UKPID MONOGRAPH
ZINC CHLORIDE
SM Bradberry BSc MB MRCP
JA Vale MD FRCP FRCPE FRCPG FFOM
National Poisons Information Service
(Birmingham Centre),
West Midlands Poisons Unit,
City Hospital NHS Trust,
Dudley Road,
Birmingham
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
Service.
ZINC CHLORIDE
Toxbase summary
Type of product
Used in smoke bombs, soldering fluxes, disinfectants, fire-proofing
agents, the textile industry and cements.
Toxicity
Zinc chloride is corrosive by ingestion and highly irritant by
inhalation.
Features
Topical
- Topical zinc chloride causes ulceration and burns and
chronic exposure has been associated with anorexia, fatigue
and weight loss.
Ingestion
- Zinc chloride is highly corrosive and ingestion of only 10
mL of a 35 per cent solution has caused oropharyngeal and
gastric burns, epigastric tenderness, pharyngeal oedema,
haematemesis and melaena (Chew et al, 1986).
- Respiratory insufficiency and CNS depression may occur in
severe cases. Recovery may be complicated by
gastrointestinal stricture formation and/or pancreatic
insufficiency.
- Hyperglycaemia, hypokalaemia, increased alkaline
phosphatase, amylase and liver transaminase activities have
been reported.
Inhalation
- Zinc chloride inhalation from smoke screen generators or
smoke bombs may cause transient cough, sore throat,
hoarseness, a metallic taste and chest pain.
- Exposure to high zinc chloride concentrations produces a
chemical pneumonitis with marked dyspnoea, a productive
cough, fever, chest pain and cyanosis. Pneumothorax and the
adult respiratory distress syndrome (ARDS) have been
reported. Fatalities have occurred (Hjortsœ et al, 1988).
Management
Dermal
1. Symptomatic and supportive measures as indicated by the severity
of the burn.
Ocular
1. Irrigate with copious lukewarm water or 0.9 per cent saline for
at least ten minutes.
2. A topical anaesthetic may be required for pain relief and to
overcome blepharospasm.
3. Ensure removal of any particles in conjunctival recesses.
4. Fluorescein staining allows identification of corneal burns.
5. Seek ophthalmological advice if symptoms persist or any
significant abnormality is detected on examination.
Ingestion
1. Most patients will vomit spontaneously. Gastric lavage is
contraindicated following zinc chloride ingestion as this salt is
corrosive.
2. Symptomatic and supportive measures with adequate fluid
resuscitation are paramount.
3. Endoscopic examination may be required (ideally within the first
24 hours).
4. Save blood and urine for zinc concentration estimations.
5. Monitor the blood count and biochemical profile including serum
amylase activity.
6. The value of chelation therapy following zinc ingestion has not
been confirmed. Discuss with NPIS if patient is symptomatic.
Inhalation
1. Remove from exposure after ensuring adequate self-protection.
2. Administer supplemental oxygen by face mask.
3. Symptomatic patients and those with abnormal respiratory physical
signs should have a chest X-ray.
4. The possibility of delayed-onset chemical pneumonitis, pulmonary
oedema and development of ARDS must be considered.
5. There is no established role for the routine use of inhaled or
systemic corticosteriods in patients with pulmonary
complications.
6. The use of antibiotics should be reserved for established
infection only.
7. The value of chelation therapy following zinc chloride inhalation
has not been confirmed. Discussion of individual cases with an
NPIS physician is recommended.
References
Allen MB, Crisp A, Snook N, Page RL.
'Smoke-bomb' pneumonitis.
Respir Med 1992; 86: 165-6.
Chew LS, Lim HS, Wong CY, Htoo MM, Ong BH.
Gastric stricture following zinc chloride ingestion.
Singapore Med J 1986; 27: 163-6.
Chobanian SJ.
Accidental ingestion of liquid zinc chloride: local and systemic
effects.
Ann Emerg Med 1981; 10: 91-3.
Hjortsœ E, Qvist J, Bud MI, Thomsen JL, Andersen JB, Wiberg-Jœgensen
F, Jensen NK, Jones R, Reid LM, Zapol WM.
ARDS after accidental inhalation of zinc chloride smoke.
Intensive Care Med 1988; 14: 17-24.
McKinney PE, Brent J, Kulig K.
Acute zinc chloride ingestion in a child: local and systemic effects.
Ann Emerg Med 1994; 23:1383-7.
Potter JL.
Acute zinc chloride ingestion in a young child.
Ann Emerg Med 1981; 10: 267-9.
Substance name
Zinc chloride
Origin of substance
Formed during ignition of zinc oxide/hexachloroethane incendiary
devices. (DOSE, 1994)
Synonyms
Butter of zinc
Zinc dichloride
Zinc muriate (DOSE, 1994)
Chemical group
A compound of zinc, a group II B (d block) transition element.
Reference numbers
CAS 7646-85-7 (DOSE, 1994)
RTECS ZH1400000 (RTECS, 1997)
UN 2331 (anhydrous) 1840 (solution) (DOSE, 1994)
HAZCHEM CODE 2X (solution) (DOSE, 1994)
Physicochemical properties
Chemical structure
ZnCl2 (DOSE, 1994)
Molecular weight
136.28 (DOSE, 1994)
Physical state at room temperature
Solid (MERCK, 1996)
Colour
White (MERCK, 1996)
Odour
Fume has an acrid odour. (HSDB, 1997)
Viscosity
NIF
pH
The aqueous solution is acid to litmus; pH about 4.
