i§ll MAY 9 080
SNARL for 1, 1 ,1-Trichloroethane
Office of Drinking Water
U.S. Environmental Protection Agency
Washington, .D.C. 20460
THE OFFICE. OF DRINKING WATfi'R -.SNARLS" PROGRAM
' •' *:
. t
The Office of Drinking Water provides advice on health
effects upon request, concerning unregulated contaminants
found in drinking water supplies. This information suggests
the level of a contaminanti in drinking water at which -;adverse
health effects woaia not b^ anticipated with a margin o.f
safety; it is call,e_d a SNARL (suggested no adverse response
'level). Normally values are provided for one.-diay , 10-day
and longer-term exposure periods where available data exists.
A SNARL does not condone the presence of a contaminant in
drinking water, but rather provides useful information to
assist in the setting of contrail priorities in cases when
they have been found. .;•.
In the absence of a formal drinking water standard for ''
1 , 1 , 1 -trichloroethane the Office of Drinking Water has
estimated a suggested no adverse response level (SNARL)
following the state-of-the-art concepts in toxicology for
non-carcinogenic risk for short and long term exposures.
For carcinogenic risk, a range of risk estimates is provided
for life-time exposures using a model and computations from
the NAS Report (1979) entitled "Toxicity of selected drinking
water contaminants." However, SNARLS are given on a case-
by-case basis in emergency situations such as spills and
accidents. The SNARL calculations for short-term and chronic
exposures ignore the possible carcinogenic risk that may
result from those exposures. In addition, SNARLS usually do
not consider the health risk resulting from possible synergistic
effect of other chemicals in driiikiu^ water, food and air.
SNARLs are not legally enforceable standards; they are not
issued as an official regulation, and they may or may not
lead ultimately to the issuance of a national standard or
Maximum Contamination Level (MCL). The latter must take
into account occurrence, relative aource contribution factors,
treatment technology, monitoring capability, and costs, in
addition to health effects. It is quite conceivable that
the concentration set for SNARL purposes might differ from
an eventual MCL. The SNARLs may also change as additional
information becomes < available . In short SNARLs are offered
as advice to assist those that are dealing with specific
contamination situations to protect public health.
-------
General Information and Health Effects
The organic chemical 1 , 1 , 1-trichloroethane (methyl
chloroform) is used as a cleaner and degreaser of metals and
is considered a solvent of lipophilic substances. This
substance is found in drinking water supplies in the United
States of America.
According to the National Academy of Sciences, 1,1,1-
trichloroethane is probably readily absorbed from the gastro-
intestinal tract, however, there is insufficient data on the
uptake, distribution, metabolic and excretion patterns of
this coinpound or its metabolites. Fortunately,, r.ome - toxi co-
logical data does exist following ingestion and/or inhalation
of animals and/or man. Compared to other alkyl halocarbons,
1 , 1 , 1-trichloroethane is considered less toxic perhaps due
to its relative metabolism and excretion.
The health effects from 1 , 1 , 1-trichloroethane exposure at
high doses include:
1. depression of the central neriyous system and
psychophysiological changes as demonstrated by the loss of
manual dexterity, coordination and perception;
2. some fatty vacuolation and weight gain of the
liver;
3. transient eye irritation and dizziness especially
following an inhalation exposure;
4. some cardiovascular changes including diminished
systolic pressure and premature ventricular contractions;
and (
5. weakly mutagenic activity.
1,1, 1 -Trichloroethane SNARL
Since 1 , 1 .- 1-trirhloroethane is not considered . to be a
carcinogen, is relatively low in toxicity compared to some
of the other alkyl halocarbons and has a taste and odor
threshold range of 300-500 ug/1, it would appear reasonable
to establish a chronic SNARL.
