Potassium; 2-[bis[2-[bis(carboxylatomethyl)amino]ethyl]amino]acetate; iron(3+)

Endpoint summary

Description of key information

See below at discussion

Key value for chemical safety assessment

Bioaccumulation potential:

no bioaccumulation potential

Absorption rate - oral (%):

5

Absorption rate - dermal (%):

0.001

Absorption rate - inhalation (%):

5

Additional information

No much data could be found on the toxicokinetics of DTPA-FeK or DTPA-Fe-sodium salts. With regard to EDTA-FeNa (also Fe(III)) the following is known: most iron absorbed after EDTA-FeNa is ingested is released to the physiological mucosal uptake system before absorption. Only a very small fraction of the EDTA-FeNa complex (less than 1%) is absorbed intact, and it is completely excreted in the urine. An additional small fraction (probably less than 5%) of the EDTA moiety itself is absorbed, presumably bound to other metals in the gastrointestinal tract, and it is also completely excreted in the urine. Although the absorption of the EDTA moiety from administered EDTA-FeNa has not been measured directly in humans, physicochemical considerations indicate that EDTA absorption from EDTA-FeNa would be similar to that from other metal complexes, such as EDTA-CaNa2 and CrEDTA. As described above, poor absorption of the intact EDTA-FeNa can be inferred from measurements of urinary radio iron excretion after the oral administration of Na59-FeEDTA.

It is expected that with regard to toxicokinetics DTPA-FeK will not differ to a large extent from EDTA-FeNa.

The following is known on DTPA (see also read across document in section 13):

Absorption:

Oral:

In studies conducted using rats, dogs and humans, (Dudley et al., 1980ab; Stevens et al., 1962; Resnick et al., 1990) the oral absorption of DTPA and DTPA salts appears to be very low, with an average intestinal absorption of 3 to 5% across all species.

Dermal:

There are no data available on the dermal absorption potential of DTPA, however in a risk assessment by the European Chemicals Bureau (2004), a structurally related chelating agent, EDTA was reported as having very low dermal penetration potential, with approximately 0.001% absorption through the skin. Considering the larger molecular weight of DTPA compared to EDTA it is believed that the dermal penetration of DTPA will be equally low, i.e. approximately 0.001%.

Inhalation:

Exposure to DTPA is also possible via inhalation of the powdered or a microgranulated form of the chelating agent. Therefore, considering the potential for absorption via the lung following exposure to inhaled powder, the potential for absorption will depend on the proportion of the inhaled powder that reaches the deeper lung, since much of the material that impacts higher up in the respiratory tract will be carried up into the mouth via the mucocilliary transport. Taking this into account, the ICRP (1994) reported that particles above 10μm are only partially inhaled. Some of the particles are sufficiently large not to be drawn in with an inspired breath (40%). Of the 60% inhaled, 50% are deposited in the extrathoracic air ways and only 10% enter the lung and result in a true inhalation dose. Therefore only 10% of the powder particles less than 10μm in diameter are available for absorption via the lungs, the remaining powder is either not inhaled or deposited higher up in the respiratory tract and eventually swallowed.

Considering the potential for absorption via the lung following exposure to microgranulated form which is delivered to downstream users, the potential for absorption is not likely, since there are no particles with aerodynamic diameter less than 100μm (Szymaniak J., 2018, Report No. 14/2018).Thus, it is very unlikely, that big amounts of the substance reach the lung. It is expected that 100% of the inhaled substance will be deposited in the upper respiratory tract, where the particles may be moved by mucociliary transport to the throat and where the substance is swallowed and, conclusively, enters the stomach. The particles are not expected to reach alveolar region. If the substance reaches the lung, it is not very likely that the substance is taken up rapidly (based on physical-chemical properties). The substance is expected to be predominantly in chelated form since pH of healthy lungs is between 7.38 and 7.43 (Effros and Chinard, 1969).

 

Based on this information, the absorption by inhalation is expected to confine to the amount of DTPA-FeK deposited in upper airways which can be swallowed. Therefore, as worst case, 5% absorption by inhalation (similar with oral absorption) is considered appropriate for the purposes of hazard assessment (DNEL derivation). 

 

Distribution / Excretion:

 

Following exposure, the portion of the dose that is absorbed and thus available systemically is excreted via the urine very quickly. Intravenous administration of DTPA to man (Stevens et al., 1962) resulted in almost complete excretion via the urine within 24 hours, with a half life of approximately 2 to 4 hours. DTPA does not appear to become sequestered by any particular tissues, and in pregnant rats DTPA does not appear to pass into the fetal circulation (Zylicz et al., 1975). Thus DTPA does not give rise to any concerns regarding bioaccumulation.

 

Following an oral dose, the unabsorbed material remains in the gastrointestinal tract and is excreted via the faeces. There appears to be little or no excretion of absorbed DTPA via the faeces (Stevens et al., 1962).

 

Effect of DTPA on excretion of metals

 

There are many studies where the effects of administering DTPA to animals and man on the excretion of essential metals such as calcium, zinc, iron, manganese, magnesium etc. have been studied. Systemic administration of DTPA (intravenous, intraperitoneal, subcutaneous) causes increased urinary excretion of zinc, calcium and to a lesser extent iron and manganese. The reason for the increase in the urinary excretion of certain metals following systemic exposure to DTPA is due to its formation of complexes with ‘free’ metals in the blood and lymph. These complexes are then excreted via the urine, carrying the metals out of the body.

 

DTPA has a high affinity for zinc and as such, zinc is one of the metals most affected by administration of DTPA. The increased excretion of zinc following prolonged administration of DTPA to humans has manifested as a zinc deficiency, treatable with supplementation of zinc sulphate, or administration of the zinc complex of DTPA.

 

The removal of metals from the body by DTPA is dependent on a number of factors:

1)     The dosing regime. Due to the short half life of DTPA in the body, a single dose is less effective at removing endogenous metals than multiple doses or a continuous transfusion.

2)     The availability of unbound or ‘free’ metals in the circulation. Due to the limited availability of ‘free’ zinc in the body, the dose of DTPA administered is not directly proportional to the amount of zinc excreted (Havliceket al., 1967). Small doses will bind more zinc per mole of chelant compared to larger doses.

3)     The presence of other metals in the circulation. DTPA has a strong affinity for zinc however it also binds manganese, calcium, iron, sodium, potassium. The presence of higher concentrations of these will therefore affect how much zinc is bound by DTPA

4)     The metal complex administered. Zinc complexes of DTPA are more stable and so less likely to cause an increase in excretion of metals. Sodium, potassium and calcium salts do dissociate more easily and so the chelating agent is released and capable of chelating other metals, increasing their excretion/preventing their absorption.