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Toxicological information

Repeated dose toxicity: oral

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Administrative data

Endpoint:
repeated dose toxicity: oral, other
Type of information:
read-across based on grouping of substances (category approach)
Adequacy of study:
key study
Justification for type of information:
READ-ACROSS CATEGORY APPROACH
The complete Read-across justification text is attached in chapter 13 "Read-across Justification_2017" (two documents attached).
Read-across justification EDTA-DTPA-HEDTA aminocarboxylic acid-based metal chelants (2016). Category approach according to REACH Practical guide 6: How to report read-across and categories; REACH TGD, Chapter R.6: QSARs and grouping of chemicals.
Part 1: Physical Chemistry & Toxicology
Part 2: Environmental Fate & Ecotoxicology
Cross-referenceopen allclose all
Reason / purpose for cross-reference:
read-across source
Reference
Endpoint:
sub-chronic toxicity: oral
Type of information:
experimental study
Adequacy of study:
weight of evidence
Reliability:
2 (reliable with restrictions)
Rationale for reliability incl. deficiencies:
study well documented, meets generally accepted scientific principles, acceptable for assessment
Qualifier:
no guideline available
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
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


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
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
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
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
Key result
Dose descriptor:
NOAEL
Effect level:
>= 500 mg/kg bw/day (nominal)
Sex:
male
Basis for effect level:
clinical signs
food consumption and compound intake
mortality
Critical effects observed:
not specified

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 neither 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 Na2H2EDTA                                                                                            

Reason / purpose for cross-reference:
read-across source
Reference
Endpoint:
chronic toxicity: oral
Type of information:
experimental study
Adequacy of study:
weight of evidence
Reliability:
2 (reliable with restrictions)
Rationale for reliability incl. deficiencies:
study well documented, meets generally accepted scientific principles, acceptable for assessment
Principles of method if other than guideline:
A study for possible carcinogenicity was conducted by administering the test material in feed to Fischer 344 rats. The chemical was administered to 50 males and 50 females at low and high concentrations, for 103 weeks. Matched-control groups were composed of 20 males and 20 females. Animals were analysed for mortality, clinical signs, histopathological as well as gross pathological changes.
GLP compliance:
no
Limit test:
no
Species:
rat
Strain:
Fischer 344
Sex:
male/female
Details on test animals or test system and environmental conditions:
TEST ANIMALS
- Source: Schmidt, Madison, Wisconsin, USA
- Weight at study initiation: 85-110 g
- Age at study initiation: 28 days
- Housing: four per cage in solid polycarbonate cages
- Diet: prepared from Wayne Lab Blox Meal (Allied Mills, Inc.) ad libitum
- Water: acidulated water ad libitum
- Acclimation period: 14 days

ENVIRONMENTAL CONDITIONS
- Temperature (°C): 21-25°C
- Humidity (%): 45-55%
- Air changes (per hr): 15 times per hour
- Photoperiod (hrs dark / hrs light): 16/8

Route of administration:
oral: feed
Vehicle:
unchanged (no vehicle)
Details on oral exposure:
DIET PREPARATION
- Rate of preparation of diet (frequency): 3 times/week
- Mixing appropriate amounts with (Type of food): Wayne Lab Blox Meal (Allied Mills, Inc.)
- Storage temperature of food: 4°C

Analytical verification of doses or concentrations:
yes
Details on analytical verification of doses or concentrations:
- Analyses were performed, using FDA methods to determine the efficiency of the mixing procedure and the stability of the test chemical in feed. Recoveries were found to be 90.3 + / -1.4% of the theoretical value at 7500 ppm EDTA and 90.4 + / - 3.4% of the theoretical value at 3750 ppm. It was concluded from these results that the preparations contained reasonably accurate concentrations of EDTA and were mixed homogeneously, and that the chemical was stable in feed for at least a week.
Duration of treatment / exposure:
103 weeks
Frequency of treatment:
daily
Dose / conc.:
248 mg/kg bw/day (nominal)
Remarks:
original data: 3750 ppm (conversion according to EU risk assessment)

Dose / conc.:
495 mg/kg bw/day (nominal)
Remarks:
original data: 7500 ppm (conversion according to EU risk assessment)
No. of animals per sex per dose:
50 (except for the control, which consisted of only 20 animals)
Control animals:
yes, plain diet
Observations and examinations performed and frequency:
CAGE SIDE OBSERVATIONS: Yes
- Time schedule: twice daily

