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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.

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    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)
    



    See Also:
       Toxicological Abbreviations