Document B5oqOKxn2qBKveannvg31RrG4

V- ORGANISATION MONOtALE DE LA SANTt CENTRE INTERNATIONAL OE RECHERCHE SUR LE CANCER INTERNATIONAL AGENCY FOR RESEARCH ON CANCER ISO, COURS ALBERT THOMAS - 69 372 ITON CCDEX 1 - PRANCE TtL 75.SI.S1 - TELEBH.: UNICANCER - Lyon - T.I.. 3S0073 - '-'SlF -RECEIVE0 With the compliments jun i 1913 Dr John Higginson Director Q/vl<A, r Vj -- Avec les compliments du Dr John Higginson Directeur 1.;a { f' * 1 . * % ,ye -; \, t TRICHLOROETHYLENE This compound was previously evaluated by an LARC Working Group in February, 1976 (IARC, 1976a). Since that time new data have become available and are included in this monograph. Two reviews are available (Lyman, 1978; Mercier, 1977). 1. Chemical and Physical Data 1.1 Synonyms and trade names Chem. Abstr. Services Reg. No.: 79-01-6 Chem. Abstr. Name: Trichloroethane Acetylene trichloride; i-chloro-2,2-dichloroethylene; l,l-dichloro-2/ chloroethylene; ethinyl trichloride; ethylene trichloride; T^E; Tri; trichloroethylene^ 1,1,2-trichloroethylene Algyleh; Anamenth; Benzinol; Blacosolv; Blancosolv; Cecolene; jn. J Chlorilen; Chlorylen; Chlorylea; Ch^orylen; Circosoly; Crawhaspol; Densinxluat; Dow-Tri; Dukeron; Fleck-Flip; Flock Flip; Fluate; / /emalgene; Germalgene; Lanadin; Lethurin; Narcogen; /Narosoid; A-- !5_ Nialk; Perma-A-Chlor; Perm-A-Clor; Petzinol; Philex; Threthylen; Threthylene; Trethylene; Triad; Trial; Triasol; Trichloran; Trichloren; Triclene; Tri-Clene; Trielene; Trielin; Trilen; Trilene; Triklone; Triline; Trimar; Triol; TRI-plus; TRI-plus M; / Vestrol; Vitran,* Westrosol 1.2 Structural and molecular formula/"and molecular weight c: C! H Cl Mol. wt: 131.4 1.3 Chemical and physical properties of the pure substance From Weast, (1976), unless otherwise noted. (a) Description: Colourless liquid (Irish, 1963) (b) 3oiling point: 87C ^ 034682 (c) Melting point: -73C Od) Freezing point: -86.8C (Irish, 1963) (e) Density: d3'0 1-4642 (f) Refractive index: n^ 1.4773 X* (S) Spectroscopy data: '> vapour * 200 nm; infrared, Raman, nuclear magnetic resonance, and mass spectral data have also been tabulated (Grasselli & Ritchey, 1975) (h) Solubility: Miscible (0.12 w/v at 20C) with water (Irish, 1963); miscible with acetone, ethanol, diethyl ether, chloroform and oils (Lloyd etal., 1975) (i) Volatility: Vapour pressure is 77_ mm Hg at 25C (Irish, 1963) (j.) Vapour density: 4.54 (air ~ 1) (Irish, 1963) (k) Stability: Nonflammable; when pure and containing a stabilizer, it is stable in presence of air, moisture, light, and in contact with metals up to 130C {Bardie,-1 19 6Aft. When heated with ozone, it decomposes rapidly into products such as hydrogen chloride, _ ^ phosgene, carbon monixide and chlorine peroxide. At 700C and above, the vapouf decomposes to give a mixture of dichloroethylene, tetrachloroethylene, carbon tetrachloride, chloroform, and methyl chloride (Hardle, 1964). Upon contact with certain metals, open flames' Or ultra-violet, it decomposes almost instantly to phosgene and/or hydrogen chloride, chlorine and dichloroacetyl cb -ftJS Occupaiiuual Safely ainl~Uiiallh-Admioisarati.-Ai, 1975) ie presence of alkali, trichloroethylene decomposes to highly toxic dichloroacetylene (US Occupational Safety and Health Administration) (1) The most-1 important reaction -of trichloroethylene is its oxidative breakdown of atmospheric oxygen, greatly accelerated by elevation of temperature, exposure to light, especially ultra-violet; not hydrolyzed by water under normal conditions; reacts with alkali under pressure at 150C to produce glycolic acid and with sulphuric acid to give monochloroacetic acid (Eardie, 1964) (a) Conversion factor: 1 ppm in air is equivalent to 5.37 mg/m3 SL 034683 1.4 Technical produces and impurities Trichloroethylene is available in the US in high purity, electronic, USP, technical, metal degreasing and extraction grades (Hawley, 1971). Typical analysis of a commercial grade is: boiling range at 760 am, ,/ 86.6-87.8C; density, di5 1,467-1.471; acidity (as HC1), 0.0062 max,; rn ' alkalinity (as NaOH), 0.0012 max; no free halogen; residue on evaporation, 0.005 max.; moisture content, not cloudy at -12C. d Antioxidants, such as amines (0.001 to 0.012 or more) (Copelin, 19^7) / or combination of epoxides such as epichlorohydrin (See also IARC, 1976/) and esters (0.2 to 22 total) (Starks, 1956), are added to trichloroethylene. Specifications for trichloroethylene produced in Japan are: specific gravity (15C/40C), 1.4680; boiling range, 86.5-88.2C; non-volatile matter, 0.0052 max.; acid content (as HC1), 0.00022 max. 2. Production, Use, Occurrence