UKPID MONOGRAPH ANTIMONY TRISULPHIDE WN Harrison PhD SM Bradberry BSc MB MRCP ST Beer BSc 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. ANTIMONY TRISULPHIDE Toxbase summary Type of product Used as a plasticizer and pigment, and in pyrotechnics and explosives. Toxicity Acute antimony trisulphide poisoning is rare. Exposure may occur in industry. Fatal dose not known. Features Topical - Irritant to the skin and eyes. - "Antimony spots" (papules and pustules around sweat and sebaceous glands) may develop after repeated exposure, especially in warm conditions. Ingestion Moderate ingestions: - Features usually occur within 2 hours with a metallic taste, nausea, vomiting, abdominal pain and diarrhoea. A garlic odour on the breath has been described following ingestion of other antimony compounds. Substantial ingestions: - Severe vomiting and diarrhoea (which may contain blood) and haemorrhagic gastritis may ensue. Myocardial depression, vasodilation and fluid loss may cause shock with hypotension, electrolyte disturbances and acute renal failure. Cerebral oedema, coma and convulsions are possible. Inhalation - Irritant to the respiratory tract and mucous membranes causing conjunctivitis, laryngitis, pharyngitis, tracheitis, rhinitis and bronchitis, and rarely non-cardiogenic pulmonary oedema. - There may be radiological evidence of pneumonitis. - Chronic occupational inhalation may cause pneumoconiosis with cough, wheeze and diffuse, punctate opacities in the middle and lower zones on chest X-ray. - ECG T-wave changes and sudden deaths attributed to antimony- induced cardiotoxicity have been reported rarely following occupational exposure. Management Dermal 1. If possible the patient should remove soiled clothing and wash him/herself. 2. Wash contaminated hair and skin with soap and copious amounts of water. 3. Pay special attention to skin folds, fingernails and ears. 4. A physician may need to examine the area if irritation or pain persists after washing. Ocular 1. Immediately irrigate the affected eye thoroughly with tepid water or 0.9% saline for at least 10-15 minutes. 2. Any particles lodged in the conjunctival recesses should be removed. 3. Continue irrigation with saline infusion using drip tubing. 4. Repeated instillation of local anaesthetic may reduce discomfort and help more thorough decontamination. 5. Corneal damage may be detected by instillation of fluorescein. 6. Patients with corneal damage and those whose symptoms do not resolve rapidly should be referred for ophthalmological assessment. Ingestion Minor ingestions (very mild or no symptoms): 1. Gastrointestinal decontamination is unnecessary. 2. Symptomatic and supportive measures only. Moderate/substantial ingestions: 1. Gastric lavage should be considered only if the patient presents within one hour; its value is unproven. 2. Symptomatic and supportive measures as dictated by the patient's condition. 3. Monitor the ECG, biochemical and haematological profiles. 4. Collect urine and blood for antimony concentration measurements to confirm diagnosis although these assays are not widely available. Check with NPIS. 5. Chelation therapy with dimercaprol, DMSA or DMPS may be considered; seek specialist advice from an NPIS physician. Inhalation Acute exposure 1. Remove from exposure. 2. Secure cardiorespiratory stability. 3. Perform a chest X-ray in symptomatic patients. 4. Treat symptomatically. 5. If significant respiratory symptoms occur investigate for systemic toxicity: ECG, biochemical and haematological profiles and blood and urine samples for antimony concentration determination. Chronic exposure 1. Investigate as for other causes of pneumoconiosis. 2. Obtain blood and urine for antimony concentration measurements to confirm diagnosis. However, these assays are not widely available. Check with NPIS. 3. Consider the possibility of systemic toxicity. References Bailly R, Lauwerys R, Buchet JP, Mahieu P, Konings J. Experimental and human studies on antimony metabolism: their relevance for the biological monitoring of workers exposed to inorganic antimony. Br J Ind Med 1991; 48: 93-7. Lauwers LF, Roelants A, Rosseel M, Heyndrickx B, Baute L. Oral antimony intoxications in man. Crit Care Med 1990; 18: 324-6. Renes LE. Antimony poisoning in industry. Arch Ind Hyg Occup Med 1953; 7: 99-108. Werrin M. Chemical food poisoning. Q