DRAFT CRITERIA DOCUMENT
FOR 1,1,1-TRICHLOROETHANE
FEBRUARY 1984
HEALTH EFFECTS BRANCH
CRITERIA AND STANDARDS DIVISION
OFFICE OF DRINKING WATER
U.S. ENVIRONMENTAL PROTECTION AGENCY
WASHINGTON, D.C. 20460
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TABLE OF CONTENTS
PAGE
I. SUMMARY I - 1
II. CHEMICAL AND PHYSICAL PROPERTIES II - 1
III. METABOLISM AND PHARMACOKINSTIC EFFECTS Ill - 1
A. Metabolism Ill - 1
1. Absorption Ill - 1
2. Distribution Ill - 6
3. Biotransformation Ill - 11
4. Excretion Ill - 15
B. Pharraacodynamic Effects -
Animal and Human.... Ill - 19
•A,
1. CMS .Effects ...;..., Ill - 19
2. Cardiotoxicity
3. Hepatotoxicity and Nephrotoxicity
4 . Pneumotoxicity
IV. HUMAN EXPOSURE* IV - 1
V. HEALTH EFFECTS - ANIMAL V - 1
1. Acute Toxicity . V 1
2. Subacute Toxicity V -5
3. Chronic Effects V - 9
4. M,utagenicity V - 12
5. Carcinogenicity V - 16
6. Teratogenicity V - 19
VI . HEALTH EFFECTS - HUMANS VI - 1
1. Acute Toxicity VI - 1
2. Subacute Toxicity VI - 5
3. Epidemiology...., VI - 5
VII. HUMAN RISK ASSESSMENT VII- 1
1. Current Levels of Exposure.. VII. - 1
2 . Existing Guidelines and Standards VII,-.^ ,,1
,'',--.,> r- '• i • •
VIII. QUANTIFICATION OF TOXICOLOGICAL EFFECTS VI!II;;- I
IX. REFERENCES. Ji.HiX.i~ 1
/.
*Prepared by the Science and Technology Branch
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TABLES
PAGE
Table II - 1
Table III - 1
Table III - 2
Table III - 3
Table III
Table III
Table V
Table VI
Table VI
Table VI
Table VII
Table VII
Table VIII
Table VIII
Table VIII
Table VIII
Figure II -
Physical Properties of Methyl II
Chloroform
Absorption of Methyl Chloroform III
Physical Properties and Absorption III
of Inhaled Vapors
Concentrations of Methyl Chloroform III
in Tissues of Mice Following Inhala-
tion Exposure
- 4 Methyl Chloroform Excretion in Exhaled III
Breath
- 5 Liver Effects of Methyl Chloroform and
Other Chlorinated Hydrocarbons III
- 1 Effects of Trichloroethane Isomers on
Mice V
- 1 Urinary Metabolite Concentration in VI
Workers Exposed to Methyl Chloroform
- 2 Result of Physical Examinations of VI
Workers Exposed to Methyl Chloroform
- 3 Exclusions from Healthy Category by VI
Class of Disorder
- 1 Chloroethane Exposures and Production VII
- 2 Chloroethane Exposure Standards VII
- 1 Summary of Effects in Mice After VIII
Continuous Inhalation Exposure to
Methyl Chloroform
- 2 RMCL and Health Advisory for Methyl VIII
Chloroform
- 3 ' Mutagenicity Testing of Methyl Chloro- VIII
form
- 4 Estimated Lifetime Cancer Risk to VIII
Humans at a Dose of 1 ug/liter
FIGURES
1 Metabolic Route Suggested for Methyl III
Chloroform
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PREFACE
The objective of this document is to assess the
health effect information of the contaminant 1,1,1-Trichloroethane
in drinking water and to quantify toxicological effects.
-To achieve this objective, data on pharmacokinetics, assessment
of human exposure, acute and chronic health effects in animals,
human health effects including epidemiology and mechanisms of
toxicity were evaluated. Only the reports which were considered
pertinent for the derivation o,f the maximum contaminant level
are cited in the document. Particular attention was paid
toward the utilization of primary references for the assessment
of health effects. Secondary references were used rarely.
For comparison, standards and criteria developed by other
organizations are discussed in Section VIII, Quantification of
Toxicological Effects.
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I. SUMMARY
In 1978, the estimated production of methyl chloroform
in the U.S. amounted to 623 million pounds. Methyl chloroform
is used extensively for industrial metal cleaning, and in the
manufacturing of adhesives and various aerosol products. All
of these quantities, whether used industrially or for consumer
products are eventually transmitted into the environment,
primarily in the form of atmospheric emissions.
The atmospheric level of methyl chloroform has been
generally measured in the low parts per billion (ppb) or
parts per trillion (ppt) range. Methyl chloroform undergoes
a slow photochemical decomposition in the troposphere to
produce carbon monoxide, hydrogen chloride, phosgene, and
various other halogenated products.
Methyl chloroform has been detected in the drinking
water of several cities throughout the United States. It may
be of interest to note that near manufacturing sites, methyl
chloroform has been detected also in surface and ground water.
Inhalation is the major route of exposure in humans,
followed by food and water consumption, and dermal contact.
f
Methyl chloroform, in its unmetabolized form, is rapidly
excreted in the breath after exposure. For example, within
the first hour after human inhalation of a single breath of
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1-2
methyl chloroform, 44% of the dose was excreted on the breath
unchanged. Rats treated with an- injected dose or inhalation dose
excreted 98.7% on the breath in an unchanged form. Metabolism
studies conducted on methyl chloroform indicated the fate of
the compound in rats, mice, and man is relatively similar.
The initial step in the biotransformation of methyl chloroform
is the formation of the metabolic trichloroethanol which
subsequently is excreted from the body as trichloroacetic
acid or as trichloroethanol glucuronide.
Inhalation (exposure) estimations have been made
for occupational exposure concentrations of methyl chloroform
in the air surrounding various industries ranging widely from
1.5-16.6 in the metal industry to 12.0-118.0 ppm in soldering
degreasing plants. Concentrations which have been reported
to cause transient, mild eye irritations have been in the
range of 500-1000 ppm range. Regression analysis has indicated
a linear relationship between vapor concentrations of methyl
chloroform and the levels of urinary metabolites.
The odor threshold of methyl chloroform covers a
wide range (16 - 700 ppm) suggesting that individual
sensitivity may play a part in determining resultant irritation
and sensivity of various organs. The American Conference of
Governmental Industrial Hygienists has recommended a Threshold
Limit Value of 350 ppm.