In the absence of definitive information on the chronic
toxicity -of ingested 1,1,1-trichloroethane, the NAS chose to
identify a dose of 750 mg/kg given to mice and rats in a NCI
study as the observed adverse effect level. At this dose a
depression in body weight gain was observed in males while
diminished survival times were noted for both male and
female rats. Consequently, the NAS .calculated the chronic
SNARL value to be 3.8 mg/1 as follows:
-------
(750 mg/kg)(5 days)(20% D.W.)(70 kg man) = 3.8 mg/1
(7 days)(2 I/day)(1,000)
where: 750 mg/kg = observed adverse effect dose
5/7 = fraction converting from 5 to 7-day exposure
20% D.W. = relative source contribution from drinking water
70 kg = average weight of an adult
1000 « uncertainty factor via 100 factor for an
animal study and 10 factor because data
did not specify the no observed adverse
effect level
2 I/day = adult consumption per day
Extrapolation of an inhalation threshold limit value
(TLV) of the National Institute of Occupational Safety and
Health to an equivalent chronic ingestion limit for drinking
water for the general population could be made which supports
the HAS lifetime SNARL for the adult. This can be obtained
by assuming a TLV of 200 ppm or 1092 mg/m where 10 m are
inhaled/day, a 30% absorption factor and 20% contribution
from drinking water, 2 I/day consumption by adults, and a
100 safety factor for extrapolating an adult occupational
exposure to the general population. Numerically a supporting
lifetime SNARL for the adult could be determined to be 3.3
mg/1:
(1092 mg/m3)(10 m3/day) (0.30 ) (0.20) = 3.27 mg/1
(2 I/day)(100 safety factor)
In order to protect the child and most sensitive members
of the population, the Health Effects Branch feels that the
10 kg child should be considered with the assumption that a
child drinks water 1 liter/day. Applying this concept to the NAS
data, the chronic SNARL value .becomes approximately 1 mg/1.
This value is obtained as follows:
(750 mg/kg) (5)(.20)(10 kg) = 1.07 mg/1
(7)(1 l/day)(1000)
where: 750 mg/kg = observed adverse effect dose
5/7 = fraction converting from 5 to 7-day exposure
.20 = relative source contribution (20%) via
drinking water
10 kg = average weight of a child
1000 - uncertainity factor via 100 factor for an
animal study and 10 factor be.cause data did
not specify the no observed adverse effect level
1 I/day • child consumption of drinking- water each
day
-------
It should be concluded that based on health a 1 mg/1 chronic
SNARL should protect the public especially since 1,1,1-
trichloroethane was negative in the NCI cancer bioassay.
It should also be remembered that the taste and odor concen-
tration for 1 , 1 , 1-trichloroethane ranges from 300-500 ug/1.
Consequently, the limiting concentration to protect the
aesthetic value of drinking water should also protect public
health.
-------
1, 1,1-TRICHLOROETHANE
1,1,1-Trichloroethane (TCE), or methyl chloroform, is
used widely as an industrial chemical for such purposes as a
cleaner and degreaser of metals, a spot remover, and a
solvent of lipophilic substances. It is a clear, colorless
liquid at room temperature; its solubility in water is 4,400
mg/1 at 20°C (Verschuerer, 1977) ; its boiling point is 7u<»C;
and its vapor is heavier than air and nonflammable. Oioxane
is commonly added to promote its stability. TCE has been
identified in drinking water supplies in the United States
(USEPA, 1978).
METABOLISM
There have been extensive studies on the uptake and
distribution of TCE in humans and laboratory animals that
have been exposed to the chemical by inhalation.
Unfortunately, there is little information on the
pharmacokinetics of ingested TCE. One would expect that
this compound would be readily absorbed from the
gastrointestinal.tract in light of the report by Stewart and
156
-------
Dodd (1964) who found that it penetrated intact human skin.
Astrand et al. (1973) reported rapid absorption of inhaled
TCE and measurable levels of the chemical in the arterial
blood of human subjects after inhaling 250 ppm TCE for 10
seconds. The arterial blood contained substantially higher
TCE levels than the venous blood throughout a 2-hour
exposure, indicating ready uptake of the compound from blood
into tissues. Blood concentrations of 3-5 ppm have been
measured in.humans breathing 350 ppm TCE (Astrand et al.,
1973; Samberale and Hultengren, 1973; Stewart et al., 1961),
the current threshold limit value for occupational exposure
in the United States. Apparently, there are no data on
blood levels of the compound following oral exposures.
