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EC number: 215-572-9
CAS number: 1332-65-6
The copper Risk Assessment Report (2008) and REACH Chemical
Safety Report (2010) have provided detailed information on (1) the
essentiality of copper; (2) the homeostatic control of copper; (3)
the mechanisms of action of copper-ions; (4) the comparison between
copper toxicity from dietary versus waterborne exposures.
The data clearly demonstrate that:
Essential Trace Element
Copper is an essential micronutrient, needed for optimal
growth and development of micro-organisms, plants, animals and
humans. It plays a vital role in the physiology of animals: for
foetal growth and early post-natal development, for haemoglobin
synthesis, connective tissue maturation especially in the
cardiovascular system and in bones, for proper nerve function and
bone development, and inflammatory processes. Copper acts as an
active cofactor in over 20 enzymes and proteins, notably the
respiratory enzymes haemocyanin and cytochrome oxidase and the
anti-oxidant superoxide dismutase (WHO, 1998).
Copper deficiency has been observed in intensive cultures of
fish, crops and farm animals. The most striking examples of copper
deficiency come from farming practices. Insufficient bioavailable
copper in soils has been shown to reduce agricultural yields and to
produce metabolic copper deficiencies in animals. Copper deficiency
was first recognised in Europe in the 1930s and its incidence
increased with the intensification of arable farming over the last
50 years. Copper deficiency has also been noted in a wide variety of
soils world-wide (IPCS 1998).
Depending on the organism’s metabolic need, different copper
levels are found in tissues from different strains, species and life
Differences among species and strains:Aquatic
invertebrates such as gastropods, some crustacea and bivalves,
relying on haemoocyanin as respiratory pigment, have typically
higher copper levels than invertebrates relying on haemoglobin as
respiratory pigment (e.g. Timmermans et al, 1989).
In higher organisms (vertebrates), homeostatic control of
copper supply is achieved mainly by storage in the liver and biliary
secretion (Underwood and Suttle, 1999). Copper is bound to proteins
such as ceruloplasmin and metallothionenin, functioning as copper
storage and mobilised as needed.
Differences within species: Of all factors that affect
the physiology of animals, body size exerts the major effect and
provides an integrated value of all physiological processes (Marsden
and Rainbow, 2004). In aquatic environments, several investigators
demonstrated an inverse relation between copper tissue levels and
the length or weight of the organisms (e.g. Timmermans et al, 1989).
Different copper needs are of relevance to both agricultural
and medical practices:
Copper supplements are provided to piglets and pigs to enhance
growth. Considering the high needs during the fast growth stages,
copper levels given to piglets are much higher than those given to
The copper concentration in the liver of a mammalian and human
foetus is much higher during the last term of pregnancy than in an
adult. This is because of the high copper need during this period,
as well as during the first months after birth, and because breast
milk contains little copper. Consequently, the milk formulae for
premature babies contain higher copper levels than those for
In summary, as an essential element, all organisms will
naturally accumulate copper without deleterious effects. Different
levels of accumulation in tissue reflect differences in nutritional
Homeostatic control, uptake and depuration of copper ions
The natural copper levels, available for plants,
micro-organisms and animals, living in a specific environment,
depend on the natural geological and physico-chemical
characteristics of the water, sediments and soils. Homeostatic
regulation of copper allows organisms, within certain limits, to
maintain the physiologically required levels of copper in their
various tissues, both at low and high copper intakes.
The molecular mechanism of copper homeostasis is related to 2
key elements: P-type ATPases that can pump copper across biological
membranes in either direction or copper chaperones, important for
intracellular copper homeostasis (Odermatt et al, 1992). The latter
is considered to be universal as the sequences of copper chaperones
are highly conserved between species (Wunderli et al. 1999).
Besides these active cellular regulation mechanisms, some
groups of organisms have developed additional mechanisms (molecular
binding to e.g. metallo-thioneins and sequestration in granules) to
prevent copper excess (Borgmann, 1993 and Rainbow, 1980, 1985, 1989;
Marsden and Rainbow, 2004).
Vertebrate dietary copper exposure studies (fish, mammals,
birds and humans) demonstrate additional organ-related homeostasis.
Intestinal adsorption/biliary excretion of copper is regulated with
varying dietary intakes (WHO, 1998).
