Ferric ammonium citrate

Endpoint summary

Additional information

Introduction

The European Food Safety Authority (EFSA) panel on food contact materials, enzymes, flavourings and processing aids has previously evaluated the safety of ferric ammonium citrate (CAS 1185-57-5) to human health in accordance with Commission Regulation (EC) No 1565/2000. Ferric ammonium citrate is an approved flavouring substance in the EU. The panel based the evaluation of data on iron toxicity and previously studied iron complexes and salts (EFSA 2009). The approach by EFSA is based on the assumption that once the substance is ingested, it will dissociate into its constituent ions yielding iron, ammonium and citrate. Due to the ubiquitous nature of ammonium and citrate and their high throughput as endogenous substances, no further consideration to the toxicity of these constituents was given, but the potential adverse effects of iron were evaluated (EFSA 2009). A similar approach is adapted for human health in this CSR, with detailed consideration per endpoint of the behaviour of the reaction mass of ammonium iron (III) citrate and ammonium sulfate, with focus on largely on iron. Ammonium sulfate is not expected to contribute to toxicity, which is supported by a 2 year carcinogenicity study in rat which reports no remarkable toxic effects. An expert report is provided to support to read across approach and data waiving with more detailed information on iron metabolism and complexation, which can be found attached to Section 13 of the IUCLID Dossier <REFERENCE IN PREPARATION>.

 

 

Iron is an essential element, and plays an important role in biological processes, and its homeostasis (biochemical mechanisms maintaining constant concentration in the cell) is under strict control (McCance and Widdowson, 1938). Absorption, storage, mobilisation and excretion of iron are all regulated at the surface of cells by a homeostatic mechanism. (Hostynek, 1993). Unabsorbed iron that does not remain intact with its respective ligands ammonium sulfate and citrate, is deemed not relevant to systemic toxicity because the non-absorbed iron is unable to influence normal homeostasis. The toxicokinetics of the reaction mass of ammonium iron (III) citrate and ammonium sulfate itself have not been studied.

 

 

 

Absorption

 

Oral

In humans the absorbance and uptake of iron salts from the digestive system is usually rather poor to the extent that treatment of simple anaemia by such means is of limited effectiveness. This is because iron can only be absorbed as the ferrous ion, but the ferrous ion can only exist in an acid medium. Therefore once in the small intestine the ferrous ion cannot exist. Iron absorption in the rat is higher than in human (Mahoneya and Hendricksa, 1984); consequently, rat studies are considered unreliable models for iron toxicology in humans. Uptake is facilitated by the formation of iron chelates such as those with citrate and ascorbate that are present in the diet and in their absence iron absorption by the small intestine is very poor. Additionally, the presence of appreciable amounts of plant tannins may complex iron and further prevent its absorption. The result of this low solubility and low uptake by the human gut means that for healthy individuals, the presence of non-complexed iron in the diet rarely results in iron overload conditions.In the case of the registered substance, the reaction reaction mass of ammonium iron (III) citrate and ammonium sulfate, ferric citrate complexes exist which would imply potential for increased uptake. However, direct oral exposure of humans from the intended REACH uses is not likely.

 

There is some evidence that water-soluble iron salts are better absorbed than water-insoluble iron compounds. In both humans and animals, iron absorption from the digestive tract is adjusted to a fine homeostasis with low iron stores resulting in increased absorption and, alternately, sufficient body stores of iron decreasing absorption (Elinder, C.G., 1986).

 

Significant differences in iron absorption from salts and food have been noted between rats and humans, with uptake significantly higher from identical meals in rats (Reddy, M.B. and Cook, J.D., 1991), although rats poorly absorb haem (Bjorn-Rassmussen, E., 1974). Dietary enhancers and inhibitors appear to affect non-haem iron absorption in humans to a greater extent than in rats (Reddy M.D. and Cook, J.D., 1991). Growth requirements for iron in the rat are greater, and the dietary intake is about 100 times greater than that of humans, expressed on a body weight basis (WHO, 1983).

 

Dermal

Percutaneous absorption of iron has been reported only for chelated forms administered as ointments in mice (Hostynek, J.J., 1993). There are no reliable acute or repeated dose dermal studies that can be consulted for evidence of absorption via the dermal route.However, in the case of the registered substance the stability of the ferric-citrate complex is such that citrate binds strongly to iron and favours binding to citrate over binding to many other metal ions. Citrate, iron(III) and ammonium form a variety of coordination complexes in aqueous solution. Key factors determining the species formed in laboratory studies are the pH and the iron:citrate ratio. At neutral pH and approximately equimolar amounts of iron and citrate, equilibrium between various mono and polynuclear species might be expected, with 3:3 iron/citrate species being important. In the environment and in vivo, the species formed will be dependent on the pH, the presence of other metal ions, the presence of other complexing agents, the presence of iron and citrate from other sources and the temperature. It is expected that very little absorption via the dermal route will occur.