and Analysis k 2.1 Production and Use / (a) Production Trichloroethylene was prepared by Fischer in 1864 during experiments on the reduction of hexachloroethane with hydrogen (Hardie, 1964). The first conmercial method for its preparation was the dehydrochlorination of acetylenederived 1,1,2,2-tetrachloroethane (see monograph, p, ) by reaction with calcium hydroxide or by gas-phase pyrolysis. Although this method is still used today, over 902 of the trichloroethylene produced in the US is prepared by the chlorination and dehydrochlorination of 1,2-dichloroethane (see monograph, p. ). This is also the process used in Japan. Trichloroethylene has been produced commercially in Austria and the UK since 1908, in Germany since 1910, in the US since 1925 (Hardie, 1964), and in Japan since 1935. Production of trichloroethylene in the US in 1977 was 132 million kg (US International Trade Commission, 1977). Output has been decreasing since 1970, when a reported 277 million kg were produced by seven companies (US Tariff Commission, 1972). This decrease in production is due primarily to legislation restricting the use and emissions of L trichloroethylene and to the closing of three acetylene-based and one ethylen/- s based plants. SL 034684 US exports of trichloroethylene in 1976 were 16 million kg, mostly to the Federal Republic of Germany (3.8 million kg), France (3.4 million kg), Mexico (2.1 million kg) and Brazil (2 million kg)(US Department of Commerce, 1977a). US imports during that year totalled 7 million kg (US Department of Commerce, 1977b). It is estimated that at least 9 companies produce trichloroethylene in western Europe with total production in excess of 200 million kg/year. In at least three countries dFrance,.the Federal Republic of Germany?) and the United Kingdom) annual production is estimated to exceed 50 million kg/year. These countries, and Italy engage in both imports and exports of trichloroethylene in the range of 10-50 million kg/year. Annual production of trichloroethylene in the COMECON countries is estimated to be greater than 100 million kg. In Japan, fopf companies produced 80 million kg trichloroethylene in 1976, compared to 106 million kg in 1972. In 1976, 11 million kg trichloro ethylene were exported from Japan. (b) Use Of the trichloroethylene produced in the US in 1977, 82% was used for vapour degreasing of fabricated metal parts; 15% was exported; and the remainder (3%) was used in a variety of miscellaneous applications. Trichloroethylene is widely used in vapour degreasing, since all of its physical and chemical properties fall within the limits required in vapour degreasing processes. One disadvantage of trichloroethylene in this use is its high photochemical reactivity, causing smog, and leading to restrictions on its use. Since trichloroethylene decomposes rapidly upon exposure to high temperature, open flame or ultraviolet light (See section 1.3 (k)) a proposed standard was issued by the US Occupational Safety and Health Administration on October 20, 1975, which requires that operations involving high temperature, open flames or ultraviolet light be outside of areas in which trichloroethylene vapours are present, unless such operations are appropriately shielded and ventilated (US Occupational Safety and Health Administration, 1975). Miscellaneous applications of trichloroethylene include its use as a solvent in the textile industry; as a solvent for adhesives, and lubricants; and as a low temperature heat transfer fluid. It has also b en used as a component in several consumer products (Lloyd et al., 1975). SL 034685 A pharmaceutical grade of trichloroethylene is used as a general anaesthetic in surgical, dental and obstetrical procedures and as an analgesic in the treatment of trigeminal neuralgia. It has been used as a disinfectant and detergent for skin, minor wounds and surgical instruments. It has also been used on a variety of animals as a volatile anaesthetic. The use of trichloroethylene as an extraction solvent (e.g., for use in manufacture of decaffeinated coffee and extraction of spice oleoresins) has been approved by the US Food and Drug Administration (FDA) for many years. However, on September 27, 1977, the FDA proposed regulations prohibiting the use of trichloroethylene as a food additive, directly or indirectly. Specific examples and practices to be prohibited included use in hop extraction, decaffeination of coffee, the isolation of spice oleoresins, adhesive coatings and components, and in vinyl chloride-hexane-1 copolymers. Food containing any added or detectable level of trichloroethylene will be deemed to be adulterated when the final order has issued. On the same data, the FDA also proposed a regulation that any human drug containing trichloroethylene is a new drug and will be deemed to be misbranded. Under this regulation anesthetics containing trichloroethylene would be banned. Also it was proposed to declare trichloroethylene a deleterious substance, thereby causing any cosmetic product to be deemed to be adulterated under existing law. The FDA also proposed a regulation prohibiting the use of trichloroethylene as an additive to animal and pet food.suar-i ~ in in ^iia nr a r* tv ' Tl 1 nnr--liy-Hrr m -j-*-.