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Administrative data

Link to relevant study record(s)

Description of key information

Iron can only be absorbed orally as the ferrous ion. Iron absorption in the rat is higher than humans. The presence of non-complexed iron in the diet rarely results in iron overload conditions. 
There are no reliable acute or repeated dose dermal studies that can be consulted for evidence of absorption via dermal route.
The water soluble inorganic iron salts do not undergo metabolism.
Iron can be inhaled as the ferric or ferrous ion. Ferric and ferrous ions precipitate in lysosomes of alveolar cells. However, it is not clear how fast the clearance of iron particles from pulmonary tissues is.
Iron is uniformly distributed via blood. Greatest concentrations are in liver, bone marrow and spleen.
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. 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. Only 0.01 to 0.02 % of the resorbed iron in humans are excreted daily. The daily losses of iron from the human body correspond to a biological half-time of iron of 10 to 20 years.
The foetus is protected from the effects of excess iron in the mother.

Key value for chemical safety assessment

Bioaccumulation potential:
low bioaccumulation potential

Additional information

Justification for read-across

This endpoint is covered by the category approach for soluble iron salts (please see below for the category justification/report format).

In addition to the category members, the surrogate material ammonium iron(III) citrate was used for read-across (McCance & Widdowson 1938). This substance also dissociates at physiological pH to the same species produced by the ferric (iron III) salts. As discussed in the category justification section, the equilibrium to iron II species is quickly established. In result iron species burden is assumed to be comparable to equimolar exposure to the iron category member salts. The additional ammonium and citrate are considered not influencing the iron kinetics.

Introduction

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 (McCance & Widdowson 1938). Absorption, storage, mobilisation and excretion of iron are all regulated at the surface of cells by a homeostatic mechanism (Hostynek 1993). The counter ions of the soluble inorganic iron salts in question enter the body’s normal homeostatic processes, and are not discussed further.

 

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 humans (Mahoney & Hendricks 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 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 (Elinder 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 and Cook, 1991), although rats poorly absorb haem (Bjorn-Rassmussen 1974). Dietary enhancers and inhibitors appear to affect non-haem iron absorption in humans to a greater extent than in rats (Reddy & Cook 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).

EFSA (2012) concludes for FeSO4 on rapid absorption (10 % up to 60 % in case of iron deficiency) within 2 to 6 hours.

Dermal

The water solubility (estimated at 300 g/L) of ferric chloride 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 in mice (Hostynek 1993). There are no reliable acute or repeated dose dermal studies that can be consulted for evidence of absorption via the dermal route.

Inhalation

In contrast to the wealth of data available on the human toxicology of ingested iron salts, there is only one available study (Johansson et al. 1992) on the potential for adverse health effects via inhalation. In this 2-month repeated dose inhalation study in rabbit, only local pulmonary effects were investigated. Here, macrophages were affected due to ferric chloride (FeCl3). Alveolar macrophages were increased in number in both exposed groups. There were prominent changes in the macrophages such as enlarged Lysosomes containing fibrous-looking structures or iron-rich inclusions leading to accumulation of iron. Since the lungs have a neutral pH of approximately 7.4, it is assumed that ferrous ion following a progressive oxidation in the presence of oxygen will transform to insoluble Fe(OH)3. Since a recovery group in Johansson (1992) study was not investigated, no information is available in regard to reversibility of occurring effects and the clearance of iron particles. Elinder (1986) indicated that yearly lung clearance of iron dust in humans is estimated to be 20 - 40 % of the deposited amount (data obtained from iron welders). This reference could be a hint that clearance of deposited iron in oxidized form from the lungs is relatively slow and possibly not complete.

Distribution

The average adult human stores about 1 to 3 grams of iron in the 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 or 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 et al.1990). This finding suggests that the foetus is protected from the effects of excess iron in the mother.

Metabolism

These water soluble inorganic iron salts do not undergo metabolism per 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 & 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).