DETAILED CLINICAL OBSERVATIONS: Yes
- Time schedule: twice daily

BODY WEIGHT: Yes
- Time schedule for examinations: approximately once a month

FOOD CONSUMPTION AND COMPOUND INTAKE: No
OPHTHALMOSCOPIC EXAMINATION: No
HAEMATOLOGY: No
CLINICAL CHEMISTRY: No
URINALYSIS: No
NEUROBEHAVIOURAL EXAMINATION: No
Sacrifice and pathology:
GROSS PATHOLOGY: Yes; all major organs, not specified but presumably all organs used for histopathology: skin, lymph nodes, mammary gland, salivary gland, bone marrow, trachea, lungs and bronchi, heart, thyroids, parathyroids, esophagus, stomach, small intestine, large intestine, liver, gallbladder, pancreas, spleen, kidneys, adrenals, urinary bladder, prostate or uterus, testis or ovary, brain, and pituitary.
HISTOPATHOLOGY: Yes;
skin, lymph nodes, mammary gland, salivary gland, bone marrow, trachea, lungs and bronchi, heart, thyroids, parathyroids, esophagus, stomach, small intestine, large intestine, liver, gallbladder, pancreas, spleen, kidneys, adrenals, urinary bladder, prostate or uterus, testis or ovary, brain, and pituitary.
Statistics:
- Statistical tests of differences in survival between groups are compared using the method of Cox (1972) for two groups and an extension of this method by Tarone (1975) for more than two groups.
- Statistical analysis of the incidence of tumors was made using the Fisher exact test (Cox, 1970) to compare a control group to a group of treated animals at each dose. In addition, the Armitage and Cochran test for linear trend in proportions, with continuity correction (Armitage, 1971), was used.
Clinical signs:
effects observed, non-treatment-related
Description (incidence and severity):
No significant signs were observed among test animals during the first year of the study. In the 6 months preceding termination of the test, corneal opacities, ascites, and urine stains, occurred in both treatment and control groups.
Mortality:
mortality observed, non-treatment-related
Description (incidence):
The male rats exhibited a negative dose-related trend in survival with the probability level of P = 0.103; the treated and control groups of male rats can thus be considered as comparable to each other in survival. The female rats also exhibited a negative dose-related trend in survival. Even though this effect was statistically significant, it is most likely a chance finding as treated animals did not exhibit any deviations from the control group in regard to clinical signs or pathology.
Body weight and weight changes:
no effects observed
Description (incidence and severity):
Average body weights of treated male and female rats were comparable to those of the matched controls throughout the study.
Gross pathological findings:
effects observed, non-treatment-related
Description (incidence and severity):
Inflammatory and degenerative changes were observed in about the same frequency in all groups. These lesions appeared to be related to age and no to the administration of the chemical.
Histopathological findings: neoplastic:
effects observed, non-treatment-related
Description (incidence and severity):
The incidence of neoplasms was high in the reproductive and endocrine systems and lower in the hematopoietic, respiratory, integumentary, and digestive systems. No neoplasms were observed in the nervous, musculoskeletal, or urinary systems or in organs of special sense. A number of tumors occurred in other organ systems of both sexes, controls as well as treated animals. In some instances the incidence of tumors in the controls exceeded that of the treated animals. With the possible exception of endocrine tumors in the males, no clear association between the incidence of tumors, treatment, or sex could be established (see table 1 and 2).
Key result
Dose descriptor:
NOAEL
Effect level:
>= 495 mg/kg bw/day (nominal)
Sex:
male/female
Basis for effect level:
body weight and weight gain
clinical signs
mortality
Critical effects observed:
not specified

Table 1: Analyses of the Incidence of Primary Tumors at Specific Sites in Male Rats Fed EDTA Trisodium Salt in the Diet

Morphology (p-value) Control 250 mg/kg bw/day 500 mg/kg bw/day
Hematopoietic System: Leukemia, Malignant Lymphoma and Lymphocytic Leukemia 3/20 (n.s.) 4/50 (n.s.) 4/50 (n.s.)
Adrenal: Pheochromocytoma 2/20 (n.s.) 5/49 (n.s.) 4/50 (n.s.)
Thyroid: C-cell Adenoma 0/17 (n.s.) 6/45 (p = 0 0.08) 3/38 (n.s.)
Pituitary: Chromophobe Adenoma 0/18 (p = 0.089) 3/47 (n.s.) 5/44 (n.s.)
Lung: Alveolar/Bronchiolar Adenoma and Carcinoma 1/18 (n.s.) 2/50 (n.s.) 3/49 (n.s.)
Liver: Hepatocellular Adenoma and Neoplastic Nodule 0/20 (n.s.) 1/48 (n.s.) 1/50 (n.s.)
Testis: Interstitial-cell Tumor 19/20 (n.s.) 43/50 (n.s.) 44/50 (n.s.)

