MONOGRAPH FOR UKPID TETRACHLOROETHYLENE Henrietta Wheeler National Poisons Information Service (London Centre) Medical Toxicology Unit Guy's & St Thomas' Hospital Trust Avonley Road London SE14 5ER UK 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. 1 SUBSTANCE/PRODUCT NAME 1.1 Origin of substance Tetrachloroethylene is a synthetic chemical with no natural sources (Ware, 1988). 1.2 Name 1.2.1 Brand/trade name Ankilostin; Antisal 1; Dee-Solv; Didakeno; Dowclean EC; Dow-per; ENT 1860; Fedal-Un; Nema; Perawin; Perclene; Percosolv; Perklone; PerSec; Perwin; Tetlen; Tetracap; Tetralax; Tetraleno; Tetravec; Tetroguer; Tetropil. 1.2.2 Generic name Tetrachloroethylene. 1.2.3 Synonyms Carbon bichloride, carbon dichloride, ethylene tetrachloride, PCE, per, perc, perchlor, perchlorethylene, perchloroethylene, percosolve, perk, tetrachlorethylene, tetrachloroethylene, 1,1,2,2-tetrachloroethylene, tetrachloroelthylenum. 1.2.4 Common names/street names 1.3 Chemical group/family Halogenated aliphatic hydrocarbon. 1.4 Substance identifier and/or classification by use Halogenated aliphatic hydrocarbon. 1.5 Reference numbers CAS 127-18-4 RTECS/NIOSH KX 3850000 EINECS 2048259 UN 1897 1.6 Manufacturer Not applicable. 1.7 Supplier/importer/agent/ licence holder Not applicable. 1.8 Presentation 1.8.1 Form Halogenated aliphatic hydrocarbon. 1.8.2 Formulation details 1.8.3 Pack sizes available 1.8.4 Packaging The European Economic Commission regulations state that the label should read that tetrachloroethylene is harmful if inhaled or swallowed, and should be kept out of reach of children. Contact with the eyes must be avoided (WHO, 1984). 1.9 Physico-chemical properties Chemical structure C2Cl4 Physical state liquid Colour Clear and colourless Odour ether-like odour at 50 ppm. Odour threshold 0.3 ppm in water; 1.0 ppm in air. Solubility Water at 25°C 150 mg/L. Organic solvents: miscible with alcohol, ethyl, ether, chloroform benzene, solvent hexane, and most of the fixed and volatile oils. Autoignition temperature No data available Important chemical interactions Mixtures of tetrachloroethylene and dinitrogen tetroxide are explosive when subject to shock (Commission of the European Communities, 1986). tetrachloroethylene reacts violently or explosively with certain alkali or alkaline earth metals. Granular barium in contact with tetrachloroethylene is susceptible to detonation. A mixture of lithium shavings and tetrachloroethylene is impact-sensitive and will explode, possibly violently. When heated together, potassium and tetrachloroethylene explode at 97-99°C. A tetrachloroethylene sodium mixture does not explode under similar conditions (Commission of the European Communities, 1986; Sax, 1984). Major products of combustion/pyrolysis Tetrachloroethylene is slowly decomposed by light and by various metals in the presence of moisture (Commission of the European Communities, 1986; Reynolds, 1993). Tetrachloroethylene decomposes upon heating above 150°C forming phosgene and hydrochloric acid. Trichloroacetyl chloride is described as a major degradation product and phosgene a lesser one (Commission of the European Communities, 1986). Explosion limits No data Flammability non-flammable Boiling point 121.2°C Density 1.6227 g/ml (at 20°C) Vapour pressure 18.47 mmHg (at 25°C) Relative vapour density 5.83 Flash point None 1.10 Hazard/risk classification 1.11 Uses Tetrachloroethylene was first commercially produced in USA in 1925. Tetrachloroethylene has been the solvent of choice in the dry cleaning industry since the 1950s (Blair et al, 1979) and is used extensively in textile processing as a scouring solvent to remove the oil from the fabrics (Ellenhorn and Barceloux, 1988; Sax, 1984; Torkelson, 1994; Ware, 1988). It is used in manufacturing fluorocarbons, as a drying agent for metals and some other solids, as a fumigant for insects and rodents (Gehring et al, 1991), as a heat transfer medium, and as a degreasing solvent (Sax, 1984; Torkelson, 1994). It is also used in aerosol cleaners, ignition wire driers, spot removers, fabric and wood cleaners (Ellenhorn and Barceloux, 1988; Finkel et al, 1983; Sax, 1984; Torkelson, 1994). An unfortunate number of deaths from tetrachloroethylene have been from sleeping bags that have not been properly cleaned of the dry cleaning chemical prior to use (Finkel et al, 1983). Tetrachloroethylene is active against hookworms ( Ancylostoma and Necator), its use of was prevalent in the 1920s and 1930s in India and the Pacific Islands (Ware, 1988). Tetrachloroethylene may still be used in endemic areas although it has generally been superseded by drugs that are less toxic and easier to administer (Reynolds, 1993). It has also been used in the treatment of fasciolopsiasis (Reynolds, 1993). 1.12 Toxicokinetics 1.12.1 Absorption Pulmonary absorption is the primary route of entry of tetrachloroethylene under industrial conditions (Baselt and Cravey, 1990). Human volunteers at rest absorbed about 25% of tetrachloroethylene administered by inhalation exposure at 72 or 144 ppm over a 4 hour period. At first the compound was absorbed rapidly, but uptake decreased as exposure continued. The uptake was influenced more by (lean) body mass than by respiratory minute volume or adipose tissue (Monster and Houtkooper, 1979). During work the uptake and minute volume increased to 3 fold the value at rest. In the post-exposure period the quotient of the blood concentrations and exhaled air concentrations of tetrachloroethylene remained at nearly 23. Following exposure about 80 to 100% of the uptake was excreted unchanged by the lungs, whereas 70 hours after exposure the amount of trichloroacetyl chloride (TCA) excreted in urine represented about 1% of the uptake (Monster et al, 1979; Monster and Houtkooper, 1979; Monster, 1979). Dermal absorption was rapid in both mice and guinea-pigs, peak concentrations of tetrachloroethylene in the blood of guinea-pigs being reached 30 minutes after application. The level of tetrachloroethylene in the blood of rats reached a maximum 1 hour after oral ingestion, or immediately after 6 hour inhalation (WHO, 1984; Pegg et al, 1979). 