(MERCK, 1996)
Solubility
Water: 432 g/L at 25°C, 614 g/L at 100°C.
Soluble in methanol, ethanol, diethyl ether and dimethyl ether.
(MERCK, 1996; SAX'S, 1996)
Autoignition temperature
NIF
Chemical interactions
Zinc chloride forms an explosive reaction with copper (II)
sulphide.
Soluble zinc salts are precipitated as zinc hydroxide by ammonium
hydroxide.
A mixture of potassium and zinc chloride produces a strong
explosion on impact. (SAX'S, 1996; HSDB, 1997)
Major products of combustion
Fumes of chloride and zinc oxide (SAX'S, 1996)
Explosive limits
NA
Flammability
Not flammable (HSDB, 1997)
Boiling point
732°C (DOSE, 1994)
Density
2.907 at 25°C (DOSE, 1994)
Vapour pressure
133.322 Pa at 428°C (DOSE, 1994)
Relative vapour density
NIF
Flash point
NA
Reactivity
When heated to decomposition it emits toxic fumes of chloride and
zinc oxide. (SAX'S, 1996)
Uses
In smoke bombs used for crowd dispersal, fire-fighting exercises
and military screens.
In dentifrices.
Treatment of skin complaints.
Deodorant.
Flux in plating, soldering and welding.
Pigment.
In wood preservatives and fire-proofing agents.
Astringent. (DOSE, 1994)
Hazard/risk classification
Index no. 030-003-00-2
Risk phrases
C; R34. Causes burns.
Safety phrases
S(1/2) 7/8-28-45. Keep locked up and out of the reach of
children. Keep container tightly closed and dry. After contact
with skin, wash immediately with plenty of (to be specified by
the manufacturer). In case of accident or if you feel unwell,
seek medical advice immediately (show label where possible).
EEC No: 231-592-0 (CHIP2, 1994)
INTRODUCTION
Zinc is an essential trace element required for the function of over
200 metallo-enzymes, including alkaline phosphatase and carbonic
anhydrase (Sandstead, 1994). Zinc also plays a critical role in the
regulation of DNA and RNA synthesis (via interaction with DNA binding
proteins), in hormone-receptor interactions and in the
"second-messenger" system of cellular signal transduction (Walsh et
al, 1994).
Zinc chloride is an acidic salt encountered most frequently in solder
fluxes or as a constituent of 'smoke-bomb' emissions when zinc oxide
and hexachloroethane are burned together.
EPIDEMIOLOGY
Inhalational exposure to low zinc chloride concentrations typically
occur during military or civilian fire-drill exercises (Schenker et
al, 1981; Allen, 1992). In an early report the accidental ignition of
several smoke generators at a storage site led to severe zinc chloride
poisoning affecting 70 persons, ten of whom died (Evans, 1945).
There are several reported cases of accidental or deliberate self-harm
involving zinc chloride ingestion, usually as soldering flux
(Chobanian, 1981; Hedtke et al, 1989; McKinney et al, 1994). No deaths
have occurred but debilitating sequelae include gastrointestinal
stricture formation (secondary to corrosive damage) and chronic
pancreatic insufficiency (McKinney et al, 1994).
MECHANISM OF TOXICITY
Excess zinc has been shown to reduce serum free thiol groups and
disrupt hepatic enzyme activities (IPCS, 1996).
Zinc chloride is directly corrosive to the mucous membranes of the
respiratory and gastrointestinal tracts. Anaemia resulting from excess
zinc uptake is usually due to zinc-induced copper deficiency via
impaired gastrointestinal copper absorption. This probably involves
zinc-induced increased metallothionein synthesis with increased
copper-metallothionein retention in intestinal mucosal cells (Fischer
et al, 1981).
TOXICOKINETICS
Absorption
Zinc chloride exposure occurs primarily via inhalation and ingestion.
Available zinc toxicokinetic data involve exposure to non-corrosive
zinc salts. Gastrointestinal zinc absorption is a function of a
cysteine-rich intestinal protein (CRIP) which sequesters zinc within
enterocytes prior to active transport into plasma (Hempe and Cousins,
1992; Walsh et al, 1994). Metallothionein contributes to zinc
homeostasis at higher exposures, primarily via retaining excess zinc
within mucosal cells which are subsequently shed into the intestinal
lumen (Hempe and Cousins, 1992). Zinc absorption is affected by diet;
it is inhibited by calcium, phosphorus and phytates and facilitated by
dietary protein (Hunt et al, 1991). In one study less than 15 per cent
of dietary zinc was absorbed from a high phytate diet compared to 40
per cent from a diet with a high animal protein content (Sandstrom,
1995).
In ten healthy volunteers Nève et al (1991) observed a peak serum zinc
concentration some 2-3 hours after ingestion of 45 mg zinc (as zinc
sulphate).