Bull Assoc Food Drug Offic 1963; 27: 38-45. White Jr GP, Mathias CGT, Davin JS. Dermatitis in workers exposed to antimony in a melting process. J Occup Med 1993; 35: 392-5. Winship KA. Toxicity of antimony and its compounds. Adverse Drug React Acute Poisoning Rev 1987; 2: 67-90. Substance name Antimony trisulphide Origin of substance Produced by the addition of sodium thiosulphate to antimony potassium tartrate. Occurs naturally as the ore stibnite. IARC, 1989) Synonyms Antimonous sulphide Antimony vermilion Antimony glance Diantimony trisulphide Antimony orange (CSDS, 1989) Chemical group A compound of antimony, a group VA element Reference numbers CAS 1345-04-6 (CSDS, 1989) RTECS C 9450000 (CSDS, 1989) UN 1549 (CSDS, 1989) HAZCHEM NIF Physicochemical properties Chemical structure Sb2S3 (CSDS, 1989) Molecular weight 339.68 (HSDB, 1997) Physical state at room temperature Crystalline powder (CSDS, 1989) Colour Grey-black (CSDS, 1989) Odour NIF Viscosity NA pH NIF Solubility Practically insoluble in water, soluble in concentrated hydrochloric acid or excess alkali. (CSDS, 1989) Autoignition temperature NA Chemical interactions Reacts with water or steam to produce flammable vapours of hydrogen sulphide. (HSDB, 1997) Major products of combustion When heated to decomposition emits fumes of sulphur and antimony oxides. (HSDB, 1997) Explosive limits NA Flammability Burns with blue flame. (HSDB, 1997) Boiling point 1150°C (CSDS, 1989) Density 4.63 at 20°C (CSDS, 1989) Vapour pressure NA Relative vapour density NA Flash point NA Reactivity Reacts violently with water and oxidizing agents. (HSDB, 1997) Uses Used in pyrotechnics and explosives. Plasticizer and pigment in the rubber industry. (CSDS, 1989) Hazard/risk classification NIF INTRODUCTION Antimony trisulphide is a trivalent antimony compound which occurs naturally as the ore stibnite. It is used in the production of antimony trioxide and often is associated with arsenic. It is produced also by the addition of sodium thiosulphate to a solution of an antimony salt. Antimony trisulphide is used as a primer in ammunition and smoke markers. It is used also in red and yellow pigments and in ruby glass manufacture. EPIDEMIOLOGY The main source of antimony trisulphide exposure is in the milling and refining of stibnite for antimony trioxide production (Renes, 1953; Schnorr et al, 1995). Exposure has occurred also in the production (Bulmer and Johnston, 1948) and use (Brieger et al, 1954) of antimony trisulphide powder in industry. lntentional ingestion of a veterinary preparation containing antimony trisulphide has been reported (Bailly et al, 1991). Accidental intoxication has also occurred after antimony leached from an agate container into an acidic beverage (Werrin, 1963). MECHANISM OF TOXICITY The mechanism of toxicity of antimony compounds is unclear but may involve disruption of thiol proteins via binding to sulphydryl groups (de Wolff, 1995). TOXICOKINETICS Absorption Antimony trisulphide may be absorbed by inhalation and ingestion, though gastrointestinal absorption in man is poor. Distribution Absorbed trivalent antimony readily enters red blood cells and accumulates primarily in the spleen, liver and bone (IPCS, 1996). Lauwers et al (1990) estimated that the total body antimony pool in a patient who died following accidental antimony potassium tartrate ingestion was only five per cent of the ingested dose with high antimony concentrations in the liver, gall bladder and gastrointestinal mucosa. This is consistent with antimony undergoing enterohepatic circulation (see below). Excretion Antimony compounds are eliminated mainly in the urine, with small amounts appearing in faeces via bile after conjugation with glutathione. A significant amount of antimony excreted in bile undergoes enterohepatic circulation (Bailly et al, 1991). Some 6-24 months after parenteral antimony therapy, Mansour et al (1967) reported increased urine antimony concentrations (range 5.8-145.3 µg/L) compared to untreated controls (range 2.9-9.1 µg/L). Gerhardsson et al (1982) reported significantly (p<0.001) higher antimony concentrations in the lung tissue of 40 deceased smelter and refinery workers who had been exposed to antimony for some 30 years, compared to 11 unexposed controls. The time from last exposure to death varied from 0-23 years. The antimony concentration