Additional references of this section, not entered as studies

  • 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. 53:247-55.
  • 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 et al (1990). An ovine model of maternal iron poisoning in pregnancy. Ann. Emerg. Med 19:632-38.
  • EFSA European Food Safety Authority (2012). Conclusion on Pesticide Peer Review. Conclusion on the peer review of the pesticide risk assessment of the active substance iron sulphate. Self-published, Parma, Italy. EFSA Journal 10(1):2521. 48 p.
  • Elinder (1986) Iron. In: Friberg L, Nordberg GF, Vouk VB, eds., 1986. Handbook on the toxicology of metals. 2nd ed., the: Elsevier, 277-297 (Vol II).
  • EVM Expert Group on Vitamins and Minerals (2003). Safe upper levels for vitamins and minerals. Report of the Expert Group on Vitamins and Minerals. ISBN 1-904026-11-7 Self-published in May by the Food Standards Agency, U.K. 360 p. http://cot.food.gov.uk/pdfs/vitmin2003.pdf
  • Hostynek (1993). Metals and the Skin. Critical Reviews in Toxicology 23(2):171-235
  • Johansson, Curstedt, Rasool, Jarstrand, Camner (1992). Macrophage Reaction in Rabbit Lung following Inhalation of Iron Chloride. Environ Res 58:66-79.
  • Mahoney, Hendricks (1984). Potential of the rat as a model for predicting iron bioavailability for humans Nutrition Res. 4(5):913-22.
  • McCance, Widdowson (1938), The absorption and excretion of iron following oral and intravenous administration. J. Phys. 94:148.
  • Reddy, Cook (1991). Assessment of dietary determinants of nonheme-iron absorption in humans and rats. Am. J. Clin. Nutr. 54:723-8.
  • Tenenbein (2001). Hepatotoxicity in Acute Iron Poisoning Clin. 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

Chemical Category Reporting Format according to ECHA Guidance

The following definition complies with the ECHA (2008, chapter R.6) Guidance on QSARs and grouping of chemicals. It should be used in the discussions of the IUCLID 5 section 7 (Toxicology).

Table: Reporting Format for the Chemical Category According to ECHA Guidance R.6.2.6.2

1.

Category definition and its members: Soluble iron salts

1.1.

Category Definition

a.

Category Hypothesis

In solid form iron element exists free, or in iron-containing compounds. In aqueous solution, it exists in one or two oxidation states, Fe2+, the ferrous form, and Fe3+, the ferric form. Many of the key biological functions of iron in living systems rely on the high redox potential, enabling rapid conversion between the Fe2+ and Fe3+ forms. The redox potential is relatively harmful in terms of the capacity for oxidative damage to cellular compound such as fatty acids, proteins and nucleic acids. However, iron within the body is normally bound to carrier proteins and/or molecules with antioxidant properties, which minimise the capacity of the free ion to cause oxidative stress (EVM 2003).

In the first assumption, due to the neutral pulmonary pH (of about 7.4) the iron ions will precipitate in hydroxide or oxide of ferrous or ferric form and undergo rapid oxidation to ferric form. Therefore iron salts will act as identical material for the both iron oxidation forms.

In the second assumption, independently of exposure route, the anions of iron salts are irrelevant for the toxicity: this category covers as well the anions of inorganic ferrous and ferric salts, i.e. chloride, sulphate and their crystalohydrate forms. All of these salts will dissociate immediately in contact with aqueous media to the respective anions and kations, and then be subject to further change of oxidation and speciated state according to the conditions.

In the third assumption, the local effects could be slightly different depending on iron oxidation forms, but it should be not relevant in the regulatory context.

In the fourth assumption, bioavailability of iron is regulated by homeostasis mechanisms. It is also known that the ferrous ion (Fe2+) has a higher oral bioavailability than the ferric ion (Fe3+) that could impair the category approach. However, this difference is not that significant to be relevant in the regulatory context. Regarding the long-term exposure, a tolerance development could be assumed. Therefore it is not necessary to make any differentiation between category members and read-across between the salts can be used freely for the toxicological property data sets.

b.

Applicability Domain of the category

This category comprises five soluble iron salts (ferric and ferrous chloride and ferrous and ferric sulphate and ferric chloride sulphate, including their various hydrated forms).

c.

