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EC number: 205-358-3 | CAS number: 139-33-3
Repeated dose toxicity: oral
Administrative data
- Endpoint:
- sub-chronic toxicity: oral
- Type of information:
- experimental study
- Adequacy of study:
- key study
- Reliability:
- 2 (reliable with restrictions)
- Rationale for reliability incl. deficiencies:
- study well documented, meets generally accepted scientific principles, acceptable for assessment
Data source
Reference
- Reference Type:
- publication
- Title:
- The Toxicity and Pharmacodynamics of EGTA: Oral Administration to Rats and Comparisons with EDTA
- Author:
- Wynn, J.E. et al.
- Year:
- 1 970
- Bibliographic source:
- Toxicology and Applied Pharmacology 16, 807-817 (1970)
Materials and methods
- Principles of method if other than guideline:
- A 13-week feeding study on rats was performed using 3 different dose groups and one control group. After 13 weeks 50 % of the animals of each group were sacrificed and tissues examined for gross and histopathologic changes. The remaining animals were placed on control diet for 4 weeks. Thereafter animals were sacrificed and examined for gross and histopathologic changes.
- GLP compliance:
- no
Test material
- Reference substance name:
- Disodium dihydrogen ethylenediaminetetraacetate
- EC Number:
- 205-358-3
- EC Name:
- Disodium dihydrogen ethylenediaminetetraacetate
- Cas Number:
- 139-33-3
- Molecular formula:
- C10H14N2Na2O8
- IUPAC Name:
- disodium dihydrogen 2,2',2'',2'''-(ethane-1,2-diyldinitrilo)tetraacetate
- Test material form:
- solid
Constituent 1
Test animals
- Species:
- rat
- Strain:
- other: Holtzman
- Sex:
- male
- Details on test animals or test system and environmental conditions:
- TEST ANIMALS
- Weight at study initiation: 120 ± 6 g
- Diet: Ground Purina Laboratory Chow
Administration / exposure
- Route of administration:
- oral: feed
- Vehicle:
- unchanged (no vehicle)
- Details on oral exposure:
- DIET PREPARATION
The top level (10 %) diet was prepared by adding the appropriate amount of Na2H2EDTA to the basic diet. This was then diluted with the basic diet to prepare the 5 % diet. Lower concentrations were similarly prepared by dilution of the next highest concentration.
- Analytical verification of doses or concentrations:
- no
- Duration of treatment / exposure:
- 13 weeks
- Frequency of treatment:
- daily
Doses / concentrationsopen allclose all
- Dose / conc.:
- 500 mg/kg bw/day (nominal)
- Remarks:
- original data: 1 % ; conversion factor: 20
- Dose / conc.:
- 2 500 mg/kg bw/day (nominal)
- Remarks:
- original data: 5 % ; conversion factor: 20
- Dose / conc.:
- 5 000 mg/kg bw/day (nominal)
- Remarks:
- original data: 10 % ; conversion factor: 20
- No. of animals per sex per dose:
- 10
- Control animals:
- yes, plain diet
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 :
- Mean food consumption g/animal
WATER CONSUMPTION
- not specified
HAEMATOLOGY: Yes
- Time schedule for collection of blood: at the end of the 4th and 13th week
- Parameters checked: hematocrit, hemoglobin, total and differential white blood cell counts, prothrombin times
CLINICAL CHEMISTRY
- Time schedule for collection of blood: at the end of the 4th and 13th week
- Parameters checked: calcium level
URINALYSIS: Yes
- Time schedule for collection of urine: not specified
- Parameters checked: Calcium
OPHTHALMOSCOPIC EXAMINATION: No
CLINICAL CHEMISTRY: No
NEUROBEHAVIOURAL EXAMINATION: No - Sacrifice and pathology:
- GROSS PATHOLOGY: liver, kidney, spleen, lung, heart, urogenital system, digestive organs, and muscle
HISTOPATHOLOGY: Yes
Results and discussion
Results of examinations
- Clinical signs:
- effects observed, treatment-related
- Description (incidence and severity):
- 500 mg/kg bw/day dose group: nothing abnormal detected
2500 mg/kg bw/day dose group: diarrhea starting at the third day
5000 mg/kg bw/day dose group: animals were emaciated, diarrhea starting at the third day - Mortality:
- mortality observed, treatment-related
- Description (incidence):
- 2500 mg/kg bw/day dose group: 2/10 animals died
5000 mg/kg bw/day dose group: 6/10 animals died - Body weight and weight changes:
- effects observed, treatment-related
- Description (incidence and severity):
- 500 mg/kg bw/day dose group: no difference to the control group
2500; 5000 mg/kg bw/day dose group: statistically significant reduced body weight gain (control: 326 g; 2500 mg/kg bw/day dose group: 185 g; 5000 mg/kg bw/day dose group: 4 g) - Food consumption and compound intake (if feeding study):
- effects observed, treatment-related
- Description (incidence and severity):
- 500 mg/kg bw/day dose group: normal food consumption
2500; 5000 mg/kg bw/day dose group: statistically significant lower food consumption than the control - Water consumption and compound intake (if drinking water study):
- effects observed, treatment-related
- Description (incidence and severity):
- 500 mg/kg bw/day dose group: nothing abnormal detected
2500 mg/kg bw/day dose group: twice the water consumption of the control
5000 mg/kg bw/day dose group: nothing abnormal detected - Haematological findings:
- effects observed, treatment-related
- Description (incidence and severity):
- after 4 weeks: hematocrits and hemoglobins of the 5000 mg/kg bw/day dose group slightly depressed
after 13 weeks: nothing abnormal detected in any of the groups - Clinical biochemistry findings:
- no effects observed
- Description (incidence and severity):
- serum calcium level did not differ from the control
- Urinalysis findings:
- effects observed, treatment-related
- Description (incidence and severity):
- total calcium:
500 mg/kg bw/day dose group: no difference to the control
2500; 5000 mg/kg bw/day dose group: ca. twice as much as in the control - Gross pathological findings:
- effects observed, treatment-related
- Description (incidence and severity):
- 500; 2500 mg/kg bw/day dose group: nothing abnormal detected
5000 mg/kg bw/day dose group: pale livers - Histopathological findings: non-neoplastic:
- no effects observed
Effect levels
- Key result
- Dose descriptor:
- NOAEL
- Effect level:
- >= 500 mg/kg bw/day (nominal)
- Based on:
- test mat.
- Sex:
- male
- Basis for effect level:
- body weight and weight gain
- clinical signs
- food consumption and compound intake
- mortality
Target system / organ toxicity
- Critical effects observed:
- not specified
Any other information on results incl. tables
RECOVERY
Once the survivors were placed on a control diet the diarrhea, when present, subsided the within 24 hours. The animal that had previously received 5000 mg/kg bw/day Na2H2EDTA still had low food consumption and died within l week. All other animals survived this 4-week period . The animals that had received 2500 mg/kg bw/ day Na2H2EDTA gained weight more slowly than did the other animals and weighed significantly less than controls at the end of the 4-week withdrawal period. The chelating agent was not detectable in the urine after 2-3 days, nor in the feces after 7 days. The autopsies revealed no significant findings.
- EGTA was better tolerated in the diet than EDTA
Applicant's summary and conclusion
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