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EC number: 238-729-3 | CAS number: 14689-29-3
- 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
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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 BL, Oser M. Spencer HC
- Year:
- 1 963
- Bibliographic source:
- Toxicology and Applied Pharmacology 5, 142-162
Materials and methods
Test guideline
- Qualifier:
- no guideline followed
- Principles of method if other than guideline:
- In a 2 year feeding study on Wistar rats including reproductive and lactation experiments in four successive generations groups of 25 male and 25 female animals were exposed to CaNa2EDTA at dietary levels providing daily doses of approximately 50, 125, and 250 mg/kg bw .
- 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
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 exposure:
- See section 7.5.1
- 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
- Details on analytical verification of doses or concentrations:
- In the studies reported, a 25% solution of calcium EDTA was used. Two samples were prepared and stored in polyethylene bottles
at room temperature. Portions for use in the experimental work were withdrawn as needed. Analytical studies demonstrated that these solutions
were stable throughout the period covered by this work. - Duration of treatment / exposure:
- 2 years
- Frequency of treatment:
- continuously
Doses / concentrations
- Remarks:
- Doses / Concentrations:
0, 50, 125, 250 mg/kg bw
Basis:
nominal in diet
- No. of animals per sex per dose:
- 23
- Control animals:
- yes, plain diet
- Positive control:
- No
Examinations
- Parental animals: Observations and examinations:
- CAGE SIDE OBSERVATIONS: Yes
- Time schedule:
BODY WEIGHT: Yes
- Time schedule for examinations:
FOOD CONSUMPTION AND COMPOUND INTAKE (if feeding study):
- Food consumption for each animal determined and mean daily diet consumption calculated as g food/kg body weight/day: No
- Compound intake calculated as time-weighted averages from the consumption and body weight gain data: No data
HEMATOLOGY
BLOOD CHEMICAL
URINARY EXAMINATIONS
See also section 7.5.1. - Oestrous cyclicity (parental animals):
- Not determined
- Sperm parameters (parental animals):
- Not determined
- Postmortem examinations (parental animals):
- See also section 7.5.1.
- 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)
General toxicity (P0)
- Clinical signs:
- no effects observed
- Body weight and weight changes:
- no effects observed
- Food consumption and compound intake (if feeding study):
- no effects observed
- Organ weight findings including organ / body weight ratios:
- no effects observed
- Histopathological findings: non-neoplastic:
- no effects observed
- Other effects:
- not examined
Reproductive function / performance (P0)
- Reproductive function: oestrous cycle:
- not examined
- Reproductive function: sperm measures:
- not examined
- Reproductive performance:
- no effects observed
Details on results (P0)
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.
URINARY ANALYSIS
Essentially normal.
REPRODUCTIVE PERFORMANCE: see below
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, they were not dose related.
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
Effect levels (P0)
- Dose descriptor:
- NOAEL
- Effect level:
- >= 250 mg/kg bw/day (nominal)
- Based on:
- test mat.
- Sex:
- male/female
- Basis for effect level:
- other: no significant effects at 250 mg/kg bw/day
Target system / organ toxicity (P0)
- Critical effects observed:
- no
Results: P1 (second parental generation)
Effect levels (P1)
- Dose descriptor:
- NOAEL
- Effect level:
- >= 250 mg/kg bw/day (nominal)
- Based on:
- test mat.
- Sex:
- male/female
- Basis for effect level:
- other: no significant effects at 250 mg/kg bw
Target system / organ toxicity (P1)
- Critical effects observed:
- no
Results: F1 generation
General toxicity (F1)
- Clinical signs:
- no effects observed
- Mortality / viability:
- no mortality observed
- Body weight and weight changes:
- not examined
- Sexual maturation:
- not examined
- Organ weight findings including organ / body weight ratios:
- not examined
- Gross pathological findings:
- not specified
- Histopathological findings:
- not examined
Details on results (F1)
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:
- other: no significant effects at 250 mg/kg bw
Target system / organ toxicity (F1)
- Critical effects observed:
- no
Results: F2 generation
Effect levels (F2)
- Dose descriptor:
- NOAEL
- Generation:
- F2
- Effect level:
- >= 250 mg/kg bw/day (nominal)
- Based on:
- test mat.
- Sex:
- male/female
- Basis for effect level:
- other: No significant effects at 250 mg/kg bw/day
Target system / organ toxicity (F2)
- Critical effects observed:
- no
Overall reproductive toxicity
- Reproductive effects observed:
- no
Any other information on results incl. tables
REPRODUCTIVE PERFORMANCE
- Sometimes poor performance (see Table 1) however these effects 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
Applicant's summary and conclusion
- Conclusions:
- There was no evidence for an influence of EDTA-CaNa2 on the fertility of rats.
- Executive summary:
In 2 -year feeding studies with rats receiving diets containing calcium EDTA at levels to provide 50, 125, or 250 mg per kilogram body weight, no adverse effects on growth or food efficiency were observed. Hematologic examination, conducted periodically, and determination of prothrombin time, blood sugar, NPN, and serum calcium were likewise normal throughout the test period. Responses similar to those seen in the parent generation were observed in the rats of the three succeeding generations maintained on the same diet. Under the stresses of repeated pregnancies and lactation, no adverse effect of calcium EDTA was observed as measured by any of the usual indexes of reproduction or lactation efficiency. At autopsy neither gross examination nor the weights of the major organs disclosed any significant differences between the test and control groups. The histopathologic findings likewise revealed no consistent or dose-related effects.
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