The majority of systemically absorbed TCE is eliminated
via the lungs. Hake et al. (1960) reported that about 98.75
of a 700 mg/kg dose of radio-labeled TCE, which was injected
intraperitoneally into rats, was exhaled unchanged within 25
hours. They also observed small amounts of radio-labeled
carbon dioxide in expired air and of the glucuronide
conjugate of 2,2,2-trichloroethanol in urine. Later studies
revealed trichloroacetic acid to be a second metabolite,
although the amounts that were formed in the urine of both
rats (Eban and Kimmerle, 1974; Ikeda and Ohtsuji, 1972) and
humans (Stewart et al., 1969) were substantially less than
those for trichloroethanol. No chloral hydrate was detected
in the blood or tissues of the rat by Eben and Kimmerle
157
-------
(197«») . In studies by Van Dyke and Wineman (1971) and Ikeda
and Ohtsuji (1972) on the metabolism of a series of alkyl
halocarbons, TCE was one of the least extensively
metabolized compounds. Nevertheless, it is known to exhibit
Type I binding characteristics with cytochrome P-450
(Pelkonen and Vainio, 1975) and to be capable of inducing
microsomal enzyme and P-«»50 activity (Fuller et al.. 1970).
A progressive increase in urinary output of trichloroethanol
vas observed in humans that had been subjected to five daily
inhalation exposures to TCE. This indicates that TCE
induces its own metabolism (Stewart et al.. 1969)..
Upon termination of TCE exposure, the chemical is rather
quickly eliminated in exhaled air. Levels in the blood and
alveolar air decrease exponentially, showing an initial
rapid fall, followed after several hours by a somewhat
slower decline (Astrand et al., 1973; Stewart et al., 1969).
This latter stage probably reflects slow mobilization of the
agent from lipoidal tissues. Stewart et al. (1969) reported
that a slight amount accumulated in humans who inhaled TCE
at 500 ppra, 6.5-7 hours/day, for 5 days, despite the
relatively rapid loss of TCE from the body. These
investigators also found TCE in breath samples from one
subject 1 month after exposure. Thus, it appears that TCE
can accumulate in the body if intake is frequent enough
and/or of sufficient magnitude.
158
-------
TCE's relative lack of toxicity,. in comparison to
certain other alky! halocarbons, can be attributed to TCE's
relatively rapid elimination and stability. This compound
is much more volatile (Ikeda and Ohtsuji, 1972) and,
therefore, more readily excreted via the lungs (Morgan et
al., 1970). than the more toxic congener
1,1,2-trichlorethane. Although neither halocarbon is
metabolized to a significant degree, Carlson (1973) observed
that microsomal enzyme induction with phenobarbital
potentiates hepatotoxicity of both TCE and 1,1,2-trichloro-
ethane. Thus, it appears that metabolite(s) of each
compound are responsible for cytotoxicity, although the
identity and mechanism of the actual toxicant (s) remain
unknown.
HEALTH ASPECTS
Observations in Humans
The primary toxic effects in humans that have been
subjected to short-term, high-level exposure to TCE are
manifestations of depression of the central nervous system.
In the majority of reports of human fatalities resulting
from TCE inhalation, death is attributed to a functional
depression of the central nervous system. Levels of TCE in
the victim*s blood vary considerably, generally ranging from
60 (Hatfield and Maykoski, 1970; Stahl et al., 1969) to 720
159
-------
ppm (Hall and Bine, 1966). As might be predicted, the
highest concentrations of TCE are found in the brains of
victims (Caplan et al., 1976; Stahl et al.. 1969). Due to
i
problems that are inherent in analyses of volatile toxicants
in autopsies, it is difficult to establish lethal TCE
concentrations in blood or tissue.
Inhalation of high concentrations of TCE can cause
irritation of the respiratory tract and minimal organ
damage, as well as depression of the central nervous system.
Acute pulmonary congestion and edema typically found in
fatalities result from inhalation of TCE (Bonventre et al.,
1977; Caplan et al., 1976). There are also scattered
reports of modest fatty vacuolation in the liver t Cap Ian et
a^., 1976; Hall and Hine, 1966; Stahl et al., 1969). In
most such instances there probably would have been
insufficient time between exposure and death for
hepatotoxicity to be fully expressed. Stewart (1971)
reported the case histories of four individuals who were
monitored clinically after being overcome by TCE vapors. In
each case, recovery from depression of the central nervous
system was quite rapid and largely uneventful. However, one
of the four patients exhibited elevated urinary urobilinogen
but no alteration of other indices of hepatotoxicity. These
studies indicate that TCE possesses a limited capacity to
exert hepatic injury in cases of acute, high-level
inhalation exposure.