in liver and kidney was not significantly different between the two groups, suggesting that following occupational inhalation antimony may be retained in the lung for several years without significant systemic distribution. Kentner et al (1995) estimated a renal elimination half-life of four days following occupational inhalation of antimony trioxide and stibine in 21 employees at a starter battery manufacturing plant. CLINICAL FEATURES: ACUTE EXPOSURE Dermal exposure Antimony trisulphide is an irritant although antimony dermatitis typically occurs during chronic occupational exposure to antimony trioxide. Ocular exposure Antimony trisulphide is an eye irritant. Ingestion Acute poisoning is rare. Antimony trisulphide is poorly soluble and is not absorbed readily from the gastrointestinal tract. Gastrointestinal toxicity A 24 year-old woman was admitted to hospital within an hour of ingesting an unknown quantity of antimony trisulphide used in veterinary practice. The patient complained of epigastric pain, dysphagia and a metallic taste although clinical examination was normal. Immediate gastric lavage was followed by forced diuresis (10-14 L/24 h), repeated gastric aspiration and chelation therapy with dimercaprol 200 mg tds for five days. At presentation the blood antimony concentration was approximately 5 µg/L, dropping to 2 µg/L 20 hours post ingestion, then falling to 1.5 µg/L during the course of treatment. The corresponding urine antimony concentration rose to 600 µg/L 20 hours after ingestion and fell to <100 µg/L over the next six days. Routine biological tests remained in the normal range. No clinical signs of intoxication developed and the patient was discharged after six days (Bailly et al, 1991). One hundred and fifty children developed nausea, vomiting, abdominal pain and diarrhoea some 15 minutes after drinking antimony contaminated lemonade. The lemonade had a pH of 2.5-3.1 and leached an estimated 30 mg/L antimony into solution from an agate pot in which it was stored for 20-22 hours. Most of the affected children recovered within a few hours, the remainder recovering within a few days (Werrin, 1963). Cardiovascular and peripheral vascular toxicity Electrocardiographic abnormalities are associated typically with chronic antimony exposure. Following acute antimony ingestion two patients had "moderate bradyrhythmic dysfunctions" at presentation (Lauwers et al, 1990). Phlebitis occurred in four patients who accidentally ingested antimony potassium tartrate (Lauwers et al, 1990). Inhalation Pulmonary toxicity Dusts and fumes of antimony trisulphide are irritant to the respiratory tract and mucous membranes and inhalation causes laryngitis, pharyngitis, tracheitis, rhinitis, epistaxis and bronchitis (Renes, 1953). However, most reports are of concomitant exposure to antimony trioxide produced from smelting antimony trisulphide ore. Metal fume fever has been described (Anonymous, 1984) though less frequently than following exposure to zinc oxide. Radiological evidence of pneumonitis was found in six workers exposed to antimony smelter fumes for 2-12 hours. Inflammatory changes were characteristically peri-hilar with no evidence of peripheral parenchymal damage. Symptoms were alleviated by removal from exposure (and treatment with penicillin aerosols). The average airborne antimony concentration was 10-12 mg/m3 with a maximum measured breathing zone concentration of 70.7 mg/m3 (Renes, 1953). Gastrointestinal toxicity Workers heavily exposed (not specified) to antimony trioxide in a smelter plant developed "gastritis", abdominal pain, diarrhoea and vomiting. Urine antimony concentrations ranged from a trace up to an "exceptionally high" 600 mg/L (Renes, 1953). Neurotoxicity "Neuritis", dizziness and headache were reported amongst workers exposed to antimony trioxide fumes at an antimony smelting plant (Renes, 1953). Nephrotoxicity Albuminuria was reported in a "severely ill" worker with a urine antimony concentration of 600 mg/L after exposure to antimony trioxide in a smelting plant (Renes, 1953). Removal from exposure and supportive care for several days "provided relief". CLINICAL FEATURES: CHRONIC EXPOSURE The major source of antimony trisulphide exposure is as an ore (which may also contain arsenic) used in the production of antimony and antimony trioxide. Inhalation and dermal contact