1.12.2 Distribution The deposition of tetrachloroethylene in man is poorly understood (Baselt and Cravey, 1990). Tetrachloroethylene is lipophilic and accumulates in the liver, brain, kidney, lung and adipose tissue, with gradual redistribution (Lukaszewski, 1979; Ware, 1988). It crosses the blood-brain barrier (Ware, 1988). In human tissue at autopsy, ratios of fat-to-liver concentrations are greater than 6:1 (McConnell et al, 1975). The fat-to-blood ratio is about 90:1 and the half-life for saturation of the fat to 50% of its equilibrium concentration is about 25 hour (Monster, 1979). Tetrachloroethylene has an estimated volume of distribution of 8.2 L/kg after an oral dose of 400 mg. A postmortem after a fatal tetrachloroethylene exposure revealed an eight times greater concentration in the brain compared to the blood (Lukaszewski, 1979), whereas in another postmortem the liver contained the highest tetrachloroethylene levels (Levine, 1981). 1.12.3 Metabolism Less than 4% of the estimated absorbed dose of tetrachloroethylene is metabolised and excreted as trichloroacetic acid in humans (Fernandez et al, 1979; Ferroni et al, 1992). Tetrachloroethylene is stored in the fat and adipose tissue and slowly metabolised with the loss of chlorine (Gosselin et al, 1984). Once absorbed, the highest concentrations of tetrachloroethylene are found in the adipose tissue, reflecting its high lipid solubility (Ware, 1988). The principle site of metabolism is the hepatic microsomal cytochrome P450 mixed-function oxidase system in a dose-dependent manner (Gehring et al, 1991; Torkelson, 1994). Tetrachloroethylene is probably transformed by oxidation to perchloroethylene oxide and subsequently by rearrangement to trichloroacetyl chloride and then by hydrolysis to trichloroacetic acid (TCA) (Lukaszewski, 1979; Yllner, 1961). Metabolism takes place mainly in the liver. The maximum concentration of TCA is reached at 20 hours after exposure (Monster, 1979). The major urinary metabolite seems to be trichloroacetic acid, over half appears as the acid and its conjugate. Much smaller amounts of oxalic acid, trichloroethanol, dichloroacetic acid and N-trichloroacetyaminoethanol or its conjugate are excreted (Commission of the European Communities, 1986; Skender et al, 1991; Torkelson, 1994). Tetrachloroethylene may give rise to reactive intermediate metabolites that may impair the tubero-infundibular dopaminergic system (Ferroni et al, 1992). This mechanism may involve neuroendocrine changes accounting for gynaecological disturbances eg oligo-menorrhoea and reduced fertility (Zielhuis et al, 1989) and spontaneous abortion or perinatal death (Olsen et al, 1990). 1.12.4 Elimination There seems to be no apparent difference in elimination pathways or metabolism in animals exposed by oral or inhalation routes. The major determinant of metabolism and tissue distribution is body burden (Pegg et al, 1979). The majority of tetrachloroethylene (about 80%) is eventually excreted unchanged in expired air; initial elimination is rapid but a proportion may be retained and excreted slowly (Baselt and Cravey, 1990; Reynolds, 1993; Skender et al, 1991). 15% of an inhaled dose is eliminated unchanged within 1 hour, 3% is metabolised and excreted via the urine over a 67 hour period (Baselt and Cravey, 1990; Commission of the European Communities, 1986; Koppel et al, 1985). Approximately 25% of an inhaled dose is excreted unchanged in the breath over 40 hours following exposure (Baselt and Cravey, 1990). Elimination is then slow due to the release from the fat store, repeated daily exposures leads to accumulation of tetrachloroethylene in man (Ellenhorn and Barceloux, 1988). Alveolar breath concentrations of tetrachloroethylene approach 50% of the atmospheric concentration of the chemical during constant exposure (Baselt and Cravey, 1990). In subjects exposed to 100 ppm of the vapour, breath concentrations averaged 15 ppm during the first hour after exposure, 8 ppm after 15 hours and 4.5 ppm after 71 hours (Stewart et al, 1970). Chlorinated metabolites of tetrachloroethylene generally do not exceed concentrations of 100mg/L in urine workers exposed to the vapor at air concentrations of up to 400 ppm (Ikeda et al, 1972). 1.12.5 Half-life The biological half-life of tetrachloroethylene on inhalation has been estimated from pulmonary excretion data as between 3 and 72 hours (Baselt and Cravey, 1990). Trichloroacetic acid, as a metabolite of tetrachloroethylene, is eliminated with a half-life of 144 hour via the urine (Ware, 1988). The biological half-life of tetrachloroethylene appears to be 144 hours following ingestion (Gosselin et al, 1984; Ikeda, 1977; Koppel et al, 1985; Lukaszewski, 1979). 1.12.6 Special populations No data. 2 SUMMARY 3 EPIDEMIOLOGY OF POISONING Tetrachloroethylene was introduced in to the dry cleaning industry in the late 1930s, but did not replace other synthetic solvents until shortly after the second world war. By 1977, about 74% of dry cleaning outlets used tetrachloroethylene (Brown and Kaplan, 1987). At least 1.6 million workers in US are potentially exposed to tetrachloroethylene annually (Brown and Kaplan, 1987). 4 MECHANISM OF ACTION/TOXICITY 4.1 Mechanism Systemic toxicity after acute overexposure to tetrachloroethylene vapour is characterised by central nervous system depression, hypotension, cardiac arrhythmias, hepatic and renal injury; death may be due to respiratory failure. The major response to tetrachloroethylene at high concentrations is CNS depression. It is not, however, sufficiently effective to be considered a useful anaesthetic (Torkelson, 1994). Tetrachloroethylene may sensitise the myocardium to adrenaline and other catecholamines at high levels of exposure (Hathaway et al, 1991; Torkelson, 1994). The vapour and liquid are irritating to the skin and mucous membranes. There may be nausea and gastrointestinal upset at high concentrations. Changes in the liver and kidneys may be seen following excessive exposure; however the effects are not as severe or striking as they are with other hydrocarbons, e.g. carbon tetrachloride (Ellenhorn and Barceloux, 1988; Torkelson, 1994). Dependence may follow habitual inhalation of small quantities of tetrachloroethylene vapour. 