signs:
effects observed, non-treatment-related
Description (incidence and severity):
The histologic changes observed in the experimental groups were similar to those seen in the control group.
Dermal irritation (if dermal study):
not examined
Description (incidence and severity):
no data
Mortality:
mortality observed, non-treatment-related
Description (incidence):
Several deaths occurred during the course of the study. These were distributed amont the groups: 4 animals dying in the sodium tartrate group.
It was impossible to determine the cause of death in every case because of autolysis but there appears to be no connection between the feeding of the test materials and mortality.
Body weight and weight changes:
effects observed, non-treatment-related
Description (incidence and severity):
Food intake and body weights were recorded at weekly intervals
The mean body weights (kg) at week
0: 1.97 (15)
4: 2.15 (14)
8: 2.49 (10)
16: 2.82 (5)
22: 2.80 (5)


Food consumption and compound intake (if feeding study):
effects observed, non-treatment-related
Description (incidence and severity):
Mean total food intake: 17.0 kg.
As animals were removed for necroscopy examinations, the remaining rabbits often did not eat for a time, and their weights remained static or declined. As they resumed their normal intake of food, they gained weight at a faster than normal rate.
Food efficiency:
not examined
Description (incidence and severity):
no data
Water consumption and compound intake (if drinking water study):
not examined
Description (incidence and severity):
no data
Ophthalmological findings:
not examined
Description (incidence and severity):
no data
Haematological findings:
effects observed, non-treatment-related
Description (incidence and severity):
After 60 days of feeding, the erythrocyte, leucocyte, and differential leucocyte counts were all within normal limits. The blood sugar and nonprotein nitrogen values were normal, and revealed no differences among the four groups.
Clinical biochemistry findings:
not specified
Description (incidence and severity):
no data
Urinalysis findings:
effects observed, non-treatment-related
Description (incidence and severity):
The examination of the urine revealed no differences amont the four groups.
Behaviour (functional findings):
not specified
Description (incidence and severity):
no data
Immunological findings:
not examined
Description (incidence and severity):
no data
Organ weight findings including organ / body weight ratios:
effects observed, non-treatment-related
Description (incidence and severity):
The following organs were weighed at autopsy: adrenals, bladder, brain, heart, kidneys, liver, lung, prostate, spleen, stomach,- testes, and thyroid.
There were no significant differences ·in mean weight of any of these among the groups.
The weights of testes and thyroid are of particular concern.
Testes: 1.57+/-0.194 g
Thyroid: 0.11+/-0.048 g
Gross pathological findings:
effects observed, non-treatment-related
Description (incidence and severity):
Gross liver lesions of coccidiosis, often seen in the rabbit, were observed in each group. In addition, several animals in each group exhibited focal atelectasis and multiple infarcts of the kidney.
These changes are not to be attributed to the experimental feeding.
Three animals receiving sodium tartrate exhibited small testes, and 1 control animai showed calcification of the right testicle. The smaller gonads appeared to be related to an inguinal rather than a scrotal position.
It should be noted that variations in position and size are frequently found in the rabbit.
Neuropathological findings:
not examined
Description (incidence and severity):
no data
Histopathological findings: non-neoplastic:
effects observed, non-treatment-related
Description (incidence and severity):
The histologic changes observed in the experimental groups were similar to those seen in the control group.
Mild focal pyelonephritis, moderate congestion, mild hyperplasia of tubular epithelium, and occasional protein casts and hyaline droplet' degeneration were noted in the
kidneys, while livers of rabbits in all groups exhibited pericholangitis, bile duct proliferation, and dilatation as well as moderate congestion.
These changes are not unusual in rabbits and are not to be attributed to the experimental feeding.
Histopathological findings: neoplastic:
not specified
Description (incidence and severity):
no data
Other effects:
not examined
Reproductive function: estrous cycle:
not specified
Description (incidence and severity):
no data
Reproductive function: sperm measures:
effects observed, non-treatment-related
Description (incidence and severity):
3 animals exhibited small testes, and 1 control animal showed calcification of the right testicle. The smaller gonads appeared to be related to an inguinal position.
Examination of the testes revealed that the seminiferous tubules, the interstitial cells, and spermatogenesis were normal in all groups.
Slight peritubular fìbrosis and mÌld strotnal hyalinization were observed in each group after 150 days of feeding
Reproductive performance:
not specified
Description (incidence and severity):
no data
no data
Dose descriptor:
dose level:
Effect level:
> 7.7 other: %
Based on:
test mat.
Sex:
male
Basis for effect level:
other: No significant toxic effeet oceurred in rats fed diets containing 7.7% of sodium tartrate
Remarks on result:
not determinable
Remarks:
no NOAEL identified Generation: no data (migrated information)
Critical effects observed:
