SM Bradberry BSc MB MRCP
    ST Beer BSc

    National Poisons Information Service
    (Birmingham Centre),
    West Midlands Poisons Unit,
    City Hospital NHS Trust,
    Dudley Road,
    B18 7QH

    This monograph has been produced by staff of a National Poisons
    Information Service Centre in the United Kingdom.  The work was
    commissioned and funded by the UK Departments of Health, and was
    designed as a source of detailed information for use by poisons
    information centres.

    Peer review group: Directors of the UK National Poisons Information


    Toxbase summary

    Type of product

    Nickel chloride is a soluble nickel salt used in nickel plating, in
    the dye and printing industry, and as an adsorbent of ammonia in gas


    An important cause of contact dermatitis.  May precipitate
    occupational asthma.  Gastrointestinal irritation has occurred
    following ingestion but severe poisoning is rare.


         -    Primary skin and eye irritant and an important cause of
              contact dermatitis.


    Mild/moderate ingestions:
         -    Small ingestions of dilute solutions may produce no
              symptoms.  Nausea, vomiting, abdominal pain and diarrhoea
              occur within two hours in more significant ingestions,
              possibly associated with headache, giddiness and myalgia.

    Substantial ingestions:
         -    Severe gastrointestinal irritation and haemorrhage may
         -    Transient hyperbilirubinaemia, albuminuria or a
              reticulocytosis have been reported and first degree heart
              block has been described.

         -    A potential cause of occupational asthma.  Chronic
              inhalation may cause rhinitis, sinusitis, anosmia and
              perforation of the nasal septum.



    1.   Remove from exposure.
    2.   Symptomatic and supportive measures as required.
    3.   Chelation therapy in nickel contact dermatitis cannot be
         advocated routinely but is an area of research interest.  Discuss
         with an NPIS physician.


    1.   In mild cases symptomatic and supportive measures will suffice.
    2.   Gastric lavage is best avoided in view of potential oesophageal
    3.   In symptomatic patients measure blood and urine nickel
    4.   Ensure a good urine output in those with suspected or confirmed
         nickel toxicity.


    1.   Remove from exposure.
    2.   Symptomatic and supportive measures as required.
    3.   Occupational asthma should be managed conventionally.


    Sunderman Jr FW, Dingle B, Hopfer SM, Swift T.
    Acute nickel toxicity in electroplating workers who accidentally
    ingested a solution of nickel sulfate and nickel chloride.
    Am J Ind Med 1988; 14: 257-66.

    Wall LM, Calnan CD.
    Occupational nickel dermatitis in the electroforming industry.
    Contact Dermatitis 1980; 6: 414-20.

    Substance Name

         Nickel (II) chloride

    Origin of substance

         Nickel chloride may be prepared from nickel oxide by
         chlorination, or by reaction with hydrogen chloride.
                                            (HSDB, 1997)


         Nickel chloride
         Nickel dichloride
         Nickelous chloride                 (DOSE, 1994)

    Chemical group

         A compound of nickel, a transition metal (d block) element.

    Reference numbers

         CAS            7718-54-9           (DOSE, 1994)
         RTECS          QR6470000           (RTECS, 1997)
         UN             NIF

    Physicochemical properties

    Chemical structure
         NiCl2                              (DOSE, 1994)

    Molecular weight
         129.62                             (DOSE, 1994)

    Physical state at room temperature

         Green (hexahydrate)
         Golden-yellow (anhydrous salt)     (MERCK, 1996)

         Odourless                          (HSDB, 1997)


         The aqueous solution is acidic.    (MERCK, 1996)

         Soluble in water: 642 g/L at 20°C. Soluble in ethanol, ethylene
         glycol and hydrazine.              (DOSE, 1994)

    Autoignition temperature

    Chemical interactions
         Nickel chloride may explode on impact when mixed with potassium.
                                            (NFPA, 1986)
         Nickel chloride reacts readily with strong acids.
                                            (HSDB, 1997)

    Major products of combustion
         When heated to decomposition very toxic fumes of hydrogen
         chloride may be emitted.           (HSDB, 1997)

    Explosive limits

         Non-flammable                      (HSDB, 1997)

    Boiling point
         987°C (sublimes)                   (DOSE, 1994)

         3.55 at 20°C                       (DOSE, 1994)

    Vapour pressure
         133.3 Pa at 671°C                  (HSDB, 1997)

    Relative vapour density

    Flash Point


         Nickel chloride is used in the nickel-plating of cast zinc, and
         in ink manufacture.  The anhydrous salt is used as an adsorbant
         for ammonia in gas masks.          (MERCK, 1996)

    Hazard/risk classification


    Nickel chloride is a soluble nickel salt.  Poisoning by ingestion is
    rare although occupational cases have been described (Sunderman et al,
    1988).  Nickel chloride inhalation may cause occupational asthma in
    metal platers (McConnell et al, 1973).  Nickel chloride is used in
    nickel patch testing.