4.2 Toxic dose Inhalation: Dose Exposure Symptoms Comments Reference (ppm) time 50 8 hours No physiological Odour threshold Commision of the effects (very faint) to European unacclimatised Communities, 1986 216 45 mins- Respiratory Rowe et al, 1952 2 hours irritation 275 3 hours Coma for 1 hour. Concentration of Hathaway et al, 1991 then then Deranged LFTs tetrachloroethylene 100 30 minutes for 2-3 weeks in expired air, post-exposure diminished slowly over 2 weeks 400 2 hours Eye irritation, Odour strong, but Commision of the slight nasal tolerable European Communities, irritation, ataxia 1986 600 10 minutes Numb mouth, dizzy, Odour very Commision of the ataxic for 10 strong but European Communities, minutes post- tolerable 1986 exposure 1,060 1-2 minutes Not tolerated for Exposed in Rowe et al, 1952 more than 2 minutes chamber 1,500 30 minutes 'Gagging', irritation Odour almost Commision of the of eyes and intolerable European Communities, respiratory tract 1986 (almost intolerable), loss of consiousness (Continued) Dose Exposure Symptoms Comments Reference (ppm) time 5,000 6 minutes Vertigo, nausea and Hathaway et al, 1991 confusion for 10 minutes post- exposure Two adults who died shortly after massive exposure of tetrachloroethylene fumes in dry cleaning establishments were found to have the following concentrations (mg/L or mg/kg) of tetrachlorethylene (Baselt and Cravey, 1990): Patient Blood Brain Lung Liver Kidney Patient 1 44 360 3 - - Patient 2 4.5 69 30 240 71 Chronic inhalation: Twenty dry cleaning workers exposed for an average of 7.5 years to concentrations of 1-40 ppm had altered electrodiagnostic and neurological rating scores (Hathaway et al, 1991). Abnormal EEG readings were found in 4 out of 16 factory employees exposed to concentrations ranging from 60-450 ppm for 2 to 20 years (WHO, 1984). Ingestion: A 6 year old boy ingested 8-10 ml of tetrachloroethylene and became comatose. He developed a peak blood level of 22 mg/L but survived (Koppel et al, 1985). 5 FEATURES OF POISONING 5.1 Acute 5.1.1 Ingestion Ingestion of tetrachloroethylene may cause gastric irritation with nausea and vomiting. It may cause CNS depression, dizziness, inebriation, lightheadedness, mental dullness and incoordination (Hathaway et al, 1991; Stewart et al, 1970). CNS depression may range form mild narcosis to coma with respiratory depression or death (Hathaway et al, 1991). Respiratory effects include coughing, wheezing, pulmonary oedema and increasing cyanosis. These may occur due to aspiration or following large inhalation exposure. Full recovery may be seen if exposure is minimal. Tetrachloroethylene is thought to sensitise the myocardium to endogenous catecholamines which may cause arrhythmias and sudden death after massive acute exposures. Ingestion of tetrachloroethylene has been associated with the development of toxic epidermal necrolysis (Potter, 1960). 5.1.2 Inhalation Tetrachloroethylene vapours are irritant to nasal, ocular and respiratory mucosa (Rowe et al, 1952). Headache, fatigue, ataxia, dizziness, nausea, vomiting, hypotension, mental confusion and temporary blurred vision have been reported after inhalation (Baselt and Cravey, 1990; Clement International Corporation, 1993; Rowe et al, 1952). Tetrachloroethylene is a CNS depressant and causes drowsiness that can lead to coma or death. Tetrachloroethylene is thought to sensitise the myocardium to endogenous catecholamines which may cause arrhythmias and sudden death after massive acute exposures. Short-term exposure tests prove that the visual system is one of the target organs of acute tetrachloroethylene toxicity. 5.1.3 Dermal Tetrachloroethylene is irritant to the skin. It may cause dry, scaly skin, blisters and dermal burns (Baselt and Cravey, 1990; Finkel et al, 1983). Erythema and a severe burning sensation may occur if tetrachloroethylene is left on the skin for 40 minutes or longer (Hathaway et al, 1991). Dermatitis is caused by defatting of the skin (Torkelson, 1994). 5.1.4 Ocular Tetrachloroethylene vapours are irritating to eyes at high concentrations (Ellenhorn and Barceloux, 1988; Grant and Schuman, 1993; Torkelson, 1994). An ocular splash exposure is expected to cause lacrimation and burning but no permanent damage (Rowe et al, 1952; Torkelson, 1994). Spraying rabbits in the eyes with tetrachloroethylene caused immediate blepharospasm and pain. The corneal epithelium became granular and optically irregular patches of epithelium were lose, both eyes recovered completely within 2 days (Grant and Schuman, 1993). 5.1.5 Other routes Tetrachloroethylene has been found to be weakly nephrotoxic and hepatotoxic following subcutaneous injection in mice. Dogs were killed by intravenous doses of 85 mg/kg; the few that received 75 mg/kg or less survived (Gehring et al, 1991). 5.2 Chronic toxicity 5.2.1 Ingestion When tetrachloroethylene was administered in drinking water for 90 days to mice, body weight was decreased and there were suggestions of liver effects but no clear evidence of injury at 1400 mg/kg/day (Gehring et al, 1991; Torkelson, 1994). There is no human data available. 5.2.2 Inhalation Since tetrachloroethylene is minimally metabolised, slowly excreted, and presumed to be accumulative, chronic exposure to a lower vapour concentration could conceivably result in human injury or organ dysfunction (Monster and Houtkooper, 1979; Stewart, 1969; Stewart et al, 1970). In a chronic overexposure, post-mortem findings included haemorrhagic pneumonitis and pulmonary oedema (Trense and Zimmerman, 1969). Tetrachloroethylene is thought to sensitise the myocardium to endogenous catecholamines which may cause arrhythmias and sudden death after massive acute or chronic exposures. Chronic occupational exposure has been known to produce multiple ventricular premature beats (Abedin et al, 1980). Odour tolerance seems to be exhibited in chronically exposed humans. Sixteen subjects were exposed to 100 ppm over a 7 hour period, initially 100% were able to detect a faint odour; by the end of exposure only 40% were still able to detect the odour of the solvent. Subjects exposed for 5 consecutive days reported that their ability to perceive the odour progressively diminished during the course of the week. Although initially the odour was detected on entering the chamber upon the second day, within two hours only three were able to smell tetrachloroethylene (Stewart et al, 1970). Chronic occupational exposure of three years resulted in peripheral neuropathy, hepatitis, confusion, disorientation, muscle cramps, fatigue, agitation and damage to liver, kidney and spleen (Baselt and Cravey, 1990). One case of fatal chronic poisoning showed lobular necrosis of the liver at postmortem (Trense and Zimmerman, 1989). Liver enlargement was still present 6 months after cessation of exposure in one chronic occupational poisoning (Meckler and Phelps, 1966). A connective tissue disorder characterised by Reynauld's phenomenon, alopecia, myositis and strongly positive antinuclear antibodies in patients chronically exposed to tetrachloroethylene has been described by Sporrow in 1977 (Baselt and Cravey, 1990). Tetrachloroethylene may give rise to reactive intermediate metabolites that may impair the tubero-infundibular dopaminergic system (Ferroni et al, 1992). This mechanism may involve neuroendocrine changes accounting for gynaecological disturbances eg oligo-menorrhoea and reduced fertility (Zielhuis et al, 1989) and spontaneous abortion or perinatal death (Olsen et al, 1990). Chronic low level exposures of tetrachloroethylene may effect colour vision although the pathogenesis is unclear (Cavalleri et al, 1994). The effect does not seem to be rapidly reversible. Chronic low levels of tetrachloroethylene may significantly impair performance and affect pituitary function, thus causing increased levels of the dopaminergic modulation of prolactin (Olsen et al, 1990). 