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Diss Factsheets

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:
1981
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:
1981
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

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

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