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Toxicological information

Carcinogenicity

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Administrative data

Endpoint:
carcinogenicity: oral
Type of information:
experimental study
Adequacy of study:
key study
Reliability:
2 (reliable with restrictions)
Rationale for reliability incl. deficiencies:
guideline study with acceptable restrictions
Justification for type of information:
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.

Data source

Reference
Reference Type:
publication
Title:
The comparative chronic toxicities of fumaric, tartaric, oxalic, and maleic acids.
Author:
Fitzhugh OG, Nelson AA.
Year:
1947
Bibliographic source:
J Am Pharm Assoc Am Pharm Assoc 1947; 36 (7): 217-219.

Materials and methods

Test guideline
Qualifier:
no guideline followed
GLP compliance:
not specified

Test material

Reference
Name:
Unnamed
Type:
Constituent
Details on test material:
fine white crystalline material
Specific details on test material used for the study:
no data

Test animals

Species:
rat
Strain:
Osborne-Mendel
Details on species / strain selection:
no data
Sex:
male/female
Details on test animals and environmental conditions:
equally divided between sexes, weanling rats (21 days).
All animals were kept in individuaI cages in a room with the temperature and humidity controlled for the duration of the experiment and were given free access to their respective diets and water. The

Administration / exposure

Route of administration:
oral: feed
Vehicle:
not specified
Details on exposure:
Ground commercial rat biscuits with 1% added cod-liver oil serverd as the basic diet. The acid was mixed the basic diet by means of a rotary batch mixer.
Analytical verification of doses or concentrations:
not specified
Details on analytical verification of doses or concentrations:
no data
Duration of treatment / exposure:
2 years feeding study
Frequency of treatment:
daily
Post exposure period:
no data
Doses / concentrationsopen allclose all
Dose / conc.:
0.1 other: %
Remarks:
equivalent to approximately 100 mg/kg/day
Dose / conc.:
0.5 other: %
Remarks:
equivalent to approximately 500 mg/kg/day
Dose / conc.:
0.8 other: %
Remarks:
equivalent to approximately 800 mg/kg/day
Dose / conc.:
1.2 other: %
Remarks:
equivalent to approximately 1200 mg/kg/day
No. of animals per sex per dose:
first experiment: 12 groups of 24 rats (total)
second experiment:
Control animals:
yes
Positive control:
Basic diet supplied

Examinations

Observations and examinations performed and frequency:
The weights of individuaI animals (Effect on Growth) and their food consumption were deterrnined at weekly intervals.
Sacrifice and pathology:
Autopsy was done on nearly all the rats used in these experiments, a few being omitted because of advanced post-mortem autolysis.
A greater amount of microscopic pathological examination was done than would have been necessary to.demonstrate the relativeIy minimal nature of the pathological changes produced by the acids.
Other examinations:
no data
Statistics:
no data

Results and discussion

Results of examinations

Clinical signs:
not specified
Description (incidence and severity):
no data
Dermal irritation (if dermal study):
not specified
Description (incidence and severity):
no data
Mortality:
not examined
Description (incidence):
Statistical tests cannot be applied to the mean survival time since alI surviving animals were sacrificed at the conclusion of two years on the experiment.
Most of the deaths, exeept for a few animals distributed throughout all groups and killed because of middle ear disease, occurred during the second year of the experiment.
The difference between the mortality rate of either group of experimental animals and that of the controls was not significant.
There was no signifieant difference between the mortality rate of the rats on any dosage level of tartaric acid.
Body weight and weight changes:
no effects observed
Description (incidence and severity):
all animaIs made a normal gain in weight during the first fifty-two weeks of the experiment.
No difference between the mean gain in weight of the controls and that of tartaric acids.
Food consumption and compound intake (if feeding study):
no effects observed
Description (incidence and severity):
When the data for the weekly food consumption of eaeh group during the first twenty-six weeks of the experiment were analyzed. The differenees between the control and experimental animals were not statistieally significant.
Food efficiency:
not specified
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
Haematological findings:
not examined
Clinical biochemistry findings:
not examined
Urinalysis findings:
not examined
Behaviour (functional findings):
not examined
Immunological findings:
not examined
Organ weight findings including organ / body weight ratios:
not examined
Gross pathological findings:
no effects observed
Description (incidence and severity):
A relativeIy minimal nature of the pathological changes was produced by the acid.
In 213 rats, hematoxylin-eosin stained paraffin sections of the following structures were routinely made: lung, heart, liver, spleen, pancreas, stomach, small intestine, kidney, adrenal, and testis. The following additionai structures were sectioned frequently enough to make it reasonably certain that no changes in them were being caused by the acids: colon, bone marrow, Ieg bones, Ieg musèles, Iymph nodes, uterus, ovary, thyroid, and parathyroid.
In all the foregoing structures, no difference could be seen between treated and control anirnals except the following.
the gross and microscopic findings in this series of rats showed no difference between controi and treated animals.
Neuropathological findings:
not examined
Histopathological findings: non-neoplastic:
no effects observed
Description (incidence and severity):
Tumors and other more or Iess frequently occurring spontaneous diseases of older rats, such as periarteritis nodosa-like arteriallesions, bile duct proliferation in the liver, et cetera, showed no difference in incidence among the various animaI groups
Histopathological findings: neoplastic:
no effects observed
Description (incidence and severity):
Tumors and other more or Iess frequently occurring spontaneous diseases of older rats, such as periarteritis nodosa-like arteriallesions, bile duct proliferation in the liver, et cetera, showed no difference in incidence among the various animaI groups
Other effects:
not specified
Description (incidence and severity):
no data
Details on results:
No significant toxic effeet occurred in rats fed diets containing 1.2 % of tartaric acid
Relevance of carcinogenic effects / potential:
No evidence of a treatment-related increase in tumor incidence compared to controls.

Effect levels

Dose descriptor:
other: highest tested level
Effect level:
1.2 other: %
Based on:
test mat.
Sex:
male/female
Basis for effect level:
body weight and weight gain
food consumption and compound intake
gross pathology
histopathology: non-neoplastic
histopathology: neoplastic
Remarks on result:
not determinable due to adverse toxic effects at highest dose / concentration tested

Applicant's summary and conclusion

Conclusions:
At the end of the 2 years no evidence of a treatment-related increase in tumor incidence compared to controls was revealed.
Executive summary:

Data are given on the effeets of the oral administration of tartaric and other organic acids. The result of the study indicate a low degree of toxicity for tartaric acid. Tartaric acid was not toxic in concentrations as high as 1.2% and no evidence of a treatment-related increase in tumor incidence compared to controls was reported.