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    1,1,2-TRICHLOROETHYLENE

    Explanation

         1,1,2-trichloroethylene (trilene, TCE) has been evaluated for
    acceptable daily intake for man by the Joint FAO/WHO Expert Committee
    on Food Additives in 1976 (see Annex I, Ref. 40, p. 115) and 1980 (see
    Annex I, Ref. 51). A toxicological monograph was prepared in 1976 (see
    Annex I, Ref. 41).

         Since the previous evaluation, additional data have become
    available and are summarized and discussed in the following monograph.
    The previously published monograph has been expanded and is reproduced
    in its entirety below.

    BIOLOGICAL DATA

    BIOCHEMICAL ASPECTS

    Absorption, distribution and excretion

         Probably between 71% and 76% of inhaled trilene is rapidly
    absorbed through the lungs. In man, most absorption occurs within the
    first few minutes of exposure and then decreases to an equilibrium
    between air/blood concentrations. Moderate absorption can occur
    through intact skin and from the gastrointestinal mucosa after
    ingestion (von Oettingen, 1955).

         In the rat, rabbit and dog absorbed trilene is distributed among
    all organs and tissues but concentrates mostly in fat and brain and
    least in skeletal muscle; lung and liver also retain low levels
    (Barrett et al., 1939; Clayton & Parkhouse, 1962; yon Oettingen,
    1955). Similar organ concentrations were found in guinea-pigs but high
    levels were also found in ovaries and adrenals (Fabre & Truhaut,
    1952). In the rat, trilene and trichloroacetic acid may be selectively
    bound to erythrocytes, hence giving high spleen levels (Fabre &
    Truhaut, 1952) but plasma proteins may also be involved (Soucek &
    Vlachova, 1960). In man, trilene is detectable in the blood within 
    30 minutes of inhalation (Stewart et al., 1962).

         The elimination of trichloroethylene in male Wistar rats given
    i.v. doses of 3, 6, 9, 12 or 15 mg/kg of trichloroethylene fits a two
    compartment model at the lower dose and a three compartment model at
    the higher doses (Withey & Collins, 1980).

    Metabolism

         Trilene is metabolized slowly to chloralhydrate (via an epoxide)
    and then rapidly to 2,2,2-trichloroacetic acid (CCl3COOH) and
    2,2,2-trichloroethanol (CCl3CH2OH), these latter two metabolites are

    excreted as urinary glucuronides (e.g. trichloroethanol glucusiduronic
    acid) with very little unchanged trilene appearing in the urine
    (Powell, 1945; Butler, 1949; Uhl & Haag, 1958; Williams, 1959; Smith,
    1966). Dogs excreted 5-8% of absorbed trilene as trichloroacetic acid
    and 15-20% as trichloroethanol up to four days after exposure (Barrett
    et al., 1939; Barrett & Johnston, 1939; von Oettingen, 1955). The lung
    and spleen, less so the liver, are probably the main sites of
    metabolism (Fabre & Truhaut, 1952; Defalgue, 1961). Rats excrete about
    4% of inhaled trilene as trichloroacetic acid, the lung and spleen
    being the main sites of metabolism in vitro and in vivo, the liver
    being less important (Fabre & Truhaut, 1952).

         Male rats (250-300 g bw) were dosed with 0.5 ml of a 20% solution
    of trichloroethylene (TCE) in olive oil. Urine was analysed daily for
    a seven-day period. Maximal excretion of the metabolites occurred
    24-48 hours after dosing. Twenty-four hours following administration
    of the TCE in olive oil, 0.82% of the dose was excreted as
    trichloroacetic acid, 0.12% as trichloroethanol and 11.3% as the
    trichloroethanol glucuronide. During the seven-day period the
    metabolites in urine accounted for 16.44% of the administered dose
    (2.14% as trichloroacetic acid, 0.82% as free trichloroethanol and
    13.8% as trichloroethanol glucuronide). Free TCE was not detected in
    urine or a 24 hour expired air sample, No metabolites of TCE were
    detected in the faeces. When rats were given a single oral dose of
    TCE (0.25 or 0.5 ml) urinary metabolites accounted for 18% of the
    administered dose (Daniel, 1957a, b). 36Cl-labelled trilene was
    given to rats by gavage. Ten to 20% was excreted in the urine as
    trichloroacetic acid (1-5%), trichloroethanol (10-15%), 0-0.5% in
    the faeces and 72.85% probably as trilene in the expired air. The
    metabolites were formed by intra-molecular rearrangement.
    Radioactivity was excreted for up to 18 days after single dosing
    (Daniel, 1963). In vitro studies on rat liver microsomes showed
    conversion of trilene to chloral (Byington & Leibman, 1965). Rabbits
    excrete 0.5% of absorbed trilene as trichloroacetic acid (Fabre &
    Truhaut, 1952; Defalgue, 1961) and after oral dosing by gavage no
    significant effects were seen on urobilin, blood glucose level or
    serum cholesterol (Dervillee et al., 1938). Guinea-pigs show presence
    of trichloroacetic acid in their urine after inhalation (Fabre &
    Truhaut, 1952). Calves similarly metabolize orally administered
    trilene to trichloroacetic acid (1%) and trichloroethanol (13-25%)
    appearing in their urine together with a trace of trilene. The balance
    is probably exhaled or excreted in the faeces (Seto & Schultze, 1955).