160
-------
Clinical experience and scientific investigations
suggest that acute high-level inhalation of TCE can
adversely affect the cardiovascular system of humans.
Dornette and Jones (1960) used concentrations of 10,000-
26,000 ppm TCE to anesthetize surgery patients. They noted
that both induction of and recovery from anesthesia were
quite rapid. No evidence of respiratory depression or
hepatotoxicity was seen. However, there were disturbing
cardiovascular effects including diminished systolic
pressure, premature ventricular contractions, and,-in one
patient, even cardiac arrest.
Bass (1970) reported a syndrome termed "sudden sniffing
death** in persons dying abruptly while inhaling volatile
solvents for self-intoxication. TCE was one of the most
frequently implicated solvents in such incidents. The
fatalities were tentatively attributed to cardiac
arrhythmias that resulted from a combined action of the
solvent and endogenous biogenic amines. Recent
investigations of the phenomenon with laboratory animals are
discussed below.
A single account of ingestion of TCE by a human has
appeared in the literature (Stewart and Andrews, 1966) . A
47-year-old male mistakenly consumed 1 oz of TCE
(approximately 0.6 g/kg). He became nauseated within 30
minutes and developed progressively severe vomiting and
diarrhea over the next few hours. Clinical evaluation
161
-------
following gastric lavage revealed neither drowsiness nor
difficulty with coordination. Orinalysis and clinical
chemistry tests revealed evidence of only minimal
hepatorenal injury early in the course of hospitalization.
After resolution of the vomiting and diarrhea, the patient
was asymptomatic during a 2-week observation period.
Since depression of the central nervous system is the
predominant effect of TCE on humans, certain manifestations
of the depression should be the most sensitive indices of
the physiological action of small quantities of the solvent.
Early studies with volunteers indicate that inhalation of
500 ppm TCE far several hours has no significant effect
other than transient, mild eye irritation (Stewart et al..
1961a, b; Torkelson et al. , 1958). Stewart and his
coworkers (1969) concluded in a later study that 500 ppm may
be excessive for persons who are particularly susceptible to
the chemical's depressant effects on the central nervous
system. In an even more recent investigation, inhalation of
350 ppm TCE for 4 hours was not effective, but 450 ppm
elicited subjective complaints of transient eye irritation
and dizziness (Salvini et al., I9?1a, b). Although a
battery of psychopnysiological tests did not reveal a
statistically significant degree of functional inhibition,
lower scores resulted when tests were conducted during TCE
exposure than when under control conditions. Results of an
investigation by Gamberale and Hultengren (1973) indicated
162
-------
that inhalation of 350 ppm TCE can significantly inhibit
psychophysiological functions of humans. Blood levels in
these "inhibited1* subjects averaged approximately 3-4 ppm,
'\
although the investigators noted wide intersubject
differences in blood and alveolar air concentrations.
Samberale and Hultengren concluded that it would be
difficult, with any degree of accuracy, to set a threshold
•
for the vapor concentration of TCE that would not alter
function of the central nervous system. Their tests of
psychophysiological function are certainly more sensitive
and objective than the indices used in the earlier studies
of Torkelson et al. (1958) and Stewart et al. (.1961, 1969).
Nevertheless, the current U.S. threshold limit value for
occupational exposure to TCE remains at 350 ppm. This
standard is designed to protect the majority of workers from
raucous membrane irritation and performance inhibition. One
interesting facet of the studies by Torkelson et al. (1958)
and Stewart et al. (1969) is their failure to find any
evidence of organ damage in humans that were subjected to
acute TCE inhalation regimens.
Short-term exposure to TCE appears to be no more harmful
to humans or laboratory animals than does acute exposure.