List of endpoints covered (numbers refer to the IUCLID 5 sections)

7. Toxicological information

7.1 Toxicokinetics, metabolism and distribution

7.2 Acute toxicity

7.3 Irritation / corrosion (limitation: differently as in this category, FeSO4 is irritant for eye)

7.4 Sensitization

7.5 Repeated dose toxicity

7.6 Genetic toxicity

7.7 Carcinogenicity

7.8 Toxicity to reproduction

1.2

Category Members

Common name

EC number

CAS number

Ferric chloride

231-729-4

7705-08-0

Ferrous chloride

231-843-4

7758-94-3

Ferric sulphate

233-072-9

10028-22-5

Ferrous sulphate

231-753-5

7720-78-7

Ferric chloride sulphate

235-649-0

12410-14-9

The definition of these salts also covers a number of chemical identities relating to specific hydrates. Under REACH all hydrates are covered by the registration of the anhydrous salt. As the hydrates influence the molecular weight, correction should apply as the hydrate weight is considered in CLP according to ECHA Guidance on the Application of the CLP Criteria Version 2.0 (2012, p 535, Example D).

The following hydrates are identified in the public domain though not all are necessarily commercially relevant:

Chemical name (CAS name)

CAS number

Molecular formula

Iron chloride (FeCl3), monohydrate (9CI)

60684-13-1 

Cl3 Fe . H2O

Iron chloride (FeCl3), hydrate (2:3) (9CI)

58694-76-1

Cl3 Fe . 3/2 H2O

Iron chloride (FeCl3), dihydrate (9CI)

54862-84-9

Cl3 Fe . 2 H2O

Iron chloride (FeCl3), trihydrate (9CI)

58694-75-0

Cl3 Fe . 3 H2O

Iron chloride (FeCl3), hexahydrate (8CI, 9CI)

10025-77-1

Cl3 Fe . 6 H2O

Iron chloride (FeCl3), nonahydrate (9CI)

58694-79-4

Cl3 Fe . 9 H2O

Iron chloride (FeCl3), dodecahydrate (9CI)

58694-80-7

Cl3 Fe . 12 H2O

Iron chloride (FeCl3), hydrate (8CI, 9CI)