Due to the homeostatic regulation of copper (and other
metals), BCF/BAFs are not independent of exposure concentration
(e.g. Mc Geer et al., 2003). Increased/decreased copper
intakes/eliminations, lead to BCFs and BAFs that are inversely
related to exposure concentration (i. e. decreasing BCF/BAFs with
increasing exposure concentration (water and diet). For copper, this
inverse relationship was clearly demonstrated for BCFs, BAFs and
biota-sediment accumulation factors (BSAFs) (Adams et al., 2003).
The observed inverse relationship has been explained by homeostatic
regulations of internal tissue concentrations At low metal
concentrations, organisms are actively accumulating metals in order
to meet their metabolic requirements, while at high ambient metal
concentrations, organisms are able to excrete excess metals or limit
Additionally, different BCFs for different species, life
stages and seasons have been observed, depending on the organism’s
metabolic need (in e.g. Cu-enzymes). Further complicating the
application of BCF and BAF to metals is that many aquatic organisms
store metals in detoxified forms, such as in inorganic granules or
bound to metallothionein-like proteins. The use of granules is of
particular note in the context of BCFs, because high body burdens
are often associated with this storage mechanism, but there is a
lack of adverse effects.
Using BCF and BAF for essential metals and their compounds to
assess ecotoxicity therefore ignores fundamental physicochemical and
toxicological properties associated with these substances.
Compared with the diffusional uptake of neutral organics,
metal uptake is complex. It includes a diversity of mechanisms,
accumulation of both essential and non-essential elements from the
natural background, homeostatic control of accumulation, as well as
internal detoxification, storage and elimination.
Mechanism of action of copper toxicity/deficiency
From the copper risk assessment, it was clearly concluded that
the most sensitive uptake route for acute and chronic copper
toxicity is directly from the water with free Cu-ions as most potent
Cu-species. The key indicator of copper toxicity is disturbance of
the sodium homeostasis (e.g. Paquin et al., 2002; De Schamphelaere
and Janssen, 2003; Kamunde et al., 2001 & 2005). The key target
tissue for copper toxicity is therefore the water/organism
interface, with cell wall and gill-like surfaces acting as target
biotic ligands in all species investigated.
The importance of water-borne exposure was confirmed from the
freshwater chronic ecotoxicity database, demonstrating:
influence of water chemistry on chronic copper toxicities (influence
of DOC, pH,... on chronic NOECs)
small inter-species variability in observed NOECs (after BLM
normalisation) (max/min NOEC ratio of 23 for 27 species),
acute to chronic ratios (typically a factor of 1 to 3)
sensitivity of smaller compared to larger organisms (Grosel et al.,
concern of secondary poisoning from copper mesocosm studies:
(2007) reported for a lentic mesosocm study a low sensitivity of the
predating fish compared to the invertebrates and algae.
freshwater pond mesocosms (Schaefers et al, 2002 and Rousel (2007)
and the marine pond mesocosm (Foekema et al 2010) did not show a
concern from copper secondary poisoning.
Freshwater and marine organisms face very different ion- and
osmo-regulatory problems related to living in either a very dilute
or concentrated salt environment. These differences in ion- and
osmo-regulatory physiology may also lead to differences in metal
accumulation and metal toxicity (Prosser, 1991; Wright 1995;
Rainbow, 2002). Marine organisms are, as freshwater organisms, also
exposed via the gills. But in addition, they take in water via the
gut exposing an additional series of epithelial structures to the
metals (Wang and Fisher 1998; Glover et al 2003; Mouneyrac et al
2003). Both the epithelia of gills and gut are thus important and
potentially sensitive targets because they provide a variety of
essential physiological functions such as the energy dependent
transport of nutrients across the interface and the maintenance of
homeostatic balance. Despite these apparent physiological
differences, it has been shown that marine fish also suffer from
osmo-regulatory disturbances under metal exposure.
The importance of waterborne exposure was confirmed from
marine ecotoxicity databases, demonstrating:
mitigating effect of DOC on the marine NOECs/EC10s.
absence of a higher copper sensitivity with increasing trophic chain
the bivalve Mytilus edulis, the short term (48 hrs) early life stage
NOEC was similar to the 10 days growth inhibition NOEC.