Workers occupationally exposed to zinc fumes may have increased urine
zinc concentrations (Hamdi, 1969) as evidence of systemic zinc uptake
via the lungs. However, some inhaled zinc is undoubtedly swallowed
(and absorbed via the gastrointestinal tract) following clearance via
the mucociliary mechanism. Systemic zinc uptake following zinc
chloride inhalation may also occur due to damage to the mucosal
barrier. In two soldiers who died following zinc chloride inhalation,
plasma zinc concentrations gradually increased during their illness
although at autopsy zinc concentrations in major organs and tissues
were normal save for a slightly increased lung zinc concentration in
one case (Hjortsœ et al, 1988).
Zinc is absorbed through broken skin when zinc oxide paste is used to
treat wounds and burns (Hallmans, 1977).
Distribution
Most intravascular zinc is contained within erythrocytes. Plasma zinc
is bound predominantly to albumin, the remainder bound to other
proteins, particularly alpha2-macroglobulin, for distribution to
tissues. Excess zinc is stored as a metallothionein complex, mainly in
the liver (Abdel-Mageed and Oehme, 1990; IPCS, 1996).
Some ninety per cent of total body zinc is in muscle and bone (Wastney
et al, 1986).
Appreciable amounts of zinc are found also in the kidney, lung, spleen
and brain (IPCS, 1996).
Zinc crosses the placenta slowly and is found in breast milk (Agency
for Toxic Substances and Disease Registry, 1997).
Excretion
Most ingested zinc is eliminated in faeces via bile, pancreatic fluid
and intestinal mucosal cells, with up to ten per cent appearing in
urine (Abdel-Mageed and Oehme, 1990). Zinc is also eliminated in sweat
and saliva. The kidneys do not play an important role in regulating
total body zinc (IPCS, 1996).
The whole-body zinc half-life is some 5-16 months (IPCS, 1996).
CLINICAL FEATURES: ACUTE EXPOSURE
Dermal exposure
Topical zinc chloride exposure causes ulceration (Beliles, 1994) and
burns (Evans, 1945; Chew et al, 1986). Contact dermatitis also has
been described but without reference to original case data (Poisindex,
1996).
Ocular exposure
Zinc chloride is highly irritant to the eyes causing pain and erythema
(Evans, 1945) which may be complicated by corneal oedema, burns and
ulceration, iritis, glaucoma and cataract formation. Discrete grey
spots on the lens ("glaukomflecken") as typically seen in acute
glaucoma also have been described (Grant and Schuman, 1993).
A plumber who was accidently splashed in the eye with a 30 per cent
zinc chloride solution experienced an immediate reduction in visual
acuity with conjunctival haemorrhage and inflammation, corneal
opacification, a bullous keratopathy and "glaukomflecken" (Houle and
Grant, 1973).
Inhalation
Pulmonary toxicity
Exposure to zinc chloride fumes occurs primarily from smoke screen
generators or smoke bombs when equal quantities of zinc oxide and
hexachloroethane are burnt together. Following detonation of a smoke
bomb participants in an airport disaster drill experienced cough, sore
throat, hoarseness and chest pain in association with gastrointestinal
upset (Schenker et al, 1981). Most symptoms resolved within 48 hours
and none experienced permanent injury.
In contrast, exposure to high zinc chloride concentrations produces a
chemical pneumonitis with productive cough, dyspnoea, fever, chest
pain, cyanosis and diffuse pulmonary infiltrates (Allen et al, 1992).
In one study these features occurred following exposure to a zinc
chloride concentration of approximately 4075 mg/m3 (1955 mg
zinc/m3) (Johnson and Stonehill, 1961). The development of
emphysematous bullae (which may be complicated by pneumothorax) has
been reported (Matarese and Matthews, 1986). Severe cases may develop
non-cardiogenic pulmonary oedema (the adult respiratory distress
syndrome) (Hjortsœ et al, 1988) sometimes after several days of
apparent clinical stability (Homma et al, 1992).
Hjortsœ et al (1988) described two soldiers who died following
exposure to fumes (for one and two minutes respectively) from smoke
ammunition bombs (primarily zinc chloride). The first (exposed for two
minutes) experienced immediate cough and dyspnoea but initial chest
examination was unremarkable. Inhaled steroids (beclomethasone 100 µg
qds) were prescribed. The following day he was pyrexial (38.4°C) with
bilateral lower zone pulmonary infiltrates. Oral prednisolone 40 mg
daily plus oral antibiotics were instituted. Sputum cultures were
negative but the patient gradually deteriorated and some 15 days post
exposure required mechanical ventilation for worsening hypoxia.
Pulmonary angiography on the 17th day showed diffuse vascular
obstruction. On day 19 the patient was commenced on intravenous and
nebulized N-acetylcysteine plus intravenous L-3,4-dehydroproline 35
mg/kg/day in an attempt to inhibit pulmonary fibrosis. Despite these
measures hypoxaemia and hypercapnia progressed and the patient died 32
days after exposure. A similar clinical course was observed in the
second patient who died on the 25th day.
Adverse effects occurred in 34 of 70 persons exposed in a tunnel to a
mixture of zinc chloride (estimated concentration 33,000 mg
zinc/m3), carbon and carbon dioxide following accidental ignition of
several smoke bomb generators (Evans, 1945). Immediate symptoms
included dyspnoea, hoarseness, chest pain and a productive cough. Two
individuals died before reaching hospital; both showed severe
respiratory distress and one had aspirated their stomach contents.
