Acetic acid, oxo-, sodium salt, reaction products with ethylenediamine and hydroxybenzenesulfonic acid monosodium salt, iron sodium salts

Endpoint summary

Description of key information

Fe(3Na)EDDHSA has low absorption potential via all exposure routes. If absorbed, it is expected to be distributed predominantly in intravasal compartment. The substance is not expected to be metabolised and will be excreted mainly unchanged via the faeces and/or urine. 10% absorption  is considered as appropriate for all routes of exposure since physico-chemical characteristics of the substance are not in the ranges suggestive for extensive absorption into the body (TGD, Part I, 2003).

Key value for chemical safety assessment

Bioaccumulation potential:

no bioaccumulation potential

Absorption rate - oral (%):

10

Absorption rate - dermal (%):

10

Absorption rate - inhalation (%):

10

Additional information

General

There are no ADME studies available for Fe(3Na)EDDHSA.The toxicokinetic profile of the test substance was not determined by actual absorption, distribution, metabolism or excretion measurements. Rather, the physical chemical properties of this substance were integrated with the toxicological data on structurally related substances to create a prediction of its toxicokinetic behaviour (please refer to an extended version of “Assessment of toxicokinetic behaviour” based on physico-chemical properties attached to the IUCLID file under section 13).

Toxicological profile of Fe(3Na)EDDHSA

There are no studies available for toxicological endpoints for Fe(3Na)EDDHSA and therefore read-across from its closely related substances Fe(3K)EDDHSA (EC 462-490-6) and its methylated analogue Fe(Na)EDDHMA (84539-53-7) was performed. The target substance and its nearest neighbours show very similar physical/chemical properties (high water solubility, low Pow, no hydrolysis in water, low vapour pressure) and are thus believed to behave very similar in aqueous solutions (please refer to read-across statement attached to the IUCLID file under section 13).

The structurally similar chelates are of low acute toxicity via the oral and dermal route of exposure. All animals survived the applications of test substances in good health and LD50 values greater than 2000 mg/kg bw were reported in these studies. The substances are not skin or eye irritants and do not fulfil the requirements to be classified for these endpoints. The nearest analogue Fe(3K)EDDHSA is not a skin sensitiser but Fe(Na)EDDHA possesses a weak sensitising potential. The chelates are not mutagenic in various bacterial and mammalian test systems.

A NOAEL of 1000 mg/kg bw, the highest dose tested, was established for the nearest analogue Fe(3K)EDDHSA in an oral 28-day repeated dose toxicity study in rats. No clinical signs were noted in the animals treated with the substance. All blood chemistry parameters were unaffected and no findings at necropsy were observed.

In a subacute 28-day dermal toxicity study conducted with Fe(Na)EDDHA, a NOEL of 100 mg/kg bw was established based on slight effects on the liver and skin and due to increased adrenal weight noted at the high dose level of 1000 mg/kg bw/day (CIBA-GEIGY, 1996b).

In an one-generation reproduction toxicity study performed in rats with Fe(Na)EDDHMA, a NOAEL of 200 mg/kg bw was established for reproductive performance/fertility based on a slight decrease in the conception indices and a minimal delay in precoital time noted at the high and systemically toxic dose level of 750 mg/kg bw/day (NOTOX, 1997). In agreement with the proposed read-across approach, this NOAEL is considered to represent a reliable key value for chemical safety assessment of Fe(3Na)EDDHSA.

In the key developmental oral toxicity study in rats with Fe(Na)EDDHA, a NOEL of 500 mg/kg bw, a systemically toxic high dose level, was established for developmental effects based on the absence of embryo-/foetotoxic or teratogenic effects (CIBA-GEIGY, 1995).

 

Toxicokinetic analysis of Fe(3Na)EDDHSA

The substance Fe(3Na)EDDHSA is an odourless, dark red solid in a microgranulated form (MW above 641.27 g/mol) at 20°C. The substance is soluble in water (290 g/L at 25°C) and has a negative partition coefficient (could not be determined as the substance does not dissolve in n-octanol (the quantities are under detection limit of HPLC (Valagro, 2012)). It has a very low vapour pressure and does not melt up to 600 °C under atmospheric conditions. Its boiling point and vapour pressure were not determined, as the melting point is above 300 °C. Hydrolysis as a function of pH does not apply, as the substance forms extremely stable complexes.

Absorption

Oral absorption is favoured for molecules with MW below 500 g/mol. Based on the high molecular weight, high water solubility and the very low logPow value, Fe(3Na)EDDHSA is expected to be too hydrophilic to be readily absorbed via the gastrointestinal (GI) tract, but may be taken up by passive diffusion. However, absorption of very hydrophilic substances by passive diffusion may be limited by the rate at which the substance partitions out of the gastrointestinal fluid. As the substance’s molecular weight is higher than 500 g/mol, Fe(3Na)EDDHSA is very unlikely to pass through aqueous pores or be carried through the gastrointestinal epithelial barrier by the bulk passage of water. This thesis is supported by the fact that the read-across substance Fe(3K)EDDHSA (nearest analogue) was not acutely toxic by the oral route (gavage) in rats (LD50 is > 2000 mg/kg bw) and did not show toxic effects at the highest dose of 1000 mg/kg bw/day in an oral 28-day repeated dose toxicity study. Therefore, it can be concluded that only limited direct absorption across the gastrointestinal tract epithelium will occur when Fe(3Na)EDDHSA is applied orally. 10% oral absorption is considered appropriate since physico-chemical characteristics are not in a range suggestive of absorption from the gastro-intestinal tract.