not specified
Clinical signs:
not examined
Description (incidence and severity):
no data
Dermal irritation (if dermal study):
not examined
Description (incidence and severity):
no data
Mortality:
not examined
Description (incidence):
no data
Body weight and weight changes:
not examined
Description (incidence and severity):
no data
Food consumption and compound intake (if feeding study):
not examined
Description (incidence and severity):
no data
Food efficiency:
not examined
Description (incidence and severity):
no data
Water consumption and compound intake (if drinking water study):
not examined
Description (incidence and severity):
no data
Ophthalmological findings:
not examined
Description (incidence and severity):
no data
Haematological findings:
not examined
Description (incidence and severity):
no data
Clinical biochemistry findings:
not examined
Description (incidence and severity):
no data
Urinalysis findings:
not examined
Description (incidence and severity):
no data
Behaviour (functional findings):
not examined
Description (incidence and severity):
no data
Immunological findings:
not examined
Description (incidence and severity):
no data
Organ weight findings including organ / body weight ratios:
not examined
Description (incidence and severity):
no data
Gross pathological findings:
not examined
Description (incidence and severity):
no data
Neuropathological findings:
not examined
Description (incidence and severity):
no data
Histopathological findings: non-neoplastic:
not examined
Description (incidence and severity):
no data
Histopathological findings: neoplastic:
not examined
Description (incidence and severity):
no data
Other effects:
not examined
Description (incidence and severity):
no data
Details on results:
no data
Reproductive function: estrous cycle:
not examined
Description (incidence and severity):
no data
Reproductive function: sperm measures:
not examined
Description (incidence and severity):
no data
Reproductive performance:
not examined
Description (incidence and severity):
no data
no data
Clinical signs:
not examined
Description (incidence and severity):
no data
Dermal irritation (if dermal study):
not examined
Description (incidence and severity):
no data
Mortality / viability:
not examined
Description (incidence and severity):
no data
Body weight and weight changes:
not examined
Description (incidence and severity):
no data
Food consumption and compound intake (if feeding study):
not examined
Description (incidence and severity):
no data
Food efficiency:
not examined
Description (incidence and severity):
no data
Water consumption and compound intake (if drinking water study):
not examined
Description (incidence and severity):
no data
Ophthalmological findings:
not examined
Description (incidence and severity):
no data
Haematological findings:
not examined
Description (incidence and severity):
no data
Clinical biochemistry findings:
not examined
Description (incidence and severity):
no data
Urinalysis findings:
not examined
Description (incidence and severity):
no data
Sexual maturation:
not examined
Description (incidence and severity):
no data
Organ weight findings including organ / body weight ratios:
not examined
Description (incidence and severity):
no data
Gross pathological findings:
not examined
Description (incidence and severity):
no data
Histopathological findings:
not examined
Description (incidence and severity):
no data
Other effects:
not examined
Description (incidence and severity):
no data
Behaviour (functional findings):
not examined
Description (incidence and severity):
no data
Developmental immunotoxicity:
not examined
Description (incidence and severity):
no data
no data
Clinical signs:
not examined
Description (incidence and severity):
no data
Dermal irritation (if dermal study):
not examined
Description (incidence and severity):
no data
Mortality / viability:
not examined
Description (incidence and severity):
no data
Body weight and weight changes:
not examined
Description (incidence and severity):
no data
Food consumption and compound intake (if feeding study):
not examined
Description (incidence and severity):
no data
Food efficiency:
not examined
Description (incidence and severity):
no data
Water consumption and compound intake (if drinking water study):
not examined
Description (incidence and severity):
no data
Ophthalmological findings:
not examined
Description (incidence and severity):
no data
Haematological findings:
not examined
Description (incidence and severity):
no data
Clinical biochemistry findings:
not examined
Description (incidence and severity):
no data
Urinalysis findings:
not examined
Description (incidence and severity):
no data
Sexual maturation:
not examined
Description (incidence and severity):
no data
Organ weight findings including organ / body weight ratios:
not examined
Description (incidence and severity):
no data
Gross pathological findings:
not examined
Description (incidence and severity):
no data
Histopathological findings:
not examined
Description (incidence and severity):
no data
Other effects:
not examined
Description (incidence and severity):
no data
Behaviour (functional findings):
not examined
Description (incidence and severity):
no data
Developmental immunotoxicity:
not examined
Description (incidence and severity):
no data
no data
Reproductive effects observed:
no
Lowest effective dose / conc.:
5 other: %
Treatment related:
no
Relation to other toxic effects:
not specified
Dose response relationship:
no
Relevant for humans:
not specified

