Registration Dossier

Toxicological information

Repeated dose toxicity: oral

Currently viewing:

Administrative data

Endpoint:
sub-chronic toxicity: oral
Type of information:
migrated information: read-across from supporting substance (structural analogue or surrogate)
Adequacy of study:
key study
Reliability:
2 (reliable with restrictions)
Rationale for reliability incl. deficiencies:
other: Study meets generally accepted scientific principles For read-across justification refer to section 13.

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:
1970
Bibliographic source:
Toxicology and Applied Pharmacology 16, 807-817 (1970)

Materials and methods

Principles of method if other than guideline:
A 13 weeks 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
Name:
Unnamed
Type:
Constituent

Test animals

Species:
rat
Strain:
other: Holtzman
Sex:
male
Details on test animals 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 (10.0% ) 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 5.0% 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 / concentrations
Remarks:
Doses / Concentrations:
500; 2500; 5000 mg/kg bw/day (original data:1; 5; 10%; conversion factor: 20)
Basis:
nominal in diet
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

Details on results:
CLINICAL SIGNS AND MORTALITY
500 mg/kg bw/day dose group: nothing abnormal detected
2500 mg/kg bw/day dose group: 2/10 animals died; diarrhea starting at the third day
5000 mg/kg bw/day dose group: 6/10 animals died; animals were emaciated, diarrhea starting at the third day

BODY WEIGHT GAIN
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
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
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

HAEMATOLOGY
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 CHEMISTRY
serum calcium level did not differ from the control

URINALYSIS: 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 PATHOLOGY
500; 2500 mg/kg bw/day dose group: nothing abnormal detected
5000 mg/kg bw/day dose group: pale livers,

HISTOPATHOLOGY:
Nothing abnormal detected

Effect levels

Dose descriptor:
NOAEL
Effect level:
>= 500 mg/kg bw/day (nominal)
Sex:
male

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