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Methyl chloroform has been found in small amounts
as a contaminant in various food stuffs. Amounts of this
compound in meat, oils, fats, tea, -fruits, and vegetables
ranged from 1 to 10 ug/kg. These levels are reportedly higher
-than the concentrations found in drinking water of U.S. cities.
The predominant health effects of exposure to
anesthetic levels of methyl chloroform is the narcotic effect
on the central nervous system (CNS). Man is the most responsive
\
species in demonstrating such CNS effects of methyl chloroform.
Most studies showed behavioral or narcotic changes on
experimental animals at much higher levels of exposure than
those reported for man. The effects of methyl chloroform in
the CNS are similar to a general anesthetic agent; these are
functional changes which, according to available reports, are
entirely reversible. Inhalation of high concentrations of
methyl chloroform for extended time periods could be fatal
without any occurrence of organic or toxicological symptoms.
Nausea and prolonged restlessness have been observed as side
effects in humans receiving anesthetic doses, but consciousness
returns within minutes after breathing air free of the compound.
The Romberg test (a neurological test which measures
proprioceptive control) has been used to measure the narcotic
effects of methyl chloroform within the range of 500 ppm (no
CNS effects) to 2,650 ppm. Impairment of motor control has been
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1-4
demonstrated in humans with concentrations as low as 350
ppm. However, this finding was not collaborated by other
investigators.
It is generally believed that high concentrations
of the chlorinated hydrocarbons can sensitize the heart of
some individuals and thereby make the heart abnormally
responsive to epinephrine. One of the effects of epinephrine
in man and animals is cardiotoxicity. Since methyl chloroform
either has arrthymic effects of its own or makes epinephrine
effects more pronounced, there is a potential for serious
cardiac effects resulting from exposure during excitement or
stress when the body normally releases high levels of
epinephrine. If an additional factor of an old cardiac scar
or other cardiovascular problem is added, there is a
physiological potential for serious cardiac effect from high
levels of exposure.
The subcutaneous absorption of methyl chloroform
appears to be dependent on the area of exposure. The rate of
absorption during exposure may affect its toxic potential.
Biochemical effects on the liver also occur with
methyl chloroform exposure. The liver changes occurring in
man and experimental animals after exposure are not secondary
to either CNS or cardiac effects of this solvent.
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However, these changes consist of actual cellular or bio-
chemical damage while the CNS effects like those of most
anesthetic agents are reversible.
Human liver effects have been assessed in some
reports by measuring urinary urobilinogen (a bile pigment
processed by liver cells and released only in small amounts
by a healthy liver). Serumvis frequently analyzed for enzymes
(SGPT and SCOT) which increase in liver disease. The exposure
level resulting in liver change has been delineated in humans
and experimental animals. Animal toxicity data have shown
that the guinea pig is the most sensitive species to the
liver effects of methyl chloroform. Fatty changes in rodent
livers were reported after chronic exposure at 1,000 ppm in
four studies. However, animal experiments investigating the
influence of methyl chloroform on liver function yield
controversial results highly dependent on species, dose and
treatment schedule. Results vary from no organic damage in
guinea pigs at 1,500 ppm at 7 hr/day for 3 months to actual
damage at the 1,000 ppm for 30-90 min/day exposure for 3 months.
Repeated exposure to methyl chloroform has been
shown to increase the excretion of metabolites in both animals
and man, probably by the mechanism of enzyme induction. The
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1-6
importance of this induction is twofold. First, it is a
mechanism by which man and anima-1 excrete methyl chloroform
more rapidly on chronic exposure; because of this apparent
capability/ fewer chronic effects would be expected to occur
with methyl chloroform compared with compounds that deposit
in tissues. Second, stimulation or induction of some of these
liver enzymes changes the action of many presecription and
non-prescription drugs since the same enzymes that are induced
by methyl chloroform are responsible for the metabolism of
many types of drugs (i.e., sedative hypnotics and anti-
psychotics). Thus, some drugs may have reduced or increased
effects in persons chronically exposed to methyl chloroform.
Nephrotoxicity, as measured by tubular damage,
phenosulfonpthalein, glucose, and protein excretion data
has been investigated in animals and man with reference to
methyl chloroform. Although some kidney damage has been
reported in laboratory animals, it appears that methyl
chloroform damages the liver before it affects the kidneys.
The National Cancer Institute (NCI) conducted
s
carcinogenesis bioassays on methyl chloroform. Rats and mice
were orally dosed with methyl chloroform five times per week
for 78 weeks. Rats received either 1,500 or 750 mg/kg of the
compound; mice (male and female) received either 5,615 or
6
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2,807 mg/kg. The dose levels administered in both experiments
were sufficiently high to result in early death within each
group; a maximum of 40% of the initial groups remained alive
by end of dosing. Within the survival groups, no consistent
pattern of cancerous tumors was observed. Due to the low
survival rate, statistical analysis could not be performed in
either study.
The CAG has calculated an upper-limit cancer risk
estimate based on the 1983 NCI bioassay. This study showed a
marginally statistically significant increase in hepatocellula
carcinomas in femal^mice receiving 1500 or 3000 mg/kg methyl
chloroform by gavage in corn oil five times per week for 103
weeks. The responses were 6.1%, 10.2%, and 20.4% for the
control, low-dose, and high dose groups, respectively. They
stated that consuming 2 liters of water per day over a lifetime
at a methyl chloroform concentration of 2200 ug/L, 220ug/L
or 22 ug/1 would increase the risk of one excess cancer per
10,000 (10-4), 100,000 (10~5), or 1,000,000 (10~6) people
exposed, respectively.
Chronic Animal Studies
Although a number of studies have indicated chronic
changes in the heart, nervous reflex activity, respiratory
function, and hepatic changes resulting from "long-term"
exposure to methyl chloroform, most of these studies have
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1-8
used continuous exposures, which are not typical of the
ingestion through water. Therefore, studies investigating the
chronic effects of long-term exposure to methyl chloroform
should be conducted that utilize exposure schedules to those
encountered through water.
Mutagenicity, Teratogenicity, Carcinogenicity.
\
Mutagenic properties of methyl chloroform have been
investigated yielding weakly positive responses in certain
Ames tests to negative responses in some other test systems.