         Man excretes 6-16% of inhaled trilene as trichloroacetic acid
    (Ahlmark & Forssmam, 1951); others found 7-27% of retained trilene
    being excreted as trichloroacetic acid (Powell, 1945; Soucek et al.,
    1952) as well as trichloroethanol, monochloroacetic acid and
    chloroform (Soucek et al., 1952; Defalgue, 1961). Small amounts of
    trichloroacetic acid may continue to be excreted in the urine for up
    to 12 days after single exposure (von Oettingen, 1955). Five human

    subjects exposed for five hours to trilene excreted 4% of the retained
    dose as monochloroacetic acid, 19% as trichloroacetic acid and 50% as
    trichloroethanol over the next 14 days (Soucek & Vlachova, 1960;
    Defalgue, 1961). In another experiment eight subjects inhaled trilene
    for five hours, 51-64% of the inhaled trilene was retained, the rest
    exhaled unchanged. Of the remaining trilene, 38-50% was excreted as
    urinary trichloroethanol and 27-36% as urinary trichloroacetic acid.
    8.4% of trichloroacetic acid and trichloroethanol was excreted in
    the faeces. Sweat and saliva also contained both metabolites
    (Bartonicek, 1962). In all species most of the trichloroacetic acid
    and trichloroethanol is excreted in the first two days after exposure
    but excretion may go on up to 53 days. Some two to four hours elapse
    after single exposure before trichloroacetic acid appears in the blood
    reaching a maximum in 20-50 hours (Ahlmark & Forssman, 1951; Defalgue,
    1961). Trichloroethanol appears to be the main metabolite and is much
    more toxic (Bartonicek & Teisinger, 1962). Disulfiram decreases the
    excretion of trichloroacetic acid and trichloroethanol by acting
    either on converting enzymes or on trilene release from fat depots
    (Bartonicek & Teisinger, 1962) while glucose and insulin increase
    production (Soucek & Vlachova, 1960).

         Chronic exposure may cause disturbance of protein metabolism by
    an increase in the ▀-globulin to 16-21% (normal 10-14%) and in fat
    metabolism by an increase in unsaturated fatty acids (Guyot-Jeannin &
    Van Steenkiste, 1958). Repeated inhalation or oral ingestion by rats
    causes transitory elevation of SGOT levels for 24 hours after the last
    exposure, the SGPT levels remaining normal. SGOT levels return to
    normal within nine days after exposure. No such transitory effects are
    seen in rabbits (Tolot et al., 1966; Viallier & Casanova, 1965).
    Previous ingestion of ethanol potentiates trilene toxicity in rats as
    shown by a rise in SGOT, SGPT and SICD (isocitric dehydrogenase) and
    widespread degenerative lipid infiltration as well as early
    centrilobular necrosis of the liver (Cornish & Adefuin, 1966).

         The biological half-life (T1/2) of the urinary metabolites of TCE
    was studied in factory workers between 20 and 50 years old (24 males
    and six females). The mean T1/2 of total trichloro-compounds was
    approximately 41 hours (Ikeda & Imamura, 1973).

         In a study rats and hamsters were exposed to trichloroethylene
    vapour with or without pretreatment with phenobarbital. Pretreatment
    with phenobarbital resulted in a marked increase in the rate of
    urinary excretion of trichloro-compounds. Liver preparations from rats
    treated with phenobarbital showed a marked increase in the rate of
    trichloroethylene metabolism compared to untreated rats. Pretreatment
    of rats with trichloroethylene failed to induce this enzyme (Ikeda &
    Imamura, 1973).

         Single exposure of mice to the inhalation LD50 of
    trichloroethylene showed some hepatotoxicity as evidenced by a
    rise in SGPT (Gehring, 1968).

         Trichloroethylene passes readily through the placenta and occurs
    in foetal blood in higher concentrations (Helliwell & Hutton, 1950).
    Orally administered trilene has no effect on rat liver glutathione
    levels (Johnson, 1965).

         In adult male Aderly Park Strain Swiss mice, administration of a
    single gavage dose of 2.0 ml/kg of trichloroethylene resulted in the
    appearance in the urine of small amounts of dichloroacetic acid in
    addition to the previously reported trichloroacetic acid metabolite
    (Hathaway, 1980). Administration by i.p. injection of 1 ml/kg of
    trichloroethylene in adult male Sprague-Dawley rats reduced the
    disappearance of labelled hexobarbital from the blood and liver. Eight
    hours after trichloroethylene administration, microsomal cytochrome
    P-450, cytochrome b5 and total protohemene were unchanged in non-
    pretreated rats; however, in phenobarbital pretreated rats cytochrome
    P-450 and total protoheme were reduced. Repeated i.p. injection with
    trichloroethylene for five days (0.25 ml/kg twice on day 1, 0.5 ml/kg
    twice on day 2, and 1 ml/kg twice daily on days 3-5) resulted
    in increases in liver to body weight ratio, microsomal protein,
    NADPH-cytochrome C reductase activity, aniline hydroxylase activity,
    p-nitrophenol glucuronyl transferase activity and covalent binding of
    labelled trichloro-ethylene metabolites to microsomal proteins in
    vitro. However there were decreases in cytochrome P-450,
    ethylmorphine demethylase and hexobarbital hydroxylase activity
    (Pessayre et al., 1979).