--.--I --' -" * j c..,u practices as the use of trichloroethylene for the extraction of oil-seed products would be prohibited. The FDA also proposed an order prohibiting the use of trichloroethylene in animal drug products, such as its use as an inhalation anesthetic, skin disinfectant, and in detergents (US Food and Drug Administration, 1977). No data on use patterns in Europe were available. The estimated 1977 Japanese consumption pattern for trichloroethylene is: metal cleaning, 63%; solvent and other uses, 23%; and exports, 14%. It was reported in May 1978 that trichloroethylene has been accepted by the US Environmental Protection Agency as a candidate for issuance of a notice of a rebuttable presumption against renewal (RPAR) of registration > T SI 034686 (see 'General Remarks on Substances Considered', p. possible oncogenicity (Anon., 1978). ) on the basis of The US Occupational Safety and Health Administrations health standards for exposure to air contaminants require that an employee's exposure to trichloroethylene does not exceed an eight-hour time-weighted average of 535 og/m3 (100 ppm) in the working atmosphere in any eight-hour work shift of a forty-hour work week (US Occupational Safety and Health Administration, 1975). The corresponding standard in the Federal Republic of Germany is 260 mg/m3, in the German Democratic Republic, 250 mg/m3, in Sweden, 160 mg/m3, and in Czechoslovakia, 250 mg/m3 (Winell, 1975). The US Occupational Safety and Health Administration proposed on October 20, 1975, that the maximum allowable concentration be reduce from f ,^200 ppm) to,/150 ppm)(US Occupational Safety and Health Administration , 1975). The maximum acceptable ceiling concentration in the USSR is 10 mg/m3 (Winell, 1975). The US National Institute for Occupational Safety and Health has a. recently recommended that occupational exposure to halogenated anesthetic agents, including trichloroethylene, be controlled so that no worker is exoosed at concentrations greater than/f2 ppmy(NI0SH, 1977b). 2.2 Occurrence Trichloroethylene is not known to occur as a natural product. The occurrence of trichloroethylene in air, water, soil and sediments, food, marine organisms, and man have been reviewed (Battelle Columbus Laboratories, 1977) . U) Air The US Environmental Protection Agency has estimated that approximately 60% of the total annual world production of trichloroethylene is released to the environment, with annual emissions of about 540 million kg to the atmosphere and 9.1 million kg to the ocean (Fuller, 1976). The dispersive uses of trichloroethylene (metal cleaning and solvent applications) have been estimated to result in annual emission' of 192 million kg in the US (Fuller, 1976) and 100 million kg in Japan (Ohta et at., 1976). The background ambient air concentration of trichloroethylene has been reported for several world-wide locations including: (1) Western Ireland, at levels of 80 ng/m3 (15 ppt) (Lovelock, 1974); (2) over the Q3A687 sl dtiI Wk t jev* North Atlantic, at less than 27 ng/m3 (5 ppt) (Lovelock, 1974); (3) `/iC' s* -JJs-n c >V| _ , 'j>{; -- rural area/27 ng/m3 (5 ppt)/and (4) the northern hemisphere, at a level f' , * of about 80 ng/m (15 ppt), and the southern hemisphere, at a level of about 8 ng/m3 (1.5 ppt) (Cox et at., 1976). Trichloroethylene has also been detected in ambient air in: (1) the North eastern US, at typical levels of 1 yg/m3 (0.18 ppb) in urban areas and less than 0,1 yg/m3 (0.02 ppb) in rural areas (Lillian et at., 1975); (2) Michigan, at levels of 150-500 ng/m3 (30-90 ppt) (Russell & Shadoff, 1977); (3) at 4 California sites at levels of 83-1670 ng/m3 (15.6-310.8 ppt) (Singh, 1976); (4) at five US land stations ranging from 2 to 28 ng/m3 (0.4-5.2 ppt) and eleven sea stations ranging from 1 to 22 ng/m3 (0.2-4 ppt) (Murray & Riley, 1973); (5) Tokyo, Japan, at twenty-six sites, at average levels of 6.4 yg/m3 (1.2 