5.2.3 Dermal Chronic skin exposure may cause reddening and chapping of the skin. Dry, scaly and fissured dermatitis may also occur from repeated skin contact. 5.2.4 Ocular Chronic low level exposures of tetrachloroethylene may affect colour vision although the pathogenesis is unclear (Cavalleri et al, 1994). The effect does not seem to be rapidly reversible. 5.2.5 Other routes No human data available. 5.3 Systematic description of clinical effects 5.3.1 Cardiovascular Tetrachloroethylene may sensitise the myocardium to adrenaline and other catecholamines. However, in dogs exposed to highly anaesthetic levels of tetrachloroethylene (5000 to 10,000 ppm) cardiac arrhythmias were not detected (Hathaway et al, 1991). The significance of these findings for humans exposed to allowable concentrations is very questionable (Torkelson, 1994). Multiple ventricular premature beats occurred in a worker with chronic exposure and tetrachloroethylene was detected in the blood. No arrhythmia was noted one month after the exposure was discontinued (Abedin et al, 1980). 5.3.2 Respiration Upper respiratory tract irritation may occur with exposure to high concentrations of airborne tetrachloroethylene (Clement International Corporation, 1993; Finkel et al, 1983; Torkelson, 1994). Respiratory failure may occur in massive overexposure (Rowe et al, 1952). In a chronic overexposure, postmortem findings included haemorrhagic pneumonitis and pulmonary oedema (Trense and Zimmerman, 1969). 5.3.3 Neurological Ingestion or inhalation of tetrachloroethylene causes CNS depression, dizziness, headache, inebriation, slurred speech, lightheadedness, mental dullness and incoordination (Hathaway et al, 1991; Stewart, 1969; Stewart et al, 1970). CNS depression may range form mild narcosis to coma with respiratory depression or death (Hathaway et al, 1991). A 62 year old man presented with inebriation following exposure to 500 ppm. He recovered within 6 hours (McMullen, 1976). 19 volunteers exposed to tetrachloroethylene vapor concentrations of 20, 100 and 1,500 ppm for 1 month (5 days/week). EEG changes were recorded in 7 out of 19 subjects during 100 ppm exposure. The EEG changes were characterised by a reduction in overall wave amplitude and frequency, most evident in the occipital leads. The altered EEG pattern was similar to that seen in healthy adults during drowsiness, light sleep and first stages of anaesthesia (Stewart et al 1981). In 4 volunteers exposed acutely to 1,000-1,500 ppm dizziness for less that 2 hours suffered mood changes, ataxia, dizziness and faintness. Following exposure to 2,000 ppm for 7.5 minutes, subjects experienced a sensation of impending collapse (Carpenter, 1937). Long exposures have resulted in collapse, coma and seizures (Hake and Stewart, 1977). Chronic low levels of tetrachloroethylene affects attention and executive function, and mood functions thought to be mediated by the frontal and limbic system of the brain (Echeverria et al, 1995). Peripheral neuropathy has been described following chronic exposure (Hathaway et al, 1991). 5.3.4 Gastrointestinal Nausea and vomiting occur following exposure by inhalation or ingestion (Baselt and Cravey, 1990; Torkelson, 1994). 5.3.5 Hepatic Liver damage may result from chronic or severe acute exposure (Hathaway et al, 1991; Reynolds, 1993; Stewart, 1969; Stewart et al, 1970). The liver is a target organ in humans, particularly in those accidentally exposed to high concentrations. Hepatocellular damage was documented by biopsy in a case study of a women exposed occupationally to tetrachloroethylene fumes (Meckler and Phelps, 1966). Liver damage also has been diagnosed by the presence of hepatomegaly, icterus and elevations of serum biomarkers of liver dysfunctions (Hake and Stewart, 1977; Meckler and Phelps, 1966). In a chronic exposure liver enlargement was still present 6 months after cessation of exposure to tetrachloroethylene (Meckler and Phelps, 1966). Chronic occupational exposure has resulted in hepatitis, muscle cramps and agitation (Baselt and Cravey, 1990). 5.3.6 Urinary Proteinuria and haematuria has occurred following massive acute exposure. Proteinuria lasted 20 days in a 60 year old man found lying in a pool of tetrachloroethylene. Oliguric renal failure has occurred from inhalation exposure from a self-service dry-cleaning machine (Hake and Stewart, 1977). 5.3.7 Endocrine and reproductive system A small scale study on menstral disorders in dry cleaning workers was carried out by Zielhuis et al (1989). Although there were limitations upon the study, the results indicated that menstral disorders (dysmenorrhoea, unusual cycle length, menorrhagia and premenstrual syndrome) were higher than in the control group. Several recent case-control studies in dry cleaning workers suggest that women have an increased risk of spontaneous abortion (Clement International Corporation, 1993; Kyyrönen et al, 1989). Eskenazi et al (1991) found that the sperm of male dry cleaning workers exposed to tetrachloroethylene had more amplitude of lateral head displacement (ALH) and less linearity in their sperm swimming paths compared to a control group. Although their semen was considered to be within normal limits the quality was diminished. As exposure to tetrachloroethylene increased, men were found to have fewer narrow sperm but more round sperm. Infertility has been reported in men with mostly round headed sperm. These sperm lack an acrosome and are unable to penetrate the ovum. Although proportions of round sperm are increased and dose-related in tetrachloroethylene exposed men, these proportions are considerably lower than those noted in a group of infertile men. Tetrachloroethylene may give rise to reactive intermediate metabolites that may impair the tubero-infundibular dopaminergic system (Ferroni et al, 1992). This mechanism may involve neuroendocrine changes accounting for gynaecological disturbances