         Difference absorption spectroscopy measurements of rabbit liver
    microsomes incubated with NADPH and purified trichloroethylene have
    provided additional evidence for the formation of the previously
    postulated epoxide intermediate (2,2,3 trichloro-oxirane) in hepatic
    metabolism of trichloroethanol (Uehleke et al., 1977).

    TOXICOLOGICAL STUDIES

    Special biochemical studies on hepatotoxicity

         Irreversible binding of labelled trichloroethylene to microsomal
    protein was demonstrated in an in vitro incubation system using
    microsomes prepared from male Sprague-Dawley rats. Binding was
    enhanced by pretreatment of rats with phenobarbital, and markedly
    enhanced by the addition of an epoxide hydrase inhibitor to the
    incubation system. Binding was decreased by SKF-24A, a known inhibitor
    of the metabolism of P-450 substrates (Van Duuren & Banerjee, 1976).
    These same authors have also demonstrated binding of trichloroethylene
    metabolites to liver microsomal protein of male and female B6C3F1
    mice. Binding to microsomal proteins from stomach, lung and kidney

    tissues of male mice was also demonstrated as well as binding to
    salmon sperm DNA in the presence of hepatic microsomes from male mice
    (Banerjee & Van Duuren, 1970).

         Administration of labelled trichloroethylene to male Sprague-
    Dawley rats resulted in the irreversible binding of a labelled
    metabolite to liver protein. In vitro studies with hepatic
    microsomes and labelled trichloroethylene showed that an NADPH
    generating system was necessary for irreversible binding of a labelled
    metabolite to microsomal proteins. Rats pretreated with 70 mg/kg i.p.
    of phenobarbital showed histopathological liver damage 12 hours after
    i.p. administration of 1 ml/kg of trichloroethylene, whereas animals
    not pretreated with phenobarbital did not show liver damage after
    similar trichloroethylene administration. Similarly, serum SGPT levels
    were higher following i.p. administration of up to 2 ml/kg of
    trichloroethylene in animals pretreated with phenobarbital; and
    cytochrome P-450 levels dropped in phenobarbital pretreated but
    not untreated rats following i.p. administration 1 ml/kg of
    trichloroethylene (Allemand et al., 1978; Cunningham et al., 1981).

         In studies of labelled trichloroethylene administered in an
    inhalation chamber, male B6C3F1 mice metabolized more inhaled
    trichloroethylene on a per kg body weight basis than male Osborne-
    Mendel rats, the mice also activated more of the inhaled
    trichloroethylene to a reactive tissue binding metabolite in the
    liver and kidney than the rat. Doses of 0, 250, 500, 1200 or 
    2400 mg/kg of trichloroethylene were given by gavage to male B6C3F1 
    mice five days per week for three weeks. There was a dose-related 
    increase in liver weight up to 177% of control and histopathological 
    damage with centrilobular hepatocyte swelling, giant cell inflammation 
    and mineralized cells at the highest dose. When 1100 mg/kg/day was
    given in the same dosing regimen to male Osborne-Mendel rats no
    histopathological changes were observed, liver weight increased to
    118% of control and hepatic DNA synthesis was increased. No renal
    histopathological changes were observed and body weight was not
    affected. In mice given 1200 mg/kg of 14C radiolabelled
    trichloroethylene by gavage, an estimated maximum DNA alkylation level
    of 0.62 alkylations/106 nucleotides was reported in three to four
    treated mice, while no alkylation was reported in the fourth animal
    (Stott et al., 1982).

    Special studies on carcinogenicity

    Mouse

         Groups each of 100 weanling (45-day-old) mice (c57BL/C3H strain)
    equally divided by sex, were dosed daily, five days per week with TCE
    dissolved in corn oil (Industrial Grade Containing "Inhibitors").
    Initial dosage levels were 1000 and 2000 mg/kg for males and 700 and
    1400 mg/kg for females. These doses were increased once to 1200 and

