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EC number: 231-843-4
CAS number: 7758-94-3
Acute toxicity, oral: H302: Harmful if swallowed, Category 4, OECD TG 423; study Choi 2005Acute toxicity, inhalation: No adverse effect observed in limit study, EPA OPP 81-3; US EPA 1993/Robbins 1991Acute toxicity, dermal: Non-toxic, OECD TG 402; study Choi 2004
This endpoint is covered by the category approach for soluble iron salts
(please see the section Toxicokinetics, metabolism and distribution for
the category justification/report format).
• animal data:
A plethora of acute oral studies conducted with the different members of
the iron salt category are available. The available reliable studies for
the different metal salts have been compiled (see the below Table).
There is marked variability in the values quoted for acute toxicity for
all salts. This is probably a reflection of the variety of protocols
used and the duration over which observations were recorded. In addition
when looking at species differences it is noted that mice seem to be a
bit more susceptible to iron toxicity than rats. Nevertheless all
substances clearly have LD50 values > 300 mg/kg bw. Study Choi (2005)
using FeCl2 as test item is chosen as the representative key study as it
is, of the reliable studies, the one reporting the most critical LD50
value. This is in line with the assumption that the ferrous ion (Fe(II))
has a higher oral bioavailability than the ferric ion (Fe(III)). Choi
(2005) followed closely the protocol of OECD TG 423 and GLP using gavage
in rats and therefore is deemed fully reliable. Hypoactivity and
piloerection were reported at both 300 and 2000 mg/kg bw, prone
position, reddish change and oedema on ears, fore-legs and hind-legs
were only seen in the higher dose. At 2000 mg/kg bw, nasal discharge
(reddish or clear) was observed externally in all animals. Haemorrhage
on lymphatic nodes, stomach and intestine in all animals and haemorrhage
on the thymus of one animal was observed. At 300 mg/kg bw, haemorrhage
on lymphatic nodes and intestine were observed in the one animal (of
totally six) that died during the study. At 200 mg/kg bw all 3 animals
died. This distribution of deaths in the two dose groups is indicative
of a LD50 of 500 mg/kg bw according to the OECD TG 423.
Table: Overview on acute toxicity measurements
Iron salt species analysed
Identifier of the study
Klimisch score and relevance
LD50/LC50 based on tested substance
LD50/LC50 based on Fe
1278 (871 - 1830, 95 % CV)
440 (300 -630, 95 % CV)
500 (300 – 2000, toxic classes tested)
220 (132 – 881, toxic classes tested)
K4 to date SS
500 – 2000 (females), > 2000 males
139 – 558 (females), > 558 males
1025 (802 - 1311, 95 % CV)
377 (295 - 482, 95 % CV)
2625 (2323 -2966, 95 % CV)
965 (854 -1090, 95 % CV)
FeSO4 x 7 H2O
Bayer AG 1985
3200 (2900 -3700, 95 % CV)
643 (583 -743, 95 % CV)
670 (females) 680 (males)
246 (females), 250 (males)
Substance is irritating
BASF AG 1977
LC0 is larger than the saturation concentration of a mist generated from a 40 % (w/w) solution when exposed for 8 h
US EPA 1993
• human data:
The Expert Group on Vitamins and Minerals (EVM 2003) considered that the
following acute toxic doses apply:
- for infants (under the age of six years) 20 mg/kg for gastrointestinal
irritation, with systemic effects not occurring below 60 mg/kg bw
- for children, 200-300 mg/kg bw
- for adults 1400 mg/kg bw acute oral toxicity in humans. It is not
stated in the source material whether the toxicity values are mg salt/kg
bw, or mg Fe/kg bw. It is not always stated which salt was used.
McElhatton (1991) reports that in a follow up study of 49 pregnancies
where iron overdose was a factor there was no evidence of a correlation
between serum iron concentrations and birth weight. No causal
relationship between iron overdose or Desferoxamine (DFO) treatment and
malformations was observed. There was no evidence to suggest that DFO
caused toxicity in the mother or baby.
A summary entry of ACGIH (1980) & Ellenhorn (1988) describes the
estimated fatal dose in humans for soluble ferric salts to be 30 g.
