Potassium [[N,N'-ethylenebis[N-(carboxymethyl)glycinato]](4-)-N,N',O,O',ON,ON']ferrate(1-)

Endpoint summary

Key value for chemical safety assessment

Effects on fertility

Link to relevant study records

Reference

Endpoint:

toxicity to reproduction

Remarks:

other: 4-generation test

Type of information:

migrated information: read-across from supporting substance (structural analogue or surrogate)

Adequacy of study:

supporting study

Study period:

not applicable

Reliability:

2 (reliable with restrictions)

Rationale for reliability incl. deficiencies:

other: Extended review on all toxicological endpoints of EDTA and related substances

Reason / purpose for cross-reference:

reference to same study

Qualifier:

no guideline followed

Principles of method if other than guideline:

4-generation test

GLP compliance:

no

Limit test:

no

Species:

rat

Strain:

Wistar

Sex:

not specified

Route of administration:

oral: feed

Vehicle:

not specified

Reproductive effects observed:

not specified

Conclusions:

There were no effects on reproduction up to and including a level of 250 mg/kg bw.

Executive summary:

Heimbach summarized studies on reproductive and developmental toxicity in animals. Here is the summary of the reproductive toxicity:

Oser et al. (1963) maintained Wistar rats (25 animals/sex/group) on nutritionally adequate diets (i.e. standard laboratory feed supplemented with inorganic salts, vitamins and cottonseed oil) and adjusted to provide 0, 50, 125 and 250 mg CaNa2EDTA/kg bw/ day for up to 2 years. Feeding was carried out through four successive generations (F0, F1, F2, F3) to examine potential adverse effects on reproduction and lactation. 10 rats from each treatment group representing the F1 generation were raised to maturity and allowed to produce two litters; a similar regimen was followed for the F2 and F3 litters. The second litters from each generation (control and 250 mg/kg bw/day groups only) were maintained without change in dietary treatment until the end of the 2-year period for the F0 generation. This protocol permitted observations to be made on rats receiving test diets for 0.5, 1, 1.5 or 2 yr in the F3, F2, F1 and F0 generations, respectively. Investigators reported no treatment-related differences in growth, survival, gross or histopathology, reproductive performance, or haematology, urinalysis or blood chemistry parameters when animals were fed up to 250 mg/kg bw/day CaNa2EDTA in the diet (reported by the authors to be equivalent to a dietary concentration of 5000 ppm) for four generations.

The studies summarized above reveal a lack of reproductive and developmental toxicity associated with EDTA compounds when administered orally along with nutritionally adequate diets (Oser et al., 1963; Shardein et al., 1981), or when purified diets were fortified with zinc (Swenerton and Hurley, 1971).

Effect on fertility: via oral route

Endpoint conclusion:

no adverse effect observed

Quality of whole database:

Based on the information indicated above, and in view of tests with other metal chelates, no classification is needed for EDTA-FeK for this endpoint (see also read across document in section 13).

Effect on fertility: via inhalation route

Endpoint conclusion:

no study available

Effect on fertility: via dermal route

Endpoint conclusion:

no study available

Additional information

Based on read across with other EDTA compounds such as EDTA-CaNa2 and EDTA-MnNa2 it is concluded that reproductive effects were not present at levels up to 250 or 500 mg/kg bw, respectively. This was also concluded by Heimbach et al. (2000) and in the RAR on EDTA-H4 and EDTA-Na4 (2004). Heimbach et al. (2000) concluded that EDTA compounds are not reproductive toxicants when fed with a nutrient sufficient diet or minimal diets supplemented with Zn. If animals were treated with EDTA-FeK and not with an empty chelate such as EDTA-H4 or EDTA-Na4, binding of zinc will even be less.

Short description of key information:

Studies with levels up to 250 mg/kg bw EDTA-CaNa2 did not give any indication for effects on reproduction. A study on EDTA-MnNa2 showed decreased sperm motility at a level of 1500 mg/kg bw but not at 500 mg/kg bw. In the latter study, no changes were found on female reproduction.

Justification for selection of Effect on fertility via oral route:

Nice overview of EDTA-FeNa available.

Effects on developmental toxicity

Description of key information

Studies with levels up to ca. 1000 mg/kg bw EDTA-compounds did not give any indication for effects on development; higher levels revealed developmental effects including malformations. A study on EDTA-MnNa2 in rats showed a decreased number of females with liveborn pups, a decreased number of (live) pups and an increased post-implantation loss at a level of 1500 mg/kg bw but not at 500 mg/kg bw; maternal toxicity was also observed at 1500 mg/kg bw. In an oral study with EDTA-MnNa2 in rabbits developmental effects were also seen in the presence of maternal toxicity (see also read across document in section 13).  

Link to relevant study records

Reference

Endpoint:

developmental toxicity

Type of information:

migrated information: read-across from supporting substance (structural analogue or surrogate)

Adequacy of study:

supporting study

Reliability:

2 (reliable with restrictions)

Rationale for reliability incl. deficiencies:

other: Extended review on all toxicological endpoints of EDTA and related substances

Reason / purpose for cross-reference:

reference to same study

Abnormalities:

not specified

Developmental effects observed:

not specified

Conclusions:

It was concluded that EDTA compounds are not developmental toxic when administered orally along with nutritionally adequeate diets.