There are three studies on the teratogenic and fetal toxicity
of methyl chloroform, two of which were via inhalation and
one by ingestion. The results of these suggested that methyl
chloroform was not teratogenic to mice or rats at given levels
of exposure.
In the repeat NCI bioassay in rats and mice, there
was an increase in hepatocellular carcinomas occurrence in
low and high dose males and high dose females. NCI concluded
that (1) methyl chloroform was not carcinogenic for male rats
(2) the study was considered inadequate for carcinogenesis
evaluation in female rats, (3) the association between the
administration of methyl chlorofjrAn and the increased incidences
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1-9
of hepatocellular carcinomas in male mice was considered
equivocal, and (4) methyl chlorof£4m was carcinogenic for
feamle mice, causing an increased incidence of hepatocellular
carcinomas.
Synergistic Effects
Ingestion of ethanol was shown to increase the hepato-
toxicity of methyl chloroform. However, from a review of
\
the literature, it is evident that research must be intitated
to answer important questions concerned with exposure to
methyl chloroform and that a concerted effort must be directed
toward determining the possible additive, synergistic or
inhibitory effects of methyl chloroform, in combination with
other hydrocarbons and organic solvents, on dose-response
relationships.
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II-l
II. CHEMICAL AND PHYSICAL PROPERTIES
1,1,1-Trichloroethane (-CH30013), also called
methyl chloroform, is a colorless nonflammable liquid which has
a characteristic odor. Its line formula is:
H Cl
I I
H-C C-C1
I I
H Cl
\
Table II-l shows some of its important chemical and
physical properties.
TABLE II-l. PHYSICAL PROPERTIES OF METHYL CHLOROFORM
Solubility in water @ 25°C 0.44 gm/100 gm
Boiling point @ 760 torr 74°C
Vapor pressure @ 20°C 100 torr
Vapor density (air = 1) 4.6
Molecular weight 133.41
In the atmosphere, methyl chloroform is subject to
free radical attack and reaction with hydroxyl radicals is
the principal way in which it is scavenged from the atmosphere.
Photo-oxidation products of methyl chloroform include hydrogen
chloride, carbon oxides, phosgene, and acetyl chloride
(Christiansen elt al^. , 1972). The principal tropospheric
photo-oxidation product has been reported to be trichloroacetal-
dehyde.
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II-2
In water, methyl chloroform is slowly hydrolyzed to
predominantly acetic and hydrochloric acids (Billing e_t al.,
1975). Billing e_t a_l. (1975) reported a half-life of hydrolysis
of 6 months at 25°C.
Anhydrous methyl chloroform is generally noncorrosive,
but in the presence of water it can react to form hydrochloric
acid, which is a corrosive of metals (Keil, 1979). Addition
of epoxides can neutralize l;he generated acid (Keil, 1979).
Anhydrous methyl chloroform when heated to 360° to 440°C,
decomposes to 1,1-dichloroethylene and hydrogen chloride.
When methyl chloroform is heated in the presence of water at
temperatures between 75° and 160°C, it decomposes upon
contact with metallic chlorides or sulfuric acid to acetyl
chloride, acetic acid, and acetic anhydride. Noweir e_t al.
(1972) have observed that when methyl chloroform comes in
contact with iron, copper, zinc, or aluminum, at elevated
temperatures, phosgene is produced.
10
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III-l
III. METABOLISM AND PHARMACODYNAMIC EFFECTS
A. Metabolism
1. Absorption
In assessing the relationship of absorption of
methyl chloroform, one needs to consider the types of action
involved in the chlorinated hydrocarbons. They are all
neurodepressants and they are all affected by the rate of
absorption during exposure by inhalation, the most common
route of exposure in man.
Differences in the rate of absorption, as reflected
in the partition coefficients, could account for the
approximately ten-fold greater toxicity of the 1,1,2-isomer
over the toxicity of methyl chloroform (Fairchild e_t al.,
1977). The blood/air partition coefficients are 1.4 for
methyl chloroform and 44.2 for 1,1,2-trichloroethane (Morgan,
et^ al., 1972). The body content of the latter will increase
much more rapidly than the former during exposure to equal
concentrations of vapor. Following exposure, the body content
of methyl chloroform will decrease much more rapidly by
excretion in breath than that of its 1,1,2-isomer, leaving
less in the body to be metabolized.
11
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III-2
*
t
According to Stewart and Dodd (1964), cutaneous
absorption depends on the area of exposure. Methyl chloroform
is more readily absorbed through the skin than is trichloroethy-
lene. Because continuous immersion of both hands in methyl
chloroform for 30 minutes has been estimated to be equivalent
to a 30-minute vapor exposure to 100-500 ppm of the
compound, skin absorption would present only a limited health
hazard. In Stewart and Dodd's experiments, both male and
female subjects ranging in age from 25 to 62 years were used.
v
Three kinds of hand exposure were tested: thumb immersion;
total hand immersion; and topical hand application, which
consisted of brief immersion, withdrawal, solvent evaporation,
and reimmersion. Alveolar air samples were measured during
and following exposure. Methyl chloroform in the alveolar
air increased rapidly during immersion and dropped off slowly
following exposure. The results are shown in Table III-l.
Considerable effort was taken that the exposure through the
skin was not confounded by vapor inhalation. Periodically,
during the.skin exposure, samples of breathing zone air were
analyzed. Inhalation, as a source of the methyl chloroform
in this experiment, was not a factor (Stewart and Dodd, 1964).
S
Male and female human subjects ranging in age from 25 years
to 62 years were used. Three types of exposures were tested:
thumb immersion, hand immersion, and topical application on
the hand.
12
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III-3
The experiment was carefully designed to prevent the subjects
from inhaling the chemical. The authors concluded that
cutaneous absorption presents no health hazard since immersion
of both hands for 30 minutes is equivalent to a 30-rainute
vapor exposure to 100-500 ppm of the chemical.
Table III-l
ABSORPTION OF METHYL CHLOROFORM
Length of
exposure
(min)
30
30
30
Type of
exposure
Thumb (immersion
Hand (immersion)
Hand (topical)
ppm
Average Peak
breath
concentration
) 1.0
21.5
0.65
Average breath
concentration
2 hr postexposure
0.31
1.55
0.31
Adapted from: Stewart and Dodd (1964).
Fuk£bori, e_t a^l. (1976) studied the percutaneous
absorption of methyl chloroform applied on 12.5 cm^ of the
skin of the forearm^ Four men ranging from 24 years to 51
years of age were used. Application of the chemical for two
hours a day on five consecutive days resulted in a maximum
13
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III-4
concentration of 7 ppm in the expired air and 9 mg/ml in the
blood immediately after termination of the daily application.
