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Key value for chemical safety assessment

Effects on fertility

Description of key information
Additionally, several in vitro tests on the teratogenic effects of EDTA are available. However, they gave inconsistent results and were generally not well reported. Therefore they have not been considered for the risk assessment. 2 cases of pregnant woman treated with CaNa2EDTA for lead intoxication are available. However, as these treatments have been carried out late in pregnancy, these data have been not considered for the risk assessment. 
Additional information

In a 2 year feeding study on Wistar rats including reproductive and lactation experiments in four successive generations 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 bw (Oser et al ., 1963). No significant differences in behavior 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. Evaluations of various tissues and organs (weight, histopathologic examinations) including gonads (testes) gave negative results even in the high dose group. Criteria for reproductive and lactational effects were evaluated as proportion of matings resulting in pregnancy (fertility index), proportion of pregnancies resulting in live litters (gestation index), proportion of pups that survive 4 days or longer (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 no adverse effect of CaNa2EDTA was observed as measured by any of the usual indices of reproduction or lactation efficiency even under the stresses of repeated pregnancies and lactation. The NOAEL derived from this study is >= 250 mg/kg bw/day for the parent and F1 to F3 generation.

In a poorly documented summary of a reproduction study preliminary data on the effects of exposure of Wistar albino rats to diets containing 0.5, 1.0, and 5.0% Na2EDTA (according to about 300, 600, and 3,000 mg/kg bw/day) were presented (Yang,1964). It was reported, that the parent generations of the two lower exposure groups 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. Also data on the second generation were not available.

Additional information related to fertility were obtained from a further oral administration study (Muralidhara, 1991). Administration of 5, 10, and 15 mg Na2EDTA/kg bw to male adult Swiss albino mice for five consecutive days did not affect neither absolute or relative weights of epididymides and testes nor histoarchitecture of these two organs assayed at 1, 3, 5, and 7 weeks after treatment. Likewise, 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. Furthermore treatment of male mice with 10 mg Na2EDTA/kg bw 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 are not reliable as they were obtained in the same study which reported invalid results in the micronucleus assay.

Short description of key information:
Fertility studies using tetraammonium EDTA are not available. Therefore studies with CaNa2EDTA of Na2EDTA have used for risk assessment. (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 for doses of up to 250 mg/kg bw/day. For estimating a NOAEL other studies were not taken into consideration because of methodological flaws. Hence the NOAEL is 250 mg/kg bw/day for CaNa2EDTA.
As ammonium ion are ubiquitous in the human body it is unlikely that the ammonium ions may posses any effect on fertility below the NOAEL derived from the studies with CaNa2EDTA.

Effects on developmental toxicity

Description of key information
Teratogenicity studies using tetraammonium EDTA are not available. Therefore studies with other EDTA salts or the free acid have used for risk assessment. After repeated treatment of dams during various periods of gestation and with the use of different routes of substance application (diet, gavage, s.c., i.m.) impaired embryo/fetal 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. 
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 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 fetotoxicity under the same experimental conditions. For the dams significant drug-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% Na2EDTA 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 Na2EDTA. While obviously complete reproductive failure occurred with the 3% Na2EDTA/100 ppm zinc diet fed during g.d. 0-21, with the 2% Na2EDTA/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% Na2EDTA/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% Na2EDTA 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 Na2EDTA 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 Na2EDTA 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% Na2EDTA amounting to an average dose of 954 mg Na2EDTA/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 Na2EDTA/ 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.

Toxicity to reproduction: other studies

Additional information

Several in vitro tests for teratogenicity have been performed. In a study of Schmid (1985) 9.5 days old rat embryos were cultured in heat inactivated male rat serum containing Aroclor induced liver S9-mix and 10 - 300 µg/ml EDTA (unclear whether the free acid or a salt was tested). After 48 h incubation no effects on crown-rump and head length or degrees of differentiation were observed. There were also no malformations observed. In another study there was also no interference with normal cell differentiation of murine neuroblast cells (clone N1E-115) (no information regading the concentrations available) (Mummery, 1984). However, severe cytotoxicity was observed with an EC 100 of 292 µg/ml and an NEC of 2.9 µg/ml.

(1984) conducted a teratogenic test in vitro with cell cultures of forelimb buds and midbrains of 13 day old rat embryos. He reported that up to 500 µg/ml EDTA had no effect on forelimb bud differentiation, but inhibited CNS differentiation at with an IC50 of 2.8 µg/ml and an NEC of 1 µg/ml. 292 µg/ml EDTA also inhibited the cell differentiation to myotubes and ganglia in Oregon R Drosophila embryonic cultures (Bournias-Vardiabasis,1983).

In an additional study by(1984) 40 mg/kg bw of EDTA sodium salt were administered to rabbits on the 12th day of gestation. 16 h later embryos were removed and midbrain and forelimb buds cultured for 5 days. EDTA inhibited cell culture development by less than 20%. It was stated that EDTA interferes with the cell culture development.

In a not very reliable study by Gassett (1977) 0.1 or 3% EDTA solution were dropped into the eye of 4 rabbits 6 times a day. The treatment was performed from sixth to the eighteenth day of gestation. Fetuses were obtained by cesarian section at day 29 of gestation. No teratogenic effect was reported for both EDTA concentrations, however at the 3% dose group the number of fetuses alive dropped from 23 in the 0.1% dose group to 8. In parallel the number of aborted or resorbed fetuses increased from 3 to 19.

Two additional reports on the treatment of pregnant woman with CaNa2EDTA are available. In one case a 8 months pregnant woman was treated for 7 days with 75 mg/kg bw/day CaNa2EDTA for lead poisoning (Angle 1964). 4 weeks later the mother delivered of normal infant (3.2 kg); developmental assessment of this boy at age 4 3/4 revealed nothing abnormal.

In the other case a 7th month pregnant woman was treated with 0.5 g CaNa2EDTA/day intravenously 3 times a week for 4 weeks (Abendroth, 1971). The delivered infant was healthy and a follow up check at age of 4 also revealed nothing abnormal.

Justification for classification or non-classification

Based on the results obtained in the toxicity studies and taking into account the provisions laid down in Council Directive 67/548/EEC and CLP, a classification has not to be done with respect to toxicity to reproduction.

Additional information