The 83 days marine mesocosm study (Foekema et al., 2010),
furthermore showed that the safe level in the mesocosm could be
predicted from the single-species SSD and DOC correction, developed
for water-only exposure.
The interaction between free copper-ions and “gill-like
structures” induce osmo-regulatory stress. Osmo-regulatory
disturbance from waterborne exposure is recognised as the primary
symptom of copper toxicity to aquatic organisms.
Copper toxicity from dietary versus waterborne exposures
Invertebrates:A few key studies
- De Schamphelaere and Janssen (2003) demonstrated the
influence of water characteristics on the chronic toxicity of D.
magna and showed that, for D. magna, waterborne copper and not
dietary copper uptake is responsible for copper toxicity (De
Schamphelaere and Janssen, 2004).
Similarly, Allinson (2002) investigated the bioaccumulation of
copper through a simple food chain (Lemna minor – C. destructor) and
observed regulation of copper by the crayfish, C. destructor, with
the gills being the main site for absorption and depuration of
copper to and from the water column. C. destructor does not appear
to be sensitive to dietary copper.
- Kamunde, 2001 observed that dietary copper pre-exposure
decreased the uptake of copper across the gills, providing further
evidence of homeostatic interaction between the two routes of
uptake. Rainbow trout regulated dietary copper at the level of the
gut by increasing clearance to other tissues, at the liver by
increasing biliary copper excretion, and at the gill by reducing
waterborne copper uptake in response to dietary exposure. The modest
morphological changes in the intestinal tract suggested high cell
and organelle turnover and local regulation of copper. In spite of
possible increased energy demand for regulation and tissue repair,
there was no significant growth inhibitory effect following dietary
- Blust et al., 2007, reviewed the literature on copper
toxicity after dietary copper exposures of fish and compared
waterborne versus diet borne toxicity of copper to fish. After
detailed evaluation of the Clearwater et al., 2002 review paper,
Blust derived critical diet borne toxicity effects value for
Atlantic salmon and Rainbow trout of respectively 15.5 and 44 mg
Cu/kg fresh weight/day. Blust et al, 2007 further assessed if the
waterborne exposures, PNEC of 7.8 µg Cu//l, as derived in the copper
risk assessment, would result in a dietary copper dose or copper
food concentration exceeding a critical level. The concentrations in
food were calculated from the regressions presented in McGeer et al.
(2003) which allow the estimation of the whole body copper
concentration, for different types of aquatic organisms, as a
function of the copper waterborne concentration. The results of the
simulations show that aquatic invertebrates exposed to 8µg Cu/l
waterborne copper reach mean Cu body levels of 53-84 mg Cu/kg dry
weight (depending on the diet). The resulting daily uptake by fish
at 7.8 µg Cu/L was < 4.20 mg Cu/kg fresh weight/day. These results
lead to the conclusion that the copper concentrations in food items
and daily dietary copper dose in fish are unlikely to cause negative
effects at the threshold waterborne copper concentration of 7.8 µg/l.
Comparison of the dietary copper levels and “normal”
background Cu levels in live food items
Cu is a naturally occurring element and is essential to all
living organisms. Naturally, a background Cu burden is present in
all organisms to fulfil their biochemical requirements. Table 1
presents a summary of a few ‘background’ Cu concentrations in
freshwater biota that may serve as food items for fish.
Background Cu burdens of selected freshwater biota that may be
considered food items for fish.
Cufood(mg/kg dry wt)
10.2 - 22.1
Bossuyt et al. (2005a,b)a
20 - 120
Borgmann et al. (1993)
or 6thgeneration daphnids taken from a multi-generation
exposure; 1µg/L was sufficient to avoid deficiency
Bossuyt et al. (2005a, b) reported background body burdens of
40d-old D. magna at 1 µg Cu/L between 10.2 and 22.1 mg Cu/kg-1 dry
wt. Juvenile daphnids of up to 2 days old seemed to have higher
copper body burdens between 20 and 120 mg Cu/kg-1 dry wt. Borgmann
et al. (1993) report a Cu burden inHyalella. aztecaof 79 mg
Cu/kg-1 dry wt in organisms exposed to control conditions, i.e. 3.5
The background copper burdens (10 - 120 mg Cu/kg dry weight)
as determined above, furthermore encompass the simulated Cu body
levels of 53 - 84 mg Cu/kg dry weight calculated for aquatic
invertebrates exposed to 8 µg Cu/l waterborne copper and therefore
provide additional evidence that the Cu concentrations in food items
and daily dietary Cu dose in fish are unlikely to cause negative
effects at the threshold waterborne Cu concentration of 8 µg/l.