The following organs were weighed at autopsy: adrenals, bladder, brain, heart, kidneys, liver, lung, prostate, spleen, stomach, testes, and thyroid. The histologic changes observed in the experimental groups were similar to those seen in the control group. Mild focal pyelonephritis, moderate congestion, mild hyperplasia of tubular epithelium, and occasionai protein casts and hyaline droplet' degeneration were noted in the kidneys, while livers of rabbits in ali groups exhibited pericholangitis, bile duct proliferation, and dilatation as well as moderate congestion. These changes are not unusual in rabbits and are not to be attributed to the experimental feeding.

Examination of the testes revealed that the seminiferous tubules, the interstitial cells, and spermatogenesis were normal in all groups. Slight peritubular fibrosis and mild stromal hyalinization were observed in each group after 150 days of feeding.

Conclusions:
No significant differences attributable to the experimental feeding could be found in any case; either grossly or microscopically. Thus, the rabbit does not appear to be affected by the inclusion of these substances in the diet for a period of 150 days.
It must be noted that the rabbits' testes are generally small, diffuse, easily dehydrated, and subject to variation in size and position. This species, therefore, is not ideai for the study of testicular pathology.
Executive summary:

A subchronic study with 15 male rabbits for 150 days were performed. The rabbits were maintained on a diet containing 7.7% sodium tartrate (equivalent to 5% of tartaric acid) (isomer not specified). Examination of the adrenals, heart, kidneys, liver, lung, bladder, brain, prostate, stomach, spleen, testes, and thyroid were conducted at intervals during the study and at the conclusion of the study. There was no effect on growth, mortality, or foodi consumption, and no histopathological changes could be attributed to sodium tartrate.

Effect on fertility: via oral route
Endpoint conclusion:
no adverse effect observed
Study duration:
chronic
Species:
rabbit
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 to the fertility of tartaric acid and its salts.
Effect on fertility: via inhalation route
Endpoint conclusion:
no study available
Effect on fertility: via dermal route
Endpoint conclusion:
no study available
Additional information

Tartaric acid was investigated for its toxicity to the fertility in rabbits, mice, rats and hamsters. The substance did not affect the parameters related to the reproductive performance.

Based on the chemical structure, it is considered that the toxicity to reproduction of tartaric acid is the same of that ones of its salts (i.e. monosodium, monopotassium, sodium potassium, sodium, potassium and calcium tartrate) and, therefore, the assessment of this endpoint may be jointly performed using all available data for these substances.

Overall, tartaric acid and its salts do not have toxicity to reproduction.


Short description of key information:
Tartaric acid and its salts do not have toxicity to reproduction.

Justification for selection of Effect on fertility via oral route:
Although an endpoint study record has been selected, the assessment of the toxicity to the fertility is based on the weight of evidence since the available studies took into account different relevant parameters.

