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EC number: 200-449-4 | CAS number: 60-00-4
- Life Cycle description
- Uses advised against
- Endpoint summary
- Appearance / physical state / colour
- Melting point / freezing point
- Boiling point
- Density
- Particle size distribution (Granulometry)
- Vapour pressure
- Partition coefficient
- Water solubility
- Solubility in organic solvents / fat solubility
- Surface tension
- Flash point
- Auto flammability
- Flammability
- Explosiveness
- Oxidising properties
- Oxidation reduction potential
- Stability in organic solvents and identity of relevant degradation products
- Storage stability and reactivity towards container material
- Stability: thermal, sunlight, metals
- pH
- Dissociation constant
- Viscosity
- Additional physico-chemical information
- Additional physico-chemical properties of nanomaterials
- Nanomaterial agglomeration / aggregation
- Nanomaterial crystalline phase
- Nanomaterial crystallite and grain size
- Nanomaterial aspect ratio / shape
- Nanomaterial specific surface area
- Nanomaterial Zeta potential
- Nanomaterial surface chemistry
- Nanomaterial dustiness
- Nanomaterial porosity
- Nanomaterial pour density
- Nanomaterial photocatalytic activity
- Nanomaterial radical formation potential
- Nanomaterial catalytic activity
- Endpoint summary
- Stability
- Biodegradation
- Bioaccumulation
- Transport and distribution
- Environmental data
- Additional information on environmental fate and behaviour
- Ecotoxicological Summary
- Aquatic toxicity
- Endpoint summary
- Short-term toxicity to fish
- Long-term toxicity to fish
- Short-term toxicity to aquatic invertebrates
- Long-term toxicity to aquatic invertebrates
- Toxicity to aquatic algae and cyanobacteria
- Toxicity to aquatic plants other than algae
- Toxicity to microorganisms
- Endocrine disrupter testing in aquatic vertebrates – in vivo
- Toxicity to other aquatic organisms
- Sediment toxicity
- Terrestrial toxicity
- Biological effects monitoring
- Biotransformation and kinetics
- Additional ecotoxological information
- Toxicological Summary
- Toxicokinetics, metabolism and distribution
- Acute Toxicity
- Irritation / corrosion
- Sensitisation
- Repeated dose toxicity
- Genetic toxicity
- Carcinogenicity
- Toxicity to reproduction
- Specific investigations
- Exposure related observations in humans
- Toxic effects on livestock and pets
- Additional toxicological data
![](https://echa.europa.eu./o/diss-blank-theme/images/factsheets/A-REACH/factsheet/print_toxicological-information.png)
Toxicity to reproduction
Administrative data
- Endpoint:
- multi-generation reproductive toxicity
- 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:
- Safety Evaluation Studies of Calcium EDTA
- Author:
- Oser, B.L. et al.