are the most common routes of exposure. Dermal exposure Dermatitis following contact with antimony compounds is well described (McCallum, 1989). Typical lesions arise on the arms, legs and in the flexures, sparing the face, hands and feet (Renes, 1953; McCallum, 1989). Papules and pustules predominate around sweat and sebaceous glands with areas of eczema and lichenification (Paschoud, 1963). These so- called "antimony spots" occur mainly in the summer (McCallum, 1989) and are usually associated with antimony trioxide exposure. Skin lesions developed in 23 men employed at an antimony trioxide production plant. Most of those affected were furnace workers with lesions typically appearing within two weeks of exposure. Itching, erythematous papules and pustular eruptions were characteristic, usually on dust laden sweaty skin areas. The lesions usually resolved over two weeks in individuals removed to cooler parts of the factory. Histological examination showed epidermal cellular necrosis associated with an acute dermal inflammatory reaction. Antimony trioxide patch testing was negative whilst injection of methacholine into the affected areas cause enlargement of the lesions. The author concluded that antimony trioxide dust initiated an irritant reaction when it penetrated the sweat ducts (Stevenson, 1965). White et al (1993) described three cases of occupational antimony dermatitis following several months exposure to antimony dust and antimony trioxide fumes. Symptoms resolved when exposure ceased. In one patient patch testing for antimony was negative and in another the urine antimony concentration was 53.2 µg/L ("normal" <1.0 µg/L). Positive patch testing to antimony trioxide has been noted in enamellers and decorators in the ceramics industry (Motolese et al, 1993). Ocular exposure Antimony compounds are irritant to the eye. Conjunctivitis was reported in 14 of 51 workers exposed to antimony trioxide dust in a smelting plant (Potkonjak and Pavlovich, 1983). Inhalation Pulmonary toxicity Chronic occupational exposure to antimony compounds may cause "antimony pneumoconiosis" (McCallum, 1989). Typical radiological findings include diffuse, dense, punctate, non-confluent opacities predominately in the middle and lower lung fields, sometimes associated with pleural adhesions (Potkonjak and Pavlovich, 1983). These changes developed after at least ten years working in an antimony smelting plant where the dust contained nearly 90 per cent antimony trioxide with some antimony pentoxide and small amounts (up to five per cent) of silica (Potkonjak and Pavlovich, 1983). Cough (in 31 of 51 subjects) and exertional breathlessness (in 26 cases) were the symptoms most frequently reported with wheeze, chest pain or generalized weakness in a minority. Nine workers had obstructive lung function defects with a combined restrictive/obstructive picture in five cases but no isolated restrictive defects or radiological evidence of diffuse fibrosis. Pneumoconiosis was reported also in workers at an antimony oxide production plant. Lung biopsies from two affected individuals revealed antimony concentrations of 600-3000 µg/g (Le Bouffant et al, 1987) No symptoms of respiratory and mucous membrane irritation usually associated with antimony exposure were reported in 125 workers exposed to 3.0-5.5 mg/m3 antimony trisulphide. However, an increased incidence of gastric ulcer, abnormal ECG changes and sudden deaths was noted as discussed below (Brieger et al, 1954). Perforation of the nasal septum has been described in antimony workers but these cases probably have involved concomitant arsenic exposure (McCallum, 1989). There were no cases of nasal septum perforation in 51 workers employed at an antimony smelter for 9-31 years (mean 17.9 years) (Potkonjak and Pavlovich, 1983). Cardiovascular toxicity In the Czechoslovakian literature Klucik and Ulrich (1960) reported subjective cardiac complaints and ECG changes (not specified in the English abstract) in 14 workers occupationally exposed to antimony trisulphide. Brieger et al (1954) attributed ECG T-wave changes and sudden deaths to antimony-induced cardiotoxicity following occupational exposure to antimony trisulphide. This compound replaced lead in a resin grinding process exposing 125 workers to some 3.0-5.5 mg/m3 for eight months to two years. Six sudden deaths and two