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Description of key information

Information relating to absorption, distribution, mobilisation and excetion of iron is collated from various handbooks and review articles in the absence of proprietary data.

Key value for chemical safety assessment

Bioaccumulation potential:
low bioaccumulation potential
Absorption rate - oral (%):
70
Absorption rate - dermal (%):
10
Absorption rate - inhalation (%):
100

Additional information

Iron is bioaccumulated to some degree since it is an essential micronutrient. However the processes of absorption, distribution and excretion are under strict homeostatic regulation and no adverse accumulation normally occurs. Iron deficiency, due to poor systemic absorption, is a more common response than adverse effects of enhanced exposure. For the same reasons the default assumptions in the absence of quantitative data, for oral, dermal and inhalation absorption are highly conservative.

Iron is an essential element, and plays an important role in biological processes, and iron homeostasis (biochemical mechanisms maintaining constant concentration in the cell) is under strict control. Absorption, storage, mobilisation and excretion of iron are all regulated at the surface of cells by a homeostatic mechanism. The counter ions of the soluble inorganic iron salts in question enter the body’s normal homeostatic processes.

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 oral administration of iron salts 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 the ferrous ion does not continue to exist once it enters the small intestine. Iron absorption in the rat is higher than humans; 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 prevents 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.

  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.

 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, although rats poorly absorb haem. Dietary enhancers and inhibitors appear to affect non-haem iron absorption in humans to a greater extent than in rats. 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.

Omeprazole-treated rats on the normal diet had no significant reduction in the absorption of ferric, ferrous, or food iron. In the rats on the iron-deficient diet, the absorption of ferrous iron decreased from 76 +/- 7.5% (mean +/- SE) in control rats to 38 +/- 8.5% in the omeprazole-treated rats (P less than 0.003) and the absorption of food iron decreased from 65 +/- 7.5% in control rats to 37 +/- 6.5% in the omeprazole-treated rats (P less than 0.016). There was no significant reduction in the absorption of ferric iron. Omeprazole therapy is unlikely to be associated with significant iron malabsorption in normal patients but may reduce iron absorption in pathological states associated with increased iron absorption such as iron deficiency. Initial ferrous iron absorption in rats fed iron-deficient diet was 76%, decreasing to 38% following omeprazole treatment. Food iron fell from an initial 65 % to 37%. Baseline iron absorption can therefore be considered to approximate to circa 70%.

Dermal

The water solubility (228 g/l) of ferrous sulphate suggests that it is unlikely to be absorbed across the lipid-rich stratum corneum. However, there are no reports of percutaneous absorption of iron in non-chelated form to support this prediction. Percutaneous absorption of iron has been reported only for chelated forms administered as ointments to mice. There are no reliable acute or repeated dose dermal studies that can be consulted for evidence of absorption via the dermal route.

A default value of 50% dermal absorption is normally used in the absence of substance specific data. Very low concentrations of iron are absorbed or excreted aand tight homeostatic controls function to maintain normal human body burdens of iron, with specific protein complexing and chelating mechanisms operating to chaperone iron systemically. Percutaneous absorption is very low since the complexing mechanisms are not available to facilitate penetration of the dermal barrier and chelated forms of iron are the only ones that show any measurable dermal absorption. Under these circumstances a dermal absorption value of 10% is considered appropriate for iron trinitrate, rather than the default 50%.

 Inhalation

In contrast to the wealth of data available on the human toxicology of ingested iron salts, there are no data available on the potential for adverse health effects via the inhalation route of exposure. There are no reliable acute or repeated dose inhalation studies that can be consulted for evidence of absorption via the inhalation route. For DNEL calculations the ECHA default assumption of 100% absorption was used.

Distribution

The average adult stores ~1 to 3 grams of iron in the body. Iron is not 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 Fe(III) 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). 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. 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 metabolism per se. Protein complexing and heamosiderin or ferritin chaperones allow for iron to be bound to transferring proteins for transport to the bone marrow. Free ionic iron is almost never found in living cells, but FeII tends to be contained within storage forms as Fe(III).

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. Menstruation increases the average daily iron loss to about 2 mg per day in pre-menopausal female adults. No physiological mechanism of iron excretion exists. Consequently, absorption alone regulates body iron stores.

  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).