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EC number: 200-573-9 | CAS number: 64-02-8
Toxicological information
Developmental toxicity / teratogenicity
Currently viewing:
Administrative data
- Endpoint:
- developmental toxicity
- 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
Cross-reference
- Reason / purpose for cross-reference:
- reference to other study
Data source
Referenceopen allclose all
- Reference Type:
- publication
- Title:
- Teratogenesis Studies with EDTA and its Salts in Rats
- Author:
- Schardein, J.L. et al
- Year:
- 1 981
- Bibliographic source:
- Toxicology and Applied Pharmacology 61, 423-428 (1981)
- Reference Type:
- secondary source
- Title:
- Teratogenesis Studies with EDTA and its Salts in Rats
- Author:
- Schardein, J.L. et al
- Year:
- 1 981
- Bibliographic source:
- Toxicol. Appl. Pharmacol., 61, 423-428, (1981) Cited in: Bibra Bulletin 21, No. 1, pp 12-13, (1982)
Materials and methods
Test guideline
- Qualifier:
- no guideline followed
- Principles of method if other than guideline:
- EDTA and four of its salts, disodium, trisodium, calcium di-sodium, and tetrasodium edetate, were studied for teratogenic potential in rats. Equimolar doses based on 1000 mg/kg bw/day were given by gastric intubation on Days 7 to 14 of gestation. On day 21 of gestation the dams of each group were sacrificed and litter data for each dam collected.
- GLP compliance:
- no
- Limit test:
- no
Test material
- 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
Constituent 1
Test animals
- Species:
- rat
- Strain:
- other: CD albino
- Details on test animals or test system and environmental conditions:
- TEST ANIMALS
- Source: Charles River Breeding Laboratories
- Weight at study initiation: mean: 241 g
- Diet: Purina Lab Chow ad libitum
- Water: tap water ad libitum
Administration / exposure
- Route of administration:
- oral: gavage
- Vehicle:
- other: 0.2 M phosphate buffer
- Details on exposure:
- -pH of dosing solution: 3.9
- Analytical verification of doses or concentrations:
- no
- Details on mating procedure:
- - Impregnation procedure: co-housed
- If co-housed:
- M/F ratio per cage: 1:1
- Proof of pregnancy: vaginal plug, sperm in vaginal smear referred to as day 0 of pregnancy - Duration of treatment / exposure:
- 7 days (day 7 to day 14 of gestation)
- Frequency of treatment:
- equally divided doses twice daily
- Duration of test:
- 21 days
Doses / concentrations
- Dose / conc.:
- 1 374 mg/kg bw/day (actual dose received)
- No. of animals per sex per dose:
- 20
- Control animals:
- yes, concurrent no treatment
- yes, concurrent vehicle
Examinations
- Maternal examinations:
- CAGE SIDE OBSERVATIONS: Yes
BODY WEIGHT: Yes
- Time schedule for examinations: once a week
FOOD CONSUMPTION AND COMPOUND INTAKE (if feeding study): Yes
POST-MORTEM EXAMINATIONS: Yes
- Sacrifice on gestation day 21
- Ovaries and uterine content:
- The ovaries and uterine content was examined after termination: Yes
Examinations included:
- Number of implantations: Yes
- Number of early resorptions: Yes
- Number of late resorptions: Yes - Fetal examinations:
- - External examinations: each fetus
- Gross inspection, slicing and visceral abnormalities: 1/3 of the litter
- Skeletal examinations: 2/3 of the litter - Statistics:
- Means and standard errors were calculated for litter size, followed by analysis of variance. Pre- and postimplantation losses, embryonic viability, and fetal survival were evaluated by analysis of covariance. Fetal weights were also evaluated by analysis of covariance following calculation of mean weight/litter by sex, the values representing means and standard errors of mean litter weights. Significant variance by either analysis of variance or covariance was further evaluated by Dunnett's t test to locate the source of variance. Sex distribution was analyzed by partitioned chi^2.