Table 2 Analyses of the Incidence of Primary Tumors at Specific Sites in Female Rats Fed EDTA Trisodium Salt in the Diet

Morphology (p-value) Control 250 mg/kg bw/day 500 mg/kg bw/day
Hematopoietic System: Leukemia, Malignant Lymphoma and Lymphocytic Leukemia 1/20 (n.s.) 8/50 (n.s.) 0/50 (n.s.)
Adrenal: Pheochromocytoma 1/20 (n.s.) 1/49 (n.s.) 1/48 (n.s.)
Thyroid: C-cell Adenoma 0/11 (n.s.) 0/36 (n.s.) 1/37 (n.s.)
Pituitary: Chromophobe Adenoma 6/19 (n.s.) 10/48 (n.s.) 11/50 (n.s.)
Lung: Alveolar/Bronchiolar Adenoma and Carcinoma 0/20 (n.s.) 3/48 (n.s.) 2/48 (n.s.)
Liver: Neoplastic Nodule 0/20 (n.s.) 1/48 (n.s.) 0/48 (n.s.)
Uterus: Endometrial Stromal Polyp 5/20 (n.s.) 6/50 (n.s.) 7/50 (n.s.)
Mammary Gland: Fibroadenoma 4/20 (n.s.) 3/50 (n.s.) 3/50 (n.s.)

n.s. = not significant
Reason / purpose for cross-reference:
read-across source
Reference
Endpoint:
chronic toxicity: oral
Type of information:
experimental study
Adequacy of study:
weight of evidence
Reliability:
2 (reliable with restrictions)
Rationale for reliability incl. deficiencies:
study well documented, meets generally accepted scientific principles, acceptable for assessment
Principles of method if other than guideline:
A bioassay for possible carcinogenicity was conducted by administering the test material in feed to B6C3F1 mice. The chemical was administered to 50 males and 50 females at low and high concentrations, for 103 weeks. Matched-control groups were composed of 20 males and 20 females. Animals were analysed for mortality, clinical signs, histopathological as well as gross pathological changes.
GLP compliance:
no
Limit test:
no
Species:
mouse
Strain:
B6C3F1
Sex:
male/female
Details on test animals or test system and environmental conditions:
TEST ANIMALS
- Source: Charles River Breeding Laboratories, Wilmington, USA
- Weight at study initiation: 19-22 g
- Age at study initiation: 28 days
- Housing: five per cage in solid polycarbonate cages
- Diet: prepared from Wayne Lab Blox Meal (Allied Mills, Inc.) ad libitum
- Water: acidulated water ad libitum
- Acclimation period: 14 days

ENVIRONMENTAL CONDITIONS
- Temperature (°C): 21-25°C
- Humidity (%): 45-55%
- Air changes (per hr): 15 times per hour
- Photoperiod (hrs dark / hrs light): 16/8
Route of administration:
oral: feed
Vehicle:
unchanged (no vehicle)
Details on oral exposure:
DIET PREPARATION
- Rate of preparation of diet (frequency): 2 times/week
- Mixing appropriate amounts with (Type of food): Wayne Lab Blox Meal (Allied Mills, Inc.)
- Storage temperature of food: 4°C

Analytical verification of doses or concentrations:
yes
Details on analytical verification of doses or concentrations:
- Analyses were performed, using FDA methods to determine the efficiency of the mixing procedure and the stability of the test chemical in feed. Recoveries were found to be 90.3 + / -1.4% of the theoretical value at 7500 ppm EDTA and 90.4 + / - 3.4% of the theoretical value at 3750 ppm. It was concluded from these results that the preparations contained reasonably accurate concentrations of EDTA and were mixed homogeneously, and that the chemical was stable in feed for at least a week.
Duration of treatment / exposure:
103 weeks
Frequency of treatment:
daily
Dose / conc.:
469 mg/kg bw/day (nominal)
Remarks:
original data: 3750 ppm; conversion factor according to EU risk assessment

Dose / conc.:
938 mg/kg bw/day (nominal)
Remarks:
original data: 7500 ppm; conversion factor according to EU risk assessment

No. of animals per sex per dose:
50 (except for the control, which consisted of only 20 animals)

Control animals:
yes, plain diet
Observations and examinations performed and frequency:
CAGE SIDE OBSERVATIONS: Yes
- Time schedule: twice daily