Comparable results were obtained when both hands were immersed
in the test compound 11 times a day for 10 minutes on four
consecutive days. The concentration of methyl chloroform
obtained in the alveolar air in these experiments was comparable
to that after exposure for two hours to 10-20 ppm in the air.
Using ci_iabeie(f| halogenated hydrocarbons, Morgan
e_t al . (1970) compared the blood-air partition coefficient,
solubility, and excretion rates of various halogenated
hydrocarbons (Table III - 2). For the excretion studies,
approximately 5 mg of labeled material was administered
by a single breath inhalation to human subjects. The subjects
held their breath for 20 seconds to ensure maximum absorption.
Exhaled air was trapped in granulated charcoal and the radioactivity
in the charcoal traps was measured by gamma-ray scintillation
spectrometry. In comparison to other halogens, the amount of
methyl chloroform which was excreted was very high, indicating
a low level of retention. Urinary excretion of total 38ci
was less than 0.01 percent per minute with most compounds.
The uptake of non-labeled methyl chloroform from
air containing 0, 100, 350, and 500 ppm of the compound was
studied in 20 male and female subjects by Stewart, e_t al.
(1975). Subjects were exposed to each concentration for 1, 3,
14
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III-5
Table III-2
PHYSICAL PROPERTIES AND ABSORPTION OF INHALED VAPORS*
Compound
Blood/Air
Partition Solubility
Coefficients (g/100 ml water)
Total Excretion
in Breath After
1 hour as
Percent of Dose
Methyl
Chloroform
1,1,2-Tri-
1.4
44.2
0.44
0.44
44
2.9
chloroethane
1,1,2-Tri-
chloroethylene
9.5
0.10
10
* Adapted from Morgan et al. (1970)
and 7.5 hours. Breath samples were taken from 1 minute to 71
hours after exposure, and were analyzed for unmetabolized compound,
Curves of the methyl chloroform remaining in the breath were
plotted to estimate the magnitude of exposure. Breathing 350
ppm methyl chloroform for 1 hour, for example, produces a
breath level of about 165 ppm, which declines to under 1 ppm
at 23 hours. On the other hand, breathing the same concentration
(350 ppm) for 7.5 hours gives a breath concentration of
approximately 244 ppm which declined to approximately 7 ppm
after 16 hours. The authors found that the rate of methyl
chloroform excretion was a function of exposure duration.
15
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III-6
The data generated a family of post-exposure breath decay
curves that could be used to estimate the magnitude of exposure
Stewart, et al. (1961) measured human urine samples
following 15 minutes of exposure to methyl chloroform; some
samples contained up to 2 ppm of the compound, some contained
only a trace, and some urine samples contained none at all.
Morgan, et al. (1970) demonstrated that in man, the
amount of absorption of methyl chloroform is increased by
inhaling the vapor and holding the breath.
Summary
Absorption of methyl chloroform is most commonly
experienced in man primarily via inhalation, and secondarily
through dermal absorption. The rate of absorption during
exposure possibly affects the toxic potential of the specific
chlorinated hydrocarbon in question.
2. Distribution
Holmberg, e_t al_. (1977), studied the distribution
of methyl chloroform in mice during and after inhalation.
Solvent concentrations in the kidney and brain were about the
same at a given exposure concentration, but concentrations in
the liver were twice those observed in the kidney and brain
following exposures to 100 ppm or more (Table III-3).
16
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III-7
Table II1-3
CONCENTRATIONS OF METHYL CHLOROFORM IN TISSUES
OF MICE FOLLOWING INHALATION EXPOSURES*
Concentration
(ppm)
10
100
1,000
5,000
10,000
Exposure
Time (h)
24
24
6
3
6
1,1, 1-Trichloroe thane
Blood
0.6 +
6.3 +
36 +
165 +
404 +
0.16 f/
3.0
16
25
158
Concentration (ug/g
Liver
1.5 +
12.2 +
107 +
754 +
1429 +
0.3
4.6
38
226
418
Kidney
1.1
5.9
60
153
752
-I- 0.2
+ 2.2
± 16
-f 27
+ 251
tissue)
Brain
0.8
6.2
57
156
739
± 0.1
± 1«3
1 17
+ 24
+ 170
f/ Mean j- SDM
*Adapted from: Holmberg et al., 1977.
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III-8
A pharmacokinetic model with both uptake and elimination of
the first order best fitted the empirical data. Hake, e_t al.
(1960) reported that 0.09 percent of a large dose of methyl
chloroform was retained in the skin of rats as the parent
compound after 25 hours of administration of an intraperitoneal
(I.P.) dose (700 rag per kg). The blood contained 0.02 percent,
the fat 0.02 percent and other sites 0.1 percent of the dose
administered. The blood, body fat, and other sites contained
0.02, 0.02, and 0.1% of the"1 administered dose, respectively.
Astrand, et al. (1973) and Astrand (1975) found
that the uptake of methyl chloroform and other solvents into
the alveolar air and arterial blood was dependent on pulmonary
ventilation and blood circulation which are affected by the
intensity of physical work. In these experiments, 12 men
(ages 21-28) were treated for 30 minutes with 250 ppm or 350
ppm of methyl chloroform during rest and exercise (50-150
watts, a unit of workload as measured on a bicycle ergometer).
The concentration of the chemical in the alveolar air (180 ppm)
and arterial blood (5 ppm) was nearly the same at an exposure
of 350 ppm at rest and at 250 ppm during light exercise-
Monster, et al. (1979) exposed six male human volunteers
18
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III-9
(ages 27-34) for four hours to 70 ppm methyl chloroform at
rest, 145 ppm at rest, and 142 ppm at rest combined with work
loads (two times 30 minutes, 100 watts). During the work
load, the lung clearance of methyl chloroform increased 2-3
times the value at rest. In the post-exposure period, the
concentration of methyl chloroform in exhaled air paralleled
that in blood; the concentration of the chemical in the blood
i
was 8.2 + 2.5 times higher 'than that in exhaled air. There
was no significant difference in the concentration of the
chemical in the blood or exhaled air of subjects in the rest
group (145 ppm exposure) and that in the rest/work group
(142 ppm exposure). The slopes of the concentration curves
in blood and exhaled air at 20 hours, 50 hours and 100 hours
after exposure corresponded to a half-life of methyl chloroform
of about 9 hours, 20 hours, and 26 hours, respectively.
