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Key value for chemical safety assessment

Effects on fertility

Description of key information

Fertility studies on the substance itself are not available. Studies are available on structural analogues of the substance (for read-across justification refer to Section 13). Data from a multigeneration study on rats with CaNa2EDTA did not give evidence for adverse effects on reproductive performance and outcome at dose levels up to 250 mg/kg/day and the NOAEL was considered to be the highest level tested viz. .>= 250 mg/kg/day.

Effect on fertility: via oral route
Endpoint conclusion:
no adverse effect observed
Study duration:
subchronic
Species:
rat
Quality of whole database:
Study with sufficient details available
Effect on fertility: via inhalation route
Endpoint conclusion:
no study available
Effect on fertility: via dermal route
Endpoint conclusion:
no study available
Additional information

A study available on a structural analogue of the substance, CaNa2EDTA investigated effects on reproductive performance and lactation experiments in four successive generations of Wistar rats in a 2 year feeding study. 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/day (Oser et al., 1963). No significant differences in behaviour or appearance nor adverse effects on the growth or on the longevity of the rats in any of the generations or among the various dose levels were reported. Evaluation of various tissues and organs (weight, microscopic examination) including gonads (testes) gave negative results even in the high dose group. Reproductive and lactational indices evaluated included fertility index, gestation index viability index and proportion of rats alive at 4 days that survive to weaning. Poor responses with respect to some of the criteria of reproductive performance occurred occasionally but were not correlated with dosage or with the number of generations through which dosage continued. The overall data for two matings in the four successive generations did not give evidence for significant treatment related differences in either of these indexes. The authors concluded that the no adverse effect level (NOAEL) of CaNa2EDTA, as measured by any of the usual indices of reproduction or lactation efficiency derived from this study is >= 250 mg/kg/day for the parental and F1 to F3 generations.

Additional information related to fertility may be obtained from another oral administration study (Muralidhara, 1991) in which administration of 5, 10, and 15 mg Na2EDTA/kg to male adult Swiss albino mice for five consecutive days did not affect neither absolute or relative weights of epididymides and testes nor the microscopic architecture of these two organs when examined 1, 3, 5, and 7 weeks after treatment. Similarly, no effects were detected on caudal sperm counts, and there were no changes in the incidence of sperm head abnormalities or in the percentage of abnormal sperms.

Justification for selection of Effect on fertility via oral route:

Best documented of the studies available

Effects on developmental toxicity

Description of key information

Developmental toxicity studies on the substance itself are not available. Studies are available on structural analogues of the substance (for read-across justification refer to Section 13). After repeated treatment of dams with Na4EDTA during various periods of gestation and with the use of different routes of substance administration (diet, gavage, s.c.) impaired embryo/foetal development and the induction of a pattern of gross malformations were observed during these investigations with the exception of one gavage study (Schardein et al ., 1981). Gross malformations, comprised cleft palate, severe brain deformities, eye defects, micro- or agnathia, syndactyly, clubbed legs and tail anomalies. These effects were almost exclusively exhibited in studies using maternally toxic dosage levels and occurred at exposure levels of approximately 1,000 mg/kg/day and above.

Effect on developmental toxicity: via oral route
Endpoint conclusion:
no adverse effect observed
Dose descriptor:
NOAEL
1 000 mg/kg bw/day
Study duration:
subacute
Species:
rat
Quality of whole database:
Studies with sufficient details available
Effect on developmental toxicity: via inhalation route
Endpoint conclusion:
no study available
Effect on developmental toxicity: via dermal route
Endpoint conclusion:
no study available
Additional information

EDTA and four of its salts were evaluated for their teratogenic potential in CD albino rats (Schardein et al., 1981). Groups of 20 females were treated by gavage during gestation days 7 to 14 with 1,000 mg EDTA/kg/day as well as with equimolar doses of disodium, trisodium, calcium disodium and tetrasodium edetate (dissolved and suspended in phosphate buffer with final pH values ranging from 3.9 to 9.2). The dose level had been selected from preliminary studies with edetic acid in which there had been some evidence of both maternal and foetotoxicity under the same experimental conditions. For the dams, significant substance-related reactions including diarrhoea and depression of activity were reported. The former occurred in all treated groups with the highest incidences for Na4EDTA (90%) and EDTA acid (80%) and lowest incidence for CaNa2EDTA (10%). Three dams died during treatment with Na2EDTA. Besides slightly decreased food intake in all test groups, treatment with all of the substances resulted in reduced weight gain in the dams during the treatment period. The mortality index of offspring in all treated groups, as measured by postimplantation loss, was comparable to that of the vehicle and untreated control group. None of the test substances significantly affected litter size at term or mean foetal body weight when compared to either control. Foetuses were examined for external, visceral and skeletal anomalies. Incidental findings of skeletal anomalies did not reveal a definitive pattern regarding treatment. The authors stated that under these experimental conditions no teratogenic effects were evidenced even at maternally toxic doses.