Stewart et al. (1969) exposed humans via inhalation to 500
ppm TCE for 6.5 hours daily for five consecutive days. They
observed some objective and subjective signs of depression
of the central nervous system, but no evidence of toxicity
163
-------
upon examination for neurological, respiratorty, and
hepatorenal function. There were also a small accumulation
of TCE and an increase in urinary trichloroethanol levels.
J. -
<
Observations in Other Species
Acute Effects. Overall results of animal
experimentation confirm the previously described findings in
humans—namely, that TCE is relatively nontoxic upon short-
term exposure. The acute oral LDSO for TCE, as determined
in several species of animals, is reported by Torkelson et
al. (1958) to range from 5.7 to 14.3 g/kg. Unfortunately, .
little other toxicological data involving oral dosing are
available. LOso values that were derived upon
administration of TCE by routes of administration other than
oral illustrate the difficulty in using such data to predict
consequences of ingestion of the chemical. In contrast with
an oral LD90 value of 11 g/kg in the mouse (Torkelson et
al., 1958), the LD50 is approximately 16 g/kg for
subcutaneous injection (Plaa et al., 1958) and approximately
4.9 g/kg for intraperitoneal injection (Klaassen and Plaa,
i
1966). By administering equivalent intraperitoneal and
oral doses of carbon tetrachloride to rats, Nadeau and
ttarchand (1973) demonstrated that significantly higher
hepatic concentrations of carbon tetrachloride and more
164
-------
expensive hepatotoxicity are manifested in the
intraperitoneally-dosed animals.
Despite the problems that are inherent in extrapolating
data from one route of chemical exposure to another, we may
gain qualitative insight into the toxicity of TCE by
examining information from studies in which the oral route
vas not used. Plaa and his colleagues found TCE to be the
least hepatotoxic of a series of alkyl halocarbons that were
given subcutaneously (Plaa et al., 1958) and
intraperitoneally (Klaassen and Plaa, 1966) to mice and
intraperitoneally to dogs (Klaassen and Plaa, 1967) and rats
(Klaassen and Plaa, 1969). Near-lethal quantities of TCE
were generally required to produce hepatotoxicity. They
observed little to no evidence of nephrototoxicity. In
contrast to TCE ^EDSO=2.5 ml/kg for SGPT elevation in mice),
its congener 1,1,2-trichloroethane was much more toxic (EDSO
=0.1 ml/kg), and tetrachloroethylene was of equivalent
potency (EOSO = 2.9 ml/kg).
In laboratory animals, as well as humans, the primary
hazard of inhalation of high concentrations of TCE is
excessive depression of'the central nervous system. Adams
et al. (19SO) reported the 3-hour LC50 in rats to be 18,000
ppm. They observed that recovery of several test species of
animals from marked depression of the central nervous system
was rapid and uneventful. The lowest and shortest exposure
that elicited histologic change in tissues of the rat was
165
-------
8,000 ppm for. 7 hours. This produced an increase in liver
weight and fatty vacuolation of hepatocytes. Disturbance of
vestibular function in rabbits that had been infused
intravenously with TCE was observed by Larsby et al. (1978)
when blood levels in the rabbits exceeded 75 ppm TCE.
Levels of TC2 in the cerebrospinal fluid were approximately
one-third of that in the blood. Although this vestibular
disturbance is physiologically significant, it should be
recalled that Samberale and Hultengren (1973) observed
inhibition of psychophysiological function in humans with
blood levels of only 3-5 ppm TCE.
A second hazard that is associated with acute exposure
to vapor containing high concentrations of TCE is
cardiovascular toxicity. The aforementioned accounts of
cardiotoxic effects of TCE in humans (Bass, 1970; Dornette
and Jones, 1960) have been confirmed in studies of dogs.
Reinhardt et al. (1973) found TCE to be more potent than
trichloroethylene in inducing arrhythmias in dogs
concomitantly dosed with epinephrine. The lowest effective
concentration of TCE was 5,000 ppm. However, Egle et al.