24290-40-2

Cl3 Fe . x H2O

Iron chloride (FeCl2), hydrate

23838-02-0

Cl2 Fe . x H2O

Iron chloride (FeCl2), monohydrate

20049-66-5

Cl2 Fe . H2O

Iron chloride (FeCl2), dihydrate

16399-77-2

Cl2 Fe . 2 H2O

Iron chloride (FeCl2), tetrahydrate

13478-10-9

Cl2 Fe . 4 H2O

Iron chloride (FeCl2), hexahydrate

18990-23-3

Cl2 Fe . 6 H2O

Sulphuric acid, iron(3+) salt (3:2), nonahydrate

13520-56-4

Fe2(SO4)3.9H2O

Sulphuric acid, iron(3+) salt (3:2), hydrate

15244-10-7

Fe2(SO4)3.xH2O

Sulphuric acid, iron(3+) salt (3:2), hexahydrate

13761-89-2

Fe . 3/2 H2SO4 . 3 H2O

Sulphuric acid, iron(3+) salt (3:2), heptahydrate

35139-28-7

Fe . 3/2 H2SO4 . 7/2 H2O

Sulphuric acid, iron(3+) salt (3:2), tetrahydrate

230310-51-7

Fe . 3/2 H2SO4 . 2 H2O

Sulphuric acid, iron(2+) salt (1:1), hexahydrate

59261-48-2

Fe . H2SO4 . 6 H2O

Sulphuric acid, iron(2+) salt (1:1), trihydrate

58694-83-0

Fe . H2SO4 . 3 H2O

Sulphuric acid, iron(2+) salt (1:1), tetrahydrate

20908-72-9

Fe . H2SO4 . 4 H2O

Sulphuric acid, iron(2+) salt (1:1), monohydrate

17375-41-6

Fe . H2SO4 . H2O

Sulphuric acid, iron(2+) salt (1:1), hydrate

13463-43-9

Fe . H2SO4 . x H2O

Sulphuric acid, iron(2+) salt (1:1), dihydrate

10028-21-4

Fe . H2SO4 . 2 H2O

Sulphuric acid, iron(2+) salt (1:1), heptahydrate

7782-63-0

Fe . H2SO4 . 7 H2O

1.3

Purity / Impurities

Iron salts are not toxic to the population (cut off category 4 and upwards) and generally only substances with comparable purity or impurity profiles can be assessed together. Technical grade materials may contain relevant quantities of impurities, which exceed the low toxicological effects of the pure compounds comprised in this category. In cases where the sum of impurities triggers the toxicity, assessment has to be based on these impurities considering their concentration and the category assessment is restricted to the iron salt components.

The purity of the category members is generally > 80 % w/w. Deviations below this purity value would normally not be acceptable since this would suggest that the substance should not be considered as a mono-constituent substance.

Impurities comprise salts of other metals up to ≤ 1 % w/w and free acid up to < 10 % w/w.

2.

Category justification

The iron salts category comprises a directly analogous group of iron Fe3+and Fe2+salts, with counter-ions (chloride and sulphate) which are ubiquitous and do not require additional consideration. The formation of a category is justified on the basis of a self-consistent model of the behaviour and properties of these substances. All of these salts will dissociate immediately in aqueous media to the respective anions and kations. The chloride and sulphate anions are of no further interest since they are already ubiquitous in vivo and do not represent health hazard. The ferric and ferrous ions will inter-convert rapidly according to the in vivo conditions that they are found in, and if one ion is introduced into a system, any effects observed may be due to that ion, the other oxidation state, or a mixture of the two. Although each form of iron could be assessed for a particular endpoint and the test substance well-characterised, as a consequence of the inter-conversion it is not always possible to determine the form of the iron responsible for a particular endpoint. In general, under oxygenated conditions, ferrous will be converted to ferric, and in the presence of water ferric hydroxides will precipitate initially. Even where the form of the iron present when the endpoint is reached can be determined there will be uncertainty regarding the species responsible, unless the toxicity can be followed as a function of this species, which means that a dose response-relationship can be established. The majority of toxicological endpoints are covered with experimental tests showing similar mode of action between iron oxidation forms and salts having different counter-ions. Therefore it is logical to consider these five salts together within a single chemical category. Where a data gap may exist for an individual salt, it is considered that relevant data for one or more of the other salts are an acceptable surrogate for the missing data, taking due account of the oxidation state present initially. The iron content of a given salt or solution may be used to convert or compare data.

3.

Data matrix

The category approach was evaluated basing on the following experimental data for the acute oral toxicity endpoint. Studies are generally considered reliable or represent the sole data point available.

Test substance

Identifier of the study

Animal species

LD50 [mg/kg bw] based on test substance

LD50 [mg Fe/kg bw] based on Fe

FeCl2

Choi 2004a

rat

500 (300 – 2000, toxic classes tested)

220 (132-881, toxic classes tested)

FeSO4.7H2O

MHLW 2002

rat

> 2000

> 401

FeSO4.7H2O

Bayer AG 1985

rat

3200 (2900-3700, 95% CV)

643(583-743, 95% CV)

FeSO4

Parent 2000

rat

3200

1176

FeSO4

Weaver 1961

rat

2625 (2323-2966, 95% CV)

964

(854-1090, 95% CV)

FeSO4

Weaver 1961

mouse

1025 (802-1311, 95% CV)

377

(295-482, 95% CV)

FeSO4

Boccio 1998

mouse

670 (females)

680 (males)

246 (females)

250 (males)

FeCl3

Hosking 1970

mouse, female

1278 (871-1830, 95% CV)

440

(300-630, 95% CV)

Fe2(SO4)3

ICI 1991

rat

500-2000 (females)

>2000 (males)

140-559 (females)

>559 males

The category approach was evaluated basing on the following experimental data for the skin irritation / corrosion endpoint. Studies are generally considered reliable or represent the sole data point available.

