Registration Dossier

Toxicological information

Toxicity to reproduction

Currently viewing:

Administrative data

Endpoint:
toxicity to reproduction
Remarks:
other: Chronic
Type of information:
experimental study
Adequacy of study:
supporting study
Reliability:
2 (reliable with restrictions)

Data source

Reference
Reference Type:
publication
Title:
Comparative subacute toxicity for rabbits of citric, fumaric, and tartaric acids
Author:
Packman EW, Abbott DD and Harrisson JWE
Year:
1963
Bibliographic source:
Toxicology and applied pharmacology 1963; 5 (2): 163-167.

Materials and methods

Test guideline
Qualifier:
no guideline followed
Principles of method if other than guideline:
no data
GLP compliance:
not specified

Test material

Reference
Name:
Unnamed
Type:
Constituent
Test material form:
not specified
Details on test material:
No further information on test material idendity are available.
Specific details on test material used for the study:
no data

Test animals

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.

Administration / exposure

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
Doses / concentrations
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

Examinations

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

Results and discussion

Results: P0 (first parental animals)

General toxicity (P0)

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 / performance (P0)

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

Details on results (P0)

no data

Effect levels (P0)

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)

Target system / organ toxicity (P0)

Critical effects observed:
not specified

Results: P1 (second parental generation)

General toxicity (P1)

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 / performance (P1)

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

Details on results (P1)

no data

Results: F1 generation

General toxicity (F1)

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

Developmental neurotoxicity (F1)

Behaviour (functional findings):
not examined
Description (incidence and severity):
no data

Developmental immunotoxicity (F1)

Developmental immunotoxicity:
not examined
Description (incidence and severity):
no data

Details on results (F1)

no data

Results: F2 generation

General toxicity (F2)

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

Developmental neurotoxicity (F2)

Behaviour (functional findings):
not examined
Description (incidence and severity):
no data

Developmental immunotoxicity (F2)

Developmental immunotoxicity:
not examined
Description (incidence and severity):
no data

Details on results (F2)

no data

Overall reproductive toxicity

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

Any other information on results incl. tables

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.

Applicant's summary and conclusion

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.