(1976) did not detect adverse cardiovascular effects in
freely moving dogs that had been exposed to 5,000 and 10,000
ppm TCE in a Preon propellant. They attributed the
disparity between their own findings and those of Reinhardt
et al. (1973) to differsnces in experimental design. Herd
al. (197ft) found TCE to exert a biphasic action on the
166
-------
cardiovascular system of anesthetized dogs, which was
characterized by an initial decrease in blood pressure that
was associated with peripheral vasodilation as well as
reflex chronotropic and inotropic effects on cardiac
function, and subsequent depression of cardiac function. In
a study of .the biochemical mechanism of TCE's
cardiotoxicity, Herd and Martin (1975) observed inhibition
•
of respiratory function and alteration of permeability
characteristics in mitochondria that were isolated from
rats. Herd et al. (1974) emphasized that studies are needed
to determine whether low-level exposure to TCE may be
injurious to the cardiovascular system.
In contrast to previous findings of microsomal enzyme
induction in mice (Lai and Shah, 1970) and rats (Fuller et
al. • 1970) that inhaled 3,000 ppra TCE for 24 hours,
inhibition of microsomal drug metabolism was observed in
rats that had been given approximately 1.4 g/kg orally
(Vainio et al., 1976) and in mice that had been given 1.0
ml/kg of undiluted TCE intraperitoneally (Shah and Lai,
1976). Shah and Lai (1976) further demonstrated that
dilution of the TCE with olive oil reduced the inhibitory
effect, while TCE that was diluted with dimethyl sulfoxide
(DMSO) potentiated the effect. These investigators
suggested that the olive oil inhibited the systemic
absorption of TCE and that the DMSO potentiated TCE's
hepatotoxicity.
167
-------
Chronic Effects. McNutt et al. (1975) exposed mice
continuously to 250 and 1,000 ppm TCE for up to 14 weeks.
Serial sacrifices were performed at weekly intervals to
ascertain the development of any histopathologic
abnormalities. Hepatocytic vacuolations and significant
increases in liver weight and triglyceride content were
observed throughout the study in the 1,000 ppm animals.
After 4 weeks of exposure to 1,000 ppm TCE a number of
ultrastructural alterations were observed in centrilobular
hepatocytes, including proliferation of smooth endoplasmic
reticulum. Such a structural alteration would be expected
in light of the reports of microsomal enzyme induction by
Fuller et al. (1970) and Shah and Lai (1976). McNutt et
al. (1975) saw a return to normal of each of the indices at
2 and 4 weeks after exposure. Quite modest ultrastructural
alterations and increases in liver weight and triglyceride
were occasionally observed in the animals that were exposed
to 250 ppm during the 14-week study. Thus, this exposure
level might be considered a threshold for a biological
effect of TCE in the mouse. Platt and Cockrill (1969)
studied biochemical changes in rat livers in response to a
series of aliphatic halocarbons. They found seven daily-
oral doses of 1.65 g/kg to enhance cytoplasmic and
microsomal protein content and to exert no hepatotoxicity.
Savolainen et al. (1977) recently reported slight decreases
in brain RNA and liver microsomal P-450 in rats inhaling 500
168
-------
ppm ICE 6 hours daily for 4 or 5 days. The significance of
these latter findings is uncertain.
The only lifetime feeding study that has been reported
was conducted as a part of the national Cancer Institute
Bioassay Program (NCI, 1977). in an initial range-finding
study, oral doses ranging from 1,000 to 10,000 rag/kg TCE in
corn oil were given to male and female mice and rats 5 days
weekly for 6 weeks. The highest "no-effect" dose for rats
was 3,160 mg/kg while that for mice was 5,620 mg/kg. '
Indices of toxicity that were evaluated included body weight
and gross evidence of organ damage. A chronic dosing study
was then initiated but had to be discontinued because of
undefined intoxication in rats receiving 3,000 mg/kg. In
the final chronic dosing study, male and female rats
received 750 or 1,500 mg/kg TCE in corn oil by gavage five
times weekly for 78 weeks. Similarly, male and female mice
were given TCE doses that were increased during the study
when it became apparent that larger quantities of the
chemical could be tolerated. The time-weighted averages for
the two dose levels in mice for the 78-week regimen were
approximately 2,300 and 5,600 mg/kg. Diminished body weight
gain and decreased survival time were manifest in both mice
and rats. Surprisingly, the incidence of histopathologic
change was no greater for TCE-dosed than for control animals
of either species. No other indices of toxicity were
evaluated.
