TOXICOLOGICAL EVALUATION OF CERTAIN FOOD ADDITIVES
WHO FOOD ADDITIVES SERIES 10
The evaluations contained in this document were prepared by the
Joint FAO/WHO Expert Committee on Food Additives*
Rome, 21-29 April 1976
Food and Agriculture Organization of the United Nations
World Health Organization
*Twentieth Report of the Joint FAO/WHO Expert Committee on Food
Additives, Geneva, 1976, WHO Technical Report Series No. 599, FAO Food
and Nutrition Series No. 1.
1,1,2-TRICHLOROETHYLENE
Explanation
1,1,2-Trichloroethylene has been evaluated for acceptable daily
intake for man by the Joint FAO/WHO Expert Committee on Food Additives
in 1970 (see Annex I, Ref. 23, p. 121).
Since the previous evaluation, additional data have become
available and are summarized and discussed in the following monograph.
Previously published monograph has been expanded and is reproduced in
its entirety below.
BIOLOGICAL DATA
Biochemical Aspects
Absorption, distribution and excretion
Probably between 71-76% 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; von 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 tri-chloracetic acid may be selectively
bound to erythrocytes hence giving high spleen levels (Fabre &
Truhaut, 1952) but plasma proteins may also be involved (Soucek &
Vlachová, 1960). In man trilene is detectable in the blood within 30
minutes of inhalation (Stewart et al., 1962).
Metabolism
Trilene is metabolized slowly to chloralhydrate (via an epoxide)
and then rapidly to 2,2,2-trichloracetic acid (CCl3COOH) and
2,2,2-trichlorethanol (CCl3CH2OH), which latter two metabolites are
excreted as urinary glucuronides (e.g. trichlorethanol glucusiduronic
acid) very little unchanged trilene appearing in the urine (Powell,
1945; Butler, 1949; Uhl & Haag, 1958; Williams, 1959; Smith, 1966).
Dogs excrete 5-8% of absorbed trilene as trichloracetic acid and
15-20% as trichlorethanol up to 4 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 trichloracetic 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 body wt) were dosed with 0.5 ml of a 20%
solution of trichloroethylene (TCE) in olive oil. Urine was analysed
daily for a 7 day period. Maximal excretion of the metabolites
occurred 24-48 hrs after dosing. 24 hrs following administration
of the TCE in olive oil, 0.82% of the dose was excreted as
trichloroacetic acid, 0.12% as trichlorethanol and 11.3% as the
trichlorethanol glucuronide. During the 7 day period the metabolites
in urine accounted for 16.44% of the administered dose (2.14% as
trichloracetic acid, 0.82% as free trichlorethanol and 13.8% as
trichlorethanol glucuronide). Free TCE was not detected in urine or a
24 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). 36Cl labelled trilene was given to rats by
gavage. 10-20% was excreted in the urine as trichloracetic acid (1-5%)
and trichlorethanol(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
trichloracetic 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 (Dervilleé et al., 1938).
Guinea-pigs show presence of trichloracetic acid in their urine after
inhalation (Fabre & Truhaut, 1952). Calves similarly metabolize orally
administered trilene to trichloracetic acid (1%) and trichlorethanol
(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 trichloracetic acid
(Ahlmark & Forssman, 1951); others found 7-27% of retained trilene
being excreted as trichloracetic acid (Powell, 1945; Soucek et al.,
1952) as well as trichlorethanol, monochloracetic acid and chloroform
(Soucek et al., 1952; Defalgue, 1961). Small amounts of trichloracetic
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
5 hours to trilene excreted 4% of the retained dose as monochloracetic
acid, 19% as trichloracetic acid and 50% as trichlorethanol over the
next 14 days (Soucek & Vlachová, 1960; Defalgue, 1961). In another
experiment 8 subjects inhaled trilene for 5 hours, 51-64% of the
inhaled trilene was retained the rest exhaled unchanged. Of the
retained trilene 38-50% was excreted as urinary trichlorethanol and
27-36% as urinary trichloracetic acid. 8.4% of trichloracetic acid and
trichlorethanol was excreted in the faeces. Sweat and saliva contained
also both metabolites (Bartonicek, 1962). In all species most of the
trichloracetic and trichlorethanol is excreted in the first 2 days
after exposure but excretion may go on up to 53 days. Some 2-4 hours
elapse after single exposure before trichloracetic acid appears in the
blood reaching a maximum in 20-50 hours (Ahlmark & Forssman, 1951;
Defalgue, 1961). Trichlorethanol appears to be the main metabolite and
is much more toxic (Bartonicek & Teisinger, 1962). Disulfiram
decreases the excretion of trichloracetic acid and trichlorethanol by
acting either on converting enzymes or on trilene release from fat
depots (Bartonicek & Teisinger, 1962) while glucose and insulin
increase production (Soucek & Vlachová, 1960).
