Diammonium [N,N-bis[2-[bis(carboxymethyl)amino]ethyl]glycinato(5-)]ferrate(2-)

Endpoint summary

Key value for chemical safety assessment

Effects on fertility

Effect on fertility: via oral route

Endpoint conclusion:

no study 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

Based on the results of the study with the structurally related chelate 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. These results are in line with studies with other metal chelates (see also read across document in section 13).

Short description of key information:

In an extended oral OECD 422 study with the structurally related chelate 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.

Effects on developmental toxicity

Description of key information

In a study with a structurally related chelate 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

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 the structurally related chelate 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).

In rabbits, the maternal No Observed Adverse Effect Level (NOAEL) for EDTA-MnNa2 could not be established due to the occurrence of discoloured urine and increased creatine kinase levels for animals treated at 10 mg/kg and higher. At 30 mg/kg and higher reduced food intake was seen; at 100 mg/kg (with and without extra zinc) reduced body weight gain was seen which did not fully recover in animals without extra zinc. The developmental NOAEL was established as being 30 mg/kg; the developmental findings at 100 mg/kg were observed in the presence of maternal toxicity.

Toxicity to reproduction: other studies

Additional information

The results of the study with the structurally related chelate DTPA-FeHNa 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).

Subcutaneous injection is a non-physiological route but is needed to obtain high levels of bioavailable DTPA into the body as absorption from the gut is low.

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 the structurally related chelate 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 fertility 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, DTPA-FeHNa, and also DTPA-Fe(NH4)2, does not need classification for this endpoint.

Based on the results of the extended OECD 422 study (in which developmental toxicity was studied), 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. No classification is needed for developmental toxicity either.