Among the 15 patients admitted to hospital, all had evidence of upper
respiratory tract (and eye) mucosal irritation, with haemoptysis,
stridor, cyanosis and persisting chest pain in the majority, often
accompanied by neurological, cardiovascular and gastrointestinal
features (see below). Initially there were minimal pulmonary
auscultatory findings but a chemical pneumonitis with fever and
consolidation ensued in several patients during the next few days. Six
of 15 patients died. Autopsy showed respiratory tract mucous membrane
necrosis with pulmonary haemorrhage and oedema. Autopsy findings in
other cases have included diffuse pulmonary microvascular obliteration
with widespread pulmonary artery occlusion (Hjortsœ et al, 1988; Homma
et al, 1992) and interstitial fibrosis (Milliken et al, 1963; Hjortsœ
et al, 1988; Homma et al, 1992).
Gastrointestinal toxicity
A metallic taste, nausea, vomiting and epigastric pain have been
reported following zinc chloride inhalation (Evans, 1945; Schenker et
al, 1981). Gastrointestinal inflammation has been noted at autopsy of
patients who died following severe zinc chloride poisoning (Evans,
1945).
Cardiovascular toxicity
Hypotension and tachycardia have accompanied the pulmonary features of
significant zinc chloride inhalation (Evans, 1945).
Neurotoxicity
Agitation and restlessness have been described as early features
accompanying pulmonary symptoms in those exposed to zinc chloride
smoke (Evans, 1945).
Ingestion
Gastrointestinal toxicity
Zinc chloride ingestion causes corrosive damage. Initial symptoms
include burning of the mouth and pharynx with vomiting. An erosive
pharyngitis, oesophagitis and gastritis may ensue which may be
complicated by gastrointestinal haemorrhage and acute pancreatitis
(Chobanian, 1981; Potter, 1981).
In one case (Chobanian, 1981) oesophagitis, pharyngitis and acute
pancreatitis occurred in a patient who ingested some 85 mL "Ruby Red"
solder flux containing an unstated concentration of zinc chloride. An
initial serum zinc concentration (some four hours post ingestion) was
1.46 mg/L (normal 0.5-0.9 mg/L). The patient recovered over five days.
A 26 year-old woman who ingested 10 mL of a correction fluid
containing zinc chloride (35 per cent) and methanol (0.5 per cent)
presented four hours post ingestion with oropharyngeal and gastric
burns, epigastric tenderness, dysphagia and diarrhoea. Examination
revealed gross oral mucosal and pharyngeal oedema with surgical
emphysema of the neck and upper chest wall (presumably due to
pharyngeal perforation). Serum zinc on the third hospital day was
normal (0.9 mg/L). The patient subsequently experienced haematemesis
and melaena necessitating multiple blood transfusions. Recovery was
delayed further by formation of a gastric stricture requiring subtotal
gastrectomy (Chew et al, 1986).
Hedtke et al (1989) reported a 13 month-old child who ingested 9300 mg
of a moss killer containing 68 per cent zinc chloride. He presented
with vomiting, gastric mucosal erosions, hyperglycaemia and increased
alkaline phosphatase and amylase activities. The peak serum zinc
concentration was 14.2 mg/L (normal range 0.68 - 1.36 mg/L) one hour
post ingestion.
A 16 month-old child who ingested approximately one tablespoon of
soldering flux liquid (containing zinc chloride 22.5 per cent and
ammonium chloride 5.5 per cent, pH 2) immediately vomited then
developed dysphagia with inability to swallow his own saliva (McKinney
et al, 1994). Severe gastrointestinal corrosive effects ensued
(oropharyngeal, oesophageal and gastric burns). Severe gastric
scarring and outlet obstruction necessitated a gastric antrectomy. The
peak plasma zinc concentration was 12 mg/L (normal range 0.6-1.0 mg/L)
14 hours post ingestion (McKinney et al, 1994). Five months later
pancreatic exocrine insufficiency was diagnosed with an on-going
requirement for pancreatic enzyme supplements (McKinney et al, 1995).
Pulmonary toxicity
An asthmatic patient who ingested correction fluid developed an acute
episode of bronchospasm and severe oropharyngeal and laryngeal
inflammation leading to stridor and dysphonia (Chew et al, 1986). She
eventually recovered.
A child who immediately started coughing after ingesting a tablespoon
of soldering flux (see above) was noted 20 minutes later to have
widespread coarse breath sounds and wheeze in addition to features of
severe gastrointestinal toxicity. A chest X-ray some five hours later
revealed a right pleural effusion with basal atelectasis. The
pulmonary features resolved with supportive care although the child
had ongoing gastrointestinal problems (McKinney et al, 1994).
Nephrotoxicity
Microscopic haematuria without associated renal failure (Chobanian,
1981; Chew et al, 1986) and mild albuminuria (Chew et al, 1986) have
occurred following zinc chloride ingestion.
Neurotoxicity
Within 20 minutes of ingesting one tablespoon of solder flux
(containing zinc chloride 22.5 per cent and ammonium chloride 5.5 per
cent, pH 2) a 16 month-old became comatose and later developed
agitation and lethargy which persisted for several days (McKinney et
al, 1994).
