Copper and copper salts
| 1. NAME |
| 1.1 Substance |
| 1.2 Group |
| 1.3 Synonyms |
| 1.4 Identification numbers |
| 1.4.1 CAS number |
| 1.4.2 Other numbers |
| 1.5 Brand names, Trade names |
| 1.6 Manufacturers, Importers |
| 2. SUMMARY |
| 2.1 Main risks and target organs |
| 2.2 Summary of clinical effects |
| 2.3 Diagnosis |
| 2.4 First-aid measures and management principles |
| 3. PHYSICO-CHEMICAL PROPERTIES |
| 3.1 Origin of the substance |
| 3.2 Chemical structure |
| 3.3 Physical properties |
| 3.3.1 Colour |
| 3.3.2 State/form |
| 3.3.3 Description |
| 3.4 Hazardous characteristics |
| 4. USES/CIRCUMSTANCES OF POISONING |
| 4.1 Uses |
| 4.1.1 Uses |
| 4.1.2 Description |
| 4.2 High risk circumstance of poisoning |
| 4.3 Occupationally exposed populations |
| 5. ROUTES OF ENTRY |
| 5.1 Oral |
| 5.2 Inhalation |
| 5.3 Dermal |
| 5.4 Eye |
| 5.5 Parenteral |
| 5.6 Others |
| 6. KINETICS |
| 6.1 Absorption by route of exposure |
| 6.2 Distribution by route of exposure |
| 6.3 Biological half-life by route of exposure |
| 6.4 Metabolism |
| 6.5 Elimination by route of exposure |
| 7. TOXICOLOGY |
| 7.1 Mode of Action |
| 7.2 Toxicity |
| 7.2.1 Human data |
| 7.2.1.1 Adults |
| 7.2.1.2 Children |
| 7.2.2 Relevant animal data |
| 7.2.3 Relevant in vitro data |
| 7.2.4 Workplace standards |
| 7.2.5 Acceptable daily intake (ADI) and other guideline levels |
| 7.3 Carcinogenicity |
| 7.4 Teratogenicity |
| 7.5 Mutagenicity |
| 7.6 Interactions |
| 8. TOXICOLOGICAL ANALYSES AND BIOMEDICAL INVESTIGATIONS |
| 8.1 Material sampling plan |
| 8.1.1 Sampling and specimen collection |
| 8.1.1.1 Toxicological analyses |
| 8.1.1.2 Biomedical analyses |
| 8.1.1.3 Arterial blood gas analysis |
| 8.1.1.4 Haematological analyses |
| 8.1.1.5 Other (unspecified) analyses |
| 8.1.2 Storage of laboratory samples and specimens |
| 8.1.2.1 Toxicological analyses |
| 8.1.2.2 Biomedical analyses |
| 8.1.2.3 Arterial blood gas analysis |
| 8.1.2.4 Haematological analyses |
| 8.1.2.5 Other (unspecified) analyses |
| 8.1.3 Transport of laboratory samples and specimens |
| 8.1.3.1 Toxicological analyses |
| 8.1.3.2 Biomedical analyses |
| 8.1.3.3 Arterial blood gas analysis |
| 8.1.3.4 Haematological analyses |
| 8.1.3.5 Other (unspecified) analyses |
| 8.2 Toxicological Analyses and Their Interpretation |
| 8.2.1 Tests on toxic ingredient(s) of material |
| 8.2.1.1 Simple Qualitative Test(s) |
| 8.2.1.2 Advanced Qualitative Confirmation Test(s) |
| 8.2.1.3 Simple Quantitative Method(s) |
| 8.2.1.4 Advanced Quantitative Method(s) |
| 8.2.2 Tests for biological specimens |
| 8.2.2.1 Simple Qualitative Test(s) |
| 8.2.2.2 Advanced Qualitative Confirmation Test(s) |
| 8.2.2.3 Simple Quantitative Method(s) |
| 8.2.2.4 Advanced Quantitative Method(s) |
| 8.2.2.5 Other Dedicated Method(s) |
| 8.2.3 Interpretation of toxicological analyses |
| 8.3 Biomedical investigations and their interpretation |
| 8.3.1 Biochemical analysis |
| 8.3.1.1 Blood, plasma or serum |
| 8.3.1.2 Urine |
| 8.3.1.3 Other fluids |
| 8.3.2 Arterial blood gas analyses |
| 8.3.3 Haematological analyses |
| 8.3.4 Interpretation of biomedical investigations |
| 8.4 Other biomedical (diagnostic) investigations and their interpretation |
| 8.5 Overall Interpretation of all toxicological analyses and toxicological investigations |
| 8.6 References |
| 9. CLINICAL EFFECTS |
| 9.1 Acute poisoning |
| 9.1.1 Ingestion |
| 9.1.2 Inhalation |
| 9.1.3 Skin exposure |
| 9.1.4 Eye contact |
| 9.1.5 Parenteral exposure |
| 9.1.6 Other |
| 9.2 Chronic poisoning |
| 9.2.1 Ingestion |
| 9.2.2 Inhalation |
| 9.2.3 Skin exposure |
| 9.2.4 Eye contact |
| 9.2.5 Parenteral exposure |
| 9.2.6 Other |
| 9.3 Course, prognosis, cause of death |
| 9.4 Systematic description of clinical effects |
| 9.4.1 Cardiovascular |
| 9.4.2 Respiratory |
| 9.4.3 Neurological |
| 9.4.3.1 Central Nervous System (CNS) |
| 9.4.3.2 Peripheral nervous system |
| 9.4.3.3 Autonomic nervous system |
| 9.4.3.4 Skeletal and smooth muscle |
| 9.4.4 Gastrointestinal |
| 9.4.5 Hepatic |
| 9.4.6 Urinary |
| 9.4.6.1 Renal |
| 9.4.6.2 Others |
| 9.4.7 Endocrine and reproductive systems |
| 9.4.8 Dermatological |
| 9.4.9 Eye, ears, nose, throat: local effects |
| 9.4.10 Haematological |
| 9.4.11 Immunological |
| 9.4.12 Metabolic |
| 9.4.12.1 Acid-base disturbances |
| 9.4.12.2 Fluid and electrolyte disturbances |
| 9.4.12.3 Others |
| 9.4.13 Allergic reactions |
| 9.4.14 Other clinical effects |
| 9.4.15 Special risks |
| 9.5 Others |
| 9.6 Summary |
| 10. MANAGEMENT |
| 10.1 General principles |
| 10.2 Life supportive procedures and symptomatic treatment |
| 10.3 Decontamination |
| 10.4 Enhanced Elimination |
| 10.5 Antidote treatment |
| 10.5.1 Adults |
| 10.5.2 Children |
| 10.6 Management discussion |
| 11. ILLUSTRATIVE CASES |
| 11.1 Case reports from literature |
| 12. ADDITIONAL INFORMATION |
| 12.1 Specific preventive measures |
| 12.2 Other |
| 13. REFERENCES |
| 14. AUTHOR(S), REVIEWER(S), DATE(S) (INCLUDING UPDATES), COMPLETE ADDRESSES |
COPPER AND COPPER SALTS
International Programme on Chemical Safety
Poisons Information Monograph (Group Monograph) G002
Chemical
1. NAME
1.1 Substance
Copper and copper salts
1.2 Group
Copper
Cupric acetate, basic
Cupric carbonate, basic
Cupric chloride
Cupric chromate(VI)
Cupric cyanide
Cupric hydroxide
Cupric nitrate
Cupric oxide
Cupric sulphate
1.3 Synonyms
Copper acetate:
Acetate de cuivre;
Acetate de Cuivre (French);
Cupric acetate;
Acetic acid, cupric salt;
Copper acetate (cu(C2H3O2)2);
Copper diacetate;
Copper(2+) acetate;
Copper(2+) diacetate;
Copper(II) acetate;
Crystallized verdigris;
Crystals of venus;
Cupric acetate;
Cupric diacetate;
Neutral verdigris;
Octan mednaty;
Copper carbonate:
Carbonic acid, copper(2+) salt (1:1);
Copper carbonate (1:1);
Copper monocarbonate;
Copper(II) carbonate;
Cupric carbonate;
Cupric carbonate (1:1);
Xanthic acid, copper(II) salt;
Copper Cyanide:
Copper (+1) cyanide;
Copper cyanide (DOT);
Copper(I) cyanide;
Cupricin;
Cuprous cyanide;
Copper hyrdoxide:
Comac;
Copper dihydroxide;
Copper(2+) hydroxide;
Copper(II) hydroxide;
Criscobre;
Cudrox;
Cuidrox;
Cupravit blau;
Cupravit Blue;
Cupric hydroxide;
Kocide;
Kocide 101;
Kocide 220;
Kocide 404;
Kocide SD;
Kuprablau;
Parasol;
Copper oxide:
Black copper oxide;
Boliden-CCA Wood Preservative;
C.I. 77403;
C.I. Pigment Black 15;
Copper Brown;
Copper monooxide;
Copper monoxide;
Copper(2+) oxide;
Copper(II) oxide;
Cupric oxide;
Copper sulphate:
dried cuprice sulphate;
bluestone;
blue stone;
blue vitriol;
copper(II) sulfate;
cupric sulfate;
sulfate de cuivre;
copper (II) sulphate pentahydrate;
Roman vitriol;
salzburg vitriol;
1.4 Identification numbers
1.4.1 CAS number
Copper acetate: 142-71-2
1.4.2 Other numbers
Copper carbonate: 1184-64-1
Copper(II) Chloride: 7447-39-4
Copper chloride (CuCl): 7758-89-6
Copper cyanide: 544-92-3
Copper hydroxide: 20427-59-2
Copper oxide: 1317-38-0
Copper sulphate: 7758-98-7
Copper sulfate:
UN/NA NUMBER(S) : 9109
RTECS NUMBER(S) : GL8800000 GL8900000
1.5 Brand names, Trade names
1.6 Manufacturers, Importers
2. SUMMARY
2.1 Main risks and target organs
The main risks are gastrointestinal irritation, liver
and kidney damage, intravascular haemolysis and shock. Acute
poisoning occurs from ingestion of copper salts. The main
target organs are the gastrointestinal tract, cardiovascular
and circulatory system, haematopoietic system, liver, kidneys
and nervous system.