Four male Sprague-Dawley rats were exposed to 955
ppm of methyl chloroform for 73 minutes, and the concentration
measured in the breath until it was undetectable (Bcettner
and Muranko, 1969). Stewart, et al. (1961) had exposed humans
to similiar levels and compared the data. One hour following
exposure, human breath contained 1.85 times the concentration
19
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111-10
of methyl chloroform as that in rat-expired air; 10 hours
following exposure, human breath contained four times the
concentration in rat-expired air. These results showed that
humans and rats differ in any or all of the parameters of
absorption, elimination, or retention.
Concentrations of methyl chloroform in the expired
air sample of rats and man were compared at 1 hour following
different exposure indices, usually calculated as the product
of concentration and time (Stewart, e_t a_l. 1961). The results
indicated that the concentration of the solvent was of greater
importance than the elapsed time from inhalation in determining
post-exposure breath concentration. Additional studies with
concentrations from 100 to 1,000 ppm confirmed that when the
concentration of the chlorinated hydrocarbon is sufficient to
cause rapid saturation, the concentration of methyl chloroform
or total chlorinated hydrocarbon in expired air is proportional
to the concentration of the compound rather than the time of
treatment, once the saturation limit is reached.
Summary
Autopsies of humans dying from acute exposure of
methyl chloroform, reveal tissue concentrations according to
the following order: liver > brain > kidney > muscles > lung >
blood. In pregnant animal studies, methyl chloroform is readily
20
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III-ll
absorbed (both inhaled and ingested) by the fetuses. Comparison
studies of rat and human responses indicate that both species
differ in parameters of absorption, elimination, or retention
of methyl chloroform.
3. Biotransformation
The primary metabolites of methyl chloroform are
trichloroethanol and trichloroacetic acid (TCA) as shown in
\
Figure III-l (Hake, et al. 1960; Ikeda and Ohusuji, 1972).
Figure III-l
Metabolic Route Suggested for Methyl Choloroform
METHYL
CHLOROFORM TRICHLOROETHANOL
oxidation
CC13 - CH3 —> CC13 - CH2OH
glucuronide
conjugation oxidation
CClo - CH20 - glue.
TRICHLOROACETIC ACID
CC13COOH
Adapted from: Hake, et al. (1960); Ikeda and Ohtsuji (1972).
21
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111-12
On the basis of in vitro experiments with normal
gut flora, it appears that microbial degradation is not an
important process in metabolic degradation (McConnell, e_t al.
1975).
Hake and co-workers (1960) injected one female and
two male rats (170 to 183 g) intraperitoneally with 700 mg/kg
of methyl chloroform-l-14C. About 50% of the urinary
radioactivity occurred as 2,2,2-trichloroethanol in the form
\
of glucuronide conjugate. The other 50% volatilized at room
temperature. It was suggested that methyl chloroform
metabolized by an initial oxidation to trichloroethanol and
subsequent oxidation to small quantities of trichloroacetic
acid. In this study, 98.7% of the injected radioactivity was
exhaled as unchanged compound, and 0.5% as -^CC>2. Only 0.85%
of injected radioactivity was recovered in urine, and only
half of that was identified as a metabolite, indicating
insignificant bioaccumulation.
The studies on metabolism by Ikeda and Ohtsuji (1972)
compared the metabolism of methyl chloroform using both
inhalation dosage (a route of greater interest to human
work) and i.p. injection of 200 ppm for 8 hours. Eight
studies of six 50g Wistar rats per study were used. All
urine excreted in 48 hours was collected. Trichloroacetic
22
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111-13
acid (0.5 mg/kg body weight) and trichloroethanol (3.1 mg/kg
body weight) were found. A dose of 2.78 mmol/kg body weight
of methyl chloroform was also injected i.p. into a similar
group of rats to check the effects of the dosage route. The
results of the urine analysis following i.p. injection were
essentially the same as those obtained on the inhalation
experiments. The relative levels of trichloroethanol and
trichloroacetic acid seen inslkeda's experiments may indicate
that the acid is derived from the alcohol.
Fukabori and co-workers (1976) reported the metabo-
lism of methyl chloroform in humans after skin application
to two sites.
Site I
Forearm skin, 2 hr/day for 5 days
Metabolites in urine: Trichloroethanol, 2 to 6
rag/day (Day 1)
Trichloroacetic acid, slight
increase with increased
exposure
Site II
Dip both hands, seven times per day for 4 days,
Metabolite in urine: Trichloroethanol, 5 to 15
mg/day
23
-------
111-14
It should be noted that most of the methyl chloroform was in
the expired air. The concentrations of the unchanged solvent
ranged from 5 to 11 ppm (days 1 and 4) respectively, when hands
were dipped in the solvent.
Summary
Trichloroethanol and trichloroacetic acid are the
primary metabolites of methyl chloroform. Various metabolic
studies in animals of methyl^chloroform have been cited noting
that regardless of dosage route (inhalation or ingestion) the
results of urine analysis were essentially the same. Human
metabolic profiles after skin application of methyl chloroform
indicate both trichloroethanol and trichloroacetic acid
(increasing slightly with an increased exposure) in urine.
However, most methyl chloroform was found unchanged (98.7%)
in the expired air.
4. Excretion
Pulmonary excretion rates in man in the first hour
following exposure to methyl chloroform were 44% (Morgan, e_t
al., 1970). In a series of chlorinated compounds, excretion
rates were inversely proportional to the lipid solubility of
the compound.
24
-------
111-15
A summary of the excretion of methyl chloroform in
expired air sample is given in Table III-4.
Table III-4
METHYL CHLOROFORM EXCRETION IN EXHALED BREATH
Route
Species
% Dose exhaled
unmetabolized
Reference
Skin
contact
Inhalation
Injection
(i.p.)
Humans
Humans
Rats
Peak breath level
14% of estimated
150 ppm dose
44% in 1 hour
> 99% of 77 mg/kg
Stewart and Dodd
(1964)
Morgan, et al.
(1970)
Hake, e_t al.
(1960)
In the studies of Hake, e_t al. (1960), over 99% of
the i.p.-injected methyl chloroform was excreted by rats via
the pulmonary route (98.7% unchanged, 0.5% metabolized) and
less than 1% via the urine (0.85% of dose, half identified as
the glucuronide of trichloroethanol). Boettner and Muranko
(1969) have used animal pulmonary excretion data for estimation
of exposure in humans.