Somnolence and lethargy occurred in a 13 month-old (Hedtke et al,
1989) and a two year-old (Potter, 1981) following zinc chloride
ingestion.
Cardiovascular toxicity
Premature atrial beats were reported in a 13 month-old child following
the supposed ingestion of 9.3 g moss killer containing 68 per cent
zinc chloride (Hedtke et al, 1989).
Hypotension secondary to intravascular volume depletion is likely in
those with severe corrosive damage following zinc chloride ingestion.
The 16 month-old child described above who ingested solder flux
containing zinc chloride presented with clinical signs consistent with
hypovolaemic shock (pulse 120 beats per minute, blood pressure 88/62
mmHg) but following intravenous fluid resuscitation and an upper
gastrointestinal endoscopy, became hypertensive (figure not given)
requiring hydralazine and labetalol therapy. The cause of hypertension
in this case was not known but occurred prior to commencement of
chelation therapy.
Hepatotoxicity
Severe gastrointestinal corrosive effects following zinc chloride
ingestion have been associated with transiently increased liver enzyme
activities (McKinney et al, 1994).
Haemotoxicity
Gastrointestinal ulceration and burns following zinc chloride
ingestion may precipitate an acute fall in the haemoglobin
concentration. Intravascular haemolysis may occur in severely poisoned
patients (McKinney et al, 1994).
CLINICAL FEATURES: CHRONIC EXPOSURE
Dermal exposure
In an early report chronic topical zinc chloride exposure in the
pillow manufacturing industry was claimed to result in anorexia,
weight loss, fatigue and leg pains, microcytic anaemia and
thrombocytopenia (du Bray, 1937). The causative role of zinc chloride
could not be confirmed but the patient's symptoms and abnormal
investigation findings resolved when exposure ceased.
Inhalation
Occupational asthma associated with raised serum IgE concentrations
occurred in two men after several months working with soldering fluxes
containing zinc chloride and ammonium chloride (Weir et al, 1989)
although in one patient there was no reduction in FEV1 after exposure
to zinc chloride alone.
MANAGEMENT
Dermal exposure
Decontaminate with soap and water ensuring adequate self-protection.
Ideally, patients should remove their own contaminated clothing. Treat
burns conventionally. Consider the possibility of systemic zinc
uptake, particularly where the skin is broken.
Ocular exposure
Irrigate with copious amounts of lukewarm water for at least ten
minutes. A topical anaesthetic may be required for pain relief and to
overcome blepharospasm. Ensure removal of any particles lodged in the
conjunctival recesses. The instillation of fluorescein allows
detection of corneal damage. Specialist ophthalmological advice should
be sought if any significant abnormality is detected on examination
and in those whose symptoms do not resolve rapidly.
Inhalation
Remove the subject from exposure after ensuring adequate
self-protection. Symptomatic and supportive measures are the mainstay
of management. Symptomatic patients and those with abnormal
respiratory signs should have a chest X-ray, receive supplemental
oxygen and bronchodilators if necessary and be observed until symptoms
resolve.
The possibility of developing a chemical pneumonitis, delayed-onset
pulmonary oedema and/or ARDS must be considered. In these
circumstances high flow oxygen is mandatory but the value of inhaled
or systemic corticosteriods has not been confirmed. Steroid therapy
did not favourably influence the course of a soldier who died from
ARDS 32 days after a two minute exposure to zinc chloride smoke
(Hjortsœ et al, 1988). He received inhaled beclomethasone 100 µg qds
within hours of exposure substituted on the second hospital day with a
two week course of oral prednisolone 40 mg daily.
In chemical pneumonitis and ARDS it generally is recommended that
antibiotics should be reserved for established infection only. The
patient described by Hjortsœ et al (1988) (see above) also received
oral penicillin the day following zinc chloride exposure but sputum
cultures were negative and the antibiotics were discontinued after
seven days.
Intravenous L-3,4-dehydroproline (35 mg/kg/day) was administered to a
patient with zinc chloride smoke-induced ARDS in an attempt to inhibit
pulmonary fibrosis but without modification of the progressively
deteriorating course. The patient died 32 days after exposure.
Ingestion
Effective management primarily involves rapid appropriate symptomatic
and supportive care. The role of chelating agents is discussed below.
Decontamination and dilution
Vomiting is likely to occur spontaneously following significant zinc
chloride ingestion. Gastric lavage is contraindicated due to the
corrosive nature of the salt. There may be some benefit in attempting
oral dilution, if performed immediately, though this is controversial.
Burkhart et al (1990) advocated whole-bowel irrigation as an effective
gut decontamination method following zinc sulphate ingestion but there
are no controlled data to support this view.
Fluids should not be offered if the patient is not fully conscious, is
unable to swallow or protect his/her own airway, has respiratory
difficulty or severe abdominal pain. Possible complications of fluid
administration include vomiting, aspiration, perforation of the
gastrointestinal tract and worsening of oesophageal or gastric
injuries.
Supportive measures
Airway support and analgesia should be provided as required. Treat
hypovolaemic shock with intravenous colloid/crystalloid or blood.
Monitor biochemical and haematological profiles and acid/base status.