     In vitro studies demonstrate that nickel causes crosslinking of
    amino acids to DNA, alters gene expression, induces gene mutations and
    the formation of reactive oxygen species (Costa et al, 1994a and b;
    Haugen et al, 1994; Huang et al, 1994; Shi et al, 1994).  Nickel also
    suppresses natural killer cell activity and interferon production
    (Shen and Zhang, 1994).  Beyersmann (1994) has suggested that nickel
    enhances the damaging effects of genotoxins such as ultraviolet
    radiation and alkylating substances by impairing DNA repair



    Nickel chloride can be absorbed by inhalation and ingestion. 
    Percutaneous uptake can occur, and is an important source of nickel
    contact sensitivity, but does not make a substantial contribution to
    the body nickel burden.  It has been estimated that 75 per cent of
    inspired nickel is retained in the respiratory tree (Schroeder, 1970)
    and two thirds of this is eventually swallowed after clearance from
    the airways by the mucociliary mechanism.

    Distribution and excretion

    Once absorbed, nickel is transported in the blood bound principally to
    albumin (Lucassen and Sarkar, 1979).  It is concentrated in the
    kidneys, liver and lungs and is excreted primarily in the urine. 
    However, following ingestion, the concentration of nickel in faeces
    will be much higher than in urine since most is not absorbed.  A
    substantial proportion of inhaled nickel chloride will eventually also
    appear in the gut.

    Animal and human volunteer studies suggest that the distribution and
    elimination of nickel follows a two compartment model with an initial
    rapid plasma elimination phase followed by a slower clearance phase
    (IPCS, 1991).

    In ten human volunteers the plasma elimination half-life of ingested
    nickel was 28 ± (SD) 9 hours (Sunderman et al, 1989).  Among ten
    workers who accidentally drank 0.5 - 1.5 litres nickel chloride and
    nickel sulphate-contaminated water, and who  received intravenous
    fluid (150 mL/hour) for three days the serum nickel half-life was 
    27 ± (SD) 7 hours.  Among 11 individuals in whom a diuresis was not
    induced the mean serum nickel half-life was 60 ± (SD) 11 hours.

    Nickel crosses the placenta and is passed to the child in maternal
    milk (Fairhurst and Illing, 1987; IPCS, 1991).


    Dermal exposure

    There is relatively little information on the acute dermal toxicity of
    nickel chloride in humans, though at high concentrations it is likely 
    to be a primary skin irritant as is nickel sulphate (Frosch and
    Kligman, 1976).

    Dermal exposure to nickel chloride is associated mainly with the
    development of nickel contact sensitivity (see Chronic exposure).

    Ocular exposure

    Nickel chloride (0.5 per cent) produced no adverse effects when
    directly applied to rabbit eyes.  There are no human data (Grant and
    Schuman, 1993).


    Gastrointestinal toxicity

    Sunderman et al (1988) reported an industrial accident involving 32
    workers at an electroplating plant who accidentally drank water
    contaminated with nickel chloride, nickel sulphate (total nickel
    concentration 1.63 g/L) and boron (68 mg/L).  Symptoms occurred
    primarily in those who had ingested more than 500 mL and began within

    two hours of ingestion.  Gastrointestinal effects including nausea,
    vomiting, abdominal pain and diarrhoea were the most common.  Ten of
    these 32 patients required hospital admission, though all were
    asymptomatic within three days.  The mean urine nickel concentration
    the day following the incident among 15 of those exposed was 5.8 mg/L
    (range 0.23 - 37.1 mg/L) , with a mean serum nickel concentration of
    286 µg/L (range 12.8 - 1340 µg/L).  Among 11 nickel platers who did
    not drink the contaminated water the mean urine nickel concentration
    was 50 ± (SD) 13 µg/L with a mean serum nickel concentration of 4.0 ±
    (SD) 1.2 µg/L (Sunderman et al, 1988).

    Fatalities have occurred from gastrointestinal haemorrhage following
    soluble nickel salt ingestion though there are no case reports
    involving nickel chloride.


    Two of the ten patients  admitted following ingestion of 0.5 - 1.5
    litres nickel chloride/sulphate contaminated water (see above)
    developed mild transient hyperbilirubinaemia (30 µmol/L and 43 µmol/L
    respectively) but this resolved within six weeks (Sunderman et al,


    Of 20 workers who accidentally ingested water contaminated with nickel
    chloride and sulphate (see above) seven complained of giddiness, six
    of lassitude, five of headache and one of myalgia.  Symptoms resolved
    within hours in most cases and within two days in all (Sunderman et
    al, 1988).  In the same accident it was noted that the mean body
    temperature of the ten most substantially exposed patients was
    slightly diminished (mean 36.7 ± (SD) 0.3°C on day 2).  The authors
    proposed nickel-induced impaired thermoregulation (which has been
    described in animals) as the mechanism, but there are insufficient
    clinical data to substantiate this.