169
-------
A number of long-term animal studies of the toxic
potential of inhaled TCE have been conducted over the last
20 years. These studies have been directed largely towards
assessing potential hazards of TCE in occupational exposure
situations. Daily exposure of a variety of species to 500
ppm of TCE over a 6-month period elicited no recognizable
adverse effect, but 1,000 ppm produced fatty changes and —
increased weight of livers of guinea pigs (Torkelson et al.,
1958). Rowe et al. (1963) reported similar findings when
testing a solvent mixture consisting of approximately 752
TCE and 25% tetrachloroethylene. However, guinea pigs in
the latter study did show some decrease in body weight gain,
which was attributed to reduced food consumption, as well as
an increase in liver weight. In studies of responses to
even lower concentrations, Prendergast et al. (1967) exposed
rats, guinea pigs, dogs, rabbits, and monkeys to TCE vapor
continuously for 90 days. They observed depressed body
weight in rabbits and dogs inhaling 370 ppm, but no adverse
effects in any species inhaling 135 ppm. Eben and Kimmerle
(1974) detected no evidence of hepatorenal injury,
hematologic change, or histopathologic alteration in rats
that received 200 ppm TCE 8 hours daily, 5 days weekly for
14 weeks.
Mutaqenieitv. Simmon et al. (1977), when conducting a
mutagenesis screen of 71 chemicals that had been identified
170
-------
in U.S. drinking water, found TCE to be very weakly
mutagenic in vitro for Salmonella typhimurium. Mi-crosomal
activation appears to have little effect on its potency.
Carcinoqenicitv. The only study of the carcinogenic
potential of TCE that has been conducted to date failed to
reveal any evidence of carcinogenicity (NCI, 1977).
Teratocrenicity. No available data.
CONCLUSIONS AND RECOMMENDATIONS
Suggested No Adverse Response Level (SNARL)
29-hour Exposure
The literature indicates that TCE is one of the least
toxic of the commonly used alkyl halocarbons. Since
depression of the central nervous systems is its predominant
effect when inhaled, it appears that loss of manual
dexterity, coordination, perception, etc., may be the most
sensitive indices of exposure. Unfortunately, it is unclear
whether significant inhibition of psychophysiological
functions will occur in humans who ingest the chemical. The
0.6 g/kg of TCE reportedly ingested by the patient of
Stewart and Andrews (1966) might be considered to be a
minimum oral hepatorenal toxic dose. However, the nausea,
171
-------
vomiting, and diarrhea that were experienced by the patient
are toxicologically significant manifestations that must be
avoided, although the gastrointestinal upset may have
resulted from consumption of undiluted TCE. Moreover, the
vomiting, diarrhea, and gastric lavage may have prevented
systemic absorption of a portion of the TCE. . ~" "
A single case history is obviously not sufficient to
serve as a basis for setting an exposure level for acute
ingestion of TCE. However, a similar quantity of TCE in
laboratory animals appears to be what might be termed a
"minimum effect level." Vainio et al. (1976) found that a
single oral dose of approximately 1.4 g/kg depresses some
hepatic microsomal metabolic indices in rats. In light of
reports of hepatic microsomal enzyme induction in mice and
rats following inhalation of TCE, it is possible that oral
doses lower than 1.4 g/kg might also stimulate xenobiotic
metabolism. Nevertheless, it seems appropriate that
calculations for a suggested 24-hour SNARL for contamination
of drinking water by TCE be based upon a minimum (oral)
effect level that is derived from actual experimentation,
namely 1.4 g/kg. This SNAFL is based upon the assumption
that the sole source of TCE during this time will be
drinking water and that a 70-kg human consumes 2 I/day. An
uncertainty factor of 100 is applied.
1.4 g/kcr « 70 kg =490 mg/1
100 * 21
172
-------
1-week Exposure
TCE appears to be no more hazardous upon short-term
exposure than it does upon acute exposure. A study in which
humans were subjected to 500 ppm of TCE vapor on 5
consecutive days, revealed no evidence of toxicity (Stewart
et al.f 1969). PI a tt. and Cockrill (1969) reported seven
daily oral doses of 1.65 g/kg not to be hepatotoxic in rats,
but to enhance hepatic microsoraal and cytoplasmic protein
content. However, their use of liquid paraffin as a vehicle
may have markedly retarded systemic absorption of the TCE.