ppb) (Ohta at at., 1976) and (6) Manchester, England, at levels of 5.35-342 yg/m3 (1-64 ppb) (Pearson & McConnell, 1975). (b) Water A summary of reported occurrences of trichloroethylene found in ehs A -Wq- raw water samples, nt lake water sample, feea finished drinking water samples,/ e*e raw sewage sample, (Hv.v?ers and in samnles of effluent from /a* k chemical plants and fchwna sewage treatment plants is available (Shackelford & Keith, 1976). In samples of surface waters collected from 204 sites near heavily industrialized areas trichloroethylene was detected at 88 sites, at levels greater than 1 yg/1 (Ewing et at., 1977). Trichloroethylene has been detected in: (1) tap water (Dowty et at,, 1975); (2) tap, lake, spring, and subterranean water at levels of 105, 38, 5, and 80 ng/1, respectively (Grob & Grob, 1974); and (3) effluent water from a chemical production plant at levels of 0.2 mg/1 (Eurocop-Cost, 1976). Trichloroethylene has also been detected in: (1) a riverr at levels of 25 yg/1 (Rook et at., 1975); (2) the ground water near waste deposites at levels of 100 yg/1 (Kotzias et at., 1975); (3) the drinking water of five cities at levels of 0-0.5 yg/1 (Coleman et at., 1976); and (4) influent and effluent water from a sewage treatment plant, at levels of 8.6-40.4 yg/1 (Bellar et at., 1974), (c) Soil and Sediment Concentrations of trichloroethylene in soil and sediment near production and user sites in the US ranged from 0- over 100 yg/kg (Battelle Columbus Laboratories, 1977j). SL 034688 t, ii i v r i (a) Food Trichloroethylene has been detected In the following foodstuffs in England: dairy products, meats, oils and fats, beverages, and fruits and % vegetables at levels of 0.3-10, 12-22, 0-10, 0-60, and 0-5 pg/kg, respectively (McConnell et at., 1975). Traces of trichloroethylene have also been found in edible oils after extraction (Gracian & Martel, 1972). (e) Marine organisms Trichloroethylene has been detected in three species of mollusks, at levels of 0-joft^ ng/g, and five species of fish, at levels of 0-479 ng/g (dry weight) (Dickson & Riley, 1976). (f) Human Trichloroethylene has been detected in post-mortem human tissue samples, at levels of less than 1-32 Ug/kg (wet tissue) (McConnell et at., 1975) and in human expired air, at levels of 0-3.9 ug/hr/subject (Conkle &t at., 1975).. It has been estimated that about 60,000 people are annually exposed Ob- to trichloroethylene as an anesthetic (Fuller, 1976). (&) Occupational Exposure The occupational exposure to trichloroethylene has been reviewed (National Institute for Occupational Safety and Health, 1973). Trichloroethylene has been detected in the atmosphere of dry cleaning plants (Banenko, 1974). Levels, of 1076-43,000 mg/m3 (200-8000 ppm) were also found in a small factory (Kleinxeld & Tabershaw, 1954). Concentrations of vapour in a dial assembly workshop in a factory ranged from below 135 mg/m3 (25 ppm) to over 538 mg/m5 (100 ppm) and in the degreasing room, were between 800 and 1350 mg/ra3 (150-250 ppm) (Takamatsu, 1962). The concentration to which surgeons and nurses were exposed in ,operating-rooms varied from 1.6-554 mg/m3 (0.3-103 ppm) (Corbett, 1973). 8 About 5000 medic^, dental and hospital personnel are routinely exposed to trichloroethylene. The 1974 National Occupational Hazard Survey by the US National Institute for Occupational Safety and Health (NI0SH), has estimated that 034689 SI* workers primarily in the aircraft manufacturing industry, in blast furnaces, and in steel mills are exposed to trichloroethylene (NIOSH, 1977a). (h) Other Trichloroethylene has been detected as a trace impurity in US helium (Schehl, 1973). 2.3 Analysis A review of the analysis of trichloroethylene in waste-treatment plant sludge was made by Camisa (1975). The analytical methods to determine trichloroethylene in air, oleoresins, blood, and urine have also been reviewed (Kouner, 1975; Walter st al., 1976). Some methods used to determine trichloroethylene in environmental samples are tabulated in Table 1. Gas chromatography with electron capture detection has been studied collaboratively by eight European laboratories to detect trichloroethylene residues in grain. The limit of detection ranged from 0.005-0.2 mg/kg (Panel on Fumigant Residues in Grain, 1974). A system to determine trichloroethylene in water is described (Ellison & Wallbank, 1973). Use of gas chromatography has also been made by Kuchinskii (1977) and Lillian et al., (1975). 