Waterborne Cu is therefore recognised as the critical
copper exposure route for invertebrates and fish.
Critical papers of relevance to bio-magnification
The absence of copper bio-magnification, with consistent BMFs
< 1, was shown from several papers:
- Barwick and Maher (2003), compared trace metal levels in a
contaminated seagrass ecosystem in Lake Macquire, the largest
estuary in New South Wales (Australia). The structure of the
estuarine food web was studied in detail and all organisms (algae,
invertebrates, fish) were categorised as autotrophs, herbivores,
planktivores, detrivores, omnivores and carnivores. The results of
the analysis showed the absence of copper bio-magnification in this
estuarine system. Copper concentrations ranged between 0.27 µg Cu/g
dw (Omnivore: Monacanthus and 88 µg Cu/g dw (Herbivore: Bembicum
auratum (gastropod with haemocyanin)). The higher levels (e.g.B.
auratum) were associated with species with active accumulation
of copper into the respiratory pigment haemocyanin.
- Farag et al., 1998, studied copper concentration in benthic
invertebrates that represent various functional groups and sizes
from de Coeur d’Alene river, Idaho, influenced by mining activities.
The copper concentrations noted across the trophic chain,
demonstrated the absence of bio-magnification from the sediment to
herbivores, omnivores, detrivores and carnivores.
- Wang (2002) noted the bio-diminution of metals in the
classical marine planktonic food chain (phytoplankton to copepods to
fish) and explained the phenomenon as the result of the effective
efflux of metals by copepods and the low assimilation of metals by
- Quinn et al., 2003, evaluated trophic chain transfer of
metals in insects (35 species) from a stream food web influenced by
acid mine drainage with copper levels up to 100 µg Cu/L. They
demonstrated that metal concentrations were higher in water and
insects closer to the mining sites and taxa richness increased with
distance away from the site. The relation between the trophic
positions, determined from15N radio isotope determination, indicated
that the trophic chain had no effect on copper levels in the insects.
Copper is therefore not bio-magnified across the trophic
There is a substantial amount of information available on
The data clearly demonstrate that:
is an essential nutrient for all living organisms.
ions are homeostatically controlled in all organisms and the control
efficiencies increase with trophic chain. As a consequence,
BCF/BAF values decrease with increasing exposure concentrations
(water and food).
depending on the nutritional needs (seasonal, life stage, species
pending on “internal detoxification” mechanisms.
BMFs values are < 1.
waterborne exposure (and not diet borne exposure) is the exposure
route critical to copper toxicity.
Harmonised classification listed in Regulation (EC) No
Acute classification for the environment:
Copper sulphate is classified Acute Category 1. An M factor of 10
Chronic classification for the environment:
Copper chloride is classified Chronic Category 1.
Copper sulphate pentahydrate
Classification for copper sulphate pentahydrate containing
nickel sulphate as an impurity (Applicant’s proposal based on the
harmonised classifications for copper sulphate and nickel sulphate):
Copper sulphate pentahydrate, > 0.1% < 0.3% nickel sulphate
Copper sulphate pentahydrate, > 0.3% nickel sulphate impurity
Copper chloride is classified Chronic Category 1.
Updated Classification and Labelling for Copper Sulphate
RAC meeting of 4th December 2014, it was decided that copper sulphate
pentahydrate should be classified Aquatic, Acute 1 (M-factor 10). The
RAC further considered that the concept of ‘removal from the water
column’ cannot be incorporated into the environmental classification of
copper and copper compounds until such time as it has been ratified by
an international standardisation body such as the OECD. It
was therefore decided that all copper compounds should also be assigned
Aquatic, Chronic 1. However,
no chronic M-Factors have been assigned at this time, subject to further
assessment of available data by the RAC.
harmonised classification for basic copper sulphate pentahydrate was
published in the 9th adaptation to technical progress of the CLP
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