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Toxicological information

Developmental toxicity / teratogenicity

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Administrative data

developmental toxicity
Type of information:
migrated information: read-across from supporting substance (structural analogue or surrogate)
Adequacy of study:
supporting study
2 (reliable with restrictions)
Rationale for reliability incl. deficiencies:
other: Study meets scientifically accepted methods
Reason / purpose for cross-reference:
reference to other study

Data source

Reference Type:
Teratogenesis Studies with EDTA and its Salts in Rats
Schardein JL et al
Bibliographic source:
Toxicol. Appl. Pharmacol. 61, 423-428

Materials and methods

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 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:
Limit test:

Test material

Constituent 1
Reference substance name:
Edetic acid
EC Number:
EC Name:
Edetic acid
Cas Number:
2,2',2'',2'''-(ethane-1,2-diyldinitrilo)tetraacetic acid

Test animals

other: CD albino
Details on test animals or test system and environmental conditions:
- Source: Charls 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
other: 0.2 M phosphate buffer
Details on exposure:
-pH of dosing solution: 3.9

Analytical verification of doses or concentrations:
Details on mating procedure:
- Impregnation procedure: cohoused
- If cohoused:
- 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 devided doses twice daily
Duration of test:
21 days
Doses / concentrations
Doses / Concentrations:
967 mg/kg bw/ day (devided into two eaqual doses)
actual ingested
No. of animals per sex per dose:
Control animals:
yes, concurrent no treatment
yes, concurrent vehicle


Maternal examinations:

- Time schedule for examinations: once a week


- 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 ispection, slicing and visceral abnormalties: 1/3 of the litter
- Skeletal examinations: 2/3 of the litter
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

Maternal developmental toxicity

Details on maternal toxic effects:
Maternal toxic effects:yes

Details on maternal toxic effects:
- diarrhea in 80% of the animals: daily after application; it disappeared after the last day of dosing
- depression of activity in 3 animals
- decreased food intake during treatment (see table 1)
- reduced weight gain during treatment; recovery within the post treatment period

Effect levels (maternal animals)

open allclose all
Dose descriptor:
Effect level:
967 mg/kg bw/day (actual dose received)
Basis for effect level:
other: maternal toxicity
Dose descriptor:
Effect level:
>= 967 mg/kg bw/day (actual dose received)
Basis for effect level:
other: developmental toxicity

Results (fetuses)

Details on embryotoxic / teratogenic effects:
Embryotoxic / teratogenic effects:no effects

Details on embryotoxic / teratogenic effects:
- no effects on litter size, sex ratio or mortality index (see table 2)
- no drug related statisticcally significant increase of malformation could be observed in the treated animals.
(A total of 1084 pups from drug-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 drug-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)

open allclose all
Dose descriptor:
Effect level:
>= 967 mg/kg bw/day (actual dose received)
Basis for effect level:
other: teratogenicity
Dose descriptor:
Effect level:
>= 967 mg/kg bw/day (actual dose received)
Basis for effect level:
other: embryotoxicity
Dose descriptor:
Effect level:
>= 967 mg/kg bw/day (actual dose received)
Basis for effect level:
other: fetotoxicity

Fetal abnormalities

not specified

Overall developmental toxicity

Developmental effects observed:
not specified

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 recieving EDTA and EDTA salts on days 7 through 14 of gestation

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