- Year:
- 1 963
- Bibliographic source:
- Toxicology and Applied Pharmacology 5, 142-162 (1963)
Materials and methods
Test guideline
- Qualifier:
- no guideline followed
- Principles of method if other than guideline:
- A dietary multigeneration study on rats was conducted. 25 rats each sex were assigned to 3 test groups and one control group. The rats were dosed for 12 weeks and 2 rats of each sex and each group were sacrificed for histopathological examinations. The remaining rats were kept on the diet until the end of the 2 year treatment period. After approximately 13 weeks matings were set up with one male and two
females per cage. After littering lactation was allowed to continue for 3 weeks. Ten rats of each sex selected from as many litters as possible and representative of the average weight within the litters were assigned to the F1 generation groups. They were raised to maturity in accordance with the same program as the parent generation. Similarly, groups of rats from second litters of the F1 generation and, in turn, the F2 and F3 generations, were each carried through the production of two litter. When the F0 rats reached 2 years on test, the entire study was terminated. - GLP compliance:
- no
- Limit test:
- no
Test material
- Reference substance name:
- Sodium calcium edetate
- EC Number:
- 200-529-9
- EC Name:
- Sodium calcium edetate
- Cas Number:
- 62-33-9
- Molecular formula:
- C10H12CaN2O8.2Na
- IUPAC Name:
- calcium disodium 2,2',2'',2'''-(ethane-1,2-diyldinitrilo)tetraacetate
- Test material form:
- solid
Constituent 1
Test animals
- Species:
- rat
- Strain:
- other: FDRL (derived from Wistar strain)
- Sex:
- male/female
- Details on test animals or test system and environmental conditions:
- TEST ANIMALS
- Housing: individually
- Diet: "natural type diet" ad libitum
- Water: ad libitum
Administration / exposure
- Route of administration:
- oral: feed
- Vehicle:
- unchanged (no vehicle)
- Details on mating procedure:
- After approximately 13 weeks after the start of the exposure (when the rats were about 120 days of age and sexually mature) matings were set up with one male and two females per cage. As pregnancy was recognized (visually, by palpation, or by weight increments) the dam was transferred to an individual cage. If pregnancy was not established by the third week, the male was replaced. A female was regarded as infertile and matings were discontinued after two successive mating failures. Lactation was allowed to continue for 3 weeks, the pups being weighed at 4, 12, and 21 days.
After weaning, death, or destruction of their litters, the females were allowed a 1-week rest period before remating. In successive matings the males were rotated among females within their respective test groups.
Ten rats of each sex selected from as many litters as possible and representative of the average weight within the litters were assigned to the F1 generation groups. They were raised to maturity in accordance with the same program as the parent generation. Similarly, groups of rats from second litters of the F1 generation and, in turn, the F2 and F3 generations, were each carried through the production of two litters. When the F0 rats reached 2 years on test, the entire study was terminated.
The rats selected from each generation for breeding were continued on their respective diets for a 1 2-week feeding period, as described for the F0 generation. Following the weaning of the second litters in the descendant generation rats at the 50- and 125-mg/kg dosage levels were sacrificed and examined grossly post mortem, but the control and highest dosage level groups were continued without change in dietary treatment until about the end of the 2-year study. - Analytical verification of doses or concentrations:
- yes
- Duration of treatment / exposure:
- 2 years
- Frequency of treatment:
- continuously
Doses / concentrationsopen allclose all
- Dose / conc.:
- 0 mg/kg bw/day (nominal)
- Dose / conc.:
- 50 mg/kg bw/day (nominal)
- Dose / conc.:
- 125 mg/kg bw/day (nominal)
- Dose / conc.:
- 250 mg/kg bw/day (nominal)
- No. of animals per sex per dose:
- 23
- Control animals:
- yes, plain diet
Examinations
- Parental animals: Observations and examinations:
- CAGE SIDE OBSERVATIONS: Yes
BODY WEIGHT: Yes
HEMATOLOGY
BLOOD CHEMICAL
URINARY EXAMINATIONS - Postmortem examinations (parental animals):
- SACRIFICE
- Representative animals of the F0 generation were sacrificed 12 weeks after the start of the exposure. At the end of year one, two males and two females of each dose level were sacrificed and at the end of the study 10 or more rats of the control and the 250 mg/kg bw dose group.
WEIGHT
- of liver, kidneys, spleen, heart, adrenals, thyroids and gonads
HISTOPATHOLOGY
- in the animals which died or were sacrificed during the study: liver and kidney at the lower dose levels
- in the animals which were sacrificed at the end of the study: liver, anterior pituitaries, adrenals, kidneys, pancreas, heart, spleen, lungs, marrow, stomach, small and large intestines,
gonads, thyroid, parathyroid, Iymph nodes, spinal cord, and tibias of the control and the 250 mg/kg bw dose group
ADDTIONAL EXAMINATIONS
- determination of the ash content of the tibials of rats in the highest dose group and control group
- microscopic examination of the jaws of representative animals for evidence of dental caries
- xanthine oxidase determination in the liver
- carbonic anhydrase determination in serum - Statistics:
- - Duncan multiple rank and multiple F test
- Reproductive indices:
- Fertility Index (FI): the proportion of matings resulting in pregnancy
Gestation Index (GI): the proportion of pregnancies resulting in live litters - Offspring viability indices:
- Viability Index (VI), the proportion of rats born that survive 4 days or longer;
Lactation Index (LI), the proportion of rats alive at 4 days that survive to weaning.