Respiratory effects from inhalation.
Acute exposure to copper fumes: the main risk is metal fume
fever. The target organ is the respiratory tract.
Chronic exposure to copper salts: the main risk is vineyard
sprayer's disease. The target organ is the lung.
Local irritant effects from skin exposure or eye contact to
copper salt: skin, eyes.
2.2 Summary of clinical effects
Acute poisoning from the ingestion of copper metal has
not been reported and seems unlikely.
Acute poisoning from ingestion of copper salts:
Metallic taste, abdominal pain, nausea, vomiting
(greenish-blue), epigastric burning and diarrhoea.
Gastrointestinal bleeding and ulceration may occur in severe
cases.
Lethargy, headache, muscular weakness and dizziness may
complicate the intoxication.
Hypotension and shock may precede coma and death.
Jaundice, elevation of serum transaminase and serum bilirubin
levels, enlargement and tenderness of the liver,
centrilobular necrosis and biliary stasis in the liver.
Renal dysfunction including elevated blood urea nitrogen
levels, anuria and oliguria, increased
urobilinogen,albuminuria, acidosis, hyperkalemia.
Haemoglobinemia, haemolysis, haemoglobinuria and haematuria,
cyanosis (methaemoglobinaemia).
Death may occur from shock or hepatic or renal failure.
Respiratory effects from inhalation:
Acute exposure to copper fumes: burning sensation,
irritation and redness of the throat, coughing, wheezing,
sneezing, shortness of breath, nausea, vomiting, rigors and
fever.
Acute exposure to mists containing copper salts: local
irritation to respiratory tract.
Chronic exposure - vineyard sprayer's disease (lung and
liver lesions).
Local effects from skin exposure:
Skin may appear stained and casualty may complain of itching,
erythema and dermatitis.
2.3 Diagnosis
The symptoms of poisoning depend on the duration of
exposure and whether copper metal (fumes etc) or copper salts
are involved. Copper salts are gastric irritants and are
corrosive to gastrointestinal mucosae, producing nausea,
vomiting, and local bleeding; lethargy and headache are early
CNS effects; liver and kidney failure occur later in more
severe poisonings. See section 2.2 for a list of possible
symptoms.
Liver and kidney function tests may be useful to assess the
severity of poisoning.
Whole blood (but not plasma or serum) copper levels may help
to assess the prognosis.
Methaemoglobinaemia, Heinz body formation and haemolysis may
be observed.
2.4 First-aid measures and management principles
After ingestion, rinse the mouth thoroughly with water
and give water to drink.Give milk or egg white. Obtain
medical attention immediately.
Management includes emesis or gastric lavage, correction of
fluid and electrolyte imbalance and shock; treatment of
hepatic and renal damage, methaemoglobinaemia and
intravascular haemolysis; and chelation therapy.
Respiratory effects from inhalation: move the casualty to
fresh air and give oxygen if breathing is difficult.
Local effects from skin exposure or eye contact with copper
salts: remove contaminated clothing; wash skin immediately
with soap and copious amounts of water for at least 15
minutes. Wash eyes with copious amounts of warm water for at
least 15 minutes.
3. PHYSICO-CHEMICAL PROPERTIES
3.1 Origin of the substance
Copper and most copper compounds are semi-synthetic in
origin. Although some natural deposits of metallic copper
have been found, it is generally mined either as sulphide or
oxide ores and processed by grinding, washing, melting and
casting
(Stokinger, 1981; Scheinberg, 1983).
3.2 Chemical structure
The chemical structures of the main copper compounds are
as follows:
Name Structure Molecular
Weight
Copper Cu 63.57
Cupric acetate, basic Cu(C2H302)2.2H2O 199.65
Cupric carbonate, basic CuCO3.Cu(OH)2 221.11
Cupric chloride CuCl2 134.44
Cupric chromate(VI) CuCrO4 179.55
Cupric cyanide Cu(CN)2 115.58
Cupric hydroxide Cu(OH)2 97.56
Cupric nitrate Cu(NO3)2 187.56
Cupric oxide CuO 79.54
Cupric sulphate CuSO4 159.61
(Windholz et al., 1976; Stokinger, 1981; Scheinberg, 1983).
3.3 Physical properties
3.3.1 Colour
3.3.2 State/form
3.3.3 Description
Copper metal is soluble in nitric acid and hot
sulphuricacid (Sittig, 1985), very slightly soluble in
hydrochloric acid and ammonium hydroxide and insoluble
in water. Copper (II) (divalent) compounds vary in
their water solubility. The acetate, chloride, nitrate
and sulphate salts are soluble in water, whereas the
oxide, carbonate and cyanide salts are insoluble
(Weast, 1976-77). Further details on the solubility
characteristics of Cu(I) (monovalent) and Cu(II) salts
are given below:
Copper (II): Soluble Insoluble
Acetate Alcohol, Ether -
Bromide Alcohol Ether
Butyrate Alcohol -
Carbonate - Alcohol
Chlorate Alkali, Alcohol -
Chloride Water, Alcohol -
Chromate Acid Water
Chromite Water -
Citrate Acid -
Formate Water, Alcohol* -
Glycinate Alcohol* -
Ferrocyanide Alkali Acid,
Water
Copper (II): Soluble Insoluble
Fluoride Water -
Gluconate Water, Alcohol -
Hexafluorosilicate Water -
Hydroxide Acid, Alkali Water
Nitrate Alkali -
Oleate Alcohol, Ether Water
Oxalate Ether Acid,
Alcohol
Oxide Acid Water, Alcohol
Phosphate Acid, Water -
Selenate Water Alcohol
Selenite Acid Water
Stearate - Ether
Sulphate - Water
Sulphide Acid, Alkali, -
Tartrate Acid, Alkali -
Tungstate - Water
Copper (I) Soluble Insoluble
Cyanide - Alcohol, Acid
Iodide Alkali Acid, Alcohol,
Water
Mercuric iodide - Alcohol, Water
Oxide - Water
Sulphide - Water
Sulphite Alkali, Water* Alcohol
* slightly soluble
(Weast, 1976-7)
Boiling point of copper: 2,336 °C.
Melting point of copper: 1083 °C.
Most copper compounds are coloured solids at room
temperature (Weast, 1976-77).
Anhydrate: Greyish-white or greenish-white rhombic
crystals or amorphous powder.Hygroscopic on
heating.
Pentahydrate: Large, blue or ultramarine, triclinic
crystals or blue granules or light blue powder.
Monohydrate Hygroscopic: Almost white powder.
3.4 Hazardous characteristics
Copper metal is coloured reddish brown and reacts with
strong acids, strong oxidising agents, acid chlorides and
halogens, and may discolour on exposure to air and moisture.
The metal may undergo violent reaction with acetylene,
ammonium nitrate, bromates, chlorates, iodates, chlorine
trifluoride, ethylene oxide, fluorine, hydrogen peroxide,
hydrazine mononitrate, hydrogen sulphide, hydrazoic acid,
lead azide, potassium peroxide, sodium azide and sodium
peroxide. The reaction between copper wool and
trichloroacetic acid in dimethyl sulphoxide is very
exothermic (Lenga, 1988).
Copper powder is flammable and air-sensitive. It should be
stored under nitrogen and kept away from heat, sparks and
open flame. This material is capable of creating a dust
explosion (Lenga, 1988). Copper dusts and mists are
incompatible with magnesium metal (Sittig, 1985).
Copper compounds exhibit a range of reactivity, some of which
are specific for certain compounds in the class. Copper(II)
salts are readily reduced and therefore should be considered
reactive with reducing agents, strong acids, alkali metals
and finely powdered metals. Copper(I) compounds are
incompatible with oxidising agents and alkali metals and in
some cases air, light and moisture. Organic compounds
containing copper are generally reactive with oxidising
agents (Lenga, 1988).
The products of combustion of copper compounds are mainly
copper oxides and are likely to be harmful.
Guidance on safe disposal: The area of release should be
ventilated and the spilled material collected in the most
convenient and safe manner for reclamation or for disposal in
a secure sanitary landfill. Liquid containing copper should
be absorbed in vermiculite, dry sand, earth or similar
material. Copper-containing wastes can be concentrated by
using ion exchange, reverse osmosis, or evaporators to the
point where copper can be electrolytically removed and sent
to a reclaiming firm. If recovery is not feasible, the copper
can be precipitated through the use of caustics and the
sludge deposited in a chemical waste landfill (Sittig,
1985).