    2400 mg/kg for males and to 900 and 1800 mg/kg for females. Control
    mice (40) received an equivalent amount of corn oil. At week 36 of the
    study the mice were placed on a regimen of no dosing for one week,
    followed by four weeks of dosing. At week 78 dosing was stopped on the
    mice maintained until the study was terminated at week 90. The time
    weighted average intakes were calculated to be 1169 and 2339 mg/kg for
    males and 869 and 1739 mg/kg for females. During the course of the
    study the mice were housed in cages of solid polypropylene without
    filters. Ten mice were housed in each cage. Mice in this study were
    maintained in a room housing mice on other studies receiving the
    following compounds: trichloroethylene, 1,1,2,2-tetrachloroethane,
    chloroform, 3-chloropropene, chloropierin, dibromochloropropane
    (DBCP), ethylene dibromide, 1,1-dichloroethane, sulfolene, iodoform,
    methyl chloroform, 1,1,2-trichloroethane, tetrachloroethylene,
    hexachloroethane, carbon disulfide, trichlorofluoromethane, and carbon
    tetrachloride. 27/50, 14/48 and 12/20 of high, low and control groups
    of male mice and 8/47, 8/50 and 0/50 of high, low and control groups
    of female mice died during the course of the study. Histopathology of
    a variety of neoplastic and non-neoplastic lesions showed primary
    liver tumours (hepatocellular carcinoma in 1/20 control males, 26/50
    low-dose males, 31/48 high-dose females). Metastasis of the
    hepatocellular carcinoma to the lung occurred in 4/26 low-dose males
    and 3/31 high-dose males. Malignant lymphoid tumours (e.g. reticulum-
    cell sarcoma, lymphosarcoma and malignant lymphoma) were recognized in
    1/20 Control males, 4/50 low-dose males, 2/48 high-dose males, 1/20
    control females, 5/50 low-dose females and 6/47 high-dose females.
    Other tumours observed in various animals included benign fibrous
    tumours, adenoma of the Harderian gland, endometrial adenocarcinoma,
    ovarian granulosa-cell carcinoma and mammary adenocarcinoma
    (Weatherholtz et al., 1975).

         Because the trichloroethylene in the previous carcinogenic
    bioassay contained epichlorohydrin as a stabilizer (a, compound which
    is mutagenic) new studies were conducted using epichlorohydrin-free
    trichloroethylene.

         Epichlorohydrin-free trichloroethylene was administered by gavage
    using a corn oil vehicle to groups of 50 male and 50 female B6C3F1
    mice. Two batches of trichloroethylene were used during the course of
    the study. The compound was given at a dose of 1000 mg/kg bw five days
    per week for 103 weeks. The animals were then maintained without
    dosing for an additional 0-4 weeks prior to terminal sacrifice. A
    concurrent control group of 50 male and 50 female mice received the
    corn oil vehicle by gavage on the same dosage regimen. A complete
    gross and histopathological examination was conducted on all animals
    found dead or killed at termination. Mean body weights of dosed male
    mice were lower than those of controls throughout the study, while
    values for dosed females were comparable with controls. Survival in
    the dosed males was significantly reduced; no significant difference
    in survival was observed between dosed and control females.

         There was a significant increase in the incidence of hepato-
    cellular carcinoma in both male and female dosed mice. The incidence
    was 8/48 in control males and 30/50 in dosed males, and 2/48 in
    control females and 13/48 in dosed females. The carcinomas metastized
    to the lung in five of the dosed and one of the control males. The
    incidence of hepatocellular adenomas was also increased in the dosed
    mice. The incidence was 3/48 in control males and 8/50 in dosed males,
    and 2/48 in control females and 8/49 in dosed females. The combined
    incidence of alveolar/bronchiolar adenoma or carcinoma was not
    significantly elevated in dosed female mice (1/45 and 4/48 in the
    control and dosed groups, respectively); however the incidence of the
    alveolar/bronchiolar adenomas alone was significantly elevated in the
    dosed females (0/48 control and 4/48 dosed). There was no relationship
    between treatment and the incidence of these lung tumours in male
    mice. The increased incidence of the lung tumours in the female mice
    was not considered to be related to treatment. Harderian gland
    adenomas were found in 4/50 dosed males, 3/49 dosed females and none
    in controls of either sex. A squamous cell carcinoma of the stomach
    was found in one treated female and squamous cell papillomas of the
    stomach were also found in two dosed females. None of these lesions
    was found in control females or treated males, however a Squamous cell
    carcinoma was found in one control male. Although these lesions in the
    female may have been due to gavage administration of the compound they
    were not considered to be an indication of carcinogenicity at this
    site. A compound-related toxic nephrosis, designated as cytomegaly,
    was present in 90% of the dosed male and 98% of the dosed female mice
    but not in controls (National Toxicology Program, 1982).

    Rat

         Groups of 50 male and 50 female F-344/N rats were administered
    by gavage doses of 500 or 1000 mg/kg bw, epichlorohydrin-free
    trichloroethylene in a corn oil vehicle five days per week for 103
    weeks. Two batches of trichloroethylene were used during the course of
    the study. Vehicle control groups of 50 males and 50 females received
    the corn oil vehicle on the same dosing regimen and an additional
    group of 50 males and 50 females served as the untreated control
    group. A complete gross and microscopic pathological examination was
    conducted on all animals found dead or sacrificed at termination. A
    significant dose-related reduction in body weight gain was observed in
    female rats and weight gain was also significantly reduced in high-
    dose males. Mortality was significantly increased in dosed males.
    Mortality was also increased in the high-dose females but evidently
    it was not statistically significant.

         There was a significant increase in renal adenocarcinoma in
    high-dose male rats (0/48 control, 0/49 low dose and 3/49 high dose).
    Additionally, a transitional cell carcinoma of the renal pelvis and
    two renal tubular cell adenomas were found in the low-dose males. The
    tubular cell adenomas were considered to have the potential to

    progress to carcinomas. A non-specified carcinoma of the renal pelvis
    was found in a high-dose male. In addition to the rumours, toxic
    nephrosis, cytomegaly, was found in 98% of the dosed males and 100% of
    dosed females. Both dose levels of trichloroethylene used exceeded
    the maximum tolerated dose, as evidenced by the early deaths. The
    cause of the early deaths was not established, but it may reduce
    the sensitivity of the bioassay to detect a higher degree of
    adenocarcinoma. In addition, from one to 10 animals/group were killed
    by gavage error (males: vehicle control 1, low dose 3, high dose 10;
    females: vehicle control. 2, low dose 5, high dose 5) (National
    Toxicology Program, 1982).