Antibiotics should be reserved for established infection only.
If corrosive oesophageal or gastric damage is suspected panendoscopy
should be carried out, ideally within 12-24 hours, to gauge the
severity of injury (Knapp et al, 1994). A severity score based on acid
ingestions may be useful:
Grade 0: Normal examination
1: Oedema, hyperaemia of mucosa
2a: Superficial, localized ulcerations, friability, blisters
2b: Grade 2a findings and circumferential ulceration
3: Multiple, deep ulceration, areas of necrosis (Zargar et al,
1989)
Zargar et al (1989) illustrated the important prognostic value of this
grading system in the management of acid ingestions. In their series
of 41 patients endoscoped within the first 36 hours of acid ingestion,
those with grade 0 and 1 burns were discharged within one or two days,
those with grade 2a burns required only supportive care for a little
longer, whereas those with grade 2b and 3 burns required nutritional
support via jejunostomy feeding (total parenteral nutrition is an
alternative). All patients with grade 0, 1 and 2a injury recovered
without sequelae. Acute complications and death were confined to those
with grade 3 burns although several patients with grade 2b burns
developed oesophageal or gastric strictures.
An early surgical opinion should be sought if there is any suspicion
of pending gastrointestinal perforation or where endoscopy reveals
evidence of grade 3 burns.
Corticosteroids
There is no evidence to suggest any role for corticosteroid therapy in
the management of zinc chloride ingestion. In a controlled trial of
steroid use among 60 children with oesophageal burns following
corrosive ingestion (alkalis in the majority) the use of steroids
(intravenous prednisolone 2 mg/kg within 24 h and daily until oral
intake was resumed then prednisolone 2.5 mg/kg orally daily for at
least three weeks) did not influence outcome (Anderson et al, 1996).
Smaller case series have also concluded that systemic corticosteroids
confer no benefit following acid ingestion and may exacerbate or mask
symptoms of pending perforation (Hawkins et al, 1980).
Antidotes
Animal studies
Domingo et al (1988) investigated the antidotal potential of DTPA
(trisodium calcium diethylene triamine-pentaacetate), CDTA
(cyclohexane diamine tetraacetate), d-penicillamine, sodium
calciumedetate, DMSA (dimercapto-succinic acid) and the sodium salt of
DMPS (dimercaptopropanesulphonate) on reducing mortality in rodents
poisoned with intraperitoneal zinc acetate 66-330 mg/kg. This dose
range was selected to span the previously calculated intraperitoneal
LD50 (108 mg/kg) and LD99 (216 mg/kg) for this zinc salt.
Chelation therapy (or 0.9 per cent saline as control) was administered
intraperitoneally to ten mice ten minutes after dosing with zinc.
Antidote doses and outcome (measured as survival at 14 days) are
summarized in Table 1.
The very high antidote doses employed in this study necessitate
caution in interpreting the results with regard to potential clinical
value. Nevertheless at a zinc acetate dose in excess of the LD99
there was 100 per cent survival following treatment with DTPA,
d-penicillamine and DMPS. DMSA was not an impressive antidote under
these conditions.
The same research group (Llobet et al, 1988) undertook a similar
study. Intraperitoneal zinc acetate 0.49 mmol/kg (a dose approximately
equivalent to its LD50) and 1.15 mmol/kg (approximately the LD99)
was administered immediately before antidote administration to ten
mice. Outcome was measured as survival ratio. Sodium calciumedetate
(2152 mg/kg), DTPA (2262 mg/kg) and d-penicillamine (857 mg/kg),
completely protected against mortality at the LD99 for zinc acetate.
Under exactly the same conditions (each chelating agent at a dose of
5.75 mmol/kg) the survival ratios for CDTA, DMPS and DMSA were 80, 50
and 70 per cent respectively.
Table 1. Survival (%) following parenteral chelation therapy in mice
after a single zinc acetate injection (after Domingo et al, 1988)
Chelating agent Antidote dose Zinc acetate dose
(mg/kg) (mg/kg)
66 153 241
Control - 40 20 0
Na2CaCDTA 1360 100 90 90
Na2CaEDTA 1644 100 90 90
Na2CaDTPA 1569 100 100 100
d-Penicillamine 857 100 100 100
DMSA 619 80 30 10
DMPS 273 100 100 100
Several antidotes have been investigated for their potential to
enhance zinc elimination. Domingo et al (1988) measured 24 hour faecal
and urinary zinc excretion in mice administered 88 mg/kg
intraperitoneal zinc acetate followed ten minutes later by an
intraperitoneal dose of chelating agent (or saline in the control
group). The same chelating agents and doses were used as in Table 1,
again with ten mice in each treatment group. In the control group
urine zinc elimination was less than half faecal excretion. CDTA
enhanced urine zinc excretion some six fold and DTPA, DMSA and DMPS
each some four fold. d-Penicillamine enhanced 48 hour urine zinc
elimination by some 80 per cent. Sodium calciumedetate did not enhance
urine zinc excretion but was the only antidote to increase 24 hour
faecal zinc elimination (by some 20 per cent).
The effect of increasing the time delay between zinc dosing and DTPA
or CDTA administration was investigated by Llobet et al (1989).