3. Biological Data Relevant to the Evaluation of/Tarcinogenjc Risk to Humans f* 3.1 Carcinogenicity studies in animals1 (a) Oral administration Mouse: Groups of 50 male and 50 female B6C3F1 mice, 5 weeks-old, were administered trichloroethylene (99% pure; 0.19% 1,2-epoxybutane and 0.09% epichlorohydrin) (See also IARC monograph on epichlorohydrin X (IARC, 1976b)) in corn oil by oral gavage. High dose males recieved 1The Working Group was aware of ongoing studies to assess the carcindfgene'city of trichloroethylene in mice by skin, subcutaneous and oral administration (IARC, 1978a) and of an inhalation study in rats and mice carried out under contraac| to the Manufacturing Chemist's Association (Toxicology Information Progfam. /Preliminary results of the inhalation study indicate findings similar to the NCI Study( Page & Arthur, 1978) SL 034690 r Vy (~ $ .1 A J o' type Fmimi? oilon Onitjpfi nyrnp nn<l rricnpnnlntefl i fqirMfl Alt Mnrlr p 1 rro nl mr>n|ilir ret* Amli Inil AntM rut Krnl Alwo^pliere AmMrnf AmUfrjtif Wnter flrn /ind frenli writer Hrnte unfer ANALYTJCA?. 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Groups of 20 male and 20 female mice served as vehicle-treated matched controls. Survival was reduced in high dose males and control males. Hepatocellular carcinomas occurrred in 1/20 control males and 0/20 control females, in 26/50 low dose males and 4/50 low dose females, and in 31/48 high dose males and 11/47 high dose females. Ifetastases of the liver-cell tumours to the lung were found in 7/98 treated males and in 1 control male. The first IjJaU hepatocellular carcinomas were observed in a mouse treated with the high dose of trichloroethylene that died during week 27. Lung tumours occurred in both sexes in the treated groups: 5/50 (5 adenomas) and 4/50 (2 adenomas, 2 carcinomas) in males and females`of the low dose group and 2/48 (1 adenoma, 1 carcinoma) and 7/47 (5 adenomas, 2 carcinomas) in males and females treated with the high dose of trichloroethylene. In the controls, only one lung adenoma was reported among the females (National Cancer Institute, 1976). [The Working Group noted that the low dose males and females received 1 and 0.7 mg/kg bw/day epic^eiydrin and the high dose males and females received 2.1 and 1.56 mg/kg bw/day epichlorohydrin.] pi " Rat: (ioups of 50 male and 50 female Osborne- Ifendel rats, t? weeks -- of age, received by gavage trichloroethylene (99% pure; 0.19% 1,2 epoxybu(ane and 0.09% epichlorohydrin) (See also IARC, 1976b) In corn oil 5 days a week for 78 weeks. High dose animals received varying dose schedules of 1000-1500 mg/kg bw'and1 low dose animals received 500-750 mg/kg bw-. All surviving animals were killed 110 weeks after the start of treatment. The time-weighted average doses were 549 and 1097 mg/kg bw/day. A group of 20 male and 20 female vehicle-treated rat3 served as controls. In males 17/20 controls, 42/50 low dose and 47/50 high dose rats died . t ........... " j before the end of the study. In females 12/20', 35/48/controls/'lcw dosejand r\ H. 37/50( high dose]rats died. Tfedian survival time was approximately 60 weeks * / for high dose males and 85 weeks for lew dose males. In females the median survival time of high and lew dose rats was approximately 70 weeks. In males, 5/20 controls, 7/50 low dose and 5/50 high dose rats developed tumours. In females, 7/20 controls, 12/48 low and 12/50 high dose rats developed tumours. SL 034693 No liver-cell tumours occurred. The tumours occurred in various organs in ,/ ^treated and vehicle controls;and were mainly reticulum-cell sarcomas, ' r- lymphosarcomas or malignant lymphomas, fibroadenomas of the mammary gland, haemangiosarcomas at various sites, follicular adenocarcinomas of the thyroid, chromophobe adenomas of the pituitary and renal hamartomas. Toxic nephropathy was observed in rats of both sexes treated with high and low closes of trichloroethylene (National Cancer Institute, 1976) . [The Working Group noted the poor survival of treated rats and that the low and high dose animals received 0.5 and 1 mg/kg bw/day epichlorohydrin.] In a preliminary report of an ongoing study, groups of 30 male and 30 female Sprague Dawley rats, 13 weeks of age, were given 50 or 250 mg/kg bw trichloroethylene (purity unspecified) in olive oil by oral gavage 4-5 times per week for 52 weeks followed by observation for life. A group of 30 male and 30 female controls received olive oil alone. Results were reported 76 weeks.after the start of treatment at which time 46 controls, 39 low dose and 34 high dose males and females combined of each group were still alive. Among high dose rats that had died 1 lymphoid leukaemia and 1 plasmocytoma was observed (minimum latent period 38 weeks) and 2 plasmocytomas occurred in low dose animals that had died (minimum latent period 70 weeks)* NO such tumours were found ^ ifeioli, 1977). 