    Mouse (skin painting)

         In skin painting studies performed with groups of 30 female
    Ha:ICR Swiss mice a dose of 1.O mg/mouse (about 40 mg/kg for a 25 g
    mouse) of trichloroethylene applied three times per week did not
    result in skin tumours or an increase in the incidence of tumours at
    other sites as compared to concurrent controls. The animals were on
    test for about 83 weeks and histopathology was only conducted in
    animals and tissues showing a gross lesion at autopsy. Administration
    of 0.5 mg/mouse (about 20 mg/kg) of trichloroethylene by gavage once
    weekly for about 88 weeks to groups of 30 male and 30 female HA:ICR
    Swiss mice did not show an increased incidence of stomach as other
    tumours as compared to concurrent controls. Routine histopathological
    examination was only performed on sections taken from the stomach,
    liver and lung. Compared to controls administered the trioctanoin
    vehicle, a group of 30 female Ha:ICR Swiss mice given weekly
    subcutaneous injections of 0.5 mg/mouse (about 20 mg/kg) of
    trichloroethylene for about 88 weeks did not show an increase in
    injection site sarcomas. As compared to the National Toxicology
    Program mouse study where a positive result was obtained, much lower
    doses, more infrequent doses and a shorter exposure interval were used
    in the three studies using Ha:ICR mice (Van Duuren et al., 1979).

    Rat (Inhalation)

         In an inhalation carcinogenicity study, groups of 30 male and 30
    female NMRI mice, Wistar rats and Syrian hamsters of each species were
    exposed to 0, 100 or 500 ppm (0, 0.01 or 0.05%) air concentrations of
    pure trichloroethylene stabilized with an amine base for six hours per
    day, five days per week for 18 months. Remaining mice and hamsters
    were sacrificed after 30 months, and rats after 36 months. The
    following tissues were examined microscopically: spleen, liver,
    kidneys, lung, heart, CNS and tumourous tissues. Body weight gain was
    not significantly different between exposed and control animals in all
    species. Mortality was significantly increased in exposed mice of
    either sex, but not in the other species (Henschler et al., 1980). No
    significant increase in tumours were noted in any species except in
    the mouse where there was a statistically significant increase in

    malignant lymphomas in female mice. The tumour, which occurs with a
    high background incidence in females of this test species, also
    occurred significantly earlier in the exposed animals (Henschler et
    al., 1980).

    Special studies on inhalation

         Observations in animals exposed for varying periods up to 10
    months show disturbed coordination and hyperexcitability but no
    effects on liver, kidney or blood chemistry. Only the CNS showed some
    oedema and ganglion cell degeneration (Browning, 1965). Rats, guinea-
    pigs, squirrel monkeys, rabbits and dogs were exposed to 3825 mg/m3
    for six weeks without significant adverse effects. Exposure to
    189 mg/m3 for 90 days also revealed no significant pathological
    changes (Prendergast et al., 1967). Groups of 20 mice were exposed for
    one to eight weeks to 200 or 1600 ppm (0.02 or 0.16%) daily for four
    hours. Only slight transient fatty hepatic degeneration and no renal
    effects Were seem (Kylin et al., 1965).

         Guinea-pigs were exposed to vapour of trilene for two-and-a-half
    to four months without adverse effects on body weight, haematological
    findings or urinalysis results but there was slight evidence of
    hepatic parenchymal degeneration and renal glomerular and tubular
    degeneration (Lande et al., 1939). Rabbits given 0.074 g/kg trilene
    for one to five months showed little adverse effect on body weight,
    haematological finding and urinalysis, but some hepatic and renal
    lesions were seen (Lande et al., 1939). Hepatic injury as evidenced by
    BSP excretion, glycogen depletion and parenchymal degeneration as well
    as weight loss, lethargy and diarrhoea occurred but cleared on
    stopping exposure (Seifter, 1944).

    Special studies on mutagenicity

         In a dominant lethal study, groups of 50 male NMRI mice were
    exposed for 24 hours to air containing 0, 50, 202 or 450 ppm
    (0, 0.005, 0.0202 or 0.045%) of trichloroethylene. The exposed animals
    were then mated to one untreated female for four days, then mated with
    a new female. Altogether, each male was mated with 12 females. Females
    were sacrificed 13 days after removal from the male. There was no
    treatment-related effects on fertilization rate, or pre- or post-
    implantation loss (Slacik-Erben et al., 1980).

         A significant increase of sister chromatid exchanges were
    reported to occur in lymphocytes obtained from the blood of workers
    chronically exposed to trichloroethylene as compared to persons not
    exposed. Exposure in vitro of lymphocytes to a concentration of
    178 mg/ml of trichloroethylene was also reported to be associated with
    a significant increase in sister chromatid exchange (Gu et al., 1981).