    Pulmonary toxicity

    Of 21 workers who drank nickel contaminated water (nickel
    concentration 1.63 g/L), one patient with known bronchial asthma
    developed an expiratory wheeze and another patient with chronic
    obstructive airways disease developed cyanosis.  Whether these
    respiratory symptoms were nickel-induced is unknown (Sunderman et al,


    Two of the subjects described by Sunderman et al (1988) developed
    transient albuminuria in the two days following ingestion of nickel
    chloride/sulphate contaminated water (see above).  In both cases this
    resolved within five days.


    Sunderman et al (1988) reported a modest erythropoietic effect among
    ten workers who accidentally drank nickel chloride/sulphate-
    contaminated water (see above) with an increase in the mean blood
    haemoglobin concentration from 15.1 ± (SD) 0.7 g/dL on day three post
    exposure to 16.0 ± (SD) 0.6 g/L on day eight (p<0.01).  There was a
    similar statistically significant increase in the blood reticulocyte

    Cardiovascular toxicity

    Ingestion of 0.5 - 1.5 L nickel chloride/sulphate contaminated water
    (nickel content 1.63 g/L)  was associated in one patient with
    transient first degree heart block (Sunderman et al, 1988).


    Dermal exposure

    Nickel chloride is a common precipitant of allergic contact dermatitis
    (Kalimo and Lammintausta, 1984; Christensen and Wall, 1987; Serup and
    Staberg 1987 a and b; Goebeler et al, 1993) which is a cell-mediated
    (type IV) hypersensitivity response.  Chronic urticaria, a type 1
    hypersensitivity cutaneous reaction to nickel, has also been described
    (Abeck et al, 1993).

    Nickel sensitivity has been implicated in the aetiology of pompholyx,
    a vesicular eruption of the palmoplantar regions (Lodi et al, 1992).

    Primary nickel contact sensitization is more common in women
    (Peltonen, 1979) and usually follows prolonged non-occupational skin
    contact with nickel-plated objects or nickel alloys.  Common sources
    include jewellery, buttons, zips and coins (Lacroix et al, 1979;
    Gollhausen and Ring, 1991).  The amount of nickel released from these
    items depends on their resistance to corrosion and the presence of
    sweat which acts to release the metal ion as soluble nickel salts
    including nickel chloride.  Nickel ions may penetrate rubber gloves
    (Wall, 1980).

    Once an individual is sensitized, further exposure to only a very
    small quantity of nickel initiates a reaction at the site of contact. 
    Nickel valve prostheses and nickel-containing pacemakers have been
    suggested as triggers of nickel allergy (Lyell and Bain, 1974;
    Landwehr and van Ketel, 1983).

    In susceptible individuals nickel allergy may result in "secondary"
    nickel dermatitis with dissemination to skin sites distant from that
    of primary sensitization (typically the hands, flexures and eyelids). 
    It is not clear whether the latter is an endogenous phenomenon or
    simply reflects exogenous nickel contamination, for example via
    perspiring fingers (Fisher, 1986).

    Interpretation of patch test responses may be difficult.  Measurement
    of transepidermal water loss (Serup and Staberg, 1987a) and assessment
    of skin oedema by ultrasound (Serup and Staberg, 1987b) have been
    suggested to differentiate between true allergic and irritant nickel
    patch test responses.

    Simultaneous contact sensitivity to nickel and cobalt is common
    probably via a shared effect on inflammatory-cell recruitment
    (Goebeler et al, 1993).

    Investigations by Wall and Calnan (1980) following an outbreak of
    occupational dermatitis in an electroforming plant found nickel
    chloride to be a more reliable patch test allergen than nickel
    sulphate.  Patch testing with nickel sulphate alone would have failed
    to detect seven of 13 nickel allergic patients.

    There is evidence that the skin permeation rate is some 15 times
    faster for nickel chloride than nickel sulphate (Fullerton et al,
    1986).  This partly explains why a nickel chloride patch test (48 h
    occlusion) gives a "more positive and allergic toxic reaction" than
    nickel sulphate (Kalimo and Lammintausta, 1984).  A further advantage
    of nickel chloride is its greater solubility in alcohol (Christensen
    and Wall, 1987).

    Nickel chloride may be used as the stimulus of lymphocyte blast
    transformation in the  in vitro confirmation of nickel sensitivity as
    is nickel sulphate (Everness et al, 1990; Grimsdottir et al, 1994).


    Pulmonary toxicity

    Chronic exposure to aerosols of nickel chloride, emitted as mists from
    electroplating baths may lead to chronic rhinitis, nasal sinusitis,
    anosmia and perforation of the nasal septum (Mastromatteo, 1986).

    Nickel chloride inhalation may cause occupational asthma with
    circulating IgE nickel antibodies as has been reported with nickel
    sulphate (Nieboer et al, 1984); resolution of symptoms occurs when the
    individual is away from work (Block and Yeung, 1982).  Occupational
    asthma has been reported among metal platers (McConnell et al, 1973).

    It is likely that nickel allergy is involved in the aetiology of
    'hard-metal' asthma (typically associated with cobalt exposure)  with
    evidence of cross reactivity between cobalt and nickel (Shirakawa et
    al, 1990; Shirakawa et al, 1992).