eg oligo-menorrhoea and reduced fertility (Zielhuis et al, 1989) and spontaneous abortion or perinatal death (Olsen et al, 1990). A six-week old, breast-fed infant suffered an enlarged liver and obstructive jaundice under conditions where the mother's milk was found to contain up to 1 mg tetrachloroethylene per 100 ml caused by her occupational exposure (Commision of the European Communities, 1986). Rabbits exposed to 15 mg/L, one hour daily for 15 days developed gradual increases in the plasma and urine concentrations of corticosteroids, adrenaline, noradrenaline and 3-methyl-1-hydroxymandelic acid. These effects lasted for 30 days following cessation of exposure (Maxxa and Brancaccio, 1971). Similar effects have not been reported in exposed humans. An increase number of resorption delayed skull, ossifications, subcutaneous oedema, and sternal malformations were found in the offspring of rats exposed to 300 ppm tetrachloroethylene for 7 hours as day on days 6 to 15 of pregnancy (Hathaway et al, 1991). 5.3.8 Dermatological Tetrachloroethylene is irritant to the skin. It may cause dry, scaly skin, blisters and dermal burns (Baselt and Cravey, 1990; Finkel et al, 1983). Erythema and severe burning sensation may occur if tetrachloroethylene is left on the skin for 40 minutes or longer (Hathaway et al, 1991). Dermatitis is caused by defatting of the skin (Torkelson, 1994). Symptoms of coldness, stiffness, burning pain and discolouration of hands on exposure reported following tetrachloroethylene exposure (Rowell, 1977). Ingestion of tetrachloroethylene was associated with the development of toxic epidermal necrolysis (Potter, 1960). 5.3.9 Eye, ears, nose and throat Ocular splash exposure is expected to cause lacrimation and burning, but no permanent damage (Rowe et al, 1952; Torkelson, 1994). The vapour is irritating to the eyes, nose and throat at high concentrations (Ellenhorn and Barceloux, 1988; Grant and Schuman, 1993; Torkelson, 1994). 5.3.10 Haematological A 13 month old male with sickle cell trait exhibited evidence of intravascular haemolysis within 24 hours of ingestion and aspiration of tetrachloroethylene (Algren and Rogers, 1992). A father and son who were exposed to organic solvents including tetrachloroethylene was reported to have polycythemia vera, a proliferative disorder of bone marrow pluripotent stem cells. The son had 22 years exposure history, including transient exposure above 300 ppm for 5 minutes out of 3 hours (Ratnoff and Gress, 1980). Because genetic and other environmental factors may predispose a person to develop polycythemia vera, this condition cannot be related specifically to tetrachloroethylene exposure. 5.3.11 Immunological No human data available. 5.3.12 Metabolic 5.3.12.1 Acid-base disturbances No data. 5.3.12.2 Fluid and electrolyte disturbances No data. 5.3.12.3 Other No data available. 5.3.13 Allergic reactions No human data available. 5.3.14 Other clinical effects Individuals who live close to dry cleaning facilities using tetrachloroethylene have been found to have appreciable amounts of this agent in their exhaled breath (Finkel et al, 1983). 5.4 At risk groups 5.4.1 Elderly The elderly with declining organ function may be at increased risk from tetrachloroethylene exposure. 5.4.2 Pregnancy Exposure to high concentrations of tetrachloroethylene during pregnancy has been associated with spontaneous abortion in a case control study of dry cleaner and laundry workers (Kyyrönen et al, 1989). Tetrachloroethylene is excreted in breast milk and has been associated with obstructive jaundice in breast fed new born babies (Bagnell and Ellenberger, 1977). 5.4.3 Children No data available. 5.4.4 Enzyme deficiencies No data available. 5.4.5 Enzyme induced No data available. 5.4.6 Occupations Most exposures to tetrachloroethylene are occupational, workers most at risk are those working in the dry cleaning and textile industries. 5.4.7 Others No data available. 6 MANAGEMENT 6.1 Decontamination Ingestion Emesis is not recommended due to the risk of aspiration. Clear fluids should be encouraged. Gastric lavage with a cuffed endo-tracheal tube, to ensure the airway is protected as the aspiration risk is high, should be considered. Data on humans are too limited to predict with confidence a quantity at which gastric lavage should be carried out. The use and efficacy of activated charcoal has not been studied (Ellenhorn and Barceloux, 1988). Inhalation Following inhalation patients should be removed from the source with care so as not to contaminate the rescuers and monitored for signs of respiratory distress. Dermal Exposed skin should be flushed immediately with copious amounts of water. Ocular Eyes should be irrigated for at least 15 minutes with water of normal saline. The eye should be examined with fluorescein, an ophthalmological referral may be necessary. 6.2 Supportive care The most important management principles are decontamination, monitoring the level of consciousness and respiration, ECG, renal and liver function. Treatment is symptomatic and supportive. An emetic must not be given due to the risk of aspiration; sympathomimetic agents must not be given due to the risk of sensitisation of the myocardium to catecholamines. 6.3 Monitoring Monitor liver function, renal function and perform urinalysis for patients with a significant exposure. Daily urinalysis for proteinuria and haematuria may be useful after massive exposures (Torkelson, 1994). Monitor the level of consciousness and respiratory function. Oxygen should be administered if breathing difficulties occur, ventilate if necessary. A chest X-ray is advised for patients with persistent respiratory symptoms due to the risk of pulmonary oedema. Monitoring the urinary concentrations of chlorinated metabolites of tetrachloroethylene is of only limited use, because saturation of the metabolic pathways occurs at air concentrations greater than 50 ppm and there is no correlation between concentration of urinary metabolites and exposure at higher air concentrations (Baselt and Cravey, 1990). 6.4 Antidotes There are no known antidotes. 6.5 Elimination techniques Koppel et al (1985) demonstrated in a child who ingested 8-10 ml that controlled hyperventilation enhanced pulmonary elimination of tetrachloroethylene. Under this treatment, the clinical condition of the patient improved considerably. Under hyperventilation the half-life was reduced to 30 minutes and about 1% of the ingested dose was excreted via the urine in the first three days with the bulk of the dose being eliminated via the lungs (Koppel et al, 1985). This has not been demonstrated elsewhere. 