Results and discussion
Results: P0 (first parental generation)
Effect levels (P0)
- Key result
- Dose descriptor:
- NOAEL
- Effect level:
- >= 250 mg/kg bw/day (nominal)
- Based on:
- test mat.
- Sex:
- male/female
- Basis for effect level:
- clinical signs
- mortality
- Remarks on result:
- other: Highest dose tested
Results: F1 generation
Effect levels (F1)
- Dose descriptor:
- NOAEL
- Generation:
- F1
- Effect level:
- >= 250 mg/kg bw/day (nominal)
- Based on:
- test mat.
- Sex:
- male/female
- Basis for effect level:
- clinical signs
- mortality
- body weight and weight gain
- haematology
- urinalysis
- gross pathology
- histopathology: non-neoplastic
- histopathology: neoplastic
- Remarks on result:
- other: Highest dose tested
Results: F2 generation
Effect levels (F2)
open allclose all
- Dose descriptor:
- NOAEL
- Generation:
- F2
- Effect level:
- >= 250 mg/kg bw/day (nominal)
- Based on:
- test mat.
- Sex:
- male/female
- Basis for effect level:
- clinical signs
- mortality
- body weight and weight gain
- haematology
- urinalysis
- gross pathology
- histopathology: non-neoplastic
- histopathology: neoplastic
- Remarks on result:
- other: Highest dose tested
- Dose descriptor:
- NOAEL
- Effect level:
- >= 250 mg/kg bw/day (nominal)
- Based on:
- test mat.
- Sex:
- male/female
- Basis for effect level:
- clinical signs
- mortality
- body weight and weight gain
- haematology
- urinalysis
- gross pathology
- histopathology: non-neoplastic
- histopathology: neoplastic
- Remarks on result:
- other: F3-Generation, highest dose tested
Overall reproductive toxicity
- Reproductive effects observed:
- not specified
Any other information on results incl. tables
MORTALITY
At 1.5 years survival in all groups ranged from 62 to 86%. Within the last half year of the study deaths were more frequent, however this was not an effect of the treatment (average survival in the 250 mg/kg bw dose group: 61%; in the control 45%).
BEHAVIOR
- No significant abnormalities or differences in behavior or appearance of the rats in any of the generations or among the various dose levels were observed.
GROWTH
- Growth in all groups and in all four generations proceeded at a normal rate, plateauing at about 1 year. In the F0 generation the growth responses within sexes at all levels were essentially equal up to the 76th week. During the final half-year the average body weights varied somewhat more because of premortal losses and deaths, but no significant variations occurred in the intergroup relationships. Growth data for the F1, F2, and F3 generation rats in the control and highest dosage test groups was as good as or better than that of the control group.
BLOOD PARAMETERS
- The hemoglobin, hematocrit, and red blood cell counts all fell within normal ranges up to 1 year. Following this there was a slight downward trend in hemoglobin and red blood cells with advancing age in all groups, including the controls, but there were no dose-related differences. The total and differential leukocyte counts likewise disclosed no effects attributable to the test material. Prothrombin times, determined at 78 and 104 weeks in both the responses in both the 250 mg/kg bw group and the control were in the normal range as well as blood sugar, nonprotein nitrogen and serum calcium levels.
URINALYSIS
-essentially normal.
REPRODUCTIVE PERFORMANCE
- Sometimes poor performance (see table 1) however not dose related.
ORGAN WEIGHTS
- No significant differences were found for the liver, kidneys, spleen, heart, adrenals, gonads or thyroid glands.
