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

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 (%):

20

Additional information

The toxicokinetics are based on those of DTPA-FeHNa and EDTA-FeNa (see also read across document in section 13).

No much data could be found on the toxicokinetics of DTPA-FeHNa. 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 (see also below).

It is expected that with regard to toxicokinetics DTPA-FeHNa and HEDTA-FeNa 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. 1980a, b; 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:

There have been a number of studies of the effectiveness of administering aerosolised DTPA complexes to humans via the inhalation route. The substances investigated were various radionuclide complexes of DTPA such as¹¹¹In-DTPA,^99mTc-DTPA, Pu-DTPA and also the zinc and calcium salts of DTPA. These studies demonstrated that DTPA complexes are absorbed from the respiratory tract into the systemic circulation. The degree of absorption is however dependent on the site of deposition within the respiratory tract. Dudley et al. (1980b) demonstrated in dogs that the percentage of applied dose absorbed through the respiratory tract increases the further into the respiratory tract the dose is deposited. DTPA deposited high up in the respiratory tract was predominantly swallowed, with approximately 23% absorption from the nasopharyngeal region compared to approximately 90% absorption following instillation into the pulmonary region. A similar pattern was observed in rats (Stather et al. 1976, referenced in Dudley at al. 1980b). In humans, DTPA absorption following the administration of a nebulised spray containing DTPA was estimated to be 20% of the administered dose (Jolly et al. 1972). In this study the aerosol was inhaled through the mouth and mean droplet size was between 0.3 and 2 micrometers, making it more likely that droplets would travel more deeply into the respiratory tract, where absorption is more favourable.

Based on the available data it thus appears that absorption of aerosolised DTPA depends predominantly on the penetration of the droplets into the respiratory tract. The deeper the DTPA is deposited, the more likely it is that it will be absorbed. Considering the study by Jolly et al (1972) where a nebuliser was used to produce very small droplet sizes, it seems that a somewhat worst case estimate for absorption following exposure to an aerosol is approximately 20%. 

 

Exposure to DTPA is also possible via inhalation of the powdered 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 10 μm 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 10 μm 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.

 

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 as 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 dependant 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.

Toxicokinetics EDTA-FeNa

INACG and WHO have written extensive reviews on the ADME of EDTA-FeNa based on available literature. For their full review see attachments.

There are no indications from literature that, upon ingestion, EDTA or EDTA-FeNa or any other metal‑EDTA complex‑ion, will give rise to bioaccumulation. All metal‑EDTA complex-ions are highly soluble in water and when absorbed these are rapidly and completely removed by the kidneys from the blood circulation.

The total amount of iron in the human body is ca. 4 g. In general 1 mg iron per day will be lost. Females because of their monthly period, will additionally loose ca. 30 mg, which is on average also 1 mg per day. These losses will be replenished via the food intake. A normal diet contains ca. 10 to 15 mg Fe per day. The iron uptake from the gut is directly related to the to the body’s need; in case of shortage uptake from the gut will increase. 

 

Only a very small fraction of the EDTA-FeNa complex (less than 1%) in humans is absorbed intact from the gut, and due to its high water solubility it is completely excreted in the urine. Poor absorption of the intact EDTA-FeNa can be inferred from measurements of urinary radio-labeled iron excretion after the oral administration of Na⁵⁹FeEDTA.

 

After EDTA-FeNa has been ingested, the absorption of iron from ferric sodium EDTA is regulated through the same physiological mechanisms as other forms of iron. Following oral administration, the iron from ferric sodium EDTA is separated from the iron EDTA complex in the lumen of the gut by the intestinal cells of the duodenum and small intestine. As indicated above, the mucosa cells will only pick up the non-complexed ferric ions that are needed by the body, and this amount will be transported to the blood plasma where it will be coupled to transferrin, like all other absorbable iron in food. This iron joins the general non-haem iron pool that is finally incorporated into the circulating haemoglobin. The iron component of ferric sodium EDTA is subsequently handled systemically like any other source of iron; the safety and maximum tolerable intake of which has been reviewed and evaluated by a number of distinguished scientific committees such as JECFA, WHO, UK EVM, SCF, IOM and EFSA. Non-absorbed iron will be excreted via the feces.