Environmental risks: through mining and other industrial
activities, substantial amounts of copper are being
introduced into the air, water and soil. The atmosphere is
the most important medium for the transport of pollutant
copper to remote areas of the earth. Most of the copper is
ultimately deposited on the land. Local copper pollution may
be encountered around smelters and other point sources of the
metal. Although there is no evidence that the present
elevated levels of copper in the environment have adversely
affected any forms of life, dose-effect and dose-response
relationships particularly at low levels of exposure are
unknown. Moreover in view of the genetic effects of copper
(see section 7.5) any undue elevation of copper levels in the
environment should be viewed with concern (Nriagu,
1979).
4. USES/CIRCUMSTANCES OF POISONING
4.1 Uses
4.1.1 Uses
4.1.2 Description
The main use of copper is in electrical
equipment and alloy production. As a conductor of
electricity, metallic copper is used in all gauges of
wire, circuitry, coil and armature windings,
high-conductivity tubes, and many other applications.
The metal is employed also in castings, sheets, rods,
tubing, wire, gas and water piping, roofing materials,
cooking utensils, chemical and pharmaceutical
equipment and coins. In addition copper compounds are
used as pigments (e.g. copper acetoarsenite and copper
arsenite), in paints, insecticides (e.g. copper
fluoroarsenite), fungicides (copper sulphate, copper
naphthenate), as mordants, in timber preservation and
mildew prevention, as brass colourings, in
disinfectants, metallurgy, in the deodorizing and
desulphurizing of petroleum distillates, in
photography, water purification, electroplating, in
pharmaceutical preparations, varnishes, in
agriculture, animal husbandry, steel making,
analytical reagents, and solvents for cellulose in
rayon manufacture and in certain electroplating
processes (Stokinger, 1981).
Among the medicinal applications of the element is the
utilization of copper-containing intrauterine
contraceptive devices for birth control
(Gonzalez-Angulo & Aznar-Ramos, 1976; Rubenstein,
1976). Copper is also a component in certain types of
dental cement (Reid, 1968) and in dental materials
used for periodontal work (Trachtenberg, 1972).
Copper sulphate crystals are occasionally applied as a
caustic to excess granulation tissue in burns or
ulcers.
Topical application of a 1% solution is of value for
phosphorous burns of the skin (Reynolds, 1982).
Copper and zinc sulphate lotions have been used as a
wet dressing in eczema, impetigo and intertrigo.
Reagents containing copper sulphate are used in tests
for reducing sugars (Benedict's solution) (Reynolds,
1982).
4.2 High risk circumstance of poisoning
Deliberate ingestion of copper salts.
Accidental ingestion of copper in food and beverages.
Inhalation of copper-containing mists by pesticide spray
operators.
4.3 Occupationally exposed populations
Occupationally exposed populations include copper ore
miners, copper smelter workers, foundry workers, welders,
copper metal workers, copper metal polishers, pesticide spray
operators, fungicide applicators, asphalt workers, battery
production workers, persons involved in the manufacture and
use of paints, pigments, rayon and wood preservatives as well
as people involved in the tanning and electroplating
industries.
5. ROUTES OF ENTRY
5.1 Oral
Following both acute and chronic ingestion of copper
compounds (e.g. Chuttani et al., 1965; Salmon & Wright, 1971;
Walsh et al., 1977; Cross et al., 1979; Spitalny et al.,
1984; Nagaraj et al., 1985) significant amounts of copper can
be absorbed through the gastrointestinal tract.
5.2 Inhalation
The occurrence of lung lesions in workers who spray
vineyards with Bordeaux mixture, a copper sulphate-containing
fungicide, indicates that copper mists can be absorbed
through the lungs (Pimentel & Marques, 1969; Villar, 1974;
Pimentel & Menezes, 1977; Scheinberg, 1983; Plamenac et al.,
1985).
Inhalation of copper fumes can produce toxic effects on the
respiratory tract.
5.3 Dermal
Copper salts may also be absorbed through the skin
causing systemic toxicity (Holtzman et al., 1966).Copper
salts have local toxic effects on the skin (Sittig,
1985).
5.4 Eye
Copper salts do not appear to be systemically absorbed
through the eyes; however, they produce local toxic effects
(Sittig, 1985; Scheinberg, 1983).
5.5 Parenteral
No data available.
5.6 Others
Case reports of acute and chronic urticurial
hypersensitivity to copper-containing dental cement (Reid,
1968) and a copper-containing intrauterine contraceptive
device (Barkoff, 1976) have been reported suggesting
significant exposure to copper from these sources.
Repeated exposure to copper dust may lead to green-black
discolouration of the hair (Parish, 1975). Non-occupational
exposures of this type resulting from washing of hair in
copper-contaminated water (Cooper & Goodman, 1975; Nordlund
et al., 1977) and swimming in water containing high
concentrations of copper (Lampe et al., 1977) have also been
reported.
6. KINETICS
6.1 Absorption by route of exposure
Oral exposure
In man, the absorption of copper appears to occur primarily
in the stomach and duodenum where acidic conditions favour
solubility. This is evident from the study of Earl et al
(1954) who showed that following the oral administration of
radiolabelled cupric chloride (1.5 to 12.5 mg copper), the
isotope appears rapidly in the blood reaching maximum levels
within 1 to 3 hours.Strickland et al. (1972), using
radiolabelled cupric chloride and copper acetate (0.4 to 4.54
mg copper) in four human subjects, showed an average
absorption of 57% (range 40 to 70%). Data provided in the
case report by Cross et al. (1979) in which an unknown
quantity of a solution containing copper, chromium and
arsenic was ingested suggested that the uptake of copper from
the gastrointestinal tract was reasonably high. Singh & Singh
(1968) reported markedly increased whole blood and serum
direct-reacting copper concentrations within 3 hours
following the ingestion of copper sulphate thus confirming
that copper ions are rapidly absorbed from the
gastrointestinal tract into the systemic circulation.
Inhalation
Copper fumes and inhaled copper dust may lead to an increase
in serum copper level in chronically exposed patients.
Eye contact
Copper salts are not systemically absorbed through the eye.
6.2 Distribution by route of exposure
Oral
Following the absorption of copper in man it appears that
much of the copper in the serum is free (direct-reacting)
during the first 3 to 5 hours after ingestion (Singh & Singh,
1968). In serum, copper is normally about 98% bound to
ceruloplasmin with the remainder in association with albumin.
In acute intoxication, when the serum concentration of copper
rises rapidly, the metal binds to albumin rather than to
ceruloplasmin (Piscator, 1979). From the serum, copper
accumulates rapidly in red cells where it is strongly bound
(Singh & Singh, 1968). Copper is also transported to the
liver where it induces the synthesis of ceruloplasmin and is
incorporated into the protein structure. The subsequent
release of the metal-protein complex into the serum may
account for the secondary rise in serum copper concentration
which may be observed in the acutely poisoned patient (Singh
& Singh, 1968). The fall in blood copper concentration is
presumably associated with a rise in the copper content of
the tissues, particularly the liver and kidneys (Wahl et al.,
1963). This would explain the persistance of elevated serum
transaminase levels long after blood copper levels have
returned to normal (Singh & Singh, 1968). The highest
concentrations of copper are found in the liver, heart,
brain, kidneys and muscle (Piscator, 1979).
Inhalation
Interstitial lung and liver lesions induced by exposure of
vineyard workers to copper sulphate-containing fungicidal
sprays have been shown to contain copper (Pimentel & Marques,
1969; Villar, 1974; Pimentel & Menezes, 1977). Also Plamenac
et al. (1985) have presented evidence indicating the presence
of copper in macrophages obtained from the sputum of vineyard
sprayers.
6.3 Biological half-life by route of exposure
The biological half-life of copper in human beings has
been estimated to be about 4 weeks (Strickland et al., 1972;
Dekaban et al., 1975).
6.4 Metabolism
Not relevant.
6.5 Elimination by route of exposure
The main route of elimination of copper is via the bile
(Strickland et al., 1972). Excretion via the urine is
normally low. Less than 1% of an intravenous injection of
radio-labelled copper acetate has been shown to be excreted
in the urine in 72 hours in normal human subjects. In the
same time period, 9% was excreted in the faeces (Tauxe et
al., 1966).
The elimination of copper in the urine may be greatly
enhanced in the copper-poisoned patient if the body storage
sites are saturated. Thus Walsh et al. (1977) reported the
case of a child intoxicated following the ingestion of 3 g of
copper sulphate. A two hour sample of urine contained 500
microgram/100 mL Cu (normal range 5 to 25 microgram/24
hours). Urinary copper levels were maximal (2.8 to 3.0 mg/L)
between the second and third week, and fell to 0.95 mg/L by
the end of the third week. In another case report, Cross et
al. (1979) measured a urine copper concentration of 1.5 mg/L
as compared with a suggested normal value of 0.12 mg/L in a
patient who had ingested a solution containing copper,
chromium and arsenic.
7. TOXICOLOGY
7.1 Mode of Action
Copper salts such as copper sulphate are gastric
irritants and produce corrosion of the gastric and
intestinal epithelium. Patel et al. (1976) suggested that
since the copper (II) ion is a strong oxidising agent it
will oxidise oxyhaemoglobin from the ferrous to the ferric
form. In this form, haemoglobin loses its oxygen-binding
capacity resulting in methaemoglobinaemia and cyanosis
(Chugh et al., 1975; Patel et al., 1976;
Thirumalaikolundusubramanian et al., 1984; Nagaraj et al.,
1985). Furthermore, the restoration of haemoglobin to the
ferrous form depends on the transfer of electrons from NADH,
NADPH and reduced glutathione. Glucose-6-phosphate
dehydrogenase, which has a major function in maintaining the
NADPH concentration in the red cell, is inhibited by copper.