    There is some evidence that chronic inhalation of high concentrations
    of soluble nickel compounds causes increased urinary protein and renal
    tubular enzyme excretion but the significance of these findings is
    unknown (Vyskocil et al, 1994).


    Dermal toxicity

    Although primary nickel sensitization occurs only following skin
    contact, nickel dermatitis may be reactivated subsequently by ingested
    nickel (Gawkrodger et al, 1986).  This is unusual because most
    antigens induce a state of immunological tolerance when administered
    orally, an effect that has also been described in nickel sensitive
    subjects (Sjövall et al, 1987; Panzani et al, 1995).

    An exacerbation of nickel dermatitis following ingestion is localized
    often to the initial sensitization site.  This suggests that the
    antigen-presenting cells responsible for initiating the allergic
    reaction are relatively immobile (Nicklin and Nielsen, 1992).  This
    may have important implications for the prevention and treatment of
    nickel dermatitis since if the body burden of nickel can be reduced
    (for example by chelating agents), the likelihood of nickel activation
    of the antigen presenting cells may be  diminished.  Paradoxically the
    suggested mechanism of oral hyposensitization in nickel sensitive
    subjects is stimulation of suppressor T-cell production by antigen
    excess (Sjövall et al, 1987).

    Chronic urticaria, a type 1 hypersensitivity response has been
    attributed to dietary nickel (Abeck et al, 1993), but this is unusual.


    Dermal exposure

    Avoidance of exposure and symptomatic treatment of exacerbations with
    topical or systemic steroids remain the mainstay of treatment of
    nickel allergy although dietary nickel restriction (Kaaber et al,
    1978) or oral (Panzani et al, 1995) or topical (Allenby and Basketter,
    1994) hyposensitization have been advocated.  Oral cyclosporin does
    not appear to be effective (De Rie et al, 1991).  The role of
    chelation therapy is discussed below.


    Symptomatic and supportive treatment is all that is likely to be
    required in those with symptoms of respiratory tract irritation
    following acute exposure to nickel chloride.  Occupational asthma
    should be managed conventionally, and further exposure avoided.


    There is no evidence that gastric lavage reduces nickel chloride
    absorption. General symptomatic and supportive measures are likely to
    be all that are required in most cases.  Measurement of nickel
    concentrations in blood and urine need only be undertaken in
    symptomatic patients.

    Since nickel is eliminated mainly in the urine, maintenance of a high
    urine output is important in those with a confirmed or suspected
    increased nickel burden. Following inadvertent ingestion of 0.5 - 1.5
    litres nickel chloride/sulphate-contaminated water (nickel
    concentration 1.63 g/L), Sunderman et al (1988) demonstrated a mean
    serum nickel half life of 27 hours (n=10) in those treated with
    intravenous fluids compared to a half-life of 60 hours (n=11) in those
    not receiving intravenous fluids.

    The role of chelation therapy in nickel chloride poisoning is
    discussed below.


    Animal studies

    The effect of chelating agents on nickel distribution is dependent on
    their lipid solubility.  Lipophilic agents (such as
    diethyldithiocarbamate (DDC) and triethylenetetramine dihydrochloride
    (TETA)) are more able to penetrate cell membranes with potential
    redistribution of nickel to lipid rich tissues such as the liver and
    brain (Misra et al, 1987).  By contrast hydrophilic chelating agents
    (e.g. sodium calcium ethylenediamine tetraacetic acid) are more likely
    to enhance renal nickel clearance without cellular nickel accumulation
    (Misra et al, 1987).

    Misra et al (1987) observed a significant reduction (p<0.05) in renal
    nickel content in rodents following treatment with both lipophilic
    (1,4,8,11-tetra-azacyclotetradecane and triethylenetetramine) and
    hydrophilic (sodium calciumedetate, 1,2,cyclohexylenediamine
    tetraacetic acid, diethylenetriamine pentaacetic acid) chelating
    agents given subcutaneously (500 µmol/kg) 60 minutes post dosing with
    nickel chloride (250 µmol/kg subcutaneously).  By contrast the hepatic
    nickel content was increased following treatment with lipophilic
    agents, but reduced after hydrophilic drug administration (Misra et
    al, 1987).

    Oskarsson and Tjälve (1980) investigated the effect on nickel
    distribution of intraperitoneal DDC 4.1 mmol/kg and d-penicillamine
    3.4 mmol/kg in mice administered a chelating agent ten minutes before
    an intravenous bolus of 63nickel chloride (0.3 mg Ni2+/kg).  DDC
    caused increased tissue nickel retention compared to control mice
    (injected with nickel chloride alone), with the highest radioactivity
    in adipose tissue followed by the liver, kidneys, brain and spinal
    cord.  The brain nickel content of DDC treated mice was 57 times
    higher than control mice.  Following d-penicillamine the tissue nickel
    content was lower than in control mice.  For example,  the "kidney
    contained about 1% and the lung about 4%" of the radioactivity
    observed in mice given 63nickel chloride only.