6.6 Investigations Measured breath tetrachloroethylene concentrations after cessation of exposure correlate well with the amount absorbed and with the blood levels (Baselt and Cravey, 1990). This may also be of use in monitoring workers with chronic exposure (Torkelson, 1994). Blood tetrachloroethylene concentrations have generally not proved useful if exposure is known, but may be of use for diagnosis. However, Skender et al (1991) believes the most reliable indicator of tetrachloroethylene appears to be in blood. Tetrachloroethylene is radiopaque in vitro and an X-ray may be of use in confirming ingestion. 6.7 Management controversies Following large inhalation or oral exposure the patient must be kept at complete bed rest, in a quiet environment, on an ECG monitor for at least 12 hours post-exposure. The use of catecholamines (eg adrenaline) must be avoided. Koppel et al (1985) demonstrated that controlled hyperventilation enhanced pulmonary elimination of tetrachloroethylene. This has not been demonstrated elsewhere, but may be considered in cases of severe poisoning. 7 CASE DATA Ingestion: 1) A 13 month old black male, developed pneumonia and respiratory failure following the ingestion and aspiration of a dry cleaning fluid containing tetrachloroethylene. Immediately following the ingestion, he became unconscious and had a brief generalised convulsion. Upon arrival at hospital, he was intubated and stabilised with mechanical ventilation. During the next 24 hours, the serum haemoglobin concentration fell to 3.5 g/100ml, prompting further investigation to determine the etiology of the marked decrease in haemoglobin. During this time, the patient had not experienced any cardiovascular instability, and his overall condition had improved. The possibility of occult blood loss was considered but could not be substantiated. A sickle cell screen was positive. Haemoglobin electrophoresis subsequently demonstrated haemoglobin AS, consistent with sickle cell trait. No further haemolysis was observed, and transfusion was not necessary. The patient was weaned from mechanical ventilation on the fourth day and recovered without further complications (Algren and Rodgers, 1992). 2) A 6 year old boy drank 8-10 ml of tetrachloroethylene and one hour later was admitted to hospital with deterioration of his conscious state to coma. In order to prevent aspiration, the child was intubated, and a gastric lavage with paraffin oil was performed. The initial tetrachloroethylene blood level was 21.5 mg/ml; hyperventilation therapy was instigated 2 hours after ingestion. The patient received 6000 U/24 hours of heparin to prevent coagulation with intravenous infusion therapy. Under this treatment, the clinical condition of the patient improved considerably. Under hyperventilation the half-life was reduced to 30 minutes and about 1% of the ingested dose was excreted via the urine in the first three days with the bulk of the dose being eliminated via the lungs. Hyperventilation was terminated on day five. However, extubation was not possible because of a marked stridor, which necessitated intubation for a further 24 hours. On the ninth day the boy was discharged with no signs of liver or kidney damage (Koppel et al, 1985). Inhalation: 3)A 33 year old man was found unconscious after performing work on a plugged line in a commercial dry cleaning establishment. He had been left alone to work on the dry-cleaning machine for approximately 20 minutes before being found. He died on the way to hospital. The blood concentrations of tetrachloroethylene was 44 mg/L, brain tissue levels were 360 mg/L and in the lungs 3 mg/L was detected. Tests for alcohol and other drugs proved negative. The lack of metabolites in the urine was consistent with the short time interval between initial exposure and death. Absence of tetrachloroethylene in the stomach contents eliminated ingestion as the route of absorption. The level of tetrachloroethylene in the lungs, although low in comparison with the blood, does not indicate the method of absorption since tetrachloroethylene is both absorbed and excreted via the lungs. Distribution of tetrachloroethylene was consistent with its lipophilic properties, being highest in the brain and lowest in the lung tissue (Lukaszewski, 1979). 4) A 24 year old white male was admitted to hospital with a six month history of "skipping of heart beats", dizziness and headache. These symptoms became progressively worse in the two to three months prior to admission. There was no history of dyspnoea, angina pectoris, diabetes, blackouts, chest pain, hypertension, Raynaud's phenomenon or drug abuse. Seven months prior to admission the patient had begun working in a dry cleaning facility where he was responsible for the treatment of clothes with tetrachloroethylene. On examination he was alert, orientated and apyrexial with an irregular pulse of 70/minute, and a blood pressure within normal limits. On examination nothing remarkable was found. ECG on admission demonstrated sinus rhythm and multiple ventricular premature beats (VPB). All other findings were normal. The VPBs on admission did not respond to lignocaine. Continuous 24 hour ECG monitoring revealed multiple unifocal VPBs, but on the second day after admission, without any further treatment, the VPBs became less frequent. By the fourth day the patient was free from headache, dizziness and VPBs. On the fifth day he was discharged with a plasma tetrachloroethylene level of 0.15 ppm. A few days later the patient returned to work and soon began to become symptomatic again. Two weeks later he returned to hospital, physical examination was normal but resting ECG revealed frequent VPB and plasma tetrachloroethylene levels were 3.8 ppm. The patient was advised to leave his present employment; one month after exposure stopped the patient was free from neurological symptoms and cardiac arrhythmias (Abedin et al, 1980). Internally extracted data on cases Of 14 cases of tetrachloroethylene exposure reported, 2 were asymptomatic and all the other cases recovered within 5 days post-exposure. Clinical effects that were reported were nausea, vomiting, slurred speech, ataxia, drowsiness, disorientation, confusion, euphoria, restlessness, shortness of breath, nystagmus, hypotonia, tachypnoea and coma. One adult aged 20 years ingested 20 ml of tetrachloroethylene. Initially he was unconscious; he then became disorientated and aggressive and developed oculogyric crisis and a disturbance in his liver function. He received a gastric lavage, intravenous fluids and acetylcysteine. The patient was well after 3 days and was discharged. A 2“ year old boy ingested an unknown quantity of tetrachloroethylene. He developed ataxia, vomiting, drowsiness and then became unconscious. He had nystagmus, hypotonia and was tachypnoeic. ECG was normal and chest X-ray showed mild shadowing. He was discharged well 2 days post- exposure. 