NADPH is also necessary for maintaining the level of reduced
glutathione, which in turn protects the red cell against the
haemolytic effects of oxidising substances (Walsh et al.,
1977). The inhibition of this enzyme by copper (II) would
explain the haemolysis which is commonly observed in cases of
acute copper poisoning.
Intravascular haemolysis and a direct action of copper on the
kidneys often leads to tubular necrosis (Patel et al.,
1976).
Singh & Singh (1968) observed that in patients with acute
copper sulphate intoxication SGOT/AST and SGPT/ALT levels may
be persistently raised along with the presence of jaundice
but without evidence of haemolysis. This suggests that the
jaundice induced by copper is at least partly hepatic in
origin.
Saltzer & Wilson (1968) have speculated that copper forms
chemical or hapten links with a protein carrier molecule in
the skin. It is believed that the antigenic activity of this
hapten-carrier complex sensitizes a population of
thymus-derived lymphocytes, leading to a delayed
hypersensitivity reaction upon subsequent exposure.
7.2 Toxicity
7.2.1 Human data
7.2.1.1 Adults
Ingestion of inorganic copper salts
containing 10 to 15 mg of copper may cause
nausea, vomiting and diarrhoea, whilst
larger doses may lead to severe toxicity and
death.
Quantity ingested Copper level
(g) (mean ± SD,
microgram/100 mL)
1-5 3.83± 124.9
6-15 5.19± 134.3
6-30 6.84± 513.2
30+ 6.06± 146.3
(From Chuttani et al., 1965)
The mean lethal dose is approximately 10 g,
or 140 mg/kg (Hayes, 1982).
7.2.1.2 Children
An 18-month-old baby narrowly
survived an dose estimated at 262 mg/kg that
was subsequently reduced by an unknown
degree by vomiting and lavage (Walsh et al.,
1977).
7.2.2 Relevant animal data
In animals, ingestion of 3 oz (approximately
75 mL) of a 1% solution of copper sulphate has caused
serious toxicity (Hazardous substance data bank,
1985).
The oral LD50 in the rat for copper sulphate is 300
mg/kg.
7.2.3 Relevant in vitro data
No data available.
7.2.4 Workplace standards
Current ACGIH TLV-TWA standards
Copper dusts and mists:1.0 mg Cu/m3 (ACGIH, 1986)
TLV-TWA = time-weighted average for a normal 8 hour
work day and 40 hour week, adopted by the American
Conference of Governmental Industrial Hygienists.
Excursion limit recommendation
Short term exposures should not exceed three times the
(TLV - TWA) for more than a total of 30 minutes during
a workday (and under no circumstances should they
exceed five times the (TLV - TWA)) provided that the
(TLV-TWA) is not exceeded overall (Hazardous
Substance Data Bank, 1985).
Permissible concentration in water
1 mg/L Cu (Sittig, 1985)
7.2.5 Acceptable daily intake (ADI) and other guideline
levels
The human dietary intake is normally 2 to 5 mg
Cu/day. Almost none of the copper is retained and the
body content of copper in adults is constant at 100
to 150 mg, (Scheinberg, 1983).
7.3 Carcinogenicity
Although there is no direct evidence of carcinogenicity
and exposure to copper salts some individuals afflicted with
vineyard sprayer's lung developed lung cancer.
7.4 Teratogenicity
In human beings there do not appear to be any reports in
the literature of teratogenesis induced by excess copper.
Animal studies have shown teratogenic effects with copper
salts (Ferm and Hanlon, 1974; Dicarlo, 1980, Mason et al
1989).
7.5 Mutagenicity
Studies have shown mutagenic activity such as inhibition
of RNA polymerase activity, chromosome aberrations and
abnormal cell division in animal cells but the human
relevance of these findings is unknown (Agarwal et al.,
1989, 1990; Sideris et al., 1988; Wong, 1988).
7.6 Interactions
Experiments utilizing purified populations of B and T
cells indicated that penicillamine and copper sulphate
markedly inhibit helper T cell activity but not B cell
function (Hazardous substance data bank, 1985).
8. TOXICOLOGICAL ANALYSES AND BIOMEDICAL INVESTIGATIONS
8.1 Material sampling plan
8.1.1 Sampling and specimen collection
8.1.1.1 Toxicological analyses
8.1.1.2 Biomedical analyses
8.1.1.3 Arterial blood gas analysis
8.1.1.4 Haematological analyses
8.1.1.5 Other (unspecified) analyses
8.1.2 Storage of laboratory samples and specimens
8.1.2.1 Toxicological analyses
8.1.2.2 Biomedical analyses
8.1.2.3 Arterial blood gas analysis
8.1.2.4 Haematological analyses
8.1.2.5 Other (unspecified) analyses
8.1.3 Transport of laboratory samples and specimens
8.1.3.1 Toxicological analyses
8.1.3.2 Biomedical analyses
8.1.3.3 Arterial blood gas analysis
8.1.3.4 Haematological analyses
8.1.3.5 Other (unspecified) analyses
8.2 Toxicological Analyses and Their Interpretation
8.2.1 Tests on toxic ingredient(s) of material
8.2.1.1 Simple Qualitative Test(s)
8.2.1.2 Advanced Qualitative Confirmation Test(s)
8.2.1.3 Simple Quantitative Method(s)
8.2.1.4 Advanced Quantitative Method(s)
8.2.2 Tests for biological specimens
8.2.2.1 Simple Qualitative Test(s)
8.2.2.2 Advanced Qualitative Confirmation Test(s)
8.2.2.3 Simple Quantitative Method(s)
8.2.2.4 Advanced Quantitative Method(s)
8.2.2.5 Other Dedicated Method(s)
8.2.3 Interpretation of toxicological analyses
8.3 Biomedical investigations and their interpretation
8.3.1 Biochemical analysis
8.3.1.1 Blood, plasma or serum
Chowdhury et al. (1961) reported a
maximum serum Cu concentration of 5,100
microgram/L in a study of five patients
poisoned following copper sulphate
ingestion.
Chuttani et al. (1965) reported on 48
hospitalized patients and five autopsy cases
where the dosages were estimated to range
from 1 g to over 100 g of copper sulphate.
There appeared to be some correlation between
the amount ingested, the severity of symptoms
and the whole blood copper concentration.
Cross et al. (1979) reported the case of a
suicide by ingestion of an unknown quantity
of a mixture containing copper, chromium and
arsenic. The patient died 36 hours after
ingestion. Tissue copper concentrations were
generally similar to normal levels in the
blood (5.5 microgram/g dry weight tissue,
normal 9.5 microgram/g), heart (3.7
microgram/g, normal 16.5 microgram/g), kidney
(17.5 microgram/g, normal 14.9 microgram/g),
lung (11.2 microgram/g, normal 9.5
microgram/g) and spleen (3.8 microgram/g,
normal 6.8 microgram/g) but significantly
elevated in the stomach (33 microgram/g
normal 12.6 microgram/g), brain (63
microgram/g, normal 12.6 microgram/g), liver
(56 microgram/g, normal 25.5 microgram/g) and
urine (1.5 mg/L, normal 0.12 mg/L).
Spitalny et al. (1984) reported a case of
copper intoxication as a result of ingestion
of copper-contaminated water. The father and
two daughters repeatedly experienced episodes
of emesis and abdominal pain after drinking
water from the kitchen tap. Several water
samples taken over a number of months showed
copper levels in excess of the standard for
drinking water (1.0 mg/L). One early morning
water sample contained copper at 7.8 mg/L.
Hair copper levels in members of the exposed
family were significantly elevated (mean 155
microgram/g, range 130 to 1, 200 microgram/g)
in comparison with the normal range (11 to 40
microgram/g).
Walsh et al. (1977) reported the case of a
child intoxicated following the ingestion of
approximately 3 g of copper sulphate. The
poisoning was associated with
gastrointestinal toxicity, haemolytic anaemia
and renal tubular damage. The serum copper
concentration was 16.5 mg/L (normal range 1.1
to 1.7 mg/L) on admission, 2.3 mg/l 24 hours
later and 2.0 mg/L after 3 weeks. A two hour
sample of urine contained 500 microgram/100
mL Cu (normal range 5 to 25 microgram/24
hours). Urinary copper levels were maximal
(2.8 to 3.0 mg/l) between the second and
third week, and fell to 0.95 mg/L by the end
of the third week. The haemoglobin level on
the second hospital day was 5.6 g/100 mL.
Glucose-6-phosphate dehydrogenase activity
was 75 units/109 cells (normal range 250 to
500 units/109 cells). After 5 days the
haemoglobin level had stabilised at 11.2
g/100 mL. One year after the ingestion the
serum copper concentration was 1.7 mg/L.
Cole & Lirenman (1978) described the case of
a 2-year-old boy who suffered severe
poisoning after drinking approximately 30 mL
of a supersaturated solution of copper
sulphate. On admission 16 hours after
ingestion his blood pressure was 100/60 mm Hg
and heart rate 150. Haemoglobin concentration
was initially 11.3 g/100 mL but dropped to
5.7 g/100 mL over the following 18 hours.
Blood urea nitrogen was 5.7 mg/100 mL, serum
creatinine 0.5 mg/100 mL, serum bilirubin 3.1
mg/100 mL, serum copper 201 g/100 mL
(ceruloplasmin-bound 136 microgram/100 mL).
At forty hours after ingestion the serum
copper and ceruloplasmin-bound copper levels
were 214 and 180 microgram/100 mL
respectively. Serum copper concentration
dropped to 1.19 mg/L on the third day
following exchange transfusion.