Test substance

Identifier of the study

Test method & animal species

Result

FeSO4.7H2O

Clouzeau 1994

Skin irritation / corrosion in vivo, rabbit

Irritating, Category 2

FeCl2

Park 2004

Skin irritation / corrosion in vivo, rabbit

Not irritating

FeCl3

BASF 1977

Skin irritation / corrosion in vivo, rabbit

Irritating, Category 2

The category approach was evaluated based on the following experimental data for eye irritation / corrosion. Studies are generally considered as reliable or represent the sole data point available. In the study of Bayer AG (1992) FeSO4. 7H2O is classified as non-irritating, however, according to Draft Assessment Report for Iron Sulphate (September 2008), FeSO4 is classified as irritating to eyes (R36). Therefore, FeSO4 should be adopted as irritant to eyes.

Test substance

Identifier of the study

Test method & animal species

Result

FeCl2

Jeong 2004

Eye irritation / corrosion in vivo, rabbit

Corrosive to rabbit eye, Category 1

FeSO4.7H2O

Bayer AG 1992

Eye irritation in vivo, rabbit

(Not irritating)

Irritating

FeCl3water free solid

BASF 1977

Eye irritation / corrosion in vivo, rabbit

Corrosive to rabbit eye, Category 1

The category approach was evaluated basing on the following experimental data for the skin sensitisation.

Test substance

Identifier of the study

Test method & animal species

Result

FeSO4

Ikarashi 1992

Skin sensitisation in vivo

negative

FeSO4

Stitzinger 2010

Skin sensitisation – LLNA, mouse

negative

FeCl3

Storck 1962

Skin sensitisation in vivo, guinea pigs

Ambiguous, 1 of 2 guinea pigs were positive

The category approach was evaluated based on the following experimental data for repeated dose toxicity. Studies are generally considered reliable or represent the sole data point available.

Test substance

Identifier of the study

Test method & animal species

Result based on iron salt

Result based on iron

FeCl2

Beom 2004

Repeated dose toxicity: oral – OECD 422, rat

NOAEL:

125 mg/kg bw in males,

250 mg/kg bw in females

LOAEL:

250 mg/kg bw in males

500 mg/kg bw in females

NOAEL:

55.1 mg/kg bw in males,

110.1 mg/kg bw in females

LOAEL:

110.1 mg/kg bw in males

220.5 mg/kg bw in females

FeSO4.7H2O

Furuhashi 2002

Repeated dose toxicity: oral – OECD 422, rat

NOAEL:

100 mg/kg bw, LOAEL:

300 mg/kg bw for the test item;

NOAEL:

54.6 mg/kg bw, LOAEL:

163.9 mg/kg bw for anhydrous FeSO4

NOAEL:

20.1 mg/kg bw

LOAEL:

60.3 mg/kg bw

FeCl3

Sato 1992

Repeated dose toxicity: oral, 90 d rat

NOAEL:

277 mg/kg bw in males,

341 mg/kg bw in females

NOAEL:

95.4 mg/kg bw in males,

117.4 mg/kg bw in females

The category approach was evaluated based on the following experimental data for the genetic toxicity. Studies are generally considered reliable or represent the sole data point available.

Test substance

Identifier of the study

Test method & animal species

Result

FeCl2

Kim 2004

Bacterial mutagenicity – Ames test

negative with and without metabolic activation

FeCl2

Ji Yoon 2004

In vivo cytogenicity – micronucleus, mouse

negative; 2, 5, 10, 20, 50, 100 and 200 mg/ml in the dose range-finder; 1.25, 2.5 and 5 mg/mL in the micronucleus experiment

FeSO4

Bianchini 1988

In vivo micronuclei induction in GI tract, oral, mouse

negative

FeCl3.6H2O

Dunkel 1999

Bacterial mutagenicity – Ames test

negative; not a bacterial mutagen, tested up to 10’000 µg/plate (equivalent to 6001 µg/plate anhydrous FeCl3)

FeCl3

Dunkel 1999

Mammalian gene mutation – mouse lymphoma assay

negative up to 1030 µg Fe/mL -S9, up to 1.236 µg Fe/mL +S9; cytotoxicity at the highest tested concentrations

FeCl3

Schulz 2009

In vitro chromosome aberration – micronucleus assay

negative with and without metabolic activation

FeCl3

Bianchini 1988

In vivo micronuclei induction in GI-tract, oral, mouse

negative; dose related toxic effects were seen in colons of feeding animals and colon and stomach of fasting animals

The category approach was evaluated based on the following experimental data for the carcinogenicity. Studies are generally considered reliable or represent the sole data point available.