Chronic exposure may cause disturbance of protein metabolism by
an increase in the ß-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 9 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
wide-spread 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 6 females). The mean T1/2 of total trichloro-compounds was
approximately 41 hr (Ikeda & Imamura, 1973).
In a study in which rats and hamsters were exposed to
trichloroethylene vapor with or without pretreatment with
phenobarbital. Pretreatment with phenobarbital resulted in a marked
increase in 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 trilene showed
some hepatotoxicity as evidenced by a rise in SGPT (Gehring, 1968).
Trilene 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).
TOXICOLOGICAL STUDIES
Special studies on carcinogenicity
Groups each of 100 weanling (45 day old) mice (C57BL/C3H strain)
equally divided by sex, were dosed daily, 5 days per week with TCE
dissolved in corn oil. 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 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 regime of no
dosing for one week, followed by 4 weeks of dosing. At weeks 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, chloropicrin,
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 and 14/48 and
12/20 of high, low and control groups male mice and 8/47 and 8/50 and
0/50 of high, low and control groups female mice died during the
course of the study. Histopathology of a variety of neoplastic and
non-neoplastic lesions showed primary liver tumors (hepatocellular
carcinoma in 1/20 control males, 26/50 low dose males, 31/48 high dose
males, 0/20 control females, 4/50 low dose and 11/47 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 tumors (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 tumors observed in various
animals included benign fibrous tumors, adenoma of the Harderian
gland, endometrial adenocarcinoma, ovarian granulosa-cell carcinoma
and mammary adenocarcinoma (Weatherholtz et al., 1975).
Special inhalation studies
Observations in animals exposed for varying periods up to 10
months show disturbed coordination and hyperexcitability but no
effects on liver or 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 6 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
1-8 weeks to 200 or 1600 ppm daily for 4 hours. Only slight transient
fatty hepatic degeneration and no renal effects were seen (Kylin et
al., 1965).
Guinea-pigs were exposed to vapour of trilene for 2-1/2 to 4
months without adverse effects on bodyweight, 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 for 1-5 months 0.074 g/kg trilene
showed little adverse effect on bodyweight, haematological finding,
urinary analysis but some hepatic and renal lesions were seen (Lande
et al., 1939). Dogs were exposed to 150-750 ppm daily for 2-8 weeks.
Hepatic injury as evidence 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 pharmacological effects
Trilene exerts a variety of pharmacological effects. It depresses
the CNS with predominant narcotic action but needs relatively high
dosage (Defalgue, 1961). In the CNS there is a variable effect on
blood pressure. Cardiac arrhythmias are frequent with anaesthetic use
(Defalgue, 1961) and bradycardia, ectopic beats and other arrhythmias
have been seen in dogs and rabbits. Possibly some vasoconstriction in
the capillary bed may occur (von Oettingen, 1955). In the R.S. the
most common reaction is tachypnoea, especially in young children
(Defalgue, 1961). Little effects occur in the G.I. tract (Defalgue,
1961) nor were any effects seen on basal metabolic rate, liver or
kidney function (von Oettingen, 1955). Trilene absorbed through the
skin appears in the alveolar air (Stewart & Dodd, 1961).
Special studies on reproduction
Eight males and 16 female rats were fed on a diet containing 0%
or 5% of instant decaffeinated coffee solids extracted with trilene
(equivalent to a residue of 0.5 ppm 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 trilene)
was done for 2 weeks before mating until the 20th day of the 2nd
pregnancy. Foetuses were examined and resorption sites counted. No
significant deformities were noted in the test groups nor was there
any excessive resorption. Alizarin staining revealed no foetal
skeletal abnormalities (Zeitlin, 1966).