Salmon & Wright (1971) reported the case of a
15-month-old infant suffering from symptoms
consistent with pink disease as a consequence
of the ingestion of water containing elevated
levels of copper. The patient was admitted to
hospital 5 weeks after the onset of symptoms
and had a serum copper level of 2.86 mg/L
(normal 1.64 mg/L).
8.3.1.2 Urine
8.3.1.3 Other fluids
8.3.2 Arterial blood gas analyses
8.3.3 Haematological analyses
8.3.4 Interpretation of biomedical investigations
8.4 Other biomedical (diagnostic) investigations and their
interpretation
8.5 Overall Interpretation of all toxicological analyses and
toxicological investigations
Singh & Singh (1968) have recommended that it is helpful
in cases of acute copper sulphate poisoning to determine
total and direct-reacting serum copper together with whole
blood or erthrocyte copper concentrations as early as
possible. They suggest that only a very rough estimate of the
dose of copper sulphate ingested can be made from estimation
of the whole blood or serum copperconcentration and that
after the 10th day following ingestion a diagnosis of copper
poisoning would be possible only by the demonstration of
elevated copper content of the liver or kidneys. They suggest
on the basis of the data obtained in their study that for
prognostic purposes, serial studies of SGOT and SGPT levels
together with blood urea estimations appeared to be the
best.
Sample collection
Samples for copper analysis must be collected carefully.
Urine should be collected in appropriately-sized plastic
containers which have been checked for copper contamination
and cleaned if necessary. Sample collection procedures for
blood samples are critical. Blood should be collected in
plastic syringes which have been shown to be free of
measurable copper when soaked with water or serum. Following
centrifugation, serum can be removed with a glass transfer
pipette and aliquots stored in sterile polypropylene tubes at
-20 C. Blood for standard clinical laboratory analyses should
be collected in appropriate tubes.
Biomedical analysis
Examination and analysis of vomit and/or gastric lavage
aspirate (if greenish-blue) may indicate the presence of
copper. Copper concentration in blood or urine should be
monitored. Measure haematological indices (red cell count,
total and differential leucocyte counts, reticulocyte count,
haematocrit, plasma haemoglobin, plasma methaemoglobin),
tests for kidney function (blood urea nitrogen and serum
creatinine concentrations) and liver function (AST/GOT,
ALT/GPT and serum bilirubin concentration), and urinalysis
(haemoglobin, methaemoglobin, urobilinogen).
8.6 References
9. CLINICAL EFFECTS
9.1 Acute poisoning
9.1.1 Ingestion
Metallic taste in mouth, burning sensation in
the throat, nausea, vomiting, epigastric pain,
diarrhoea, hypotension, haematemesis, melaena,
haemolytic anaemia and gastrointestinal haemorrhage,
pallor, oliguria, anuria, jaundice, delirium, coma,
hepatic failure, respiratory failure and convulsions
are the features of poisoning. There is centrilobular
necrosis and biliary stasis in the liver. In some
cases hypotension leading to shock develops,
indicating a poor prognosis.
(Hopper & Adams, 1958; Semple et al., 1960; Chowdhury
et al., 1961; Gupta et al., 1962; Wahl et al., 1963;
Chuttani et al., 1965; Singh & Singh, 1968; Chugh et
al., 1975; Patel et al., 1976; Walsh et al., 1977;
Cole & Lirenman, 1978; Thirumalaikolundusubramanian et
al., 1984; Nagaraj et al., 1985).
9.1.2 Inhalation
The inhalation of copper-containing mists can
cause congestion of the mucous membranes in the nose
and pharynx, and possibly also ulceration with
perforation of the nasal septum (Scheinberg, 1983). If
the toxicant reaches the gastrointestinal tract, there
may be irritation including salivation, nausea,
vomiting, gastric pain, haemorrhage, gastritis and
diarrhoea (Sittig, 1985).
The inhalation of copper fumes (mainly copper oxide)
may produce metal fume fever with burning sensation,
irritation and redness of the throat, coughing,
wheezing, sneezing, shortness of breath, nausea,
vomiting, rigor and fever.
9.1.3 Skin exposure
Copper salts may cause irritation to the skin
(Scheinberg, 1983), itching, erythema and an allergic
contact dermatitis (Sittig, 1985). Metallic copper may
cause keratinization of the hands and soles of the
feet, but not normally dermatitis (Sittig, 1985).
Systemic toxicity (severe anaemia, haemolytic crisis
and an increase in serum concentrations of
transaminases) has been described following the
topical treatment with copper compounds for severe
burning (Holteman et al., 1966).
9.1.4 Eye contact
Copper salts may cause conjunctivitis,
ulceration, turbidity of the cornea and adhesion of
the eyelids to the eye (Sittig, 1985; Scheinberg,
1983).
9.1.5 Parenteral exposure
Several reports have described the haemolytic
effects of copper released from dialysis equipment
used in the treatment of patients with renal disease
(Manzler & Schreiner, 1970; Lyle, 1976; Eastwood et
al., 1983).
There are several reports on the effects of copper
released from copper-containing valves and stopcocks
in dialysis equipment and on the effects of copper
contamination of tap water used for exchange
transfusions. Copper can cross dialyzing membranes
even against a concentration gradient and small
amounts of copper introduced intravenously are highly
toxic (Manzler & Schreiner, 1970; Lyle, 1976; Eastwood
et al., 1983).
9.1.6 Other
Not relevant.
9.2 Chronic poisoning
9.2.1 Ingestion
Chronic ingestion of copper may lead to
clinical signs characteristic of 'pink disease'.
Symptoms include diarrhoea, progressive marasmus
(wasting), prostration, misery, red extremities,
hypotonia, photophobia, peripheral oedema and liver
abnormalities (Salmon and Wright, 1971).
9.2.2 Inhalation
The inhalation of pesticide sprays containing
copper sulphate (1 to 2%) neutralized with hydrated
lime may lead to a condition described as vineyard
sprayer's disease characterised by the formation of
lesions in the lungs and liver (Pimentel & Marques,
1969, 1977; Villar, 1974; Scheinberg, 1983; Plamenac
et al., 1985).
Prolonged or repeated exposure to copper dusts may
cause runny nose, atrophic changes and irritation of
the mucous membranes. Nasal ulceration and perforation
due to the inhalation of copper has been
reported.
9.2.3 Skin exposure
Prolonged or repeated exposure to copper salts
can cause irritation, producing itching and redness
of the skin. Some may become sensitized to copper
sulphate and develop allergic contact dermatitis
(CCOHS, 1999).
9.2.4 Eye contact
No data available.
9.2.5 Parenteral exposure
No data available.
9.2.6 Other
No data available.
9.3 Course, prognosis, cause of death
Acute poisoning following ingestion
The clinical signs and symptoms of copper sulphate poisoning
are characteristic but the progression of symptoms is
difficult to predict. Gastrointestinal symptoms appear within
10 minutes to one hour following the ingestion.
Diarrhoea usually occurs on the first or second day and may
last for 24 hours. Hypotension, shock and intravascular
haemolysis may occur on the second or third day.
Renal and hepatic damage may occur on the second or third
day.
Early death is usually associated with shock. Late death may
occur in hepatic or renal failure.
Respiratory symptoms appear after a delay of 4 to 6 hours
following exposure. Symptoms usually improve within 24 to 48
hours.
9.4 Systematic description of clinical effects
9.4.1 Cardiovascular
Acute
Copper sulphate causes hypotension, severe headache,
tachycardia, cold sweat, weak pulse, coma and other
signs of circulatory shock which usually occur early
(Gosselin et al., 1984).
Orthostatic hypotension may be observed in
haemodialysis patients exposed to dialysate
containing copper-contaminated water (Manzler &
Schreiner, 1970).
9.4.2 Respiratory
Acute
Respiratory symptoms are also observed after
inhalation of copper metal fumes. Symptoms include
cough, dyspnoea, irritation of the respiratory tract
and chest pains. Following its use as an emetic,
copper sulphate has caused respiratory failure.
Chronic
The inhalation of copper-containing mists may lead to
progressive breathlessness and/or cough. Initial
examination may show diffuse, bilateral micronodular
dissemination or reticulonodular shadowing
predominately in the lower portions of both lungs. The
condition commonly progresses to tumour-like opacities
in the upper lobes of the lung and these lesions may
calcify. The disease may remain subclinical for many
years after the termination of exposure. The diagnosis
of vineyard sprayer's lung should always be confirmed
histologically and by histochemical demonstration of
the presence of copper in the lesions (Pimentel &
Marques, 1969; Villar, 1974; Scheinberg, 1983).
Enhanced expectoration of sputum and cytological
changes in the sputum including an increased incidence
of abnormal columnar cells, squamous metaplasia
without aplasia, eosinophilia and respiratory spirals
may occur (Plamenac et al., 1985).
9.4.3 Neurological
9.4.3.1 Central Nervous System (CNS)
Acute
Severely poisoned patients may develop stupor
and/or coma which may lead to rapid death
(Chuttani et al., 1965).
Headache has been observed in haemodialysis
patients exposed to dialysate contaminated
with copper (Lyle et al., 1976).
9.4.3.2 Peripheral nervous system
No data available.
9.4.3.3 Autonomic nervous system
No data available.
9.4.3.4 Skeletal and smooth muscle
Acute
Chowdhury et al (1961) observed the
development of muscular weakness in some
patients following acute ingestion of copper
sulphate.