Toxic doses of iron overwhelm the normal gastrointestinal regulatory
mechanism (suggesting that saturable transport systems are not involved
at high concentrations); this results in massive iron absorption. Major
toxicity occurs when serum iron levels exceed the iron-binding capacity
of transferrin. Free circulating iron damages systematic blood vessels.
The release of serotonin and histamine potentiate the vascular damage
caused by free serum iron. In severe iron overdose, the coagulative
necrosis with platelet aggregation appears similar to the damage caused
by corrosive agents.
According to Gilman 1980, the studies on human subjects have established
that physical intolerance to iron does occur. With a dose of 200 mg or
iron per day divided into three equal portions, symptoms occurred in
approximately 25 % of individuals, compared to an incidence of 13 %
among those receiving placebos; this increased to 42 % when the dosage
of iron was doubled. Nausea and upper abdominal pain were increasingly
common manifestations at high dosage. Constipation and diarrhoea were
not more prevalent at higher dosage, nor was heartburn. Available
evidence suggests that the normal individual is able to control
absorption of iron despite high intake, and it is only individuals with
underlying disorders that augment the absorption of iron might develop
In IUCLID 2000 (summary of summaries) it is explained that ferrous
sulphate is widely used in iron pills for the treatment of anaemia.
There is therefore a large amount of human data on the use and misuse of
the compound. The lowest lethal dose in humans by oral ingestion is
estimated at being in the range of 40 - 1600 mg/kg. Young children
appear to be more susceptible. Other estimates are considerably higher.
The main cause of death is haemorrhagic gastritis with oedema,
(also demonstrated in animal experiments on treatments for iron
poisoning). Liver damage has also been reported after gross ingestion of
ferrous sulphate. Ferrous sulphate has been used for many years and has
been used to replace some irritant agents. However, ferrous sulphate is
regarded as a skin and eye irritant for the purposes of handling.
Hoppe (1955) reports that death has occurred from the oral ingestion of
ferrous sulphate at doses ranging from 40 to 1600 mg/kg.
According to Aisen (1990) acute symptoms of iron toxicity are
characterized by vomiting, diarrhoea, mild lethargy, upper abdominal
pain, pallor, and hyperglycaemia with more severe clinical findings
including cyanosis, stupor, acidosis, haematemesis, shock, and coma.
In addition two case studies on oral iron poisoning are available. Ling
(1988) describes the following case: A 25 year old woman fatally
ingested 200 mL ferric chloride solution (pH 1), equivalent to 230 mg/kg
bw of elemental iron. She had hypoxemia and severe metabolic acidosis
with respiratory alkalosis initially. Three hours after her ingestion
she presented with drowsy consciousness, tachycardia, tachypnea and
projected vomiting. Laboratory studies showed leukocytosis, elevated
glucose, aspartate aminotransferase, amylase, lactate dehydrogenase, and
total bilirubin, coagulation defect and haemolysis. Aspiration and
vision loss were also reported. Four hours after ingestion
cardiopulmonary arrest suddenly occurred after severe vomiting and the
woman died. Toxicological studies showed marked elevation of serum iron
Ellenhorn (1998) describes a case where
a pregnant mother died of iron poisoning (serum iron, 1700 mg/dL) after
deferoxamine was withheld.
The available human data is of low reliability or from a secondary
source (EVM 2003). Therefore for the derivation of classification and
labelling is based on the available animal data. Nevertheless it should
be emphasized that the human data is not in contradiction to the animal
For the dermal exposure route only one reliable study is available. Choi
(2004) followed closely the protocol of OECD TG 402 and GLP using 24 h
semiocclusive exposure of the test item FeCl2 in corn oil to rats (dose
group: 2000 mg/kg bw). For Fe(III)-salts no studies are available.
Nevertheless FeCl2 can be regarded as a worst case as the general
assumption is that the ferrous ion (Fe(II)) has a higher bioavailability
than the ferric ion (Fe(III)). The higher corrosivity of Fe(III)-salts
is covered under the respective chapter on irritation/corrosion.