Based on the low vapour pressure of Fe(3Na)EDDHSA, inhalation exposure is not likely. 36.1 % of the particle showed a diameter lower than 125 µm (particles with lower diameter were not determined). Moreover, the final product has a granulated form. Thus, it is very unlikely, that considerable amounts of the substance reach the lung. Nevertheless, if the substance reaches the lung, it is not very likely that the substance is taken up rapidly. Although it is very water-soluble substance, its molecular weight is 641.27 and therefore it will not be absorbed extensively through aqueous pores. Rather, the substance is expected to diffuse/dissolve into the mucus lining the respiratory tract. The negative LogPow points also to a low absorption potential across the respiratory epithelium. The related substance Fe(Na)EDDHA showed no toxic symptoms in rats after inhalation of 4200 mg/m³ (4 hours), in an acute inhalation toxicity study (CIBA-GEIGY, 1994a). Together, this indicates a low systemic availability after inhalation and if the substance were bioavailable, no toxicity effects via this route of administration would occur. Therefore, 10% inhalation absorption is considered appropriate since physico-chemical characteristics are not in a range suggestive of significant absorption via the respiratory tract.

Similarly, based on physico-chemical properties of Fe(3Na)EDDHSA, the substance is not likely to penetrate skin to a large extent as the substance is not sufficiently lipophilic to cross the stratum corneum (negative logPow and water solubility of 290 g/L). The water solubility above 10,000 mg/L together with the log P value below 0 further indicates that the substance is too hydrophilic to cross the lipid rich environment of the stratum corneum. Dermal uptake for these substances will be low. In addition, the molecular weight of 641.27 g/mol indicates a low potential to penetrate the skin as well. This is supported by the findings of the acute dermal toxicity studies conducted with the structurally analogues where a low systemic toxicity after exposure via the skin was noted (LD50 > 2000 mg/kg bw). Moreover, an acute dermal irritation / corrosion study in the rabbit (according to OECD 404) for Fe(3K)EDDHSA did not demonstrate any irritation after 14 days. This information indicates that Fe(3Na)EDDHSA is unlikely to penetrate the skin. Furthermore, application of Fe(Na)EDDHA to the skin of rats in a dermal 28-day repeated dose toxicity study did cause only slight systemic effects on body and adrenal weight at the dose of 1000 mg/kg bw/day, supporting a limited bioavailability via this route. According to TGD, Part I (2003), 10% of dermal absorption is considered for Fe(3Na)EDDHSA, due to MW of 641.27 g/mol and a negative logPow (the substance was completely not soluble in octanol (the quantities of Fe(3Na)EDDHSA were under the detection limit of HPLC and no quantitative data were reported by UV/Vis); logPow of the nearest analogues are -4.0 for Fe(3K)EDDHSA and -4.2 for Fe(Na)EDDHA).

Distribution and accumulative potential

Due to minor absorption, only a limited amount of Fe(3Na)EDDHSA is expected to be available for distribution. However, the minor amount absorbed into the body, will most likely distribute only in the intravascular compartment (due to its high molecular weight and the low LogPow) and will not reach the inner cell compartment, as the cell membranes require a substance to be soluble also in lipids to be taken up. As it is known that “substances with LogPow values of 3 or less would be unlikely to accumulate with the repeated intermittent exposure patterns normally encountered in the workplace” (TGD, Part 1), no enhanced risk for accumulation will be associated with the substance.

Metabolism and excretion

Based on the structure of the molecule and its nature, metabolism in the human body will mainly consist of phase-II metabolising steps. Glucuronidation is one of such pathways leading to a better water solubility for excretion and might also occur in case of Fe(3Na)EDDHSA. This is in compliance with the results obtained in the Ames test and in the Chromosome Aberration Assay conducted with the read-across substance Fe(3K)EDDHSA as well as in the Mouse Lymphoma Assay conducted with the analogue Fe(Na)EDDHA showing no effects with and without metabolising system. Metabolic activation leading to more toxic metabolites is thus not very likely. Further, due to the high stability constant of the iron chelate complex (K = 10^-33) (Yunta et al., 2003), it is clear that it exerts a low reactivity in the organism. Therefore, it is assumed that most of this very water soluble iron fraction will be excreted unchanged in the chelated form mainly in the faeces and in the urine. In case of formation of glucuronic acid derivatives, there is a possibility of entero-hepatic recycling, and the risk of re-entering the system, but this does not enhance the risk for the organism.

Summary

Fe(3Na)EDDHSA is expected to be poorly absorbed after oral exposure, based on its water solubility and its insolubility in n-octanol. Concerning the absorption after exposure via inhalation, as the chemical is considered to have a low vapour pressure, is highly hydrophilic, insoluble in n-octanol, and has a rather high molecular weight; it is clear, that the substance is poorly available for inhalation and will not be absorbed significantly. Fe(3Na)EDDHSA is also not expected to be absorbed following dermal exposure into the stratum corneum and into the epidermis, due to its molecular weight and its high water solubility. Concerning its distribution in the body Fe(3Na)EDDHSA is expected to be distributed mainly in the intravasal compartment, due to its high water solubility. The substance does not indicate a significant potential for accumulation. Fe(3Na)EDDHSA is not expected to be significantly metabolised but to be eliminated unchanged via urine and bile.

Reference: Yunta F., Garcia-Marco S., Lucena J.J., Gomez-Gallego M., Alcazar R., Sierra M. A. (2003b) Chelating Agents Related to Ethylenediamine Bis(2-hydroxyphenyl)acetic Acid (EDDHA): Synthesis, Characterization, and Equilibrium Studies of the Free Ligands and Their Mg2+, Ca2+, Cu2+, and Fe3+ Chelates. Inorg. Chem. 2003, 42, 5412-5421