Chills may be observed in haemodialysis
patients exposed to dialysate contaminated
with copper (Manzler & Schreiner, 1970; Lyle
et al., 1976).
9.4.4 Gastrointestinal
Following the ingestion of copper sulphate,
gastrointestinal symptoms are usually the first to
appear and are always present. These symptoms include
a metallic taste, nausea, burning in the epigastrium,
green-blue-stained vomit and diarrhoea. Melaena may
occur during the first few days post-ingestion in a
severely poisoned patient. Pathologically,
green-stained mucosa, superficial and deep erosions,
haemorrhage in areas of the stomach and small
intestine, oedema and congestion of the vessels in
the submucosa and ulceration may be observed
(Chowdhury et al., 1961; Gupta et al., 1962; Wahl et
al., 1963; Chuttani et al., 1965;
Thirumalaikolundusubramanian et al., 1984).
Parenteral exposure of haemodialysis patients to
copper-contaminated dialysate may result in
gastrointestinal disturbance including nausea,
vomiting, abdominal pain and diarrhoea (Manzler &
Schreiner, 1970; Lyle et al., 1976; Eastwood et al.,
1983).
9.4.5 Hepatic
The liver is often palpable and in severe cases
may be enlarged and tender. Jaundice occurs on the
second or third days. Hepatomegaly is often observed.
Biochemical signs show an increase of serum bilirubin,
and transaminases. Histological damage may include
fatty liver, oedematous liver, focal liver necrosis
and dilation of the sinusoids and central veins
(Chowdhury et al., 1961; Gupta et al., 1962; Wahl et
al., 1963; Chuttani et al., 1965; Singh & Singh 1968;
Thirumalaikolundusubramanian et al., 1984; Nagaraj et
al., 1985).
Chronic
Liver fibrosis, micronodular cirrhosis, and
idiopathic portal hypertension have been reported
(Pimentel & Menezes, 1977).
9.4.6 Urinary
9.4.6.1 Renal
Acute
Acute renal failure due to tubular necrosis
is characterized by oliguria, anuria,
increased blood urea nitrogen concentratons,
albuminuria, and haematuria. Renal failure
may last 2 to 3 weeks (Chowdhury et al.,
1961; Gupta et al., 1962; Wahl et al., 1963;
Chuttani et al., 1965;
Thirumalaikolundusubramanian et al., 1984;
Nagaraj et al., 1985).
9.4.6.2 Others
No data available.
9.4.7 Endocrine and reproductive systems
No human data are available. Animal data
indicate that decreased sperm counts may be a result
of high copper levels (by injection) in the body.
Reproductive effects from industrial exposure to
copper sulphate are unlikely (CCOHS, 1999).
9.4.8 Dermatological
Acute
Copper sulphate probably is mildly or non-irritant to
intact skin.
Chronic
Case reports of acute and chronic urticarial
hypersensitivity to copper-containing dental cement
(Reid, 1968) and a copper-containing intrauterine
contraceptive device (Barkoff, 1976) have been
reported suggesting significant exposure to copper
from these sources.
Repeated exposure to copper dust may lead to
green-black discolouration of the hair (see Parish,
1975). Non-occupational exposures of this type
resulting from washing hair in water contaminated by
copper (Cooper & Goodman, 1975; Nordlund et al.,
1977) and swimming in water containing high
concentrations of copper (Lampe et al., 1977).
Allergic contact dermatitis has also been reported
(Saltzer & Wilson, 1968).
9.4.9 Eye, ears, nose, throat: local effects
Acute
Copper salts may cause conjunctivitis, ulceration and
turbidity of the cornea (Sittig, 1985). Fragments of
metallic copper or copper alloys that may lodge in the
eye may lead to uveitis, abscess and loss of the eye
(Scheinberg, 1983).
Dusts and mists (copper solution) can cause irritation
of the nasal passage and throat. There is a burning
sensation of the throat (CCOHS, 1999).
Chronic
Ulceration of the nasal septum occurs after prolonged
inhalation.
9.4.10 Haematological
Acute
Acute poisoning from the ingestion of copper salts
such as copper sulphate may lead to increased
reticulocyte counts, intravascular haemolysis
including reduced haematocrit, haemoglobinaemia,
reduced erythrocytic glucose-6-phosphate
dehydrogenase activity and increased red cell
fragility, haemoglobinuria, and hematuria,
methemoglobinemia and increased prothrombin time
(Chowdhury et al., 1961; Gupta et al., 1962; Chuttani
et al., 1965; Thirumalaikolundusubramanian et al.,
1984; Nagaraj et al., 1985).
Symptoms of acute haemolytic anaemia have also been
observed in haemodialysis patients exposed to
dialysate contaminated by copper (Manzler &
Schreiner, 1970).
9.4.11 Immunological
Acute
No immunological distrubances have been reported after
poisoning.
9.4.12 Metabolic
9.4.12.1 Acid-base disturbances
Acute
Acid-base balance disturbances are observed
following diarrhoea, vomiting, acute renal
failure and hepatotoxicity.
9.4.12.2 Fluid and electrolyte disturbances
Acute
Electrolyte and fluid imbalance may be
expected to occur following vomiting and
diarrhoea and in association with acute renal
failure.
9.4.12.3 Others
Sweating may be observed in cases
where haemodialysis patients are exposed to
dialysate containing copper-contaminated
water (Lyle et al., 1976).
9.4.13 Allergic reactions
Acute
No data available
Chronic
Case reports of acute and chronic urticarial
hypersensitivity to copper-containing dental cement
(Reid, 1968), a copper-containing watch, ring and eye
glasses (Saltzer & Wilson, 1968) and a
copper-containing intrauterine contraceptive device
(Barkoff, 1976) have been reported.
9.4.14 Other clinical effects
No data available
9.4.15 Special risks
Enzyme deficiency: A reduction in erythrocytic
glucose-6-phosphate dehydrogenase activity has been
observed in cases of acute poisoning (Fairbanks,
1967; Walsh et al., 1977). It is possible that
persons with erythrocytic glucose-6-phosphate
dehydrogenase deficiency may be more susceptible than
normal persons to the haemolytic effects of copper
sulphate.
9.5 Others
No data available.
9.6 Summary
10. MANAGEMENT
10.1 General principles
Ingestion
Treatment should include a prompt effort to prevent
absorption, use of chelating agents and symptomatic
measures.
Administering egg white and other demulcents may be useful.
Ingested copper salt should be removed by induced emesis or
by lavage. Copper may also be precipitated by potassium
ferrocyanide given in a dose of 600 mg in a glass of
water.
Dimercaprol (BAL), sodium calcium edetate and penicillamine
are chelating agents all effective in binding copper. There
is little experience on which to base a choice in the
treatment of acute poisoning.
Monitor vital signs heart rate, blood pressure, central
venous pressure and diuresis.
Maintain electrolyte and fluid balance.
Control pain with a strong analgesic such as morphine or
meperidine (pethidine).
If symptoms persist or intensify give dimercaprol
intramuscularly (IM).
Treat shock vigorously with plasma expanders and vasopressor
amines.
If intravascular haemolysis is present, maintain diuresis
with mannitol and sodium bicarbonate. If haemolysis is
severe consider exchange transfusion. Take necessary
measures to treat renal and hepatic failure.
Inhalation
Remove patient away from contaminated area.
Skin contact
In the case of skin contact, wash immediately with soap and
copious amounts of water.
Eye contact
Wash eyes for 10 to 15 minutes with copious amounts of water.
10.2 Life supportive procedures and symptomatic treatment
Maintain fluid and electrolyte balance.
Give an analgesic for severe pain.
Treat shock vigorously with transfusion in severe cases.
Plasma expanders and vasopressor amines. Monitor central
venous pressure.
Watch for oliguria and renal failure which may require
periotoneal or haemodialysis.
Do regular liver function tests. Anticipate and treat liver
failure.
Do regular blood counts. If intravascular haemolysis is
present, maintain a diuresis and consider exchange
transfusion.
For inhalation, oxygen administration may be indicated if
cyanosis is present.
10.3 Decontamination
After ingestion, induce vomiting or perform gastric
lavage.
Copper may be precipitated by potassium ferrocyanide given
in a dose of 600 mg in a glass of water. It should be given
before gastric lavage.
Milk or egg white may be given because they combine with
copper to form insoluble copper proteinates.
After inhalation, remove the patient from the source of
exposure.
In the case of skin exposure, flood the affected area with
water for at least 15 minutes. Remove contaminated clothing
(Lenga, 1988).
Eye contamination should be managed by continuous irrigation
of the eye with clean luke-warm water for at least 15
minutes (Lenga, 1988). Contact lenses should be removed
before irrigating with water.
10.4 Enhanced Elimination
Active detoxification using activated charcoal (Cole &
Lirenman, 1978), peritoneal dialysis with and without added
albumin (Chugh et al., 1975; Patel et al., 1976; Cole &
Lirenman, 1978), haemodialysis (Patel et al., 1976) and
exchange transfusion (Chowdhury et al., 1961; Patel et al.,
1976; Cole & Lirenman, 1978) have been used although the
efficacy of these techniques is uncertain.
10.5 Antidote treatment
10.5.1 Adults
D-penicillamine: give up to 100 mg/kg daily by
mouth in 4 divided doses 30 minutes before meals for
about 7 days.
Dimercaprol: first 48 hours, 2.5 to 5 mg/kg deep
intramuscular (IM) injection every 4 hours. Third day,
2 mg/kg every 12 hours. A total of 10 days of
treatment are rarely necessary.