DETAILED CLINICAL OBSERVATIONS: Yes
- Time schedule: twice daily

BODY WEIGHT: Yes
- Time schedule for examinations: approximately once a month

Sacrifice and pathology:
GROSS PATHOLOGY: Yes; all major organs, not specified but presumably all organs used for histopathology: skin, lymph nodes, mammary gland, salivary gland, bone marrow, trachea, lungs and bronchi, heart, thyroids, parathyroids, esophagus, stomach, small intestine, large intestine, liver, gallbladder, pancreas, spleen, kidneys, adrenals, urinary bladder, prostate or uterus, testis or ovary, brain, and pituitary.
HISTOPATHOLOGY: Yes;
skin, lymph nodes, mammary gland, salivary gland, bone marrow, trachea, lungs and bronchi, heart, thyroids, parathyroids, esophagus, stomach, small intestine, large intestine, liver, gallbladder, pancreas, spleen, kidneys, adrenals, urinary bladder, prostate or uterus, testis or ovary, brain, and pituitary.
Statistics:
- Statistical tests of differences in survival between groups are compared using the method of Cox (1972) for two groups and an extension of this method by Tarone (1975) for more than two groups.
- Statistical analysis of the incidence of tumors was made using the Fisher exact test (Cox, 1970) to compare a control group to a group of treated animals at each dose. In addition, the Armitage and Cochran test for linear trend in proportions, with continuity correction (Armitage, 1971), was used.
Description (incidence and severity):
Ataxia occurred in a low-dose male at 8 months, and ascites was noted in mice of both sexes during the second year of the study.
Mortality:
mortality observed, non-treatment-related
Description (incidence):
No statistically significant difference in survival between the different groups in both sexes. (males: 5/50 (10%) of the low-dose group, 2/50 (4%) of the high-dose group, and 1/20 (5%) of the control; females: 0/50 low-dose female mice, 1/20 (5%) of the control group and 3/50 (6%) of the high-dose group)
Body weight and weight changes:
effects observed, treatment-related
Description (incidence and severity):
In male mice only the high-dose group showed throughout most of the test period a decrease in average body weight compared to the controls. In female mice average body weights of the treatment groups were depressed in a dose-related manner during the test period, although the effect was small. No individual data given. No information whether this effect is statistically relevant is available.
Histopathological findings: neoplastic:
effects observed, non-treatment-related
Description (incidence and severity):
A variety of neoplasms was observed in both treated and control animals. Each type observed has been encountered previously as a spontaneous lesion in the mouse. However, the incidence of neoplasms in all groups was high in the hematopoietic, endocrine, digestive, and respiratory systems. The incidence of neoplasms in other systems was variable. (See table 1 and 2)
Key result
Dose descriptor:
NOAEL
Effect level:
>= 938 mg/kg bw/day (nominal)
Based on:
test mat.
Sex:
male
Basis for effect level:
body weight and weight gain
clinical signs
gross pathology
histopathology: non-neoplastic
mortality
Critical effects observed:
not specified

Table 1: Analyses of the Incidence of Primary Tumors at Specific Sites in Male Mice Fed EDTA Trisodium Salt in the Diet

Morphology (p-value) Control 469 mg/kg bw/day 938 mg/kg bw/day
Hematopoietic System:  Malignant Lymphoma  2/20 (n.s.) 7/46 (n.s.) 7/48 (n.s.)
Thyroid: C-cell Adenoma 0/10 (n.s.) 1/29 (n.s.) 1/33 (n.s.)
Pituitary: Chromophobe Adenoma 1/13 (n.s.) 0/19 (n.s.) 1/26 (n.s.)
Lung: Alveolar/Bronchiolar Adenoma and Carcinoma 2/18 (0.096) 2/50 (n.s.) 3/49 (n.s.)
Liver: Hepatocellular Adenoma and Neoplastic Nodule 3/19 (n.s.) 10/44 (n.s.) 10/47 (n.s.)

Table 2: Analyses of the Incidence of Primary Tumors at Specific Sites in Female Mice Fed EDTA Trisodium Salt in the Diet

Morphology (p-value) Control 469 mg/kg bw/day 938 mg/kg bw/day
Hematopoietic System:  Malignant Lymphoma  5/19 (n.s.) 11/49 (n.s.) 12/47 (n.s.)
Thyroid: C-cell Adenoma 1/12 (n.s.) 3/33 (n.s.) 1/34 (n.s.)
Pituitary: Chromophobe Adenoma 2/12 (n.s.) 6/34 (n.s.) 4/29 (n.s.)
Lung: Alveolar/Bronchiolar Adenoma and Carcinoma 0/19 (n.s.) 3/47 (n.s.) 3/49 (n.s.)
Liver: Hepatocellular Adenoma and Neoplastic Nodule 0/19 (n.s.) 1/46 (n.s.) 1/47 (n.s.)