Intraperitoneal zinc acetate 0.4 mmol/kg (LD50 0.49 mmol/kg) was
followed 0-24 hours later by a single intraperitoneal dose of
chelating agent to give a chelating agent: zinc acetate molar ratio of
approximately 10:1.
Urine and faecal zinc elimination were monitored for 48 hours with
five mice in each treatment group. Urine and faecal zinc elimination
were increased significantly (p < 0.05) by both chelating agents when
administered up to two hours after poisoning but only DTPA
significantly enhanced the 48 hour urine and faecal zinc excretion
when the antidotes were given 12 hours after zinc dosing.
When there was a 24 hour delay between zinc acetate injection and
antidote administration, DTPA significantly (p < 0.05) enhanced urine
but not faecal 48 hour zinc elimination (CDTA was not effective).
In summary, animal studies suggest DTPA is the most effective zinc
antidote as judged by improved survival (100 per cent following a zinc
acetate dose in excess of the LD99) and increased zinc elimination.
CDTA produced 90 per cent survival and increased urine zinc excretion
some six fold. d-Penicillamine also gave excellent results in
mortality studies, with 100 per cent survival following administration
of zinc acetate at a dose exceeding the LD99. However,
d-penicillamine did not enhance zinc elimination significantly. Sodium
calciumedetate improved survival (90-100 per cent) and in one study
(Domingo et al, 1988) was the only chelating agent to increase faecal
zinc elimination. DMPS 273 mg/kg completely protected mice against the
lethal effects of zinc acetate at a dose in excess of the LD99 and
the same antidote dose enhanced urine zinc excretion some four fold
following administration of 88 mg/kg zinc acetate. By contrast DMSA
619 mg/kg resulted in only 10 per cent survival following 241 mg/kg
zinc acetate.
Clinical studies
Although increased renal zinc excretion has been noted during
chelation therapy instituted to enhance elimination of other toxic
heavy metals, there is no convincing evidence of benefit in human zinc
poisoning. In health, most zinc is eliminated via the gastrointestinal
tract with only a small contribution made by renal excretion. No data
have been found regarding the effect of chelation therapy on biliary
zinc excretion in man.
Dimercaprol
McKinney et al (1994) reported improved mental status in a patient
with severe zinc chloride poisoning (by ingestion) following
administration of intramuscular dimercaprol 12 mg/kg/day for 24 hours
and intravenous sodium calciumedetate 1 g/m2 for five days. This
treatment was instituted 74 hours post ingestion. Chelation therapy
was not associated with increased urine zinc elimination.
Intramuscular dimercaprol 4 mg/kg qds was instituted less than four
hours after the ingestion of 3 g each of zinc sulphate and copper
sulphate by an 86 year-old woman. This patient also received oral
d-penicillamine (see below) but both antidotes were discontinued after
48 hours due to deteriorating renal function. The patient made a full
recovery over 20 days.
A 16 year-old who ingested 12 g elemental zinc was treated some nine
days later with intramuscular dimercaprol 2.3-9.2 mg/kg daily.
Chelation was associated with clinical improvement and a reduction in
the blood zinc concentration but urine zinc concentrations were not
measured (Murphy, 1970).
Sodium calciumedetate
A 24 year-old man who developed erosive pharyngitis and oesophagitis,
hyperamylasaemia, microscopic haematuria and a serum zinc
concentration of 1.46 mg/L (normal range 0.5-0.9 mg/L) after ingesting
liquid zinc chloride, made an uneventful recovery following supportive
care and intravenous sodium calciumedetate 45 mg/kg in divided doses
over 36 hours. No zinc excretion data were given (Chobanian, 1981).
Potter (1981) utilized intravenous sodium calciumedetate 150 mg in the
management of a 28 month-old child who had ingested a zinc chloride
solution; no urine zinc excretion data were given.
The patient reported by McKinney et al (1994) who was severely
poisoned after ingesting one tablespoon of a zinc chloride-containing
soldering flux was treated with intravenous sodium calciumedetate 1
g/m2 for five days. The urine zinc excretion in the eight hours
preceding chelation was 950 µg. Urine zinc excretion was not increased
by sodium calciumedetate with only 1000 µg/24 h removed on the fourth
day of treatment (no interim data were given).
N-acetylcysteine
In response to a rising serum zinc concentration, a soldier who
developed adult respiratory distress syndrome following two minutes
inhalation of zinc chloride smoke was administered intravenous (140
mg/kg/day for three days) and nebulized (100 mg qds for 13 days)
N-acetylcysteine between days 19 and 32 in an attempt to enhance zinc
elimination. The urine zinc excretion increased from some 125 µmol/24h
on day 20 to 260 µmol/24h on day 22 (coinciding with intravenous
N-acetylcysteine administration) then rose to nearly 300 µmol/day (the
maximum observed zinc excretion) on day 24. Unfortunately no
pre-chelation zinc excretion measurements were made. There was no
clinical improvement with therapy and the patient died in respiratory
and renal failure on day 32.
d-Penicillamine
An 86 year-old woman who developed chemical pneumonitis, gastritis,
cardiac and renal failure following the ingestion (and partial
aspiration) of 3 g each of zinc and copper sulphate, received 250 mg
oral d-penicillamine qds (in addition to intramuscular dimercaprol 4
mg/kg qds) commenced less than four hours after zinc ingestion
(Hantson et al, 1996). Unfortunately there were no pre-chelation urine
zinc excretion data and treatment was discontinued after 48 hours due
to deteriorating renal function. The maximum 24 hour urine zinc
excretion, achieved on the first day of chelation therapy was some
6000 µg.