    Sodium calciumedetate 400 µmol/kg subcutaneously reduced the nickel
    content of the liver, heart, kidney and lung by 20 - 40 per cent in
    rodents administered nickel chloride (200 µmol/kg subcutaneously) 30
    minutes previously (Dwivedi et al, 1986).

    In rats (n = 20 - 25 in each group) the two week mortality following
    intraperitoneal nickel chloride (0.82 mmol/kg, estimated LD95  0.29
    mmol/kg) was zero if intravenous d-penicillamine 6.8 mmol/kg (0.3
    times its LD50) was given one minute  prior to nickel dosing (Horak
    et al ,1976).  Under the same experimental conditions
    triethylenetetramine 1.36 mmol/kg (0.6 times its LD50) reduced
    (p<0.001) the two week mortality to 25 per cent but DDC was
    ineffective.  Sodium calciumedetate 0.68 mmol/kg reduced the two week
    mortality to 32 per cent (p<0.001) when the nickel chloride dose was
    0.136 mmol/kg (greater than its LD50).

    Dimercaptopropanesulphonate (DMPS), d-penicillamine and sodium
    calciumedetate (administered intraperitoneally at a molar ratio of
    10:1 chelating agent: nickel)  increased survival in rodents
    systemically poisoned 20 minutes previously with nickel (as
    intraperitoneal nickel acetate, 62 mg/kg).  The results are summarized
    in Table 1 (Basinger et al, 1980).

    Table 1. Survival rates in nickel intoxicated mice following chelation
    therapy (see text)


    n=            Chelating agent             Survival %

     5            None                             0
    10            DMPS                            80
    10            d-Penicillamine                100
    10            Sodium calciumedetate          100

                                     (after Basinger et al, 1980)

    Shen et al (1979) studied the effect of several chelating agents
    (administered subcutaneously) on renal nickel clearance in rats
    administered a continuous nickel chloride infusion.  Each chelating
    agent was administered to a different group of six rats with eight
    controls.  d-Penicillamine 1 µmol/h increased mean renal nickel
    clearance by 53 per cent (p< 0.001) and triethylenetetramine 1 µmol/h
    by 26 per cent (p<0.025) but DDC 2 µmol/h did not affect renal nickel

    DMPS 0.5 mmol/kg significantly enhanced urine nickel excretion
    (0.001< p< 0.05) when administered subcutaneously to rats poisoned
    with intraperitoneal nickel sulphate (4 mg/kg). Similarly significant
    decreases in nickel-induced hyperglycaemia and aminoaciduria were
    noted following chelation therapy.  Faecal nickel excretion was
    unaffected and DMPS was ineffective in mobilizing nickel from the
    brain (Sharma et al, 1987).

    In a more recent controlled study, Tandon et al (1996) investigated
    the effects of chelating agents on nickel toxicity.  Groups (n=6) of
    nickel poisoned rats (1.5 mg/kg nickel sulphate intraperitoneally, 6
    days a week for 30 days) were intraperitoneally administered a
    chelating agent 0.3 mmol/kg once a day for five days.  DMSA and DMPS
    significantly (p<0.001, p<0.01 respectively) enhanced faecal but not
    urinary nickel excretion.  DDC did not enhance elimination by either
    route.  DMSA, DMPS and DDC significantly (p<0.01) reduced blood,
    liver, kidney and heart (but not brain) nickel concentrations compared
    to controls.  The DDC homologue (N-benzyl-D-glucamine dithiocarbamate)
    was the most effective of all antidotes studied, significantly
    enhancing both urinary and faecal excretion (p<0.01) and reducing
    (p<0.001) the nickel concentrations in all tissues examined.

    In mice systemically poisoned with nickel chloride (5 mg/kg),
    intraperitoneal DDC 400 µmol/kg caused redistribution of nickel to the
    brain (Xie et al, 1994).  Intraperitoneal DMSA 400 µmol/kg,
    significantly enhanced (p<0.05) the faecal and urinary excretion of
    the metal and there was no redistribution to the brain (Xie et al,
    1994). The same group recently found parenteral DMSA and
    N-benzyl-D-glucaminedithiocarbamate (BGD) effective in decreasing the
    testicular nickel concentration and so protecting against
    nickel-induced testicular toxicity in mice administered
    intraperitoneal nickel chloride (Xie et al, 1995).

    In summary, in rodents systemically poisoned with soluble nickel
    salts, renal nickel clearance is increased and mortality reduced by
    the parenteral administration of d-penicillamine or
    triethylenetetramine.  Evidence regarding the effect of DMPS and DMSA
    on renal nickel elimination is conflicting.  DDC does not enhance
    nickel excretion.

    Clinical studies

    There are no human data involving chelation therapy in nickel chloride
    toxicity save that relating to the management of nickel dermatitis.

    Diethyldithiocarbamate and disulfiram in nickel dermatitis

    Diethyldithiocarbamate (DDC) forms a chelate with Ni2+ such that:

               2(DDC) + Ni2+ -----  Nickel bis(DDC)

    which is renally excreted.