Special studies on toxic factor
Soyabean 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 scrap (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 radio labelled 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
bodyweight LD100 Reference
Mouse inhalation - 7 900 ppm (2 hrs) von Oettingen, 1955
s.c. 11.0 - Plaa et al., 1958
i.p. 2.2 - Klaassen & Plaa, 1966
Rat oral 4.92 - Smyth et al., 1969
inhalation - 20 000 ppm Adams et al., 1951
Guinea-pig inhalation - 37 000 ppm (40 min) von Oettingen, 1955
Rabbit s.c. - 1 800 mg/kg Barsoum & Saad, 1934
inhalation - 11 000 ppm Bernardi et al., 1956
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 nor
after s.c. or i.v. administration (Browning, 1965). I.p. injection of
2.5 ml/kg trilene into mice had no effect on PSP excretion and
produced no proteinuria or glycosuria, nor histological renal changes
(Plaa & Larson, 1965). Oral doses of 3-4 ml/kg bodyweight were fatal
to rats, mice and guinea-pigs with signs of gastro-intestinal
irritation (von 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 6 weeks,
with TCE at a level equivalent to 0, 1000, 1780, 3160, 5620 or
10 000 mg/kg body wt. The mice were then maintained for two weeks
under control conditions. Body wt 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 body wt dose or lower. No gross lesions were observed at
the termination of the study (Weatherholtz et al., 1975).
Rat
Groups each of 10 rats (Osborne Mendel) equally divided by sex
were dosed by intubation for five consecutive days/week for 6 weeks,
with TCE at a level equivalent to 0, 562, 1000, 1780, 3160 or
5620 mg/kg body wt. 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 labored respiration. Gross
necropsy findings at week 6 of the study included dilation of kidney
of one male, and redness of one kidney of male, both in the 1780 ppm
group, and large abscessed areas in all lobes of the lungs of the
animals. No other lesions were reported (Weatherholtz et al., 1975).
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 2 years at 0% or 5% of their
diet (equivalent to a residue of 0.5 ppm 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, 5 days per week, with TCE
dissolved in corn oil at initial dosage levels 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 4 weeks of dosing. At week 78 dosing was stopped
and the animals maintained until week 110. The time weighted average
intakes were calculated to be 1097 and 549 mg/kg body weight. 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, ethylene dichloride,
1,1,-dichloroethane, and carbon disulfide. All rats in this room were
housed in hanging galvanized steel cages without air filters.
Individual bodyweights and food consumption were recorded at weekly
intervals for the first ten 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
bodyweight 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 alterations, 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
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) 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). Psychomotor performance is not
affected by exposure to 100 ppm but there is a decline in performance
at higher inhalation levels (Stops & McLaughlin, 1967).
Eight males were exposed to 0, 100, 300 or 1000 ppm in air for 2
hours. At 1000 ppm 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 (Friborská, 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 result 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 with soda lime to form dichloracetylene
and this reacts further to generate phosgene carbonylchloride and
various acids which are all toxic (Defalgue, 1961). The TLV is 100 ppm
(Amer. Conf. Gov. Ind. Hyg., 1969).
Comments
Metabolic data from studies conducted in rats indicate a rapid
excretion of TCE or its oxidation products, trichloracetic acid,
trichlorethanol or trichlorethanol glucuronide. Pretreatment with
phenobarbital induces a marked increase in urinary metabolites.
However, urinary excretion represents less than 20% of the ingested
dose and none is detectable in the feces.
In short-term range finding studies mice were found to be more
resistant than rats challenged with similar dosage on an mg/kg basis.
Data from lifetime gavage studies in rats and mice are
compromised by the presence of other halogenated substances in the
rooms where the animals were kept. This may in part explain the life-
shortening seen in the control rats as well as the fed rats. However,
even at these high doses there was no increased incidence of tumors in
treated rats as compared to their controls.
In the mouse study survival to 90 weeks was adequate for all
groups and the tumors noted in the treated groups were generally
absent in the controls. Thus regardless of the presence of other
halogenated solvents in the same quarters as the TCE treated mice,
there is a definite dose related increase in the incidence of
hapatocellular carcinoma in the treated mice. Therefore, based on the
data from the 90-week mouse intubation study, TCE must tentatively be
considered a carcinogen. However, for a more definitive statement as
to the carcinogenesis of TCE, the mouse study should be repeated
without the uncontrolled multifactorial effects of stimulation,
suppression, synergism, etc., that may have been caused by the
presence of other halogenated solvents.
EVALUATION
Trichloroethylene has been shown to be a carcinogen in a long-
term gavage study with mice. Pending resolution of some uncertainties
in the manner in which the study was carried out the earlier tentative
approval for TCE as a solvent is withdrawn.
Further work (before an ADI can be allocated)
Well-controlled lifetime oral exposure studies in two species.
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