25
-------
111-16
Ikeda and Ohusuji (1972) compared the metabolism of
methyl chloroform after exposing Wistar rats (70 g body
weight) of both sexes to the vapor (200 ppm for eight hours)
and after intraperitoneal injection (2.78 mmole/kg). Urine
was collected for 48 hours. The total trichloro-compounds
were estimated colorimetrically by Fujiwara reaction after
oxidation of the urine. Trichloroacetic acid (TCA) was
determined by the same colorimetric method without oxidation.
The difference between the total trichloro-compounds (after
oxidation) and TCA (without oxidation) was calculated to be
trichloroethanol (TCE-). Regardless of the role of administration
of methyl chloroform, 48-hour urine samples contained 0.5
mg/kg (body weight) of TCA and 3.1 mg/kg of TCE.
The publication of recent technical reports on the
pharmacokinetics of methyl chloroform provide the disposition
characteristics of the chemical in rats and mice (Schumann,
et al. 1982a, 1982b). The animals were exposed via inhalation
to 150 or 1,500 ppm of radiolabeled material for 6 hours.
The elimination of the radioactivity was measured for 72 hours.
Following exposure to 150 or 1,500 ppm, both species excreted
greater than 96% of administered radioactivity during -the
first 24 hours. The primary route of elimination from the
body was via exhalation of unchanged methyl chloroform. In
the rat, approximately 94% and 98% of the total administered
26
-------
111-17
radioactivity was eliminated in expired air after exposure to
150 or 1,500 ppm, respectively. In the mice, the percentages
were 87% and 97% of the respective exposure concentrations.
The remaining radioactivity was detected as CC>2 in the expired
air and as nonvolatile radioactivity in urine, feces, carcass
and cage wash. Mice were found to metabolize two or three
times more methyl chloroform on a body weight basis compared
to rats. The authors stated that (1) since the biotransformation
\
of methyl chloroform occured to such a limited extent,
saturation of its metabolism did not impair markedly on the
distribution or elimination of the parent chemical, (2) the
body burden, end-exposure blood level, and tissue concentration
of methyl chloroform were found overall to increase in direct
proportion with the exposure level, and (3) radiolabeled
methyl chloroform was more concentrated in the fat of both
species than in the liver or kidneys immediately after
exposure (however it was rapidly cleared from the fat so that
by 24 hr < 2% of the initial radioactivity remained).
Morgan, et al. (1970) measured pulmonary excretion
of 38Cl-labeled methyl chloroform and trichloroethylene in
man following a single breath administration; the former was
expired more rapidly than the latter during the first hour
(i.e., 44% and 10% of the inhaled dose).
27
-------
111-18
With low level exposure (about 183 ppm), Monzani
et al. (1969) observed that (a) only one of 18 workers
excreted trichloroacetic acid in the urine, and (b) that
excretion was at a level of 9.72% ing/liter of urine.
In 1968, Tada and co-workers exposed two male subjects
by inhalation to a series of chlorinated hydrocarbons. The
urinary excretion of trichloroacetic acid was increased by
repeated exposures. However, the increase was not proportional
to vapor concentration and exposure duration.
Tada (1969) repeatedly exposed humans to 200-400
ppm methyl chloroform. There was an increase in urinary
excretion of trichloroacetic acid with a maximum reached in
4-5 days. The urinary acid levels fluctuated during the
day; the author suggested that the total 24-hour excretion
was related to time and intensity (vapor concentration), of
exposure.
Methyl chloroform was still found at a level of 0.1
ppm in the breath of an individual after 1 month of exposure
to a mixture of 370 ppm of the compound and 130 ppm
trichloroethylene, 7 hours/day for 5 days (Stewart, et al. 1969)
Methyl chloroform was also present in alveolar air 1 month
after exposure to concentrations ranging from 420-612 ppm
for 6.5 to 7 hours/day for 5 days (Stewart, e_t a_l. 1961).
28
-------
111-19
Summary
Methyl chloroform and its metabolite (identified and
unidentified) have been shown to be excreted (unchanged) in
man and rats via the lungs and urine. In rats, methyl
chloroform has been administered by 2 routes, inhalation and
intraperitoneal injection. Alveolar air was the main route
of excretion in both cases. Clinical studies indicate that
exposure to methyl chloroform and resulting urinary levels of
\
trichloroacetic acid are related to time and intensity of exposure
b. Pharmacodynamic Effects (Animal and Human)
Like other halogenated hydrocarbons, methyl chloroform
influences the functions of the CNS, heart, lungs, liver and kidneys
1. Central Nervous System (CNS) Effects
In the late 1800's, methyl chloroform was considered
superior to chloroform because it produces general anesthesia
with minimal excitation and salivation. Lazarew (1929)
determined the concentration causing complete narcosis to be
45 mg/1 and the minimal fatal concentration 65 mg/1. The ratio
between the concentration of the vapor causing the death and
that producing the loss of reflexes and that producing death
in mice was found to be 20, as compared with 15 for chloroform.
29
-------
111-20
Kranz, et al^. (1959) estimated the dosage in dogs
to be 0.45 g/kg for induction of anesthesia and 0.80 g/kg for
causing respiratory failure. The^ anesthetic index of methyl
chloroform was 1.77 for dogs and 2.15 for monkeys, which
provide greater margins of safety than those of chloroform.
Dornette and Jones (I960) used 1% to 2.6% methyl chloroform
(10,212 to 26,500 ppm) with 80% nitrous oxide for anesthesia
induction in 50 human subjects. The volunteers were kept
anesthetized up to 2 hours,^maintained with increased methyl
chloroform levels of 0.6%-2.25% (6,127 to 22,982 ppm),
administered with decreased nitrous oxide-oxygen. The
investigators attributed 75% of the anesthetic effect to
methyl chloroform and the remaining to nitrous oxide-oxygen
mixture. Light anesthesia was induced within 2 minutes, and
recovery of reflexes occurred 3 to 5 minutes after discontinuing
the anesthetic agent. Siebecker, e_t al. (1960) studied the
human electroencephalogram (EEC)in methyl chloroform (plus
nitrous oxide) anesthesia and found patterns similar to
halothane-
The Romberg test (a neurological test that measures
proprioceptive control with a subject standing, feet together,
eyes closed) has been used to measure the narcotic or anesthetic-
like effects of methyl chloroform. Stewart, e_t al. (1961)
30
-------
111-21
found 6 subjects failed to perform a normal test after 15
minutes exposure at 2,650 ppm (starting at zero concentration),
but noted no CNS effects at 500 ppm. Torkelson, e_t al. (1958)
found positive Romberg tests in all three subjects exposed to
methyl chloroform at 1,740-2,180 ppm. Lightheadedness
occurred in three of the four subjects exposed to 1,000 ppm
for 70-75 minutes.
