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Tokicokinetic Behaviour Assessment for Ammonium iron (3+) hexakis (cyano-C) ferrate (4- ), "Milori Blue" CAS No. 25869-00-5.

There were no studies available in which the toxicokinetic properties of ammonium iron (3+) hexakis (cyano-C) ferrate (4-) (a.k.a. Milori blue) were investigated. Therefore the toxicokinetic behaviour of the substance was assessed by its physicochemical properties and the following read across substances Prussian blue [ferric hexa-cyanoferrate(II)] (a.k.a ferric ferrocyanide), potassium ferric cyanoferrate and tetrasodium hexacyanoferrate (a.k.a. sodium ferrocyanide).

Milori blue is a blue odourless powder, with a molecular formula of NH4Fe33 +[Fe2+(CN)6] C6FeN6.Fe.H4N, and a molecular weight of 285.8 g/mol.

Prussian blue is also a powder with an empirical formula of Fe4[Fe (CN)6]3and a molecular weight of 859.2 g/mol.

Potassium ferric cyanoferrate (Colloidal Prussian Blue) has an empirical formula of KFe[Fe(CN)6] and a molecular weight of 306.9 g/mol.

Sodium ferrocyanide forms pale yellow crystals, has an empirical formula of Na4[Fe(CN)6] and a molecular weight of 303.9 g/mol.

Milori blue and read-across substances are similar in the fact that they contain cyanide ligands bound to ferrous iron (2+). Milorie blue is insoluble in water (< 0.02 mg/L), ferric ferrocyanide has a water solubility of 6 g/L at 25 °C, and tetrasodium ferrocyanide is highly soluble in water (i.e. 363 g/L at 20 °C). Potassium ferric ferrocyanide is slightly more soluble in water than ferric ferrocyanide.

Absorption:

Potential exposure pathways to Milori blue are via dust inhalation, dermal contact and oral uptake (including intentional uptake), especially for decorporation of radionuclides. Particle size distribution has shown approximately 97% of the particles to be smaller than 100 µm (inhalable) and 12% of the sample potentially belongs to the respirable fraction (50% of fraction < 4 µm), thus indicating that absorption via the lungs is possible. 

The substance is not lipophilic (inorganic) therefore would not have the potential to be absorbed directly across the respiratory tract epithelium. The alveolar dust fraction (12%) is predicted to be slowly dissolved and cleared by alveolar macrophages. Judging from the particle size distribution, the majority of particles will deposit in the thoracal region of the lung. Particles deposited on the mucociliary blanket will be elevated into the laryngeal region and ultimately be swallowed (ingestion). Therefore, absorption from the gastrointestinal tract should contribute most to the total systemic burden of the substance that is primarily inhaled. However, the water insolubility (< 0.02 mg/L), molecular weight of greater than 200 g/mol and inorganic nature of the substance indicates that it will not have the potential to readily dissolve into the gastrointestinal fluid or to be absorbed through aqueous pores.

However, hexacyanoferrate(II) compounds have gained the highest attention in their function as scavenging agents for cesium and thallium, which has been intensively studied between the 60s and the 80s of the last decade (Nigrovic, 1963; Nigrovic et al., 1966; Dvorak,et al., 1971). Subsequently to the reactor accident in Chernobyl in 1986, which resulted in a European wide contamination with the potential hazardous nuclides134Cs and137Cs, the use of hexacyanoferrates(II) for the prevention of enteral radiocesium uptake and decorporation of134/137Cs has gained new attention. Milori Blue revealed no systemic or local toxic effects in acute oral (gavage) toxicity studies with LD50-values of 5000 mg/kg bw and > 15000 mg/kg bw; comparably, Prussian blue did not reveal any systemic or local toxicity in an acute oral toxicity study via gavage up to the highest applied dose, either, resulting in an LD50 value of > 5110 mg/kg bw. Sodium ferrocyanide induced clinical sings at extremely high doses of 7500 mg/kg bw and higher and also mortality at doses ≥ 13000 mg/kg bw, resulting in an LD50 of 15600 mg/kg bw. The intestinal absorption of iron or cyanide from hexocyanoferrates(II) after oral application is thought to be very small or even not occurring, because no toxic side effects after long lasting treatment with insoluble Prussian blue were recognised, and no post absorption serum increase of iron, cyanide or thiocyanide after administration of high oral doses of hexacyanoferrates was observed in sheep and cows. These results suggest that the substances within the analogue approach are either of low toxicity or that there is little absorption of the substances following oral ingestion. This view is supported by the use of hexacyanoferrates(II) in the decontamination of the body from radionuclides such as thallium or caesium, where it acts as an ion exchanger in the gastrointestinal tract and increases the excretion of the radionuclides via the feces; the prerequisite for this function is a lack of enteral absorption and rapid excretion.

For dermal absorption to occur, the substance must be sufficiently soluble in water to partition from the stratum corneum into the epidermis. As Milori blue is insoluble in water (< 0.02 mg/L) and due to its ionic nature (complex salt) the rate of transfer between the stratum corneum and the epidermis will be negligible and therefore consequently will limit absorption across the skin. Overall, the water insolubility, molecular weight of 285.8 g/mol and ionic nature of the substance suggest that dermal uptake of Milori Bluein humans is considered as very limited and dermal exposure is considered negligible for hazard assessment.

 

  

Distribution:

The water insolubility of the substance suggests that it is unlikely to diffuse through aqueous channels and pores. Also since the substance is an inorganic it is unlikely to distribute into cells, and accumulation in the body fat is not to be expected.

 

Metabolism and Excretion:

Several studies with ferric ferrocyanide account for the fact that no significant amount of cyanide ions was released in the body and that the unchanged substance was excreted in feces instead. Oral administration of potassium ferric cyanoferrate and ferric ferrocyanide, respectively, radiolabelled in different positions in the molecules and administered to piglets, showed as well that nearly 100% of the radioactivity was recovered in the feces; only very minor amounts of radioactivity were found in the urine, which was shown to originate from the non-cyanide iron. The similarity between the metabolism of the described read-across substancesboth compounds is substantiated by examinations with the common components, the [Fe(CN)6]4–ion. After oral as well as after i.p administration, the [Fe(CN)6]4–ion was virtually completely excreted and there was no evidence of its decomposition.

Non-haem-bound iron, such as ferric iron (Fe3+), is poorly absorbed from the gastrointestinal tract; its absorption is regulated by the physiological iron demand. Absorbed iron enters the normal physiological pathways (haem anabolism and catabolism) once it is bound to transferrin in plasma.

The other cation, ammonium, is a physiological form of nitrogen in the human body and enters the respective physiological pathways (urea cycle).

 

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