deaths from chronic heart disease occurred during this period compared to one death (from coronary thrombosis) in the previous 16 years. One hundred and thirteen employees were examined; 14 had a blood pressure over 150/90 mmHg and 24 under 110/70 mmHg. A further 37 of 75 workers examined showed "significant" ECG changes, mostly of the T-waves. Random urine samples contained 0.8-9.6 mg Sb/L. No further cardiovascular related deaths were reported following removal of antimony trisulphide from the process though ECG changes persisted in 12 of 56 individuals examined several years later. Gastrointestinal toxicity "Gastrointestinal disturbances" were reported in workers exposed to 3.0-5.5 mg/m3 antimony trisulphide for between eight months and two years. Radiological studies revealed peptic ulcers in seven of 111 individuals examined (6.3 per cent) compared to 1.5 per cent in the total plant population (Brieger et al, 1954). MANAGEMENT Dermal exposure Ensure adequate self protection before attempting treatment. If possible the patient should remove any contaminated clothing him/herself. Affected areas of skin should be washed with copious quantities of water. Pay special attention to skin folds, fingernails and ears. The most effective treatment for antimony induced irritant dermatitis and "antimony spots" is removal from exposure. Ocular exposure Irrigate immediately with lukewarm water or preferably saline for at least 10-15 minutes. A local anaesthetic may be indicated for pain relief and to overcome blepharospasm. The use 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. Ingestion Following substantial ingestion of an antimony compound gastric lavage may be considered if presentation is within the first hour. There are no data to confirm that charcoal adsorbs antimony but the administration to a co-operative patient of 50 g activated charcoal within the first hour following a suspected substantial ingestion is reasonable. Other symptomatic and supportive measures should be dictated by the patient's condition. An ECG should be performed and biochemical and haematological profiles monitored. Blood and urine antimony concentrations are not widely available but may be of interest retrospectively to confirm systemic uptake. Inhalation Removal from exposure and measures to secure cardiorespiratory stability are the priority following acute inhalation of antimony compounds. An ECG should be performed. Respiratory symptoms in those with possible chronic antimony toxicity should be investigated as for other cases of pneumoconiosis. Urine antimony concentrations may be useful to monitor the initial extent of and subsequent reduction in exposure but these assays are not widely available. Antidotes Dimercaprol (British anti-lewisite, BAL) (Thompson and Whittaker, 1947; Braun et al, 1946), dimercaptosuccinic acid (DMSA, Succimer) (Basinger and Jones, 1981) and dimercaptopropane sulphonate (DMPS, Unithiol) (Basinger and Jones, 1981; Hruby and Donner, 1987) have antidotal activity in experimental systemic antimony poisoning (see below). These findings have not been confirmed in controlled studies in man. Dimercaprol In vitro studies Using the pyruvate oxidase system of pigeon brains as a test model, dimercaprol in a molar ratio of 6:1 dimercaprol: antimony was able to protect the enzyme system from inhibition by several antimony salts (Thompson and Whittaker, 1947). Animal studies The LD50 of intramuscular antimony tartrate administered to rabbits was raised from 90 mg Sb/kg in controls to 160 mg Sb/kg in animals treated with intramuscular dimercaprol (30 mg/kg one hour after intoxication followed by 15 mg/kg at six, 24 and 48 hours) (Braun et al, 1946). A total of 45 controls received 50-200 mg/kg antimony tartrate with 56 treated animals receiving 125-200 mg/kg. Clinical studies Four adults with antimony poisoning following the inadvertent consumption of antimony potassium tartrate were treated with intramuscular dimercaprol 200-600 mg daily. Three patients made an uneventful recovery but the fourth, who had a history of cardiorespiratory disease, died on day three. There were no pre-chelation antimony excretion data but in two survivors maximum antimony urine concentrations of 1000 µg/L and 1500 µg/L were reported some 36 and 72 hours after poisoning respectively. Urine volumes were not stated (Lauwers