Nevertheless it has to be taken into account that upon the availability
of water and oxygen FeCl2 is oxidised and hydrolysed and hydrochloric
acid is freed according to the following (idealised) equation:
4 FeCl2 + O2 + 10 H2O -> 4 Fe(OH)3 + 8 HCl
Therefore during an incubation period of 24 h FeCl2 can exhibit a
certain corrosive effect on the local skin tissue. Accordingly it can be
regarded as a good surrogate for the other iron salt in acute dermal
In Choi (2004) there were no unscheduled deaths and bodyweight gains
were normal during the study. A yellowish-brown change was observed at
the application site in all test animals, and was considered to relate
to the colour of the test article. Two males and 4 females had a reddish
nasal discharge on Day 2, which was considered a distress symptom caused
by pressure of taping on the thorax area.
During macroscopic examination, scarring was observed at the application
site on one male and one female. This was considered to relate to the
application of the test article and can most probably be assigned to the
corrosive action of the test substance. Internally, no abnormalities
According to Annex VIII as specified under section 8.5, column 2, no
testing is required via inhalation route since high reliability studies
are already in place via the oral and dermal route.
A reliability score 4 study (BASF 1977) in which a saturated atmosphere
of aerosol generated using a 40 % aqueous solution of ferric chloride
did not cause any fatalities in rats following eight hours of exposure.
In the study with rats (US EPA 1993/Robins 1991) using iron (III)
sulphate, no mortality occurred and an LC50 greater than the highest
tested concentration of 1.10 mg/L was evidenced.
- other routes:
A number of studies are available for the different iron salts that were
applied via i.v., i.p. or subcutaneous injection. None of these studies
are fully reliable and as they are not of relevance for the exposure to
chemicals they are disregarded here.
Based on the above stated assessment of the acute oral toxicity of the
iron salts, the LD50 values from reliable studies range between 300 and
2000 mg/kg bw. Accordingly the salts belonging to the iron salt category
need to be classified as “R22 Harmful if swallowed” according to
Commission Directive 2001/59/EC (28th ATP of Council Directive
67/548/EEC) and as Category 4, “Warning - H302: Harmful if swallowed”
according to CLP (5th ATP of Regulation (EC) No 1272/2008 of the
European Parliament and of the Council) as implementation of UN-GHS in
Table: Acute toxicity label elements for category 4 (CLP, 5th ATP,
Annex I, Table 3.1.3)
GHS07 exclamation mark
Hazard Statement (Oral)
H302: Harmful if swallowed
P301 + P312, P330
Based on the above stated assessment of the acute dermal toxicity of
FeCl2 which is used as surrogate for all iron salts of this category
(absence of toxicity up to 2000 mg/kg). Thus the salts belonging to the
iron salt category do not need to be classified according to Council
Directive 2001/59/EC (28th ATP of Directive 67/548/EEC) and according to
CLP (5th ATP of Regulation (EC) No 1272/2008 of the European Parliament
and of the Council) as implementation of UN-GHS in the EU.
Based on the above stated assessment of the acute inhalation toxicity of
Fe2(SO4)3 which is used as surrogate for all iron salts of this
category, the LC50 result from available study is >>1.1 mg/L (US EPA
1993/Robbins 1991). The absence of 50 % mortality up to 5 mg/L is the
upper level of relevance for classification. Therefore this study result
might be used for a precautionary classification as “R20 Harmful by
inhalation” according to Council Directive 2001/59/EC (28th ATP of
Directive 67/548/EEC) and as Category 4, “Warning - H332: Harmful if
inhaled” according to CLP (5th ATP of Regulation (EC) No 1272/2008 of
the European Parliament and of the Council) as implementation of UN-GHS
in the EU. According to CLP (5th ATP) 220.127.116.11.2., “Inhaled particles
between 1 and 4 microns mean mass aerodynamic diameter (MMAD) will
deposit in all regions of the rat respiratory tract. This particle size
range corresponds to a maximum dose of about 2 mg/L.” Based on the
measured MMAD of 2.75 µm in the study, the used gravimetric
concentration of >1.1 mg/L in can be therefore regarded as the limit
concentration for testing the substance. Together with the fact, that
neither mortality nor signs of toxicity were noted according to the
short report, the determined LC50 of >1.1 mg/L would hence not justify a
classification as Acute Tox. Cat. 4 after acute inhalation exposure.
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