3.2 Other relevant biological data (a) Experimental systems Toxic effects A wide variation in impurities and manufacturing processes produces inconsistency in the evaluation of experimental trichloroethylene toxicity (Defalque,. 1961). Pure trichloroethylene decomposes readily into highly toxic products. The extensive literature on toxicity of trichloroethylene has been reviewed by Aviado et cl. (1976), Browning (1965), Defalque (1961), US Occupational Safety and Health Administration (1975), Lloyd sz cl. (1975), Von Oettingen (1964), Smith (1966), and Walter et cl. (1976). In rats, the oral LD50 was 7.2 g/kg bw (Smyth et cl., 1969) and in mice, 2.85 g/kg bw (Aviado et cl., 1976). The i.p. LD50 in mice was 3.2 g/kg bw (Klaassen & Plaa, 1966) or 1.83 g/kg bw (Schumacher & Grandjean, 1960); that in dogs was 2.8 g/kg bw (Klaassen & Plaa, 1967). The lowest lethal 034694 SL i.v. dose for dogs 150 mg/kg bw, and in rabbits, the s.c. lethal dose was 1.8 ^g/kg bw (Barsoum & Saad, 1934). The maximum concentrations of vapour which produced no toxic effects after exposure for 7 hours daily on 5 days a week for 6 months were: rats and rabbits, 1076 mg/m3 (200 ppm); guinea-pigs, 538 mg/m3 (100 ppm); monkeys, 2150 mg/m3 (400 ppm) (Adams et al., 1951). 30 exposures (8 h dally, 5 days/weeks, to 3825 mg/m3 (700 ppm) or continuous exposure to 189 mg/m3 (35 ppm) for 90 days) did aot cause any visible sign of toxicity in rats, dogs, monkeys, guinea-pigs and rabbits (Prendergast et al., 1967). In 8 cats exposed to concentrations of 108 mg/m3 of air (20 ppm) for 1-1.5 hours per day for 4-6 months, centrilobular hepatitis, nephritis, hypertrophy of lymphoid glands and splenomegaly were observed (ifcsinger & Fiorentini, 1955). In mice, trichloroethylene caused less damage to the kidneys and liver than did carbon tetrachloride or chloroform (Klaassen & Plaa, 1966). In a chronic toxicity study the maximal tolerated oral dose of industrial grade trichloroethylene in Osborne-^fendel rats was 1100 mg/kg bw for both sexes, and 2340 mg/kg (male) and 1740 mg/kg (female) in B6C3F1 hybrid mice (National Cancer Institute, 1976). Embryotoxicity and teratogenicity }J Groups of rats and mice were exposed H hours daily on days 6-15 of gestation to 1600 mg/m3 (300 ppm) in air trichloroethylene inhalation^) without effects on the average number of implantation sites per litter, litter size, the incidence of foetal resorptions, foetal sex ratios or foetal body measurements. No treatment-related increased incidence in skeletal or visceral malformations was observed (Schwetz et al., 1975). Absorption, distribution, excretion and metabolism A review is available (Piotrowski, 1977). Following inhalation of trichloroethylene, no trichloroethylene was detected in the blood of organs of rats (Kimmerle & Eben, 1973a). Dogs exposed to trichloroethylene excreted trichloroacetic acid and the glucuronide of trichloroethanol in the urine (Barrett 4 Johnston, 1939; Butler, (1949). SL 034695 th l r y When 36Cl-trichloroethylene was given by gavage to rats, 10-20" of the dose was excreted in the urine as 1-5% trichloroacetic acid and 10-15% trichloroethanol, 0-0.5% was excreted as trichloroethylene in the faeces and 72-85% as trichloroethylene in the expired air (Daniel, 1963). The demonstration of the enzymic conversion of trichloroethylene to chlordal by liver microsomes from rabbits, rats and dogs supports the suggestion of Powell (1945) that the trichloroethylene oxide intermediate rearranges into chloralhydrate (Byington 4 Leibman, 1965; Laibman, 1965) gh1`--3-----------V- iH-'-Tif-' * ri -i in' 111 T1'Hr"1 m ir ~nim1 ' rn -1 -h^rTgnTated 1 * i jFwt-'u..ji---. "1 Q,raT\ (Chloral was also isolated in vitro as an intramolecular rearrangement product of trichloroethylene oxide; chloral is then in part reduced to trichloroethanol or oxidized to trichloroacetic acid (Bonse & Henscher, 1976; Bonse ev al., 1975) . Spectral evidence for the- formation of trichloroethylene oxide (2,2,3-trichloro-oxirane) during incubation of trichloroethylene with metabolizing hepatic microsomes was reported by Dehleke ev at, (1977). In vivo and in vitro ~yiH1nivptiii#ity wj UC-trichloroethylene is irreversibly bound to liver endoplasmic protein (Allemand st al., 1978; Bolt et at., 1977; Uehleke & Poplawski-Tabarelli, 1977 ead'Van Durren & Banerjee,* 1976)^. Binding is correlated with the activity of hepatix