n.s. = not significant
Reason / purpose for cross-reference:
read-across source
Reference
Endpoint:
short-term repeated dose toxicity: oral
Type of information:
experimental study
Adequacy of study:
supporting study
Reliability:
4 (not assignable)
Rationale for reliability incl. deficiencies:
documentation insufficient for assessment
Qualifier:
no guideline available
Principles of method if other than guideline:
A 1 month feeding study on rats was performed using 3 different dose groups. 10 days after the start of the study half of the animals of each group were sacrificed on completion of the feeding period the remaining animals were sacrificed for biochemical and morphological examinations. Additionally one group was treated with CaNa2EDTA.
GLP compliance:
not specified
Species:
rat
Strain:
not specified
Sex:
male/female
Route of administration:
oral: feed
Vehicle:
not specified
Details on oral exposure:
- TS was incorporated in the normal dietary constituents
Analytical verification of doses or concentrations:
not specified
Duration of treatment / exposure:
1 month
Frequency of treatment:
daily
Dose / conc.:
500 mg/kg bw/day (nominal)
Remarks:
original data: 1.0% of the diet, assuming an conversion factor of 20

Dose / conc.:
1 125 mg/kg bw/day (nominal)
Remarks:
original data: 2.25% of the diet, assuming an conversion factor of 20
Dose / conc.:
2 500 mg/kg bw/day (nominal)
Remarks:
original data: 5% of the diet, assuming an conversion factor of 20
No. of animals per sex per dose:
15
Control animals:
not specified
Mortality:
mortality observed, treatment-related
Description (incidence):
Some mortalities in the 2500 mg/kg bw/day dose group (no further data)
Body weight and weight changes:
effects observed, treatment-related
Description (incidence and severity):
Marked suppression of body weight in the 2500 mg/kg bw/day dose group (no further data)
Haematological findings:
effects observed, treatment-related
Description (incidence and severity):
Reduction of total leucocytes and lymphocytes, increase of bound urine nitrogen and decrease of Ca in serum in the 2500 mg/kg bw/day dose group (no further data)
Organ weight findings including organ / body weight ratios:
effects observed, treatment-related
Description (incidence and severity):
Decrease of liver, spleen and thymus weight in the 2500 mg/kg bw dose group (no further data).
Histopathological findings: non-neoplastic:
effects observed, treatment-related
Description (incidence and severity):
In the animals which were sacrificed at the 10th day of the study, some parakeratosis was detected in the oesophagus and forestomach in the 2500 mg/kg bw/day dose group.
Key result
Dose descriptor:
NOAEL
Effect level:
1 125 mg/kg bw/day (nominal)
Sex:
male/female
Basis for effect level:
body weight and weight gain
mortality
Critical effects observed:
not specified

The group treated with CaNa2EDTA showed similar, but milder effects (no further data).

Data source

Materials and methods

Test material

Constituent 1
Chemical structure
Reference substance name:
Tetrasodium ethylenediaminetetraacetate
EC Number:
200-573-9
EC Name:
Tetrasodium ethylenediaminetetraacetate
Cas Number:
64-02-8
Molecular formula:
C10H16N2O8.4Na
IUPAC Name:
tetrasodium 2-({2-[bis(carboxylatomethyl)amino]ethyl}(carboxylatomethyl)amino)acetate
Test material form:
solid

Results and discussion

Effect levels

open allclose all
Key result
Dose descriptor:
NOAEL
Effect level:
>= 500 mg/kg bw/day (nominal)
Sex:
male
Basis for effect level:
clinical signs
food consumption and compound intake
mortality
Remarks on result:
other: CAS 139-33-3
Key result
Dose descriptor:
NOAEL
Effect level:
>= 500 mg/kg bw/day (nominal)
Sex:
male/female
Basis for effect level:
other: highest dose received
Remarks on result:
other: CAS 150-38-9
Key result
Dose descriptor:
NOAEL
Effect level:
469 mg/kg bw/day (nominal)
Sex:
male
Basis for effect level:
body weight and weight gain
Remarks on result:
other: CAS 150-38-9
Dose descriptor:
NOAEL
Effect level:
1 125 mg/kg bw/day (nominal)
Sex:
male/female
Basis for effect level:
body weight and weight gain
mortality
Remarks on result:
other: CAS 139-33-3

Target system / organ toxicity

Critical effects observed:
not specified

Applicant's summary and conclusion