PATHOLOGY
By virtue of their diverse character and sporadic distribution among the groups the gross pathologic findings were considered not to be causally related to test dosage. Pulmonary changes were typical of the respiratory infection common in laboratory rats and their frequency in the test groups was, for the most part, less than in the controls. Liver abnormalities also correlated with occurred at least as frequently in the control as in the test groups. Except for mammary tumors which are fairly common in females with variance a history of continuous breeding, the character and number of tumors observed indicated them to be of an incidental nature. They occurred with a frequency comparable to that usually seen in this colony.
HISTOLOGY
Microscopically, no important aberrations were evident in the liver, kidneys, gastrointestinal tract, and tibias of the four rats in each group selected for sacrifice either at 12 weeks or at 1 year. In the 250-mg/kg bw group, in which 13 organs and tissues of each rat were examined, the findings were consistently negative.
In the histopathologic examinations of the F0 generation rats sacrificed at 2 years revealed changes in the anterior pituitaries (focal hyperplasia); adrenal cortex (focal hyperplasia); medulla (focal hyperplasia) and liver. However, the changes revealed were not dose related.
Table 1: Reproduction and lactation data for four generations of rats fed with CaNa2EDTA
Average litter size | |||||||||
Dose (mg/kg bw/day) | Generation | Total number of matings | At birth | At weaning | Average weight of pups at weaning (g) | F.I. | G.I. | V.I. | L.I. |
None | F0 | 46 | 7.7 | 5.7 | 44.9 | 70 | 94 | 57 | 78 |
F1 | 20 | 8.6 | 7.5 | 47.5 | 85 | 100 | 92 | 89 | |
F2 | 20 | 8.3 | 7.8 | 41.3 | 95 | 100 | 85 | 96 | |
F3 | 20 | 8.4 | 8.7 | 37.4 | 75 | 100 | 88 | 90 | |
50 | F0 | 41 | 8.3 | 7.3 | 41 | 90 | 100 | 69 | 82 |
F1 | 20 | 5.8 | 5.7 | 46.5 | 65 | 92 | 76 | 89 | |
F2 | 20 | 7.7 | 6.5 | 44.7 | 80 | 100 | 90 | 88 | |
F3 | 20 | 9.8 | 9.2 | 39.7 | 95 | 95 | 96 | 97 | |
125 | F0 | 44 | 9.2 | 8.7 | 42 | 57 | 96 | 46 | 76 |
F1 | 18 | 6.4 | 6.5 | 47.6 | 78 | 93 | 66 | 95 | |
F2 | 20 | 8.2 | 6.6 | 49.6 | 75 | 100 | 89 | 84 | |
F3 | 20 | 8.1 | 6.6 | 46.1 | 95 | 84 | 76 | 87 | |
250 | F0 | 46 | 8.9 | 6.9 | 42.8 | 85 | 100 | 70 | 72 |
F1 | 19 | 5.5 | 6.3 | 45.3 | 58 | 100 | 67 | 93 | |
F2 | 12 | 10.5 | 8.1 | 40.5 | 92 | 100 | 92 | 86 | |
F3 | 20 | 6.8 | 6.3 | 49.4 | 70 | 93 | 79 | 93 |
F.I. = Fertility Index = (pregnancies/mating) x 100
G.I. = Gestation Index = (litters born/pregnancies) x 100
V.I. = Viability Index = (pups alive at 4 days/pups born) x 100
L.I. = Lactation Index = (pups weaned/pups alive at 4 days) x 100
RESULTS OF ADDITIONAL TESTS
- The tibias of rats sacrificed at the 12-week period showed no evidence of abnormal calcification.
- At the end of the 2-year period, the ash content of the tibias in the control and 250-mg/kg groups were approximately the same.
- There was no difference in either the incidence or severity of dental caries.
- There were no significant differences in the two metallo-enzymes blood carbonic anhydrase and liver xanthine oxidase.
Applicant's summary and conclusion
- Conclusions:
- There was no evidence for an influence of CaNa2EDTA on the fertility of rats.
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