         Chloral hydrate, a metabolite of trichloroethylene was found to
    be weakly mutagenic in Salmonella typhimurium strain TA-100 with a
    rat liver microsomal activation system, trichloroethylene itself
    tested in a closed system designed for volatile compounds was negative
    in both strains (Waskell, 1978).

    Special studies on reproduction

         Eight male and 16 female rats were fed on a diet containing 0% or
    5% of instant decaffeinated coffee solids extracted with trilene
    (containing residue of 0.5 ppm (0.00005%) trilene). Two generations
    were studied as regards paternal and filial mortality, conception
    rate, resorption, litter size, growth and survival of litter. Organ
    weights, blood chemistry, urinalysis and histopathology of the F2
    generation were normal (Zeitlin, 1967).

    Special studies on teratogenicity

         A teratogenicity study in rats fed 5% of trilene extracted
    instant decaffeinated coffee solids (equivalent to 0.5 ppm (0.00005%)
    trilene) was done for two weeks before mating until the twentieth day
    of the second pregnancy. Foetuses were examined and resorption sites
    counted. No significant deformities were noted in the test groups nor
    were there any excessive abnormalities (Zeitlin, 1966).

    Special studies on toxic factor

         Soybean meal extracted with trilene but not with hexane or carbon
    tetrachloride has caused fatal refractory haemorrhagic aplastic
    anaemia in cattle (Stockman, 1916; Picken et al., 1955). The toxic
    factor was shown to be associated with the protein fraction (Picken &
    Biester, 1957; Seto et al., 1958). Similar effects were produced by
    trilene-extracted meat scraps (Rehfeld et al., 1958). However, chicks
    fed trilene-extracted meat scraps showed improved growth (Balloun et
    al., 1955). The toxic factor has been identified as S-trans-
    (dichlorovinyl)-L-cysteine, a reaction product of trilene and protein
    which becomes freed on protein hydrolysis (McKinney et al., 1957).
    Using radiolabelled trilene it has been shown that this reaction is
    unlikely to occur when extracting coffee (Brandenberger et al., 1969).

        Acute toxicity
                                                                                         

                                     LD50
    Animal           Route         ml/kg bw           LD100        Reference
                                                                                         

    Mouse          Inhalation        -              7 900 ppm      von Oettingen, 1955
                                                    (0.79%)
                                                    (2 hours)
                   s.c.              11.0           -              Plaa et al., 1958
                   i.p.              2.2            -              Klaassen & Plaa, 1966
                   Oral              240 mg/kg                     Tucker et al., 1982

    Rat            Oral              4.92           -              Smyth et al., 1969
                   Inhalation                       20 000 ppm     Adams et al., 1951
                                                    (2%)

    Guinea-pig     Inhalation        -              37 000 ppm     von Oettingen, 1955
                                                    (3.7%)
                                                    (40 minutes)

    Rabbit         s.c.              -              1 800 mg/kg    Barsoum & Saad, 1934
                   Inhalation        -              11 000 ppm     Bernardi et al., 1956
                                                    (1.1%)
                   Percutaneous      20                            Smyth et al., 1969

    Dog            i.v.              -              150 mg/kg      Barsoum & Saad, 1934
                   i.p.              1.9            -              Klaassen & Plaa, 1967
                                                                                         
    
         Mice, rats, guinea-pigs and rabbits dying acutely from
    inhalation, show no toxic effects on the tissues, liver or kidney or
    after s.c. or i.v. administration (Browning, 1965). I.p. injection of
    2.5 ml/kg trilene into mice had no effect on BSP excretion and
    produced no proteinuria or glycosuria or histological renal changes
    (Plaa & Larson, 1965). Oral doses of 3-4 ml/kg bw were fatal to rats,
    mice and guinea-pigs with signs of gastrointestinal irritation (you
    Oettingen, 1955). Chronic oral poisoning has caused some liver and
    renal damage in dogs and rabbits (von Oettingen, 1955).

         Trilene is a local irritant on the skin, causing blisters and
    necrosis in man and desquamation with ulceration in rabbits (von
    Oettingen, 1955).

    Short-term studies

    Mouse

         Groups each of 10 mice (C57BL/C3H strain) equally divided by sex
    were dosed by intubation for five consecutive days/week for six weeks,
    With TCE at a level equivalent to 0, 1000, 1780, 3160, 5620 or
    10 000 mg/kg bw. The mice were then maintained for two weeks under
    control conditions. Body weight gains in all surviving groups were not
    significantly affected in a dose-related manner. All mice at the high-
    dose level died during the first week of the study, and only 1/5
    survived the next highest dose level. There were no deaths at
    3160 mg/kg bw dose or lower. No gross lesions were observed at the
    termination of the study (Weatherholtz et al., 1975).