 

Inhalation

In contrast to the wealth of data available on the human toxicology of ingested iron salts, there is no data available on the potential for adverse health effects via inhalation. There are no reliable acute or repeated dose inhalation studies that can be consulted for evidence of absorption via the inhalation route. However, iron can be transported into the cells from the bathing material (the mucus film surrounding bronchial and alveolar cells), which lacks transferrin. This has been shown by the rapid uptake of iron (supplied as ferric ammonium citrate) by lung epithelial cells, and is dependent upon both time and the concentration of the ferric ammonium citrate (Ghio et al.,2006). More detailed information on iron metabolism and complexation in the lung can be found in an expert report attached to Section 13 of the IUCLID Dossier <REFERENCE IN PREPARATION>.

 

Distribution

 

The average adult stores about 1 to 3 grams of iron in his or her body.Iron is almost never found in the free ionic state in living cells in appreciable concentrations; it is chaperoned in the form of protein complexes immediately it is absorbed from the diet. In the blood plasma it is transported (as FeIII) by the protein transferrin, which passes it on to dividing cells, particularly the cells in the bone marrow that are the precursors of the red blood cells. This is mediated by the transferrin receptor. Transferrin, which binds iron with high affinity is only 20-35% saturated, thus the concentration of unbound iron is very low (0.5–1.5 mg/L (9–27 μmol/L, Tenenbein, 2001). Iron is stored principally in the liver in the large proteins haemosiderin and ferretin, although these are also found in all cells and in the blood in lower concentrations. Ferritin exists as hollow spheres of 24 protein subunits and iron is taken up in the FeII state but stored as FeIII. As with transferrin, it is stored in a redox-inactive (and therefore non-toxic) form. Ferritin is also important in recycling iron within the body and is an important biological indicator of iron balance. One consequence of the parsimonious conservation of iron is that if there is an excess of the element within the body, there is no biochemical mechanism for its excretion and this may result in both severe and chronic symptoms if large amounts are ingested.

 

Foetal exposure

It has been found that extremely elevated maternal serum iron concentrations are not accompanied by corresponding increases in foetal serum iron levels (Curryet al.,1990). This finding suggests that the foetus is protected from the effects of excess iron in the mother.

 

Metabolism

Water soluble inorganic iron salts do not undergo metabolismper se. As already mentioned iron is bound to transferrin for transport to the bone marrow or contained within storage forms.

 

Excretion

About 1 mg of iron is lost each day through sloughing of cells from skin and mucosal surfaces, including the lining of the gastrointestinal tract (EVM, 2003). Menstruation increases the average daily iron loss to about 2 mg per day in pre-menopausal female adults (Bothwell and Charlton, 1982). No physiological mechanism of iron excretion exists. Consequently, absorption alone regulates body iron stores (McCance and Widdowson, 1938).

 

The daily losses of iron from the human body correspond to a biological half-time of iron of 10 to 20 years. The yearly lung clearance of iron dust is estimated to be 20-40% of the deposited amount (data obtained from iron welders) (Elinder, 1986).

 

References

 

Bjorn-Rassmussen.et al., (1974) Food iron absorption in man. Applications of the two-pool extrinsic tag method to measure heme and nonheme iron absorption form the whole diet. J. Clin. Invest., 53, 247-255.

 

Bothwell and Charlton (1982) A general approach of the problems of iron deficiency and iron overload in the population at large. Seminars in Hematology 19, 54.

 

Curryet al.,(1990) An ovine model of maternal iron poisoning in pregnancy. Ann. Emerg. Med., 19, 632- 638.

 

EFSA (2009) Flavouring Group Evaluation 42: Ion containing organic substances from chemical group 30. EFSA Panel on Food Contact Materials, Enzymes, Flavourings and Processing Aids. European Food Safety Authority Journal 7 (9): 1191

 

Elinder (1986) Iron. In: Friberg L, Nordberg GF, Vouk VB, eds., 1986. Handbook on the toxicology of metals. 2nd ed. Amsterdam, the Netherlands: Elsevier, 277-297 (Vol II).

EVM, 2003.

 

Hostynek (1993)Metals and the Skin. Critical Reviews in Toxicology 23(2): 171-235.

 

Mahoneya and Hendricksa (1984)Potential of the rat as a model for predicting iron bioavailability for humans Nutrition Res. 4, 913-922.

 

McCance and Widdowson (1938)The absorption and excretion of iron following oral and intravenous administration. J. Phys. 94, 148.

 

Reddy. and Cook (1991) Assessment of dietary determinants of nonheme-iron absorption in humans and rats. Am. J. Clin. Nutr., 54, 723-728.

Tenenbein (2001) Hepatotoxicity in Acute Iron PoisoningClin. Toxicol.39, 721-726

 

WHO (1983)571. Iron.Toxicological evaluation of certain food additives and contaminants.WHO Food Additives Series, No. 18, 1983, nos 554-573 on INCHEMhttp://www.inchem.org/documents/jecfa/jecmono/v18je18.htm