Thus, because of the lack of more definitive information
regarding short-term minimum- or no-effect levels, the
suggested 7-day SNARL for drinking water contamination is
obtained by dividing the 24-hour SNARL by 7. Assuming that
the sole source of TCE during this period will be drinking
water:
»90 mcr/1 » 70 mg/1
7
Definitive studies in several species of animals should
be undertaken using a range of oral doses of TCE to
characterize dose-effect and dose-response relationships for
both single and multiple ingestions over a 1-week period. A
variety of tests, which are valid indices of injury to
potential target organs (e.g., heart, liver, kidneys),
should be monitored. As no data pertaining to the uptake,
distribution, metabolism, and excretion of TCE upon
173
-------
ingestion are available, pharmacokinetic studies should be
undertaken using a range of oral doses in several animal
species. Vehicles for administration should be carefully
selected to avoid discrepancy from actual exposures via
drinking water or foods.
Limited studies of ingestion of small quantities of TCE
might be undertaken in humans. These studies appear
warranted since the toxic end points that might serve as a
basis for setting standards include subjective (e.g.,
nausea) as well as subtle objective (e.g., performance)
indices. It would be valuable to determine the quantity of
TCE that must be consumed to produce a blood level of 3-<*
ppm TCE* the level that Gamberale and Hultengren (1973)
associated with inhibition of psychophysiological function.
Other indices that might be evaluated include cardiovascular
function and microsomal xenobiotic metabolism.
Chronic Exposure
TCE seems to be no more toxic upon long-term exposure
than it is upon acute or short-term exposure. Quite large
quantities of the chemical given orally to mice and rats
five times weekly for 78 weeks elicited little apparent
histopathologic change of any organ in either species (NCI,
1977)= However, decreased body weight gain, obvious ill
health, and diminished survival time in certain of these
-------
animals suggest 'that more sensitive and/or appropriate tests
may reveal adverse effects by comparable ingestion regimens.
Indeed, McNutt et al. (1975) reported increased liver
weight, liver lipid content, and ultrastructural alterations
in hepatocytes of mice that had been subjected for weeks to
a vapor concentrations as low as 250 ppm. Unfortunately,
since no information on TCE blood or tissue levels was
presented by these investigators, it is difficult to
extrapolate their data to oral exposure.
In the absence of more definitive information regarding
the chronic toxicity of ingested TCE, the lowest dosage
level that was administered to either species in the NCI
(1977) study (i.e., 750 mg/kg to rats) will be used as a
basis for calculating a chronic SNARL. Depression in body
weight gain in males and diminished survival time in both
males and females have been observed in rats that were
maintained on the 750 mg/kg oral dose. The following
calculation assumes that a 70-kg human consumes 2 1 of water
per day and that 202 of the total TCE intake is provided by
water. An uncertainty factor of 1,000 is used and the dose
is multiplied by 5/7 to convert from the 5- to 7-day
exposure.
750 mq/kq « 5 days * 0.1 1 « 70 kg * 3.8 mg/1
7 days « 1,000
The study from which this value was calculated did not
provide a no observed adverse effect level. The large
175
-------
uncertainty factor is used for this reason. Because of the
expected high use of this compound, the subcommittee
considered it important to provide some provisional
guidelines.
Appropriately designed oral, long-term dosing studies
using several species of animals and a range of doses of TCE
should be conducted in order to establish minimum toxic dose
levels with accuracy. Vehicles for administration should be
selected to assure that artificial exposure conditions are
not created, e.g., use of large quantities of corn oil, as
in the NCI '^377) %tudy. --"Sensitive indices of aliphatic "-"•"'
halocarbon exposure should also be selected carefully.
Since only one investigation of the carcinogenic potential
of TCE has been reported to date, additional research should
be conducted with doses of TCB that do not shorten the life-
span of the subjects. Vehicles for TCE
dilution/administration should not create highly artificial
exposure conditions. Appropriate studies to investigate the
mutagenic and teratogenie potential of TCE should also be
conducted.
176
------- |