         Groups of 140 male and 140 female CD-1 mice received
    trichloroethylene stabilized with 0.004% disopropylamine in their
    drinking-water at concentrations of 0.1, 1.0, 2.5 and 5.0 mg/ml
    (equivalent to about 18.4, 216.7, 393.0 and 660.2 mg of
    trichloroethylene/kg bw per day in males, the corresponding values in
    females were 17.9, 193.0, 437.1 and 793.3 mg/kg bw). The water also
    contained 1% of emulphor (a polyethoxylated vegetable oil) to dissolve
    the trichloroethylene into the water. A group of 260 animals of each
    sex received water containing emulphor only, while another group of
    140 animals per sex received water alone. The animals were on test for
    four or six months. Reduced fluid consumption was seen at the two
    highest doses in males and at the highest dose in females. There was a
    decreased body weight gain at the highest dose in both sexes. At both
    exposure times, relative liver weight was significantly increased in
    the three highest dosage groups in males and at the highest dose group
    in females and the relative kidney weight was significantly increased
    in high-dose males at six months and in high-dose females at four and
    six months. Decreased erythrocyte counts were observed at four and six
    months in high-dose males, decreased leucocyte counts-were also seen
    particularly in high-dose females. Treatment-related increases in
    fibrinogen in males and shortened clotting times in females were also

    observed. The report stated that treatment-related, gross pathological
    changes were not observed. Data on histopathological evaluation were
    not presented (Tucker et al., 1982).

         Groups of 10 male and 10 female B6C3F1 mice received O, 375, 750,
    1500, 3000 or 6000 mg/kg of trichloroethylene by gavage five days per
    week for 13 weeks. All the males and 9/10 females of the high-dose
    animals died during the course of the study. Body weight gain
    throughout the study was greater in all groups of dosed females as
    compared to controls - even in the lone surviving high-dose female. In
    the males, weight gain was depressed compared to controls except at
    the lowest dose. Relative and absolute liver weights were increased in
    a dose-related fashion. Hepatic centrilobular necrosis was seen in
    6/10 males and 1/10 females given 6000 mg/kg. In the 3000 mg/kg males,
    2/10 animals had multifocal areas of hepatic calcification and this
    lesion was also noted in one high-dose female. A hepatocellular
    adenoma was found in a female given 3000 mg/kg. The report noted that
    this is an extremely rare lesion in a 20-week-old mouse (National
    Toxicology Program, 1982).

    Rat

         Groups each of 10 rats (Osborne-Mendel) equally divided by sex
    were dosed by intubation for five consecutive days/week for six weeks
    with TCE at a level equivalent to 0, 562, 1000, 1780, 3160 or
    5620 mg/kg bw. The rats were then maintained for a further two weeks
    without administration of TCE. At the high-dose level all rats died by
    week 6. Body weight gains of all treated groups were less than
    control. Effects noted in animals at the highest dose range included
    hunching, urine stains, alopecia and laboured respiration. Gross
    necropsy findings at week 6 of the study included dilation of kidney
    in one male, and redness of kidney in another male, both in the
    1780 ppm (0.178%) group, and large abscessed areas in all lobes of the
    lungs of the animals. No other lesions were reported (Weatherholtz et
    al., 1975).

         Groups of 10 male and 10 female Fischer-344/N rats were
    administered 0, 125, 250, 500, 1000 or 2000 mg/kg of trichloroethylene
    by gavage in corn oil vehicles five days per week for 13 weeks. An
    additional group of 10 males received 2000 mg on the same dosing
    regimen. No mortality occurred during the study, and compared to
    controls, only the high-dose males suffered a reduced body weight
    gain. A minor or minimal renal tubular cytomegaly or karyomegaly of
    the inner cortex was seen in eight males in the 2000 mg/kg group and
    five of 10 females receiving 1000 mg/kg. Pulmonary vasculitis
    involving primarily small veins was seen in 6/10 high-dose males and
    6/10 high-dose females. This change was also noted in the 1/10 control
    animals of each sex, and many animals with the vasculitis also
    exhibited interstitial pneumonitis (National Toxicology Program,
    1982).

    Long-term studies

    Mouse

         (See special studies on carcinogenicity.)

    Rat

         Groups of 20 male and female rats were fed instant decaffeinated
    coffee solid extracted with trilene for two years at 0% or 5% of their
    diet (equivalent to a residue of 0.5 ppm (0.00005%) trilene) without
    deleterious effects on survival, behaviour, growth, food consumption,
    urinalysis, haematology, organ weights and histopathological findings
    (Zeitlin, 1963).

         Groups each of 100 weanling rats (Random Bred, Osborne-Mendel)
    equally divided by sex were dosed daily, five days per week, with
    industrial grade TCE dissolved in corn oil at initial dosage levels of
    1300 and 650 mg/kg. These dosages were adjusted downward at week 7 and
    again at week 16. Control mice (40) received an equivalent amount of
    corn oil. At week 36 of the study the mice were placed on a regime of
    no dosing for one week, followed by four weeks of dosing. At week 78
    dosing was stopped and the animals maintained until week 110. The time
    weighted average intakes were calculated to the 1097 and 549 mg/kg bw.
    During the course of this study the rats were maintained in a room
    housing rats on other studies and receiving the following compounds:
    trichloroethylene, dibromochloropropane, ethylnene dichloride,
    1,1-dichloroethane, and carbon disulfide. All rats in this room were
    housed in hanging galvanized steel cages without air-filters.
    Individual body weights and food consumption were recorded at weekly
    intervals for the first 10 weeks and at monthly intervals thereafter.
    Treated rats showed a decreased total weight gain during the period of
    growth, and survivors at the end of the study showed a lower body
    weight than controls. 47/50, 42/50 and 17/20 of the high, low and
    control male rats, and 37/50, 35/49 and 12/20 of the high, low and
    control female rats died before the termination of the study.
    Statistical analyses of the results indicated that the probability of
    survival was decreased by exposure to TCE. Histopathology of the
    various lesions in the test animals indicated a variety of neoplastic
    and non-neoplastic lesions in control, low-dose and high-dose rats.
    None of these lesions appeared to be compound related. The only drug-
    related lesion was a slight to moderate degenerative and regenerative
    tubular alteration, primarily affecting proximal tubular epithelium
    which was observed in low- and high-dose males and females, but not in
    controls (Weatherholtz et al., 1975).