    DDC is not available as a pharmaceutical preparation in many countries
    although disulfiram (Antabuse), which is metabolized to DDC (two
    molecules of DDC from each of disulfiram), has been employed.

    The rationale for the use of DDC and disulfiram in nickel dermatitis
    is that both agents reduce the body nickel burden and so minimise the
    amount of nickel available for the endogenous activation of
    immunocompetent cells.

    Topical DDC

    van Ketel and Bruynzeel (1982) investigated the role of topical DDC in
    the prevention of nickel sensitivity in 17 patients with known nickel
    allergy.  Prior to nickel challenge seven patients were pretreated for
    24 hours with 10 per cent DDC under an occlusive dressing.  They were
    challenged with nickel sulphate (0.01, 0.1, 1.0 and 5.0 per cent
    solutions) and a nickel coin (99.7 per cent nickel).  Ten patients
    applied 10 per cent DDC six hourly for 24 hours prior to nickel
    sulphate challenge.  There were no differences in mean patch test
    scores between DDC-treated and non DDC-treated skin in all groups.
    (Table 2).

    Table 2.  Topical DDC in nickel dermatitis


    n=   24 h              Nickel                      Mean ± SD
         Pretreatment      challenge                   patch-test score
                                                       Control      DDC

    7    10% DDC           Nickel sulphate             3.9 ± 2.1    4.0 ± 3.2
         under occlusion   (0.01, 0.1, 1.0 and 5.0%)

    7    10% DDC           Coin                        0.9 ± 0.7    1.8 ± 1.1
         under occlusion   (99.7% nickel)

    10   10% DDC           Nickel sulphate             2.9 ± 2.7    2.5 ± 3.1
         qds               (0.01, 0.1, 1.0 and 5.0%)

                                               (van Ketel and Bruynzeel, 1982)

    Systemic DDC and disulfiram

    Several uncontrolled studies report the successful resolution of
    nickel dermatitis following oral DDC or disulfiram. Uncontrolled
    studies of disulfiram therapy in nickel dermatitis are summarized in
    Table 3.

    Menné and Kaaber (1978) described a patient in whom oral DDC 400 mg
    daily for 20 days led to an improvement in dermatitis although the
    condition recurred when treatment was discontinued.

    In another patient (Spruit et al, 1978) oral DDC for two months failed
    to produce a negative nickel patch test, although less local treatment
    was required.

    Although disulfiram increases urine nickel excretion in patients with
    nickel dermatitis (Table 4), there was no overall significant
    difference between treatments in a double-blind study involving 24
    patients treated with disulfiram 200 mg daily or placebo for six weeks
    (Kaaber et al, 1983).

    Adverse effects of DDC and disulfiram

    There is concern that DDC and disulfiram may promote nickel
    accumulation in the brain (Jasim and Tjälve, 1984; Hopfer et al, 1987;
    Nielsen and Andersen, 1994). Disulfiram is also associated frequently
    with a 'flare-up' of nickel dermatitis soon after commencing treatment
    (Kaaber et al, 1979; Menné et al, 1980; Christensen and Kristensen,
    1982; Christensen, 1982 (Table 3); Klein and Fowler, 1992; Gamboa et
    al, 1993). Other reported adverse effects of disulfiram include
    abnormal liver function (Kaaber et al, 1983; Kaaber et al, 1987), an
    acne-like rash (Kaaber et al, 1983), headache (Kaaber et al, 1979;
    Kaaber et al, 1983), fatigue and dizziness (Kaaber et al, 1979) and an
    adverse reaction with alcohol. Reactivation of nickel sensitivity
    often occurs when therapy is discontinued (Kaaber et al, 1979; Kaaber
    et al, 1987; Table 3).

    Sodium calciumedetate

    Seventeen nickel allergic patients pretreated with a cream containing
    10 per cent sodium calciumedetate showed a significant reduction in
    positive patch tests to nickel sulphate (1 per cent solution) compared
    to results on untreated skin (three positive reactions compared to 14
    respectively, p<0.01) (van Ketel and Bruynzeel, 1982). The authors
    suggested use of 10 per cent sodium calciumedetate barrier creams in
    nickel sensitive subjects but this requires further study.


    A recent clinical study reported that topical administration of the
    chelating agent clioquinol (3 per cent) "completely abolished"
    reactivity to nickel in 29 nickel-sensitive subjects and the authors
    advocated its use as a barrier ointment in nickel allergic patients
    (Memon et al, 1994) but this requires confirmation.