Sodium calcium edetate: intravenous, 15 to 25 mg/kg
in 250 to 500 mL of 5% dextrose over a 1 to 2 hour
period twice daily. The maximum dose should not
exceed 50 mg/kg/day. The drug should be given in 5-day
courses with a rest period of at least 2 days between
courses. After the first course, subsequent courses
should not exceed 50 mg/kg/day.
10.5.2 Children
D-penicillamine: Give 20 mg/kg (in fruit
juice) daily by mouth in four divided doses 30
minutes before meals for about 7 days.
Dimercaprol: Dimpercaprol injection is well-tolerated
by children. The dosage should be calculated on the
basis of body weight using the same unit dose per
kilogramme of body weight as for an adult under
similar clinical circumstances (Manufacturer's Product
Information - Boots Company, 1991).
Sodium calcium edetate: the intramuscular (IM) route
is the one of choice for children. The dosage should
not exceed 35 mg/kg body weight twice daily (total
approximately 75 mg/kg/day). In mild cases, a dose of
50 mg/kg/day should not be exceeded. For young
children, the total daily dose may be given in
divided doses every 8 or 12 hours for 3 to 5 days. A
second course may be given after a rest period of 4
or more days. Procaine to produce a concentration of
0.5% should be added to minimize pain at injection
site (1 mL of 1% procaine solution for each mL of
concentrated EDTA solution, or crystalline procaine
may be used to reduce volume) (Manufacturer's Product
Information - 3M Riker, 1991).
10.6 Management discussion
Management discussion: alternatives, controversies and
research needs.
Treatment is largely symptomatic. Further clinical trials
are required to evaluate dimercaprol and penicillamine in
both acute and chronic copper poisoning (Gosselin et al.,
1984). Dimercaprol shows particular promise and may be
life-saving in systemic poisoning in which the effects are
not exclusively the result of severe gastroenteritis.
The combination of dimercaprol and sodium calcium edetate
was more effective in hastening urinary copper excretion in
a poisoned infant than was penicillamine, when it was
substituted.
However, in an experimental study in mice, dimercaprol was
far more effective in reducing copper lethality than any of
eight other chelating agents tested (Gosselin et al.,
1984).
In another study, penicillamine was the preferred agent.
However, dimercaprol is an alternative for the patient who
is actively vomiting (Jantsch et al., 1984).
11. ILLUSTRATIVE CASES
11.1 Case reports from literature
Adult, acute ingestion:
A 24-year-old woman presented about 12 hours after ingestion
of an unknown quantity of a saturated solution of copper
sulphate. She developed burning and metallic taste,
retrosternal and epigastric burning and pain, vomiting and
diarrhoea. Gastric lavage was performed. On examination she
was found to be grossly anaemic, deeply cyanosed, acidotic
and anuric. Blood samples were chocolate-brown in colour and
showed evidence of haemolysis. Methaemoglobinuria was
confirmed. Despite extensive treatment including peritoneal
dialysis, haemodialysis and exchange transfusion,
circulatory collapse occurred and she died 12 hours after
admission (Nagaraj et al., 1985).
Adult (1), children (2), sub-acute ingestion:
A man and his two children experienced episodes of vomiting
and abdominal pain after drinking water drawn from their
kitchen sink supply. Elevated copper levels were determined
in their water supply. All symptoms resolved when the
subjects stopped drinking the contaminated water (Spitalny
et al., 1984).
Child, sub-chronic ingestion
Salmon and Wright (1971) reported a case of a 14-month-old
infant suffering symptoms consistent with pink disease after
drinking water containing elevated levels of copper. Serum
copper level was 286 microgram/100 mL. Symptoms improved
after treatment with penicillamine.
Adult, chronic inhalation:
A 35 year-old male rural worker who sprayed vineyards and
cleaned tartar from wine presses was admitted for
investigation of diffuse lung lesions. He had dyspnoea on
moderate exertion. Lung function tests showed some
restriction and moderately decreased ventilatory parameters.
At thoracotomy the right lung contained extensive blue
patches, with nodules and bands which could be palpated.
Microscopically the lesions had a focal distribution with
three different patterns, a number of alveoli filled with
desquamated macrophages, granulomas in the alveolar septa,
and fibro-hyaline nodules. During the four months that the
patient was in hospital., dyspnoea disappeared with
considerable radiological improvement. Lung function tests
showed a slight improvement of ventilation (Pimentel &
Marques, 1969).
Adults, chronic inhalation:
The livers of 30 rural workers who sprayed vineyards with
Bordeaux mixture for periods that varied from 3 to 45 years
(mean 18 years) were studied. The amount of copper inhaled
was not documented although the amounts sprayed were known.
Proliferation and swelling of Kupffer cells histiocytic or
sarcoid type granulomas, liver fibrosis, cirrhosis,
angiosarcoma in one case and idiopathic portal hypertension
were found at surgery or at autopsy (Pimentel & Menezes,
1977).
12. ADDITIONAL INFORMATION
12.1 Specific preventive measures
In situations where exposure to copper mists may occur
appropriate clothing should be worn to prevent repeated or
prolonged skin contact. Eye protection should be worn to
prevent any reasonable probability of eye contact. Workers
should wash promptly if the skin becomes contaminated. Work
clothing should be changed daily if clothing becomes
contaminated, and non-impervious clothing should be removed
promptly if contaminated (Sittig, 1983).
Copper miners generally wear filtering masks when exposed to
dust from copper ores in order to retain free silica. Such
masks are also likely to minimise exposure to copper.
Workers should be particularly careful to wash their hands
well with water before eating in mines where there are water
soluble ores such as chalcanthite. Food should be kept in
covered containers to avoid exposure to finely divided ore
(Scheinberg, 1983).
12.2 Other
No relevant data.
13. REFERENCES
ACGIH (1986). Threshold limit values and biological exposure
indices with intended changes for 1986-87. American Conference of
Governmental Industrial Hygienists, Cincinatti, Ohio.
Agarwal K, Sharma A, Talukder G (1989). Effects of copper on
mammalian cell components. Chemico-Biol Interactions 69: 1-16.
Agarwal K, Sharma A, Talukder G (1990). Clastogenic effects of
copper sulphate on the bone marrow chromosomes of mice in vivo.
Mut Res 243: 1-6.
Axelson O Datilgren E, Jansson CD, Rehulund SO (1978). Arsenic
exposure and mortality: a case referent study from a Swedish
copper smelter Br J Ind Med 35: 8-15.
Barkoff JR (1976). Urticaria secondary to a copper intrauterine
device. Int J Dermatol 15: 594-595.
CCOHS (1999) Copper sulphate, CHEMINFO Record. International
Programme on Chemical Safety (IPCS) INTOX CD-ROM, Issue 98-2.
Canadian Centre for Occupational Health and Safety, Ontario,
Canada.
Chang CC, Tatum HJ (1973). Absence of teratogenicity of
intrauterine copper wire in rats hamsters, and rabbits.
Contraception 7: 413-434.
Chang CC, Tatum HJ, Kinel FA (1970). The effect of intrauterine
copper and other metals on implantation in rats and hamsters.
Fertil Steril 21: 274-278.
Chowdhury AK, Ghosh S, & Pal D (1961). Acute copper sulphate
poisoning. J Indian Med Assoc, 36: 330-336.
Chugh KS, Singhal PC, Sharma BK (1975). Methemoglobinemia in acute
copper sulphate poisoning. Ann Int Med 82: 226-227.
Chuttani HK, Gupta PS, Gulati S, Gupta DN (1965). Acute copper
sulphate poisoning. Am J Med 39: 849-854.
Cole DEC, Lirenman DS (1978). Role of albumin-enriched peritoneal
dialysis in acute copper poisoning. J Pediatrics 92: 955-957.
Cooper R, Goodman J (1975). Green hair. New Eng J Med 292:
483-484.
Cross JD, Dale IM, Smith H (1979). A suicide by ingestion of a
mixture of copper, chromium and arsenic compounds. Forensic Sci
International 13: 25-29.
Dawson MM, Moore M (1989). Interleukin-2. In: Dale, MM & Foreman
JC ed. Textbook of immunopharmacology, 2nd edition, Oxford, UK,
Blackwell Scientific Publications, pp 340-346.
Dekaban AS, Aamodt R, Rumble WF, Johnston GS, O'Reilly S (1975).
Kinky hair disease: a study of copper metabolism with use of 67Cu.
Arch Neurol 32: 672-675.
Dicarlo FJ (1980). Syndromes of cardiovascular malformations
induced by copper citrate in hamsters. Teratology 21: 89-101.
Dreisbach RH (1983). Handbook of poisoning: prevention, diagnosis
and treatment, Los Altos, California, Lange Medical Publcations,
pp. 92-96 & 469-470.
Earl CJ, Moulton MJ, Selverstone B (1954). Metabolism of copper in
Wilson's disease and in normal subjects. Am J Med 17: 205-213
(1954).
Eastwood JB, Phillips ME, Minty P, Gower PE, Curtis JR (1983).
Heparin inactivation, acidosis and copper poisoning due to
presumed acid contamination of water in a hemodialysis unit. Clin
Nephrol 20: 197-201.
Ellenhorn MJ, Barceloux DG (1988). Medical Toxicology: Diagnosis
and treatment of human poisoning, New York, Elsevier, pp.
1022-1023.
Fairbanks VF (1967). Copper sulphate-induced hemolytic anemia.
Arch Int Med 120: 428-432.
Ferm VH, Hanlon DP (1974). Toxicity of copper salts in hamster
embryonic development. Biol Reprod 11: 97-101.