    OBSERVATIONS IN MAN

    Special studies on occupational exposure

         A group of 518 male Swedish workers occupationally exposed to low
    levels of trichloroethylene was utilized in an epidemiological study
    on cancer mortality. Based on urinary excretion of trichloroacetic
    acid, a trichloroethylene metabolite in two exposure groups were
    identified. Neither of the exposure groups showed an excess of cancer
    mortality (Axelson et al., 1978).

         There is much experience from safe use of trilene as an
    anaesthetic for man and from various other analgesic inhalation
    treatments now abandoned e.g. trigeminal neuralgia, migraine, angina
    (von Oettingen, 1955). Some authorities recognize a syndrome of
    chronic intoxication (Moeschlin, 1956) and others admit only to a
    transient neurasthenic symptom complex (Anderssen, 1957). Fumes or the
    liquid can cause skin burns. No evidence exists of serious
    haematological effects. Neurological disturbances are similar to
    neurasthenic conditions with rarely apparent cardiac disturbances.
    Trigeminal palsies and optic nerve involvement may have been due to
    impurities but have not been seen with pure material. Irritation of
    the lungs and gastrointestinal symptoms have been reported after
    industrial over-exposure. Addiction has been reported (Bardodej &
    Vyskocil, 1956; Browning, 1965; Patty, 1958; Defalgue, 1961; Milby,
    1968; Mitchell & Parsons-Smith, 1969). Psychemotor performance is not
    affected by exposure to 100 ppm (0.01%) but there is a decline in
    performance at higher inhalation levels (Stops & McLaughlin, 1967).

         Eight males ware exposed to 0, 100, 300 or 1000 ppm (0, 0.01,
    0.03 or 0.1%) trichloroethylene in air for two hours. At 1000 ppm
    (0.1%) visual perception and motor skills were adversely affected
    (Vernon & Ferguson, 1969). In another experiment leucocyte alkaline
    phosphatase levels in peripheral leucocytes were elevated after
    prolonged exposure. This effect is reversible (Friborska, 1969).

         Acute human poisoning cases have recovered without hepatic or
    renal sequelae. After ingestion there is some burning of the oral
    mucosa, later nausea and vomiting with vertigo, ataxia, somnolence,
    confusion, delirium and coma (Browning, 1965). Excessive inhalation
    has been blamed for hepato-nephritis but the incidence is very low and
    it is possible that liver and renal involvement are the results of
    underlying previous disease (Roche et al., 1958). Untoward effects on
    the circulation, cardiac irregularities and excessive capillary oozing
    with tachypnoea but no adverse hepatic effects have been reported
    after anaesthetic use (von Oettingen, 1955). Ingestion of 60 ml
    appears to be fatal in man (Pebay-Peyroula et al., 1966). At
    elevated temperatures trilene reacts further to generate phosgene
    carbonylchloride and various acids which are all toxic (Defalgue,
    1961). The TLV is 100 ppm (0.01%) (Amer. Conf. Gov. Ind. Hyg., 1969).

    Comments

         Previous lifetime studies in rats and mice with TCE were not
    acceptable for evaluating the safety of the food use of this compound
    because the studies were carried out with an industrial grade of TCE
    containing a stabilizer (epichlorohydrin) which has been shown to be
    mutagenic. This grade TCE had not been approved for food use. Lifetime
    studies in rats and mice, dosed with epichlorohydrin-free TCE, have
    been completed. In the rat study, the dose levels used exceeded the
    maximum tolerated dose, and resulted in extensive toxicity and early
    deaths. A number of animals were also lost due to gavage errors. Three
    renal adenocarcinomas were found in the dosed rats. The occurrence was
    not dose related. In addition, all the treated animals showed toxic
    nephrosis and cytomegaly, and the adenomas may have been secondary to
    these toxic effects. In the mouse study, there was a significant
    increase in the incidence of hepatocellular carcinoma in the treated
    animals. However, the significance of this observation as an
    indication of carcinogenicity is complicated because (1) only one dose
    level was used in this study, and (2) the known variability in the
    background level of this rumour in the mouse strain was used. An
    additional problem in the interpretation of these studies is in the
    use of two batches of TCE each containing different impurities in each
    of the studies.

         TCE was inactive in a dominant lethal study and when tested
    against Salmonella typhimurium strain TA-100, with and without
    activation.

         The available data are not adequate to determine if TCE is a
    carcinogen.

    EVALUATION

    Estimate of an acceptable daily intake for man

         No ADI allocated.

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    See Also:
       Toxicological Abbreviations