        Table 3.  Uncontrolled studies of disulfiram in nickel dermatitis


    n=            Disulfiram                      Effect on dermatitis                       Study
            Dose        Duration    & Early       %            %               % 
            (mg/day)    (wks)       flare         "Healed"     "Improved"      Rebound1

     1      300         8           -             -            100             100           Menné & Kaaber, 1978

    11      200-400     "4-10"      82            64           18              55            Kaaber et al, 1979

    11      200-400     ?           82            73           -               -             Menné et al, 1980

    11      200         8           100           18           73              100           Christensen & Kristensen, 1982

     3      50-200      18 (mean)   100           33           66              33            Christensen, 1982

    61      50-400      12 (mean)   ?2            46           30              85 (n=27)3    Kaaber et al, 1987

    98                              -             47           32              66 (n=64)

    1 Rebound dermatitis when disulfiram discontinued
    2 Flares of dermatitis "frequently seen" but number not stated
    3 Only 27 patients were followed for incidence of rebound dermatitis which occurred in 23 cases
    Table 4.  Disulfiram in nickel dermatitis: urine nickel excretion

    n=    Disulfiram         Mean ± SD urine        Study
          dose              nickel excretion
          (mg/day)              (µg/24 h)
                        Before      Maximum during
                        treatment   treatment

    3     200-400       1.2 ± 0.3   53 ± 15.5       Kaaber et al, 1979

    6     200-400       1.7 ± 0.5   60 ± 23.8       Menné et al, 1980

    Antidotes: Conclusions and recommendations

    Nickel contact sensitivity

    1.   Nickel contact sensitivity is managed most effectively by
         avoiding exposure and treating acute exacerbations with topical
         and/or systemic steroids.

    2.   Topical DDC has no role. There is some evidence that barrier
         creams containing sodium calciumedetate or clioquinol may be

    3.   While there are two case reports claiming benefit from oral DDC
         in the treatment of nickel dermatitis, this has not been
         confirmed in a controlled clinical study.

    4.   In the only published controlled clinical study using disulfiram
         in the management of nickel dermatitis there was no overall
         benefit from treatment.

    5.   Uncontrolled studies with oral disulfiram suggest improvement in
         secondary nickel dermatitis but the incidence of significant
         side-effects is high.

    6.   Chelation therapy in nickel dermatitis cannot be advocated
         routinely but remains an area of research interest.

    Systemic nickel poisoning

    1.   There are no human data available regarding chelation therapy in
         systemic nickel chloride toxicity.

    2.   Animal studies suggest d-penicillamine is probably the most
         effective nickel antidote although there are promising results
         and less adverse effects with the newer thiol chelating agents,
         particularly DMPS.


    Prior to employment involving potential exposure to nickel special
    consideration should be given to those with a history of contact
    dermatitis or respiratory disease.

    Monitoring of nickel concentrations in blood and urine are not
    indicated routinely because while they provide evidence of recent
    exposure to soluble nickel compounds (and nickel metal powder), they
    do not reflect the total body nickel burden.

    Urine nickel concentrations vary considerably and should be
    interpreted as groups of 24 hour samples rather than individual urine
    specimens (Nickel Producers Environmental Research Association and the
    Nickel Development Institute, 1994).

    Serum nickel concentrations are used in some nickel industries since
    they avoid contamination from work-place dust and provide fairly
    consistent values within a given work environment; mean serum nickel
    concentrations ranging from 0.9 µg/L (reference range varies widely
    but a typical value for an adult is less than 1.3 µg/L) for grinders
    and polishers to 11.9 µg/L in electrolytic refining workers have been
    cited (Nickel Producers Environmental Research Association and the
    Nickel Development Institute, 1994).

    In a controlled study Torjussen and Andersen (1979) determined nasal
    mucosal, plasma and urine nickel concentrations in 318 present and 15
    retired workers all employed for at least eight years in a nickel
    refining plant. Mean nickel concentrations in all samples were
    significantly lower in the control group (n=57) than the corresponding
    values for the active (p<0.01) and retired (p<0.05) workers
    (Torjussen and Andersen, 1979).

    In the same study (Torjussen and Andersen, 1979) electrolytic workers
    exposed to nickel chloride and sulphate exhibited significantly lower
    (p<0.01) nasal mucosal nickel concentrations (178.1 ± (SD) 234.7
    µg/100g wet weight) than smelting and roasting workers exposed to
    insoluble nickel oxide and subsulphide dust (467.2 ± (SD) 594.6
    µg/100 g wet weight). Plasma and urine nickel concentrations, however,
    were significantly higher (p<0.01) in electrolytic workers than in
    those exposed to nickel oxide (Torjussen and Andersen, 1979).

    Gammelgaard et al (1992) have suggested that a nickel content of
    fingernails greater than 8 ppm indicates likely occupational (rather
    than domestic) nickel exposure in patients with nickel dermatitis but
    the reliability of this proposal has not been confirmed.


    Maximum exposure limit

    Nickel, inorganic soluble compounds: Long-term exposure limit (8 hour
    TWA reference period) 0.1 mg/m3 (Health and Safety Executive, 1997).



    Epidemiological studies have shown a significant increase in deaths
    from carcinoma of the lung and nasal sinuses among nickel refinery
    workers (Roberts et al, 1992; Andersen, 1992). The excess risk of
    death continues for several years after leaving employment (Muir et
    al, 1994).