Results and discussion
Results: maternal animals
General toxicity (maternal animals)
- Clinical signs:
- effects observed, treatment-related
- Description (incidence and severity):
- diarrhea in 90% of the animals: daily after application; it disappeared after the last day of dosing
- Body weight and weight changes:
- effects observed, treatment-related
- Description (incidence and severity):
- reduced weight gain during treatment; recovery within the post treatment period
- Food consumption and compound intake (if feeding study):
- effects observed, treatment-related
- Description (incidence and severity):
- decreased food intake during treatment (see table 1)
Effect levels (maternal animals)
- Dose descriptor:
- NOAEL
- Effect level:
- 1 374 mg/kg bw/day (actual dose received)
- Basis for effect level:
- other: maternal toxicity
Maternal abnormalities
- Abnormalities:
- no effects observed
Results (fetuses)
- Changes in sex ratio:
- no effects observed
- Description (incidence and severity):
- see table 2
- Changes in litter size and weights:
- no effects observed
- Description (incidence and severity):
- see table 2
- External malformations:
- no effects observed
- Description (incidence and severity):
- no test item related statistically significant increase of malformation could be observed in the treated animals
- Skeletal malformations:
- effects observed, non-treatment-related
- Details on embryotoxic / teratogenic effects:
- - no effects on mortality index (see table 2)
A total of 1084 pups from test item-treated dams were examined. These were compared to 237 pups from 19 dams treated with the vehicle and 278 pups from 20 untreated dams. In addition, 752 pups from dams treated with edetic acid and its salts together with 165 and 191 pups from the vehicle and untreated control groups, respectively, were cleared and examined for skeletal defects. Twenty-four pups from the test item-treated groups had abnormalities. These included 20 with bifid vertebrae, 1 with agenesis of the ribs, 2 with inhibition of osteogenesis of the skull or ribs, and 1 with malformed ribs. There was no definitive pattern regarding treatment with a particular compound and the occurrence of anomalies. None of the pups in the vehicle control group had abnormalities while 8 untreated control pups exhibited some major defect. One untreated control fetus was stunted and had multiple abnormalities including eye defect, ectrodactyly, and a curly tail. Histological examination of the eyes revealed a cataract in one eye and a dysmorphic lens and retina in the other. Five additional control pups had bifid vertebrae while 2 had malformed vertebrae or sternebrae.
Effect levels (fetuses)
- Key result
- Dose descriptor:
- NOAEL
- Effect level:
- >= 1 374 mg/kg bw/day (actual dose received)
- Basis for effect level:
- other: teratogenicity, embryotoxicity, fetotoxicity
Fetal abnormalities
- Abnormalities:
- no effects observed
Overall developmental toxicity
- Developmental effects observed:
- no
Any other information on results incl. tables
Table 1: Food consumption and weight gain in rats treated with EDTA and EDTA salts on days 7 through 14 of gestation
| Days | Control (untreated) | Vehicle Control | 967 mg/kg bw/day EDTA | 1243 mg/kg bw/day Na2 EDTA | 1245 mg/kg bw/day Na3 EDTA | 1340 mg/kg bw/day CaNa2 EDTA | 1374 mg/kg bw/day Na4 EDTA |
| Mean food consumption (g/day) | |||||||
| 0-7 | 20.7 | 21.4 | 19.9 | 20.4 | 19.9 | 20.4 | 19.0 |
| 7-14 | 22.3 | 22.5 | 18.4 | 17.5 | 19.1 | 20.9 | 18.5 |
| 14-21 | 24.7 | 25.3 | 26.7 | 27.2 | 25.7 | 26.5 | 25.6 |
| Mean body weight gain (g) | |||||||
| 0-7 | 31.9 | 35.1 | 37.6 | 35.6 | 33.2 | 37.2 | 26.9 |
| 7-14 | 28.5 | 26.1 | 16.5 | 13.7 | 20.4 | 25.1 | 18.3 |
| 14-21 | 102.7 | 93.3 | 104.4 | 100.2 | 98.4 | 108.1 | 94.2 |
Table 2: Reproductive data in dams receiving EDTA and EDTA salts on days 7 through 14 of gestation
| Fetuses | ||||||||||
| Sex | Body weight (mean g ± SE) | Number | ||||||||
| Treatment | No of dams | Litter size (mean ± SE) | Post implantation loss (%) | M | F | M | F | Dead | live | Resorbed |
| Control (untreated) | 20 | 14.0 ± 0.4 | 4 | 52 | 48 | 5.3 ± 0.1 | 5.6 ± 0.1 | 1 | 278 | 12 |
| Vehicle Control | 19 | 12.5 ± 0.1 | 3 | 50 | 50 | 5.3 ± 0.1 | 5.7 ± 0.1 | 0 | 237 | 7 |
| 967 mg/kg bw/day EDTA | 17 | 12.7 ± 0.6 | 3 | 49 | 51 | 5.5 ± 0.1 | 5.7 ± 0.1 | 0 | 216 | 6 |
| 1243 mg/kg bw/day Na2 EDTA | 19 | 12.6 ± 0.4 | 1 | 56 | 44 | 5.4 ± 0.1 | 5.6 ± 0.1 | 0 | 202 | 3 |
| 1245 mg/kg bw/day Na3 EDTA | 18 | 12.4 ± 1.0 | 8 | 48 | 52 | 5.4 ± 0.2 | 5.7 ± 0.1 | 0 | 210 | 11 |
| 1340 mg/kg bw/day CaNa2 EDTA | 17 | 13.5 ± 0.4 | 2 | 52 | 48 | 5.3 ± 0.1 | 5.6 ± 0.1 | 0 | 230 | 4 |
| 1374 mg/kg bw/day Na4 EDTA | 19 | 11.9 ± 0.7 | 4 | 47 | 52 | 5.2 ± 0.1 | 5.5 ± 0.1 | 0 | 226 | 10 |
- 2 dams had to be killed due to dosing errors
Applicant's summary and conclusion
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