mixed- function oxidase^Uehleke & Poplawski-Tabarelli, 1977); thus, treatment of -- animals with inducers of hepatii mixed function oxidase such as phenobarbital, methylcholanthrene, Aroclor 1254, hexachlorobenzene, increased the hepato- toxicity of trichloroethylene (Carlson, 1974; Moslen st al., 1977a) and depleted hepatic glutjj(athione (Moslen st at., 1977bJ>J^/In another assay with Salmonella typhimurium TA100, the oure comoound was not mutagenic either in 'o the presence or absence of rat liver microsemes; in addition it was shown that two of the impurities found in a technical trade sample of trichloroethylene, epichlorohydrin and 1,2-epoxybutane were mutagenic in the same study in the 0 absence of rat liver micrjsomes (Henschler st al., 1977). _________________ _________ Mutagenicity and other related short-term tests Trichloroethylene was mutagenic in Escherichia coli K12 and in Salmonella typhirruriian TA100 (Greim et al., 1975; Simmon et al._, 1977) in the presence of a microsomal activation system (ilajULuiei ---------------- "" In Saccharomyces cerevisiae strain XV185-14C, trichloroethylene induced reverse mutations in the presence of mouse liver microsomes and the mutation SL 034696 frequencies were concentration-dependent. On the basis of their data, the authors concluded that trichloroethylene induced base-pair as well as frameshift type mutations (Shahin & Von Borstel, 1977). Positive results had also been reported in the same species for the induction of gene mutations and mitotic gene conversion (strain D7) in the presence of mammalian microsomes as well as in host(mouse)-mediated assay (strain D4) (Bronzetti et at., 1978). Mice given single i.p. injections of trichloroethylene (in doses of 50" of LDso in diaethylsulphoxidejor five repeated injections of 1/6 LD50 (at one day invervals) showed no increase in the frequency of chromosome aberrations in their bone marrow cells (Cerna & Kypenova, 1977). In spot tests for somatic mutations, i.p. treatment of pregnant mice* with 1 <n trichloroethylene induced coat colour muations in embryos exposed in utaro (Fahrig, 1977)^., l'[lTo what extent the po* sitive mutagenic results reported with trichloroethylene are due to impurities in the test samples could not be determined by the Working Group]. (b) Humans Numerous fatalities as a result of trichloroethylene anaesthesia and of pi2, industrial intoxications were competed. Sudden death, probably due to ventricular fibrillation has been reported upon exertion shortly after intense exposure (Defalque, 1961). Chronic inhalation of trichloroethylene affects the central nervous system (Grandjean st at., 1955). Accidental ingestions produced inebriety, vomiting, diarrhoea, collapse and coma followed either by death (pulmonary oedema and liver and kidney necrosis at autopsy) or recovery with transient '"I neurological sequelae (amnesia, headache, numbness, weakness of extremeities, psychosis, or hemiparesis) (Defalque, 1961). Toxic effects on the liver have been reported (Schilttmann, 1970). It has been suggested that the toxic action in humans was mainly due to contaminants (Browning, 1965; Defalque, 1961). Psychophysiological function was depressed in volunteers exposed to 110 ppm (592 mg/m3) trichloroethylene for two 4 hr periods '(Salvini et at,, 1971). Experimental exposure of ten volunteers to 1070 mg/m3 (200 pom) trichloroethylene vapour for periods of 7 h during 5 days produced fatigue and sleepiness (Stewart ei at., 1970). Impairment of neurological and psychological functions after acute and longer exposure was also reported by Gamberale et at. (1976) and Triebig et at. (1977). SL 034697 Cutaneous reactions to trichloroethylene have been reported (Bauer & Rabens, 1974; Schirren, 1971; Stewart si al., 1974). There is an indication of enhancement of the liver-toxic effect of trichloroethylene by concomitant exposure to ethanol or isopropyl alcohol (Traiger & Plae, 1974). The uptake of trichloroethylene by the body as well as blood o concentrations of trichloroethylene has been reported (Astrand & Ovrum, 1976). The concentration of the metabolip trichloracetic acid in the urine is an indication of trichloroethylene exposure (Axelson st al., 1978; Smith, y 1978). Humans exposed to trichloroethylene excrete trichloracetic acid and trichloroethanol in the urine (Kimmerle & Eben, 1973b; Nomiyama & Nomiyama, 1971; jt Powell, 1945). Kinetic studies of formation and excretion of trichloroacetic acid and trichloroethanol have been reported (Fernandez st al., 1977; Monster st al., 1976 i'Muller st al., 1974), Chloral hydrate was identified as a trichloroethylene metabolite in the blood (Cole si al., 1975; Scansetti si al., 1959). 