Gollop BR, Glass WI (1979). Urinary arsenic levels in timber
treatment operators. N.Z. Med J 89: 10-11.
Gonzalez-Angulo A, Aznar-Ramos R (1976). Ultrastructural studies
on the endometrium of women wearing TCu-200 intrauterine device by
means of transmission and scanning electron microscopy and X-ray
dispersive analysis. Am J Obstet Gynecol 125: 170-179.
Gupta PS, Bhargava SP, Sharma ML (1962). Acute copper sulphate
poisoning with special reference to its management with
corticosteroid therapy. J Assoc Physicians India 10: 267-271.
Hazardous Substances Data Bank (1985) CHEM Source CD-ROM. Canadian
Centre for Occupational Health and Safety, Ontario, Canada.
Holtzman NA, Elliott DA, Heller RH (1966). Copper intoxication.
New Eng J Med 275: 347-352.
Hopper SH, Adams HS (1958). Copper poisoning from vending
machines. Am J Pub Health 73: 910-914.
James LS, Lazor VA, Binns W (1966). Effects of sublethal doses of
certain minerals on pregnant ewes and fetal development. Am J Vet
Res 27: 132-135.
Kucharz EJ, Sierakowski SJ (1988). Effect of copper on activation
of human T cells. J Hyg Epidemiol Micobiol Immunol 32:
147-152.
Lampe RM, Henderson AL., Hansen GH (1977). Green hair. J Am Med
Assoc 237: 2092-2094.
Lenga RE, ed (1988). Sigma-Aldrich library of chemical safety
data, Milwaukee, Sigma-Aldrich Corporation, 4098 pp.
Lyle WH, Payton JE, Hui M (1976). Haemodialysis and copper fever.
Lancet 1: 1324-1325.
Manzler AD, Schreiner AW (1970). Copper-induced acute hemolytic
anemia: a new complication of hemodialysis. Ann Int Med 73:
409-412.
Mason RW Edwards IR, Fisher LC (1989). Teratogenicity of
combinations of sodium dichromate, sodium arsenate and copper
sulphate in the rat. Comp Biochem Physiol 93C: 407-411.
Moo-Young AJ, Tatum HJ (1974). Copper levels in maternal and fetal
tissues of rabbits bearing intrauterine copper wires.
Contraception 9: 487-496.
Nagaraj MV, Rao PV, Susaraia S (1985). Copper sulphate poisoning,
hemolysis and methaemoglobinemia. J Assoc Physicians India 33:
308-309.
Newman JA, Archer VE, Saccomanno G et al (1976). Histologic types
of bronchogenic carcinoma among members of copper making and
smelting communities. Ann NY Acad Sci 271: 260-268.
Nordlund JJ, Hartley C, Fister J (1977). On the cause of green
hair. Arch Dermatol 113: 1700.
Nriagu JO (1979). The global copper cycle. In: Nriagu J.O. ed.,
Copper in the environment part 1: ecological cycling, New York
John Wiley & Sons Inc pp. 1-17.
Parish LC (1975). Green hair. N Eng J Med 292: 483.
Patel KC, Kulkarni BS, Acharya VN (1976).Acute renal failure and
methaemoglobinaemia due to copper sulphate poisoning. J Postgrad
Med 22: 180-184.
Peters HA, Croft WA, Woolson EA, Darcey BA, Olson MA (1984).
Seasonal arsenic exposure from burning
chromium-copper-arsenate-treated wood. J Am Med Assoc 251:
2393-2396.
Pimentel JC, Marques F (1969). Vineyard sprayer's lung: a new
occupationl disease. Thorax 24: 678-688.
Pimentel JC, Menezes AP (1977). Liver disease in vineyard
sprayers. Gastroenterology 72: 275-283.
Piscator M (1979). Copper. In: Friberg, L., Nordberg, GF & Vouk,
VB ed. Handbook on the toxicology of metals, Amsterdam, Elsevier
Biomedical Press, pp. 411-420.
Plamenac P, Santic Z, Nikulin A, Serdarevic H (1985). Cytologic
changes of the respiratory tract in vineyard spraying workers. Eur
J Respir Dis 67: 50-55.
Reid DJ (1968). Allergic reaction to copper cement. Br Dent J 124:
92-94.
Rubenstein E (1976). Is the copper-releasing intrauterine
contraceptive device able to induce unphysiologic cell
differentiation in the uterine cervix. Am J Obstet Gynecol 125:
277.
Salmon MA, Wright T (1971). Chronic copper poisoning presenting as
pink disease. Arch Dis Child 46: 108-110.
Saltzer EI, Wilson JW (1968). Allergic contact dermatitis due to
copper. Arch Dermatol 98: 375-376.
Schienberg HI (1983). Copper, alloys and compounds. In:
Parmeggiani, ed. Encyclopaedia of occupational health and safety,
Geneva, International Labour Organization Publications, pp.
546-548.
Semple AB, Parry WH, & Phillips DE (1960). Acute copper poisoning.
Lancet 2: 700-701.
Sideris EG, Charalambous SC, Tsolomyty A, Katsaros N (1988).
Mutagenesis, carcinogenesis and the metal-DNA interaction. Prog
Clin Biol. Res 259: 13-25.
Singh MM, Singh G (1968). Biochemical changes in blood in cases of
acute copper sulphate poisoning. J Indian Med Assoc 50:
549-554.
Sittig M, ed (1985). Handbook of toxic and hazardous chemicals and
carcinogens Park Ridge Noyes Publication pp. 256-258.
Spitalny KC, Brondum J, Vogt RL, Sargent HE, Kappel S (1984).
Drinking-water-induced copper intoxication in a Vermont family.
Pediatrics 74: 1103-1106.
Stabel JR, Spears JW (1989). Effect of copper on immune function
and disease resistance. Adv Exp Med Biol 258: 243-252.
Stokinger HE (1981). The metals. In: Clayton, GD & Clayton, F.E,
eds. Patty's Industrial Hygiene and Toxicology, volume 2A
Toxicology, New York, John Wiley & Sons Inc, pp. 1620-1630.
Strickland GT, Beckner WM, Leu ML (1972). Absorption of copper in
homozygotes and heterozygotes for Wilson's disease and controls:
isotope tracer studies with 67Cu and 64Cu. Clin Sci 43:
617-625.
Takahashi MA, Pfenninger K, Wong L (1983). Urinary arsenic,
chromium and copper levels in workers exposed to arsenic based
wood preservations. Arch Environ Hlth 38: 209-214.
Tauxe WN, Goldstein NP, Randall RV, Gross JB (1966). Radiocopper
studies in patients with Wilson's disease and their relatives. Am
J Med 41: 375-380.
Thirumalaikolundusubramanian P, Chandramohan M, Johnson ES,
(1984). Copper sulphate poisoning. J Indian Med Assoc 82: 6-8.
Tokudome S, Haratake J, Horie A et al (1988). Histologic types of
lung cancers among male Japanese copper smelter workers. Amer J
Ind Med 14: 137-143.
Trachtenberg DI (1972). Allergic response to copper-its possible
gingival implications. J Periodontol 43: 705-707.
UN (1985). United Nations transportation number from
"Recommendations on Transport of Dangerous Goods"
ST/SG/AL.10/1/Rev4 United Nations.
Underwood EJ (1977). Copper In: Trace elements in human and animal
nutrition, New York, Academic Press, pp 56-108.
Villar TG (1974). Vineyard sprayer's lung. Am Rev Respir Dis 110:
545-555.
Wahl PK, Lahiri B, Mathur KS, Kehar U, Wahl PN (1963). Acute
copper sulphate poisoning. J Assoc Physicians India 11:
93-103.
Walsh FM, Crosson FJ, Bayley M, McReynolds J, Pearson BJ (1977).
Acute copper intoxication. Am J Dis Child 131: 149-151.
Weast RC ed (1976-77). Handbook of chemistry and physics,
Cleveland, Ohio, CRC Press, pp. B109-B112.
Wicks MJ, Archer VE, Averbach O, Kuschner M (1981). Arsenic
exposure in a copper smelter as related to histological type of
lung cancer. Am J Ind Med 2: 25-31.
Windholz M, Budavari S, Stroumtsos LY, Fertig MN, eds (1976). The
Merck Index, Rahway,New Jersey, Merck & Co., Inc.
Wong PK (1988). Mutagenicity of heavy metals. Bull Environ Contam
Toxicol 40: 597-603.
Wyllie J (1957). Copper poisoning at a cocktail party. Am J Pub
Hlth 47: 617.
Zipper J, Medel M, Prager R (1969). Suppression of fertility by
intrauterine copper and zinc in rabbits: a new approach to
intrauterine contraception. Am J Obstet Gynecol 105:
529-534.
14. AUTHOR(S), REVIEWER(S), DATE(S) (INCLUDING UPDATES), COMPLETE
ADDRESSES
Authors: R.W. Mason and S.D. Jones
G.S. Elliott (Author, Sections 7.3, 7.5 & 9.4.11)
National Toxicology Group,
University of Otago Medical School,
PO Box 913
Dunedin
New Zealand
Tel: 64 3 479 7254
Fax: 64 3 477 0509
Date: 4 October 1990
Co-Authors: Dr R. Fernando
National Poisons Information Centre
General Hospital
Colombo 8
Sri Lanka
Tel: 94-1-94016
Fax: 94-1-599231
Peer Review:Newcastle-upon-Tyne, United Kingdom (January, 1991)
Editor: M.Ruse (May, 1999)