8 ANALYSIS 8.1 Agent/toxin/metabolite 8.2 Sample containers to be used 8.3 Optimum storage conditions 8.4 Transport of samples 8.5 Interpretation of data The biological tolerance of tetrachloroethylene in blood 16 hours after exposure (TVL = 50 ppm) is 6.0µmol/L (Skender et al, 1991). Tetrachloroethylene concentrations averaged 1.2 mg/L in 26 workers exposed to an average air concentration of 21 ppm for 30 minutes. Blood concentrations in 6 subjects reached an average peak level of 194 ppm of vapour (Baselt and Cravey, 199o); the compound was rapidly cleared from the blood when exposure ended and was not detectable (at sensitivity limit of 1mg/L) after 30 minutes. Blood concentrations were found to correlate with the atmospheric tetrachloroethylene concentrations as well as degree of physical activity of an individual (Monster et al, 1979). 8.6 Conversion factors 1 mg/L = 0.00289 mmol/L (blood) 1 mg/L = 147.4 ppm (air) 1 ppm = 6.78 mg/m3 at 25°C, 760 torr 8.7 Other recommendations 9 OTHER TOXICOLOGICAL DATA 9.1 Carcinogenicity Increased incidence of hepatocellular carcinomas in mice given tetrachloroethylene in doses of 500 to 1000 mg/kg for 78 days have been noted (Baselt and Cravey, 1990; Ellenhorn and Barceloux, 1988; Hathaway et al, 1991; Pegg et al, 1979). An increase in mononuclear cell leukaemia in rats inhaling doses of 200 to 400 ppm for 2 years has also been reported (Hathaway et al, 1991). Two limited epidemiological studies on the mortality of individuals with occupational tetrachloroethylene exposure in dry-cleaning and laundering operations have indicated an increase in liver cancer (Blair et al, 1979). However, these studies are not satisfactory for reaching definite conclusions about the potential for tetrachloroethylene carcinogenicity in humans (Hathaway et al, 1991). A 1987 cohort mortality study of dry-cleaning workers with exposure to tetrachloroethylene as well as other petroleum-based solvents detected an increased incidence of urinary tract cancers (Brown and Kaplen, 1987). A study in Massachusetts was carried out after tetrachloroethylene was found to have been in the drinking water for 20 years. There seemed to be an increase in leukaemia and bladder cancer in the individuals exposed, which was associated with chronic exposure (Aschengrau et al, 1993). Other cohort and proportionate mortality studies have variously reported excesses of leukaemias, lymphosarcomas and cancer of skin, cervix, oesphagus, kidney, colon, lung, liver and pancreas (Clement international Corporation, 1993; Hathaway et al, 1991). However, there have been also been a number of studies (as reviewed in Clement International Corporation, 1993) that have demonstrated that there is not enough human data or evidence to connect high concentrations of tetrachloroethylene to cancer. But this chemical is suspected as being a human carcinogen and handled as such (Hathaway et al, 1991). 9.2 Genotoxicity Assays of clastogenic effects in humans following occupational exposure to tetrachloroethylene show inconsistent results. Increases in chromosome aberrations and sister chromatid exchanges were not detected in lymphocytes from 10 workers exposed to tetrachloroethylene (Ikeda et al, 1980). 9.3 Mutagenicity Tetrachloroethylene is a weak mutagen, yielding positive results in bacterial assays, but baseline responses in mammalian systems did not find increased sister chromatid exchanges or chromosomal aberrations in lymphocytes of workers exposed to tetrachloroethylene (Ikeda et al, 1980). 9.4 Reprotoxicity Pregnant rats exposed to 300 ppm tetrachloroethylene for 7 hours a day, on days 6 through 15 of gestation had 4 to 5% reduced in body weight and twice the number of per implantation compared with controls (Ware, 1988). 9.5 Teratogenicity An increased number of resorption delayed skull, ossifications, subcutaneous oedema, and sternal malformations were found in the offspring of rats exposed to 300 ppm tetrachloroethylene for 7 hours a day on days 6 to 15 of pregnancy (Hathaway et al, 1991). No reports of teratogenicity associated with tetrachloroethylene were found in humans. 9.6 ADI 9.7 MRL 0.6 ppm (Clement International Corporation, 1993). 9.8 AOEL 9.9 TLV 50 ppm (COSHH, 1995; Ferroni et al, 1992). 9.10 Relevant animal data Experimental rats were unconscious in minutes following exposure to concentrations of 6,000 ppm or more, several hours at 3,000 ppm but not at 2,000 ppm (Rowe et al, 1952). In rats exposed via inhalation, tetrachloroethylene levels rise more or less continuously with duration of exposure in brain, lungs, and fat, but they tend to level off in blood and liver after a 3 hour exposure. Brain cerebrum concentrations of tetrachloroethylene exceed blood levels by about four-fold and brain cerebellum levels by three-fold, independent of the duration of exposure (Savolainen et al, 1977). Rats were exposed to tetrachloroethylene vapour levels of 70, 230 and 470 ppm for 7 months. Occasionally the rats were exposed to higher concentrations (averaging 7,000 ppm) and became slightly ataxic which disappeared within a few minutes post-exposure. It is thought that they developed tolerance to high concentrations. All concentrations above 2,750 ppm produce anaesthesia during acute exposure. However, after 6 exposures to concentrations of 2,750 ppm it was found that the rats did not become anaethetised even above a concentration of 10,000 ppm (Carpenter, 1937). When fed to laboratory mice, an LD50 of 8850 mg/kg was determined. Dogs and cats have survived doses of 4000 mg/kg and rabbits 5000 mg/kg. However, dogs were killed by intravenous doses of 85 mg/kg; the few that received 75 mg/kg or less survived (Gehring et al, 1991). Single oral doses of [36Cl] tetrachloroethylene were absorbed completely when administered to rats at 189 mg/kg (Daniel, 1963), as were doses of [14C] tetrachloroethylene dissolved in corn oil administered to mice at 500 mg/L (Schumann et al, 1980). Several mutagenicity studies have been performed on tetrachloroethylene which employ the Ames Salmonella/microsomes test or modifications of this test. Most tests reveal little or no evidence of mutagenic activity, except at concentrations that resulted in greater than 90% bacterial toxicity (Ware, 1988). 