Test substance

Identifier of the study

Test method & species

Result

FeCl3

Sato 1992

Similar to OECD 451, rat

no carcinogenic potential

Iron supplementation

Ullen 1997

Epidemiological, human

Protective effect of iron

The category approach was evaluated based on the following experimental data for the reproduction toxicity. Studies are generally considered reliable or represent the sole data point available.

Test substance

Identifier of the study

Test method & animal species

Result based on iron salt

Result based on iron

FeCl2

Beom 2004

Screening, oral – OECD 422, rat

NOAEL: ≥ 500 mg/kg bw/day

NOAEL: ≥ 220.5 mg/kg bw/day

FeSO4.7H2O

Furuhashi 2002

Screening, oral – OECD 422, rat

NOAEL: ≥ 1000 mg/kg bw/day

NOAEL: ≥ 200.9 mg/kg bw/day

4.

Conclusions per endpoint for C&L, PBT/vPvB and dose descriptor

Considering the acute oral toxicity, the LD50 values show marked variability (220 – 964 mg Fe/kg bw) without clear difference between Fe2+and Fe3+salts. Nevertheless all these iron salt forms clearly have LD50 values > 300 mg/kg bw, that according to CLP support a classification from category 4 to not categorized range and it could be one of the reason to handle the corresponding iron salts as one chemical category.

Considering skin irritation, all here mentioned irons salts according their mode of action and following CLP, could be classified as skin irritating – category 2.

Considering eye irritation / corrosion, iron salts could be classified as causing irreversible effects on the eye – category 1. An exception may be made for FeSO4, which is already listed in Annex I of the European Plant Protection Products Directive and classified into category 2 (eye irritant).

Considering sensitization, in general iron salts are deemed to have a no potential to cause sensitisation that is relevant for classification and could be regarded as one chemical category.

Considering repeated dose toxicity, in all reliable oral studies the LOAEL of iron salts is above 100 mg/kg bw (not categorized range according to CLP) and no clear difference between Fe2+and Fe3+is observed. The apparent effect of slightly lower or equal toxicity of FeCl3 in 90-day study is in line with the expectation of bioregulation, i.e. tolerance development. Therefore iron salts could be regarded as one chemical category. In the case of repeated inhalation toxicity, the comparability of the Fe2+and Fe3+oxidation states depends particularly on assumption 1.1.a. of the Category Hypothesis. The scientific evidence of this assumption should be relying on the brother basis of data then they become available.

Considering genetic toxicity, iron salts show no genotoxic potential and could be regarded as one chemical category.

Considering carcinogenicity, human and animal data together are in agreement that iron is not carcinogenic and accordingly no classification is necessary for the iron salts of this category.

Considering toxicity to reproduction, only for FeCl2 and FeSO4 reliable studies (conducted according to OECD TG 422) are available. As the bioavailability of ferrous iron is assumed to be initially higher than that of ferric iron, a read across from these two substances to the ferric salts of this category is deemed valid and conservative. For both substances no adverse effects were seen at the highest tested dose levels where moderate to strong parental toxicity was already present. Based on the available data it can therefore be assumed that the iron salts of this category are not reproductive toxicants.

Iron is a bioessential element and uptake of iron is highly regulated by organism, therefore no concerns exist regarding bioaccumulation.

  • EVM Expert Group on Vitamins and Minerals (2003). Safe upper levels for vitamins and minerals. Report of the Expert Group on Vitamins and Minerals. ISBN 1-904026-11-7 Self-published in May by the Food Standards Agency, U.K. 360 p. http://cot.food.gov.uk/pdfs/vitmin2003.pdf