    The exact aetiological agent is unknown, although nickel chloride,
    nickel sulphate, nickel oxide and sub-sulphide have been suspected
    (IARC, 1990; Roberts et al, 1992; Andersen, 1992). An increased
    incidence of laryngeal cancer has not been confirmed (Roberts et al,
    1992). Among employees at an aircraft engine factory lung cancer
    deaths (n = 42) between 1966 and 1976 were no more prevalent among
    nickel-exposed (exposed both to nickel alloys dust and aerosols of
    nickel sulphate and chloride) than non-exposed workmen (Bernacki et
    al, 1978).

    A study by Pang et al (1996) provided only weak evidence (observed
    8.0, expected 2.49, SMR 322) of an increased risk of stomach cancer in
    a cohort of 284 nickel platers who handled nickel chloride and nickel
    sulphate, first employed for at least three months between 1945-75.

    Fortunately, measures to improve industrial hygiene have reduced
    greatly the occupational hazard of nickel chloride exposure but
    respiratory malignancies remain notifiable diseases among nickel
    industry employees in the UK (Seaton et al, 1994).


    Animal studies have shown reduced fertility and stunted fetal growth
    following the oral administration of nickel (as nickel sulphate) and
    testicular damage following oral or dermal nickel exposure (to nickel
    sulphate) (Reprotext, 1997). Smith et al (1993) provided evidence of
    increased perinatal mortality in rats fed nickel chloride for 11 weeks
    prior to mating then during two cycles of gestation and lactation.

    These are no human reprotoxicity data specific to nickel chloride.
    Chashschin et al (1994) reported an increased incidence of structural
    malformations and spontaneous and threatened abortions in pregnancies
    among 356 nickel refinery workers exposed to nickel aerosols (as
    nickel sulphate) (range 0.077 - 0.308 mg/m3) compared to non-exposed
    controls. Unfortunately their data lacked adequate sampling and
    statistical details but suggests that the potential reprotoxic hazard
    of soluble nickel salt exposure requires further investigation.


     In vitro studies

     Salmonella typhimurium TA97, TA98, TA100, TA1535, TA1537, TA1538
    with and without metabolic activation - negative.
     Escherichia coli WP2, WP67, CM871 with and without metabolic
    activation DNA-repair test - negative.
     Bacillus subtilis H17, M45 without metabolic activation - negative.
     Saccharomyces cerevisiae D7 without metabolic activation - positive.
     In vitro Chinese hamster ovary cells DNA strand breaks - positive.
     In vitro mouse FM3A mammary carcinoma cells, Chinese hamster ovary
    cells and human peripheral blood lymphocytes: chromosomal aberrations
    and sister chromatid exchanges - positive.
     In vitro Chinese hamster ovary cells, chromosomal aberrations -

     In vivo studies

    Reduced sperm counts, sperm mobilities, induced sperm chromosomal
    aberrations, damaged testes ultrastructure, caused sperm head
    abnormalities and induced micronuclei in the polychromatic
    erythrocytes were found in mice. Intraperitoneal injection of 6-24
    mg/kg nickel in mice induced bone marrow chromosomal aberrations
    (DOSE, 1994).

    Clinical studies

    In a controlled study Waksvik et al (1984) investigated chromosomal
    aberrations in the peripheral lymphocytes of retired nickel refinery
    workers (n=9) four to 15 years post retirement. The workers who had
    been exposed to either nickel chloride, nickel oxide, nickel sulphate
    or nickel subsulphide for greater than 25 years (nickel air
    concentrations >1 mg/m3) showed an increased incidence of
    chromosomal breaks (p<0.001) and gaps (p<0.05) but no difference in
    sister chromatid exchange compared with the non nickel-exposed
    controls (n=11).

    Fish toxicity

    LC50 (96 hr) fathead minnow, blue gill sunfish 4.9-5.3 mg/L in soft
    water (20 mg CaCO3/L) or 43.5-39.6 mg/L in hard water (300 mg
    LC50 (48 hr) rainbow trout 20, 80 mg/L in soft, hard water
    LC50 (96 hr) tidewater silver side larvae, adult spot fish 30, 70
    mg/L respectively (DOSE, 1994).

    EC Directive on Drinking Water Quality 80/778/EEC

    Nickel: Maximum admissible concentration 50 µg/L.
    Chlorides guide level 25 mg/L (DOSE, 1994).

    WHO Guidelines for Drinking Water Quality

    Guideline value 0.02 mg/L, as nickel (WHO, 1993).


    SM Bradberry BSc MB MRCP
    ST Beer BSc

    National Poisons Information Service (Birmingham Centre),
    West Midlands Poisons Unit,
    City Hospital NHS Trust,
    Dudley Road,
    B18 7QH

    This monograph was produced by the staff of the Birmingham Centre of
    the National Poisons Information Service in the United Kingdom. The
    work was commissioned and funded by the UK Departments of Health, and
    was designed as a source of detailed information for use by poisons
    information centres.

    Date of last revision


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    See Also:
       Toxicological Abbreviations