Ethylenediamine-N,N'-di(acetic acid)

Endpoint summary

Key value for chemical safety assessment

Effects on fertility

Effect on fertility: via oral route

Endpoint conclusion:

no adverse effect observed

Dose descriptor:

NOAEL

250 mg/kg bw/day

Study duration:

chronic

Species:

rat

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, EDTA-CaNa2 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 EDTA-CaNa2 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 survived 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 EDTA-CaNa2, 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.

 

A poorly documented summary of preliminary data from a reproduction study on the effects of exposure of Wistar rats to diets containing 0.5, 1.0, and 5.0% (approximately 300, 600, and 3,000 mg/kg/day) EDTA-Na2H2, another structural analogue of the substance, has been reported by Yang,1964. The parental generations of the two lower exposure groups reportedly gave birth to normal first and second litters, while those animals of the highest dose level failed to produce any litters, even though they had been mated for 2 months. No more details were given and data on the second generation were also not reported.

Additional information related to fertility may be obtained from another oral administration study (Muralidhara, 1991) in which administration of 5, 10, and 15 mg/kg EDTA-Na2H2 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. Treatment of male mice with 10 mg Na2EDTA/kg body weight in distilled water for 5 consecutive days induced no increase in the incidence of post implantation embryonic deaths over a mating period of 8 weeks, except for a statistically insignificant - about twofold increase - during week 2 and 3 of mating. However, these results may not be reliable as they were obtained in the same study which reported invalid results in a micronucleus assay.

Short description of key information:

Fertility studies on the substance are not available. Studies are available on structural analogues of the substance, EDTA-CaNa2 and EDTA-Na2H2 (for read-across justification refer to Section 13). Data from a multigeneration study on rats with EDTA-CaNa2 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 regarded as being 250 mg/kg/day.

Effects on developmental toxicity

Description of key information

Developmental toxicity studies on the substance are not available. Studies are available on structural analogues of the substance, sodium salts of EDTA (for read-across justification refer to Section 13). After repeated treatment of dams with EDTA-Na4 (and several other EDTA substances) during various periods of gestation 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). 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, and are considered to be related to zinc deficiency.

Effect on developmental toxicity: via oral route

Endpoint conclusion:

no adverse effect observed

Dose descriptor:

NOAEL

1 000 mg/kg bw/day

Species:

rat

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 g.d. 7 to 14 with 1,000 mg EDTA/kg bw/day as well as with equimolar doses of disodium, trisodium, calcium disodium and tetrasodiumedetate. The dose level had been selected from preliminary studies with edetic acid in which there had been some evidence of both maternal and fetotoxicity under the same experimental conditions. For the dams significant substance-related reactions including diarrhea and depression of activity were reported. The former occurred in all drug groups with highest incidences for tetrasodium edetate (90%) and edetic acid (80%) and lowest incidence for calcium disodium edetate (10%). Three dams died during treatment with disodium edetate. Besides slightly decreased food intake in all test groups, treatment with all of the test compounds caused 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 compounds significantly affected litter size at term or mean fetal body weight when compared to either control. Fetuses were examined for external, visceral and skeletal anomalies. Incidental findings of skeletal anomalies did not reveal a definitive pattern regarding treatment with a particular compound. 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 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.

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 changes in developmental toxicity at dose levels that were not maternally toxic. In accordance with Regulation (EC) No. 1272/2008 there were no changes observed sufficient to warrant classification.