Chemical tests of motor reflex have demonstrated
\
reversible narcotic effects by methyl chloroform in human
subjects exposed to 250 ppm (Gambarale and Hultengren, 1973),
450 ppm (Salvini, e_t al. 1971), 1,000 ppm for 70 to 75
minutes (Torkelson, e_t al. 1958), and to 900 ppm for 20 to 73
minutes (Stewart e_t al. 1961). Stewart, e_t al. (1961) found
no CNS effects with balance and coordination tests following
methyl chloroform exposure at 500 ppm for 3 hours, but observed
CNS effects in four of the five subjects exposed at the same
level for a longer time (6.5 to 7 hours) (Stewart, e_t al. 1969)
Stahl, e_t al. (1969) reviewed six fatal cases of
exposure; autopsy samples showed the concentration of solvent
to be: 0.32; 2.7; 9.3; 50.0; 56.0; and 59.0 milligrams per
100 g brain tissue. Kleinfeld and Feiner (1966) noted high,
but unquantitated, levels in brain after a death from methyl
chloroform.
31
-------
111-22
Summary
The Romberg test (a neurological test which measures
proprioceptive control) has been used to measure the narcotic
effects of methyl chloroform within the range from 500 ppm
(no CNS effects) to 2,650 ppm. Impairment in motor control
after exposure to methyl chloroform has been demonstrated in
\
humans with concentrations as low as 250 ppm, but CNS effects
appear to be dependent on methyl chloroform concentration as
well as exposure time. Human autopsies following death due
to methyl chloroform show high, but unquantitated levels of
methyl chloroform in brain tissues.
32
-------
111-23
2. Cardiotoxicity
The proarrhythmic activity of methyl chloroform has
been investigated in the dog. Administration of methyl
chloroform to two dogs to induce anesthesia without premedication
was reported by Renmick et a_l. (1949) to have resulted in
sudden death. Further experiments with five dogs under
barbital anesthesia showed that ventricular extrasystoles and
ventricular tachycardia were, regular occurrence when epinephrine
was injected after administration of repeated small doses of
methyl chloroform. Maximum sensitization of the heart occurred
after administration of 0.25-0.40 ml/kg of methyl chloroform;
greater amounts raised the threshold dose of epinephrine,
partly because of severe hypotension. They concluded that
epinephrine itself, however, is known to induce ventricular
extrasystoles and tachycardia, and the effects noted may have
been due, at least in part, to epinephrine. Reinhardt, e_t
al. (1973) found the minimal concentration that causes
sensitization in the dog to be 27.8 mg/1. The effective
concentration was 40.7 mg/1 in another group of dogs examined
by Clark and Tinston (1973).
Somani and Lum (1965) and Lucchesi (1965) administered
133.6 mg/kg of methyl chloroform intratracheally and injected
epinephrine (10 ug/kg) intravenously. This combination caused
33
-------
111-24
ventricular fibrillation. However, dogs pretreated with a
beta-adrenergic blocking agent failed to exhibit any cardiotoxic
effects.
The death of a young seaman due to methyl chloroform
abuse resulted in cardiac changes (Travers, 1974). Progressive
hypotension and bradycardia and several instances of cardiac
arrest resulted in death 24 hours after collapse. Autopsy
\
showed right atrial and ventricular dilatation.
Inhalation of high levels of methyl chloroform
produces a decrease in heart rate and blood pressure during
the first few minutes of exposure. These effects have been
reported at 6,250 ppm for rabbits (Truhaut, e_t al. 1972);
8,000 ppm for dogs (Herd, e_t al_. 1974); 25,000 and 50,000 ppm
for monkeys (Belej, et al. 1974).
Cellular hypertrophy in the tissues following methyl
chloroform exposure (which is a sign of cardiovascular
toxicity) has been reported in several studies (Griffiths, et_
al. 1972; Adams, e_t al. 1950; Horiguchi and Horiguchi, 1971;
Rice, et al. 1967). Huroan autopsy reports have mentioned
tissue congestion following deaths due to methyl chloroform,
expecially after prolonged abuse or high exposure (Hall and
Hine, 1966; Stahl, et al. 1969; Hatfield and Maykoski, 1970).
34
-------
111-25
Summary
Methyl chloroform-induced cardiotoxicity has been found
in animal experiments (dogs, rabbits, and monkeys) and in
human autopsy reports, where cellular hypertrophy in the
cardiac tissues following methyl chloroform abuse or high
exposure has been present.
3. Hepatotoxicity and Nephrotoxicity
v
Liver cell damage produces an increase in cytoplasmic
transaminase, followed by lactic dehydrogenase (LDH) from the
mitochondria. To determine the organ source of these enzyme
level changes after methyl chloroform exposure, the LDH must
be electrophoretically fractionated.
Platt and Cockrill (1969) found increases in only
two of seven enzymes measured in rats given methyl chloroform
(1,650 mg/kg) orally in liquid paraffin for 7 days. The
NADPH2~cytochrome C reductase and glutamate dehydrogenase
activity of rat liver were significantly increased in the
treated animals.
Klaassen and Plaa (1969) found no elevation in liver
triglycerides within the first 36 hours after exposing rats
to methyl chloroform at 3,800 mg/kg (75% of the LD50).
35
-------
111-26
Six controlled human studies showed that the urinary
urobilinogen was the most sensitive test for ascertaining
hepatotoxicity in subjects exposed to methyl chloroform
(approximately 500 ppm or above) (Stewart, e_t al_. 1961). The
serum glutamic oxaloacetic transaminase (SCOT) values and the
15 minute phenosulfonphthalein (PSP) excretion deviated
somewhat from pre-exposure values, but remained within normal
limits.
The lowest concentration of methyl chloroform that
resulted in hepatic effects was reported by McNutt, e_t al.
(1975) who found significantly elevated triglyceride levels
in mice exposed to 250 ppm for 4 and 13 weeks. MacEwen, et
al. (1974), however, failed to produce elevated liver
triglycerides in mice exposed continuously to 250 ppm for 100
days, but observed the effects at 1,000 ppm.