Effects on developmental toxicity

Description of key information
Tartaric acid and its salts do not have developmental toxicity.
Link to relevant study records
Reference
Endpoint:
developmental toxicity
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.
Reference:
Composition 0
Qualifier:
equivalent or similar to
Guideline:
OECD Guideline 414 (Prenatal Developmental Toxicity Study)
Deviations:
not specified
GLP compliance:
not specified
Test material information:
Composition 1
Species:
mouse
Strain:
CD-1
Details on test animals and environmental conditions:
Virgin adult female albino CD-1 outbred mice were gang-housed in disposable plastic cages in temperature and humidity-controlled
quarters with free access to food and fresh tap water. They were mated with young adult males, and observation of the vaginal sperm
plug was considered Day 0 of gestation.
Route of administration:
oral: gavage
Vehicle:
water
Remarks:
10 mL/kg bw
Analytical verification of doses or concentrations:
not specified
Duration of treatment / exposure:
Beginning on Day 6 and continuing daily through Day 15 of gestation, the females were dosed with the indicated dosages by oral intubation; the controls were sham treated.
Duration of test:
10 consecutive days
No. of animals per sex per dose:
32 mated and 22 pregnants at 274 mg/kg
Control animals:
yes, sham-exposed
Maternal examinations:
Body weights were recorded on Days 0, 6, 11, 15, and 17 of gestation. All animals were observed daily for appearance and behavior
with particular attention to food consumption and weight, in order to rule out any abnormalities which may have occurred as a result
of anorexic effects in the pregnant female animal.
On Day 17 all dams were subjected to Caesarean section under surgical anesthesia, and the numbers of implantations sites,
resorptions site, and live dan dead fetus were recorded.
The body weights of the live pups were also recorded. The urogenital tract of each dam was examined in detail for anatomical
normality.
All fetuses were examined grossly for the presence of external congenital abnormalities. One-third of the fetus of each litter
underwent detailed visceral examinations employing the Wilson technique. The remaining two-thirds were cleared in potassium
hydroxide (KOH), stained with alizarin red S dye and examined for skeletal defects.
Ovaries and uterine content:
no data
Fetal examinations:
no data
Statistics:
no data
Indices:
no data
Historical control data:
no data
Clinical signs:
effects observed, non-treatment-related
Dermal irritation (if dermal study):
not specified
Mortality:
not examined
Body weight and weight changes:
not specified
Food consumption and compound intake (if feeding study):
not examined
Food efficiency:
not examined
Water consumption and compound intake (if drinking water study):
not examined
Ophthalmological findings:
not specified
Description (incidence and severity):
no data
Haematological findings:
not specified
Description (incidence and severity):
no data
Clinical biochemistry findings:
not specified
Description (incidence and severity):
no data
Urinalysis findings:
not specified
Description (incidence and severity):
no data
Behaviour (functional findings):
not specified
Description (incidence and severity):
no data
Immunological findings:
not specified
Description (incidence and severity):
no data
Organ weight findings including organ / body weight ratios:
not specified
Description (incidence and severity):
no data
Gross pathological findings:
not specified
Description (incidence and severity):
no data
Neuropathological findings:
not specified
Description (incidence and severity):
no data
Histopathological findings: non-neoplastic:
not specified
Description (incidence and severity):
no data
Histopathological findings: neoplastic:
not specified
Description (incidence and severity):
no data
Other effects:
not specified
Description (incidence and severity):
no data
Details on results:
no data
Number of abortions:
not specified
Description (incidence and severity):
no data
Pre- and post-implantation loss:
not specified
Description (incidence and severity):
no data
Total litter losses by resorption:
not specified
Description (incidence and severity):
no data
Early or late resorptions:
not specified
Description (incidence and severity):
no data
Dead fetuses:
not specified
Description (incidence and severity):
no data
Changes in pregnancy duration:
not specified
Description (incidence and severity):
no data
Migrated Data from removed field(s)
Field "Effects on pregnancy duration" (Path: ENDPOINT_STUDY_RECORD.DevelopmentalToxicityTeratogenicity.ResultsAndDiscussion.ResultsMaternalAnimals.MaternalDevelopmentalToxicity.EffectsOnPregnancyDuration): not specified
Field "Description (incidence and severity)" (Path: ENDPOINT_STUDY_RECORD.DevelopmentalToxicityTeratogenicity.ResultsAndDiscussion.ResultsMaternalAnimals.MaternalDevelopmentalToxicity.DescriptionIncidenceAndSeverityEffectsOnPregnancyDuration): no data
Changes in number of pregnant:
not specified
Description (incidence and severity):
no data
Other effects:
not specified
Description (incidence and severity):
no data
Details on maternal toxic effects:
no data
Key result
Dose descriptor:
NOAEL
Effect level:
274 mg/kg bw/day (actual dose received)
Based on:
test mat.
Basis for effect level:
other: other:
Remarks on result:
not determinable
Remarks:
no NOAEL identified
Fetal body weight changes:
not specified
Description (incidence and severity):
no data
Migrated Data from removed field(s)
Field "Fetal/pup body weight changes" (Path: ENDPOINT_STUDY_RECORD.DevelopmentalToxicityTeratogenicity.ResultsAndDiscussion.ResultsFetuses.FetalPupBodyWeightChanges): not specified
Reduction in number of live offspring:
not specified
Description (incidence and severity):
no data
Changes in sex ratio:
not specified
Description (incidence and severity):
no data
Changes in litter size and weights:
not specified
Changes in postnatal survival:
not specified
Description (incidence and severity):
no clearly discernible
External malformations:
not specified
Description (incidence and severity):
no data
Skeletal malformations:
effects observed, non-treatment-related
Description (incidence and severity):
abnormalities seen in skeletal tissues
Visceral malformations:
not specified
Description (incidence and severity):
no data
Other effects:
not specified
Description (incidence and severity):
no data
Details on embryotoxic / teratogenic effects:
Embryotoxic / teratogenic effects:no effects
Dose descriptor:
NOAEL
Effect level:
ca. 274 mg/kg bw/day
Based on:
test mat.
Sex:
not specified
Basis for effect level:
other: abnormalities seen in soft and skeletal tissues
Remarks on result:
other: the dose of substance was administere to the parental generation
Key result
Abnormalities:
effects observed, non-treatment-related
Localisation:
other: soft and skeletal tissues not otherwise specified
Description (incidence and severity):
no data
Developmental effects observed:
not specified