Another patient with zinc chloride poisoning by inhalation survived
following treatment with oral penicillamine 125 mg twice daily (Allen
et al, 1992). No blood or urine zinc concentrations were measured.
Antidotes: Conclusions and recommendations
1. There are no controlled clinical data of chelation therapy in
zinc poisoning and animal studies must be interpreted with
caution in view of the extremely high antidote doses employed.
Nevertheless, animal studies suggest that of the antidotes
readily available for clinical use, sodium calciumedetate is the
preferred agent with d-penicillamine or DMPS potential
alternatives.
2. Although case reports claim clinical benefit following parenteral
administration of dimercaprol, sodium calciumedetate and d-
penicillamine, urine and/or faecal zinc excretion data to support
these claims are lacking.
3. Chelation therapy cannot be advocated routinely in the management
of zinc poisoning; symptomatic cases should be discussed with the
NPIS.
AT RISK GROUPS
Patients with haemochromatosis are at greater risk of zinc toxicity
due to iron-induced increased metallothionein concentrations since
metallothionein has a greater affinity for zinc than iron.
MEDICAL SURVEILLANCE
Serum zinc concentrations are increased in acute zinc poisoning. The
24 hour urine zinc excretion is useful when monitoring chronic
exposure although there is no well established relationship between
the extent of exposure and urine zinc concentration. Hair zinc
concentrations are not useful (Agency for Toxic Substances and Disease
Registry, 1997).
Normal zinc concentrations in biological fluids
Plasma and serum: 1.1-1.3 mg/L (IPCS, 1996).
Whole blood: 6.8-10.8 mg/L (IPCS, 1996).
24 hour urine excretion: less than 500 µg (IPCS, 1996).
OCCUPATIONAL DATA
Occupational exposure standard
Zinc chloride, fume: Long-term exposure limit (8 hour TWA reference
period) 1 mg/m3.
OTHER TOXICOLOGICAL DATA
Carcinogenicity
There is no evidence to suggest zinc chloride is carcinogenic in
humans (Leonard and Gerber, 1989) and the Environmental Protection
Agency has concluded zinc is not classifiable with regard to its human
carcinogenicity (Agency for Toxic Substances and Disease Registry,
1997).
Marrs et al (1988) demonstrated a high incidence of pulmonary
carcinoma in experimental zinc oxide/hexachloroethane smoke poisoning.
However, a recent in vitro and in vivo study failed to show a
significant genotoxic effect and the authors concluded the smoke was
"not .... a major health hazard" (Anderson et al, 1996).
Severe gastric burns following corrosive ingestion are associated with
an increased risk of gastric carcinoma.
Reprotoxicity
There is no conclusive evidence regarding the reprotoxicity of zinc
chloride in humans (Reprotext, 1996). There were no adverse effects
following the administration of oral zinc sulphide (providing 20 mg
elemental zinc daily) to 494 women during the last two trimesters of
pregnancy (Mahomed et al, 1989).
A relationship between high amniotic fluid or maternal serum zinc
concentrations and foetal neural tube defects has been proposed, but
evidence for this is inconsistent (Reprotext, 1996; Reprotox 1996).
Pre-eclampsia, abnormal deliveries, anencephaly, and an increased
incidence of stillbirths have been associated with low maternal
serum zinc concentrations. Zinc deficiency also has been associated
with delayed sexual maturity (Reprotext, 1996; Reprotox, 1996).
Low seminal fluid zinc concentrations have been implicated in male
infertility but the use of zinc supplements to treat this condition
remains controversial (Reprotext, 1996; Reprotox, 1996).
Genotoxicity
Escherichia coli WP2 (lambda) microscreen assay-positive.
Salmonella typhimurium TA98, TA100, TA102, TA1537, TA2637-negative.
In vitro human lymphocytes, chromosomal aberrations-positive.
In vitro human lymphocytes, low concentrations stimulated DNA
synthesis, high concentrations inhibited DNA synthesis.
In vivo mouse bone marrow cells, chromosomal aberrations were
induced in calcium deficient mice but not in normal calcium
supplemented mice (DOSE, 1994).
Fish toxicity
Lethal to fathead minnow at less than 80 mg/L as zinc (exposure
unspecified) (DOSE, 1994).
EC Directive on Drinking Water Quality 80/778/EEC
Zinc: Guide level 100 µg/L at supply works, 5000 µg/L after 12 hour
contact with consumers' pipework. Chlorides: Guide level 25 mg/L
(DOSE, 1994).
WHO Guidelines for Drinking Water Quality
NIF
AUTHORS
SM Bradberry BSc MB MRCP
JA Vale MD FRCP FRCPE FRCPG FFOM
National Poisons Information Service (Birmingham Centre),
West Midlands Poisons Unit,
City Hospital NHS Trust,
Dudley Road,
Birmingham
B18 7QH
UK
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
28/1/98
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