9.11 Relevant in vitro data No data 10 ENVIRONMENTAL DATA 10.1 Ecotoxicological data Solubility in water Municipal drinking-water in the UK contains an average of 1.3 mg/L of tetrachloroethylene and the total daily food intake is about 160 mg per day (WHO, 1984). WHO drinking water guidance level based on a carcinogenic endpoint in 10µ/L (Clement International Corporation, 1993). In ground water where volatilisation does not occur, tetrachloroethylene remains for months or years. In 1988, in the US, it was estimasted that 23,000 pounds of tetrachloroethylene was released to water from manufacturing and processing facilities. Volatilisation Volatilisation seems to be the major way in which tetrachloroethylene is lost from water. Other Tetrachloroethylene is ubiquitous in air, with levels in the ppt to ppb range. Tetrachloroethylene has been detected in dairy products (milk, cheese and butter) at 0.3-13 µg/kg, meat at 0.9-1.0 µg/kg, oils and fats at 0.01-7 µg/kg, beverages at 2-3 µg/kg, fruits and vegetables at 0.7-2 µg/kg and fresh bread at 1 µg/kg (Clement International Corporation, 1993). The log octanol/water partition coefficient is 2.86. 10.2 Behaviour Adsorption onto soil Contamination of soil can occur via leachate from landfill sites. It is very mobile in soil and readily migrates to ground water. 10.3 Biodegradation Environmental fate About 85% of tetrachloroethylene used annually in the USA is lost to the atmosphere, and the world-wide emission of tetrachloroethylene has been estimated to be about 450 kilotonnes per year (WHO, 1984). In the United Kingdom, estimates for air samples range from 1-9 ppt from over the Atlantic Ocean near Lands End, 8-57 ppt on Exmoor, and 15-40 ppb at a Northern England industrial area (Commision of the European Communities, 1986). Atmospheric emissions occur from metal degreasing uses, production of fluorocarbons and other chemicals, textile industry uses, and miscellaneous solvent-associated applications. Annual mean levels of 6 ppb and 10 ppb were detected downwind of a chemical laundry and a rubber factory, respectively, in Hamburg, Germany (Bruckmann et al, 1987). Emissions also occur at landfill sites containing the chemical. Levels of 0.7 ppb and 0.9 ppb were detected 1.5 and 0.5 metres above landfill soil near the city of Bielefeld, Germany (Clement International Corporation, 1993). In 1988 it was estimated that a total of 32.3 million pounds of tetrachloroethylene was released to the air from manufacturing and processing facilities in the US (Clement International Corporation, 1993). Releases of tetrachloroethylene to surface water appear to be minor in comparison to atmospheric releases (Clement International Corporation, 1993). Release to water through aqueous waste account for 1% or less of the total releases of tetrachloroethylene to the environment (Clement International Corporation, 1993). Aeration processes at waste treatment facilities strip much of the tetrachloroethylene from the water and release it into the atmosphere as a result of the high volatility of this chemical. There are many processes of recycling tetrachloroethylene, which generate tetrachloroethylene-containing sludges and dirty filters that have been landfilled in the past. Contamination of soil can occur through leaching of tetrachloroethylene from these disposal sites. In 1988, 106,000 pounds of tetrachloroethylene was thought to be released to land from manufacturing and processing facilites in the US (Clement International Corporation, 1993). Aerobic/anaerobic Tetrachloroethylene can be transformed by reduction dehalogenation to trichloroethylene, dichloroethylene and vinyl chloride under anaerobic conditions. It has also been suggested that there is a potential that tetrachloroethylene completely mineralises to carbon monoxide in soil and aquifer systems and in biological treatment processes (Vogel and McCarty, 1985). Microbial Photolysis Benignus et al (1985) (as cited in Commission of the European Commmunities, 1986) state that tetrachloroethylene undergoes photochemical degredation in the troposphere. Trichloroacetyl chloride is described as a major degredation product and phosgene a lesser one. tetrachloroethylene exists in the troposphere for one year or less. Hydrolysis Tetrachloroethylene in the atmosphere is hydrolysed to trichloroacetic acid and then decomposes to carbon dioxide and chloride ions (Pearson and McConnell, 1975). Half-life in water, soil and vegetation Zoeteman et al (1980) estimated the half-life of tetrachloroethylene to be 3-30 days for river water and 30-300 days for lake- and ground- water. 10.4 Environmentally important metabolites Tetrachloroethylene in the atmosphere is hydrolysed to trichloroacetic acid and then decomposes to carbon dioxide and chloride ions (Pearson and McConnell, 1975). Under certain conditions, tetrachloroethylene in ground water has been reported to degrade to and then to dichloroethylene and vinyl chloride. 10.5 Hazard warnings 10.5.1 Aquatic life Concentrations of tetrachloroethylene detected in fish in the Irish Sea ranged from below detection limits to 43 ng/g (dry weight), which was only 2-25 times greater thatn levels found in seawater. Levels of 0.3-43 µg/g (wet weight) were found in 15 species of fish collected off the coast of Great Britain (Clement International Corporation, 1993). 10.5.2 Bees 10.5.3 Birds 10.5.4 Mammals 10.5.5 Plants 10.5.6 Protected species 10.6 Waste disposal data One method of disposal involves absorption by vermiculite, dry sand, earth, or a similar material and then burial in a secured sanitary landfill. A second method involves incineration after mixing with another combustible fuel. With the latter method, combustion must be complete to prevent the formation of phosgene, and an acid scrubber must be used to remove the haloacids produced (Clement International Corporation, 1993). Author Henrietta Wheeler National Poisons Information Service (London Centre) Medical Toxicology Unit Guy's & St Thomas' Hospital Trust Avonley Road London SE14 5ER UK This monograph was produced by the staff of the London 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. Peer review was undertaken by the Directors of the UK National Poisons Information Service. March 1996 REFERENCES Abedin Z, Cook R and Milberg RM. 1980 Cardiac toxicity of perchloroethylene (a dry cleaning agent). 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