et al, 1990). Bailly et al (1991) reported a 24 year-old woman who made an uneventful recovery after ingesting an undetermined amount of antimony trisulphide. She was treated with dimercaprol 200 mg tds for five days but there was no evidence of enhanced urinary antimony elimination with therapy. DMSA Animal studies DMSA was given intraperitoneally to mice at a molar ratio of 10:1 DMSA: antimony twenty minutes after administration of potassium antimonyl tartrate (120 mg/kg; twice the LD50). The survival ratio was 28/30 (Basinger and Jones, 1981). Clinical studies There are no human data. DMPS Animal studies DMPS has been shown to be an effective chelating agent in mice following intraperitoneal administration of potassium antimonyl tartrate (120 mg/kg; twice the LD50). The survival rate was 19/30 when intraperitoneal DMPS was given twenty minutes after intoxication at a molar ratio of 10:1 DMPS: antimony. However, DMSA was significantly more effective under these conditions (see above) (Basinger and Jones, 1981). Clinical studies There are no human data. Antidotes: Conclusions and recommendations 1. Clinical data regarding antimony chelation are scarce. 2. Dimercaprol effectively chelates antimony but has been superseded by the less toxic thiol antidotes DMPS and DMSA. 3. In limited animal studies DMSA is a more effective antimony chelator than DMPS. 4. Parenteral or oral DMSA therapy may be considered in antimony poisoning. The discussion of individual cases with an NPIS physician is recommended. MEDICAL SURVEILLANCE Improved occupational health measures have reduced industrial airborne antimony concentrations significantly but monitoring of ambient air antimony concentrations remains important in some industries (Bailly et al, 1991; Kentner et al, 1995). Routine examination of the skin for "antimony spots" and chest radiography for evidence of pneumoconiosis may also be useful. The potential risk of pulmonary carcinogenicity should be remembered (see below). Although Bailly et al (1991) found that urine antimony excretion among workers exposed to airborne antimony pentoxide and sodium antimoniate correlated to the intensity of exposure, a recent publication from the European Commission concluded "no indicator of effect is available" for biological monitoring of antimony (Apostoli et al, 1994). Normal concentrations in biological fluids "Normal" serum and urine antimony concentrations are quoted as approximately 3 µg/L and 0.8 µg/L respectively (Poisindex, 1997). OCCUPATIONAL DATA Maximum exposure limit Long-term exposure limit (8 hour TWA reference period) 0.5 mg/m3 (Health and Safety Executive, 1997). OTHER TOXICOLOGICAL DATA Carcinogenicity Antimony trisulphide is not classifiable as to its carcinogenicity to humans (IARC, 1989). There is some evidence that occupational antimony exposure is associated with an increased risk of lung cancer although frequent concomitant exposure to arsenic and other heavy metals precludes a definitive conclusion about its carcinogenic potential (Gerhardsson et al, 1982; McCallum, 1989; Gerhardsson and Nordberg, 1993; Jones, 1994; Schnorr et al, 1995). Antimony also has been implicated in the aetiology of bladder tumours in patients with schistosomiasis who have been treated with antimony compounds (Winship, 1987). Reprotoxicity In the Russian literature women occupational exposed to antimony aerosols were reported to have a higher incidence of spontaneous abortion, premature births and menstrual disorders. Antimony was present in the blood, urine, placentae, amniotic fluid and breast milk of these women. Further details were not available in the English abstract (Belyaeva, 1967). Genotoxicity NIF Fish toxicity Rainbow trout: LC50 for trivalent antimony 0.66 mg/L (DOSE, 1992). EEC Directive on Drinking Water Quality 80/778/EEC Maximum admissible concentration 10 µg/L, as antimony (DOSE, 1992). WHO Guidelines for Drinking Water Quality Provisional guideline value 5 µg/L, as antimony (WHO, 1993). AUTHORS WN Harrison PhD CChem MRSC SM Bradberry BSc MB MRCP ST Beer BSc 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 REFERENCES Apostoli P, Porru S, Alessio L. Antimony. In: Alessio L, Berlin A. Roi R, van der Venne MT, eds. Biological indicators for the assessment of human exposure to industrial chemicals. 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