Sodium [N-[2-[bis(carboxymethyl)amino]ethyl]-N-(2-hydroxyethyl)glycinato(4-)]ferrate(1-)

Endpoint summary

Key value for chemical safety assessment

Effects on fertility

Effect on fertility: via oral route

Endpoint conclusion:

no study available

Quality of whole database:

Several oral studies with other chelates and metal chelates are available (see 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 the results of th study with DTPA-FeHNa, viz. a decrease in sperm motility, cauda epididymis weight and in sperm reserve, as observed in male animals treated with the highest concentration of the test substance, and absed on other studies with metal chelates (see also read across doucment in section13), the No Observed Adverse Effect Level (NOAEL) for fertility for HEDTA-FeNa is also expected to be 500 mg/kg body weight/day.

Short description of key information:
In an extended oral OECD 422 study with DTPA-FeHNA male and female animals were exposed for 10 weeks, next they mated during 1 week. The gestation period lasted 3 weeks and female animals and pups were killed 4 days after birth. As such males were treated for at least 13 weeks and females for almost 14 weeks. At the high dose level the following effects were observed (see also section 7.5): decreased relative weight of epididymides, and a decrease in sperm motility and epididymal sperm reserve. See also at Discussion.

Effects on developmental toxicity

Description of key information

In the study with DTPA-FeHNa, there were no treatment-related differences in litter size and sex, and pup body weight. Macroscopic examination of the pups at birth and at necropsy, and skeletal analyses of the pups did not reveal any treatment-related changes. 

Effect on developmental toxicity: via oral route

Endpoint conclusion:

no study available

Quality of whole database:

Seeveral studies with other chelates and metal chelates are 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

Based on the results of the study with DTPA-FeHNa, which did not show any toxicological effects of the test substance on development, the No Observed Adverse Effect Level (NOAEL) for developmental toxicity is ≥1500 mg/kg body weight/day. These results are in line with studies with other metal chelates (see also read across document in section 13). The same results are expected for HEDTA-FeNa.

Toxicity to reproduction: other studies

Additional information

The results of this study are also in line with subcutaneous injection studies in rats and mice with DTPA-ZnNa3 and DTPA-CaNa3 (see also read across docuemnt in section13). DTPA-ZnNa3 did not result in developmental toxicity at a level up to 565 mg/kg bw/day in rats; in mice a level of 3000 mg/kg bw/day showed developmental effects when injected during days 5 -12 but not when injected on days 2 -6 or on days 7 -11. DTPA-CaNa3 showed developmental toxicity at lower levels which supports the notion that - because the affinity of DTPA is much higher for Fe than for Zn, and much higher for Zn than for Ca - that DTPA-FeHNa is much less developmental toxic than DTPA-CaNa3 due to less binding of Zn. Injection of pregnant mice with 300 umol/kg bw of Ca-DTPA (10 times the therapeutic dose, corresponding to ca. 149 mg Ca-DTPA/kg bw) resulted in decreased copper and zinc contents in the fetal liver. Although Zn-DTPA has been reported not to induce essential metal deficiency, a dose of 157 mg/kg bw (also 10 times recommended daily dose) decreased copper content in the fetal liver.

Justification for classification or non-classification

Based on the results of the extended OECD 422 study (comparable to a one-generation study) with DTPA-FeHNa, viz. a decrease in sperm motility, cauda epididymis weight and in sperm reserve, as observed in male animals treated with the highest concentration of the test substance, the No Observed Adverse Effect Level (NOAEL) for fertility is 500 mg/kg body weight/day. Effects were only seen at a very high level (1500 mg/kg bw) and did not result in effects on reproduction. Because these effects on ferticlity were comparable to other chelating agents like EDTA, and effects were considered to be due to Zn-binding which most probably resulted in a too low Zn-status in the male animal (see also read across document in section 13), it is expected that HEDTA-FeNa does not need classification for this endpoint.

Based on the results of the extended OECD 422 study (in which developmental toxicity was studied) with DTPA-FeHNa, which did not show any toxicological effects of the test substance on development, the No Observed Adverse Effect Level (NOAEL) for developmental toxicity is ≥1500 mg/kg body weight/day. Therefore no classification is needed for developmental toxicity for HEDTA-FeNa either.