 

With regard to the EDTA-moiety, following dissociation from ferric sodium EDTA, most of this EDTA is promptly excreted in the feces, while less than 5% is absorbed. The absorbed fraction is presumably bound to other metals in the gastrointestinal tract, and it is also completely excreted in the urine because of high water solubility. 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 EDTA-CrNa.

 

Traces of ferric-EDTA complex‑ions that might possibly be formed in the blood circulation out of absorbed EDTA molecules that are present in the form of e.g. calcium‑EDTA complex‑ions and out of ferric ions that have not been bound to transferrin, will also rapidly be removed by the kidneys.

 

The EDTA moiety does not undergo biotransformation. Evidence for this conclusion comes from studies which indicate that EDTA moieties are excreted unchanged into the urine following ingestion of EDTA-CaNa2. Biotransformation of iron does by definition not occur: ferric ions (from whatever source in the food) can only be converted into ferrous ions, and back.

 

The use of EDTA-FeNa as a food fortificant has no measurable effect on the nutrition or metabolism of calcium, copper, zinc, or magnesium. In some situations, fortifying foods with EDTA-FeNa may even have a beneficial effect on zinc nutrition by improving zinc absorption. EDTA-FeNa improves iron balance by supplying iron in a form hardly affected by dietary inhibitors such as phytic acid and additionally improves the absorption of nonhaem iron from other iron sources in the meal e.g. from vegetables and cereals.

 

Overall, based on the data available, for EDTA-FeNa, intestinal absorption was estimated to be maximally 5%, based on the EDTA-moiety as iron uptake will be guided by the body’s iron need. Dermal absorption of EDTA-FeNa was also based on EDTA (RAR, 2004, see robust summary), viz. 0.001%. Because of its high water solubility and because of the larger molecular structure, dermal absorption of EDTA-FeNa would certainly not be higher than that of EDTA. Based on the particle size distribution of EDTA-FeNa, it is expected that 90% of the inhaled substance will be deposited in the upper respiratory tract, which will finally be taken up orally. Of this, only 5% will be absorbed in the gastrointestinal tract and become available systematically, i.e. 0.9 x 0.05 = 0.045 (4.5%). The other 10% may reach the alveoli and it is assumed that this will be absorbed completely (worst case). Therefore, the total inhalation absorption factor will be 0.045 + 0.10 = 0.145 (14.5%). 

 

Discussion on bioaccumulation potential result:

With regard to EDTA:

According to the dissociation equilibrium of edetic acid, administration of different sodium salts will result in dependence on the intestinal pH-value to the formation of various anionic species of EDTA. In whatever salt EDTA is administered it is likely to chelate metal ions in vivo. It can be assumed that the oral and dermal absorption of sodium salts of EDTA and of the free acid is comparable to the low absorption of CaNa2EDTA. Calcium salts of EDTA are poorly absorbed from the gastrointestinal tract (2 to 18% within 24 h), a maxium of 5% was detected in the urine. Only 0.001% is absorbed after dermal application. Intravenously injected EDTA is excreted within 24 h in the urine, 50% of the substance in the first h and 90% within 7 h.

With regard to EDTA-FeNa:

After ingestion, based on the data available, a low bioaccumulation potential for EDTA-FeNa is concluded (see also section 7.1).

For EDTA-FeNa, intestinal absorption was estimated to be 5%, and dermal absorption 0.001%. Based on the particle size distribution of EDTA-FeNa,it is expected that 90% of the inhaled substance will be deposited in the upper respiratory tract, which will finally be taken up orally. Of this, only 5% will be absorbed in the gastrointestinal tract and become available systematically, i.e. 0.9 x 0.05 = 0.045 (4.5%). The other 10% may reach the alveoli and it is assumed that this will be absorbed completely (worst case). Therefore, the total inhalation absorption factor will be 0.045 + 0.10 = 0.145 (14.5%). Neither the iron nor the EDTA moiety of EDTA-FeNa undergoes biotransformation.