at 274 mg/kg the results were the following:

Pregnancies:

total: 22, died before day 17°: 0, to term: 22

Live litters:

total: 21

Implant sites:

total: 243, average/dam: 11.1

Resorption:

total: 18, dams with one or more site resorbed: 8, dams with all sites resorbed: 1, partial resorptions: 36.4%, total resorptions: 4.55%

Live fetuses:

total: 222, average/dam: 10.1, sex ratio (M/F): 0.87

dead fetuses:

total: 3, dams with one or more dead: 3, dams with all dead: -, partial dead: 13.6%, all dead: -, average fetus weight: 0.91.

Skeletal findings (fetuses affected/litters affected):

Live fetuses examined (at term): 155/21

Sternebrae: incomplete oss.: 32/17, bipartite: 4/3, missing: 6/4

Ribs: More than 13: 37/16

Vertebrae: 2/2

Extremities: incomplete oss: 2/2

Miscellaneous: Hyoid missing: 26/11, Hyoid reduced: 11/9

Soft tissue abnormalities:

1 pups Gastroschisis

Conclusions:
The administration of up to 274 mg/Kg (body weight) of the test material to pregnant mice for 10 consecutive days had no clearly discernible effect on nidation or on maternal or fetal survival. The number of abnormalities seen in either soft or skeletal tissues of the test groups did not differ from the number occuring spontaneously in the sham-treated controls.
Executive summary:

The administration of up to 274 mg/Kg (body weight) of the test material to pregnant mice for 10 consecutive days had no clearly discernible effect on nidation or on maternal or fetal survival. The number of abnormalities seen in either soft or skeletal tissues of the test groups did not differ from the number occuring spontaneously in the sham-treated controls.

Effect on developmental toxicity: via oral route
Endpoint conclusion:
no adverse effect observed
Study duration:
subacute
Species:
mouse
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 developmental toxicity of tartaric acid and its salts.
Effect on developmental toxicity: via inhalation route
Endpoint conclusion:
no study available
Effect on developmental toxicity: via dermal route
Endpoint conclusion:
no study available
Additional information

Tartaric acid was investigated for its developmental toxicity in mice, rats and rabbits. The substance did not cause significant increases in skeletal abnormalities, fetal survival or in other parameters, compared with the controls.

Based on the chemical structure, it is considered that the toxicity of tartaric acid is the same of that ones of its salts (i.e. monosodium, monopotassium, sodium potassium, sodium, potassium and calcium tartrate) and, therefore, the assessment of this endpoint may be jointly performed using all available data for these substances.

Overall, tartaric acid and its salts do not have developmental toxicity.


Justification for selection of Effect on developmental toxicity: via oral route:
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 substances should not be classified for the toxicity to reproduction/development because the data are judged as "conclusive but not sufficient for classification".