In a further developmental study pregnant Sprague-Dawley rats were exposed during various periods of gestation to purified diets adjusted to either 100 or 1,000 ppm zinc (provided as zinc carbonate) and containing 2 or 3% EDTA-Na2H2 corresponding to 1000 or 1500 mg/kg bw daily intake (Swenerton and Hurley, 1971). The groups of 8 to 16 females had been set on the control diet at least 5 days before breeding and mated to normal stock-fed males. The evaluation of treatment related effects to the dams was not indicated in this study, except for the report on moderate to severe diarrhea in all females that were fed diets containing EDTA-Na2H2. While obviously complete reproductive failure occurred with the 3% EDTA-Na2H2/100 ppm zinc diet fed during g.d. 0 -21, with the 2% EDTA-Na2H2/100 ppm zinc diet, the reproductive outcome was essentially comparable to that of controls, however with lower mean body weight of the pups and with 7% malformed of the fullterm fetuses. Exposure to the 3% EDTA-Na2H2/100 ppm zinc diet during the period of g.d. 6 -14, and 6 -21 resulted in respectively 40% and 54% dead or absorbed fetuses, reduced number of dams with live pubs, clearly reduced mean fetal body weight and ratios of respectively 87% and 100% malformed living offspring. Gross malformations comprised cleft palate, severe brain deformities, eye defects, micro- or agnathia, syndactyly, clubbed legs and tail anomalies. The reported fetotoxic and teratogenic effects were similar to those from earlier experiments with zinc deficient diets administered to pregnant rats for various periods of during gestation (Hurley, 1966). In contrast, the live offspring of dams fed 3% EDTA-Na2H2 supplemented with 1,000 ppm zinc from g.d. 6-21 did not exhibit any malformations, and the mean number of live pups/litter and the mean fetal body weight were comparable to those of controls. The authors concluded from this study that EDTA-Na2H2 ingested during pregnancy was teratogenic, whereas supplementation with zinc prevented the detrimental effects of EDTA. It was suggested that the congenital anomalies caused by EDTA were due specifically to zinc deficiency. This was also supported by zinc analyses of fetuses (Hurley and Swenerton, 1966), where clearly lower zinc contents were found in fetuses from deficient mothers in comparison to those from zinc supplemented dams, indicating that the reported effects rather occur because of a direct lack of zinc in fetal tissues than from indirect effects of maternal metabolism on fetal development.

The toxic and teratogenic effects of EDTA-Na2H2 were studied in female CD rats following different routes of administration (dietary, gavage, s.c) during g.d. 7-14 (Kimmel, 1977). Dietary exposure to 3% EDTA-Na2H2 amounting to an average dose of 954 mg EDTA-Na2H2/kg bw/day resulted in reduced food intake, severe diarrhea and severe weight loss in the dams during treatment and produced a significant proportion of fetal deaths (about 33% resorptions/litter), significantly lower average fetal weight and gross external, internal and skeletal malformations in about 71% of the survivors. Treatment with 1,500 or 1,250 mg EDTA-Na2H2/ kg bw/day administered by gavage (respectively 625 mg/kg and 750 mg/kg twice daily) resulted in severe toxicity to the dams (7 out of 8 animals died in the 1,500 mg dose group), in particular 36% maternal deaths, significantly reduced weight gain, and diarrhea in the 1,250 mg dose group and a significantly higher proportion of (about 21%) malformed survivors. Treatment with 375 mg/kg bw administered subcutaneously produced signs of severe pain (vocalisations and shock) to the dams and resulted in 24% maternal deaths, significantly reduced food intake and maternal weight loss during the period of treatment. Fetal toxicity (about 32% resorptions/litter, significantly reduced fetal weight) and a rate of about 4% malformed survivors/litter were reported for this route of application.

These effects were explained by the high affinity of EDTA for Zn resulting in Zn-deficiency. .

Justification for classification or non-classification

A multigeneration study of reproductive toxicity revealed no functional changes in fertility or reproductive performance. Pre-natal developmental toxicity studies revealed no effects on developmental toxicity at dose levels that were not maternally toxic. In accordance with Regulation (EC) No. 1272/2008 there were no effects observed sufficient to warrant classification.