Executive summary:

Heimbach summarized studies on reproductive and developmental toxicity in animals. Here are the developmental studies:

Swenerton and Hurley (1971) fed pregnant female Sprague Dawley rats a purified diet containing 2 or 3% Na2EDTA (equivalent to approximately 2000 or 3000 mg/kg bw/day, respectively) and 100 ppm zinc carbonate during gestation. All females fed Na2EDTA had moderate to severe diarrhoea. The 2% Na2EDTA diet caused a slight impairment of reproduction and an increased incidence of malformations (including brain, cleft palate, malformed digits, clubbed legs and malformed tails). The 3% Na2EDTA diet severely affected reproduction. In a second study, pregnant females were fed either the control diet with 100 ppm zinc, 3% Na2EDTA with 100 ppm zinc or 3% Na2ETDA supplemented with 1000 ppm zinc on gestation days 6±21. Significant increases in malformations were seen in animals given 3% Na2EDTA at the low zinc level of 100 ppm but not with 1000 ppm zinc. The investigators suggested that the observed teratogenic effects were not attributable to EDTA itself but rather to an induced deficiency of zinc that was insufficient to support normal foetal development.

Kimmel (1977) demonstrated that the route of administration of Na2EDTA had a marked effect on developmental toxicity. Groups of pregnant rats were given Na2EDTA in a semipurified diet at a dose of 954 mg/kg bw/day (3% in diet); by gavage at a dose of 1250 mg/kg bw/day (given as a split dose of 625 mg/kg bw twice/day) or 1500 mg/kg bw/day (given as a split dose of 750 mg/kg bw twice/day); or by subcutaneous injection at a dose of 375 mg/kg bw/day. Animals in all groups were dosed on gestation days 7 through 14 and foetuses were examined on gestation day 21 for skeletal and visceral malformations. Maternal toxicity was evident by decreased food consumption, diarrhoea, and reduced weight gain in groups treated by all three dose routes. Dietary administration of EDTA resulted in no maternal deaths, but malformations were seen in 71% of the offspring. By gavage, EDTA was more toxic to the dams, but resulted in fewer malformed offspring (20.5% at 625 mg/kg bw/day) than did dietary administration. By subcutaneous injection (at a dose about one-third to one-half that of the other routes), EDTA was lethal to 24% of the dams, but produced a low rate (4.3%) of malformed offspring. Kimmel (1975, 1977) and Kimmel and Sloan (1975) speculated that the mechanism by which EDTA induced developmental toxicity was the binding of zinc by EDTA resulting in zinc deficiency during embryonic development. In support of this proposed mechanism, Kimmel noted that the observed malformations were similar to those seen in zinc-deficient rats, and that the findings of their laboratory were consistent with Swenerton and Hurley (1971) when a low-zinc diet was used. Shardein et al. (1981) investigated the developmental toxicity of EDTA (acid form), Na2EDTA, Na3EDTA, Na4EDTA or CaNa2EDTA. Equimolar doses of 1000 mg/kg bw/day were given in two split doses by gavage on days 7±14 of gestation to groups of 20 pregnant rats that were maintained on a nutritionally complete, standard lab chow diet. Dams were sacrificed on day 21 of gestation and foetuses were examined for abnormalities. Diarrhoea and decreased food intake and weight gain were observed in all treated groups. EDTA, Na2EDTA, and Na4EDTA had the greatest effects on weight gain. None of the test compounds significantly affected litter size, foetal mortality, or rate of malformations. The absence of positive findings in this gavage study contrasts with the high incidence of malformations noted by Kimmel (1977) in gavage studies performed with animals receiving a semipurified diet with limited levels of zinc and other micronutrients.

The studies summarized above reveal a lack of developmental toxicity associated with EDTA compounds when administered orally along with nutritionally adequate diets (Oser et al., 1963; Shardein et al., 1981), or when purified diets were fortified with zinc (Swenerton and Hurley, 1971).

Effect on developmental toxicity: via oral route

Endpoint conclusion:

no adverse effect observed

Quality of whole database:

Based on the information indicated above, and in view of tests with other metal chelates, no classification is needed for EDTA-FeNa for this endpoint (see also read across document in section 13).

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

It was concluded that with regard to EDTA-compounds, that the mechanism by which EDTA induced developmental toxicity at high levels of EDTA was the binding of zinc by EDTA resulting in zinc deficiency during embryonic development (Heimbach et al., 2000; RAR, 2004). With regard to EDTA-FeK, binding of Zn will even be less. However, at a very high level of 1500 mg/kg bw, EDTA-MnNa2 was maternal and developmental toxic in rats; in rabbits developmental effects were also seen in the presence of maternal toxicity. Such changes were not seen with the zinc chelate of EDTA (RAR, 2004) and are therefore also not expected for iron i.e. EDTA-FeK. In contrast, Fe-shortage in dams (fed with 7.5 mg Fe per kg diet instead of 50 mg Fe per kg diet) resulted in greater pup mortality, smaller pup size, and pups with larger hearts, and with smaller kidneys and spleens.

Justification for selection of Effect on developmental toxicity: via oral route:

Nice overview of EDTA-FeNa available.

Justification for classification or non-classification

As EDTA and the zinc chelate of EDTA obviously lack a specific teratogenic potential (RAR, 2004), it is expected that this applies to EDTA-FeK too. In addition, because malformations caused by EDTA compounds have been demonstrated at relatively high oral dose levels (i.e. 1000 mg/kg bw and above) in the presence of maternal toxicity, and a steep dose response relationship can be assumed (RAR, 2004), no classification for reprotoxicity is needed.