3.3 Case reports and epidemiological studies1 An epidemiolojLgical study of cancer mortality among 518 males occupational exposed to rather low levels of trichloroethylene as estimated by trichloroacetic acid in the urine has been reported (Aanlaou si ^.l:, IPTftfr. (Exposure categories with averages below and above 100 mg/1 trlchloroacHic acid in the urine were used; 100 mg/1 roughly corresponds to an eight-hour time weighted average exposure of 160 mg/m3 (30 ppm) trichloroethylene in air). When compared to the national population rates, 49 deaths from all causes were observed versus 62 expected. With no consideration given to latency or intensity of exposure, 11 deaths due to cancer of all sites were observed versus 14.5 expected. When analyses was restricted to the time period, ten or more years since onset of exposure, no significant excess of cancer was demonstrated, either for those exposed to high or lower levels of trichloroethylene. It was concluded that this study could not rule out a 1The Working Group was aware of 2 studies in progress: a cancer mortality study of workers occupationally exposed to trichloroethylene and a follow-up study of workers exposed^to organochloride and alkylchloride compounds, to vinyl chloride, trichlonethylene and unsaturated compounds (IARC, 1978^). SL 034698 cancer risk to man, particularly for rare types of malignancies, such as liver cancer (Axelson et at., 1978). [The small size of the study group and the relatively short latend^period (mainly less than 20 years) underline this conclusion.] 4. Summary of Data Reported and Evaluation 4.1 Experimental data Trichloroethylene was tested In one experiment in mice and in one experiment in rats by oral administration. In mice, it produced hepatocellular carcinomas and lung tumours in both males and females. The experiment in rats was considered tD be inadequate. Preliminary results of an ongoing study by oral administration to rats could not be evaluated. Trichloroethylene is mutagenic in bacteria and yeast and in spot tests for somatic-mutations in mice. 4.2 Human data1 No case reports were available to the Working Group. The only epidemiological study available reported no statistically significant excess of cancer associated with exposure to trichloroethylene. However, owing to the small size of the group and the relatively short time since onset of exposure, an assessment of carcinogenicity could not be made. The extensive production of trichloroethylene fox over 50 years, together with its use as an industrial solvent and metal cleaning agent, as an inhalational anaesthetic and as a bacteriocide in drugs, food and consumer products, indicate that widespread human exposure occurs. This is confirmed by many reports of its occurrence in air, water and foods and in human tissues and expired air. 4.3 Evaluation There is limited evidence that trichloroethylene is carcinogenic in Subsequent to the meeting, the Secretariat became aware of a study of 330 deceased laundry and dry-cleaning workers who had been exposed to carbon tetrachloride, trichloroethylene and tetrachloroethylene. An excess of lung and cervical cancers and a slight excess of leukaemias and liver cancers were observed (Blair et al., 1979). 5. References Adams, E.M., Spencer, H.C., Rowe, V.K., McCollister, D.D. & Irish, D.D. (1951) Vapor toxicity of trichloroethylene determined by experiments on laboratory animals. A.M.A. Arch, industr. Hvs. occuo. Med,, 4_, 469-481 $j* / Allemand, H., Persayre, D., Descatoire, V,, Degott, C., Feldmann, G. & Benhamou, J.-P. (1978) Metabolic activation of trichloroethylene into a chemically reactive metabolite toxic to the liver. J. Pharmacol. exo. Ther,, 204, 714-723 Anon* (1978) Trichloroethylene. Pest. Tox* Chem. News. May 10, p. 2 Astrand, I. & Ovrum, P. (1976) Exposure to trichloroethylene. I. Uptake and distribution in man. Scand, J. Work Environ.Health, 4_, 199-211 Austern, B.M., Dobbs, R.A. & Cohen, J.M. (1975) Gas chromatographic determination of selected organic compounds added to wastewater. Environ. Sci. Technol., _9, 588-590 Aviado, D.M-, Zakhari, S., Simaan, J./'s Ulsamer, A.G. (1976) Methyl Chloroform and Trichloroethylene in the Environment. Cleveland, Ohio, Chemical Rubber Co., pp. 47-89 Axelson, 0., Andersson, K., Hogstedt, C., Holmberg, 3., Molina, G. & de Verdiar, A. (1978) A cohort study on trichloroethylene exposure and cancer mortality. 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