Krantz, e_t al. (1959) found no effects from methyl
chloroform on phenosulfonphthalein retention time in an
anesthetized dog, but repeated administration of the anesthesia
resulted in hepatic pathology in one of the four rats.
Horiguchi and Horiguchi (1971) reported congestion
of the liver and bile duct inflammation in male mice exposed
to 1,000 ppm of methyl chloroform (2 hours, nine times).
36
-------
111-27
Plaa (1976) summarized in Table III - 5 work on
trichloroethylene, methyl chloroform, and perchloroethylene
with respect to liver toxicity. The table shows that toxicity
is a function of the test used for all the halogenated compounds.
Hanasono, et al. (1975) exposed male rats to 1.0 ml
methyl chloroform/kg interperiotoneally 3 days after admin-
stration of alloxan which produced diabetes symptoms but no
serum glutamic pyruvic transaminase (SGPT)or triglyceride
change. The hepatotoxic effects of methyl chloroform in con-
trol and diabetic rats are evident from SGPT and trigylceride
levels, observed as follows:
SGPT Triglyceride in liver
(units/ml) (mg/g tissue)
Controls 42 + 2 5.7 + 0.5
Diabetic 65 + 19 21.6 + 13.1
Rice, e_t al. (1967) gave rats methyl chloroform (2
ml/kg) 24 hours before performing hemodynamic measurements on
the isolated, perfused livers. Under in_ vitro conditions,
hepatic blood flow was not changed by the pre-treatment,
although carbon tetrachloride did change blood flow character-
istics in the same experimental series. A subcapsular
inflammatory reaction was found in the livers of animals
pretreated with methyl chloroform.
37
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Table III-5
LIVER EFFECTS OF METHYL CHLOROFORM AND
OTHER CHLORINATED HYDROCARBONS
Relative potency rankings of the subject halogenated
hydrocarbons in mice
Compounds
24-HR LD5o)
(mmole/kg)
Compounds
(BSP Re-
tention ED50)
(mmole/kg)
Compounds
SGPT Ele-
vation ED5Q )
(mmole/kg)
Trichloroethylene
Perchloroethylene
Methyl chloroform
Compound
24
28
37
Trichloroethylene
Methyl chloroform
Perchloroethylene
23 Methyl chloroform
27 Trichloroethylene
32 •- Perchloroethylene
Potency ratios of the three subject solvents for
SGPT elevation or BSP retention in mice
2.5
18
28
BSP Retention potency
ratio (LD50/ED5Q)
SGPT Elevation potency
ratio (LD50/ED50)
Methyl chloroform
Trichloroethylene
Perchloroethylene
1.4
1.0
0.9
1.5
1.3
1.0
38
-------
111-29
Table III-5 (Continued)
Severity of liver injury induced by minimal lethal doses of the
tnree subject solvents; SGPT elevation being used as
the index of hepatic dysfunction^T
SGPT (R-F units)
Compound Dogs Mice
Perchloroethylene 400 Nil
Methyl chloroform 350 65
Trichloroethylene 250 90
3y The ranking is: most potent first and least potent last.
Adapted from: Plaa (1976).
39
-------
« •
111-30
Using in vitro experimental conditions, Fuller, et
al. (1970) found an increase in the metabolism of hexobarbital,
meprobamate, and zoxazolamine in rats following the inhalation
of methyl chloroform (2,500 to 3,000 ppm) for 24 hours.
There was an increase rn vitro of the metabolism of these
three compounds by hepatic microsomal enzymes under the
influence of methyl chloroform.
The inhalation of methyl chloroform at a level of
approximately 10,000 ppm for 4 to 6 hours had no effect on
liver function of ethanol-exposed rats, although other
chlorinated/hydrocarbons exhibited increased hepatotoxicity
(Cornish and Adefuin, 1966). Cornish, e_t al. (1973) also
failed to demonstrate increased hepatotoxicity due to methyl
chloroform in rats pretreated with phenobarbital. Carbon
tetrachloride was more hepatotoxic in the phenobarbital-
treated rats.
Ingestion of ethanol was reported by Klaassen and
Plaa (1966) to increase the hepatotoxicity of methyl chloroform,
Ethanol (60%) was administered by gavage at doses of 5 mg/kg.
In one experiment, a dose of ethanol was given on each of 3
days before intraperitoneal administration of methyl chloroform
in corn oil (0.02 ml/g) at doses of 2.5-2.75 ml/kg. In
another experiment, a single dose of ethanol was given 12
hours before the methyl chloroform. In both experiments, BSP
40
-------
111-31
retention was significantly higher in the ethanol pre-treated
rats than in control rats given only methyl chloroform. SGPT
activity was not affected in this" experiment by methyl
chloroform at a dose of 2.5 ml/kg with or without alcohol pre-
treatment, and kidney function as measured by PSP excretion
was similarly not affected by methyl chloroform doses of 2.0
ml/kg. SGPT activity was also not different from controls in
dogs given methyl chloroform doses of 0.85 ml/kg, with or
without ethanol pre-treatment (Klaassen and Plaa, 1967).
Isopropyl alcohol or acetone administered by gavage
to male Swiss-Webster mice 18 hours before i.p. injection of
methyl chloroform did not alter the response of SGPT activity
to the administered methyl chloroform (Traiger and Plaa, 1974).
The doses of methyl chloroform used in this experiment were
1.0, 2.0 and 2.5 ml/kg. The latter dose caused increases in
SGPT activity, but the increases were not affected by isopropyl
alcohol or acetone pretreatment.
In laboratory animals, liver function appears to be
readily influenced by methyl chloroform. Klaassen and Plaa
(1967) reported disturbances in liver functions in dogs.
Similarly, rabbits exhibited hepatic function changes.
Adams, e_t al. (1950) reported no adverse effects
in guinea pigs given 1,500 ppm of methyl chloroform for 7
41
-------
111-32
hours/day for 3 months. Conversely, Torkelson, e_t al^. (1958)
reported liver effects in animals exposed to both 1,000 and
2,000 ppm levels of methyl chloroform for 30 to 90 minutes/day
for 3 months. Klaassen and Plaa (1966) noted enlargement of
hepatocytes with cellular infiltration and vacuolation in
mice following methyl chloroform treatment. Slight hepatic
narcosis occurred only when the dosage was in the lethal
range. Von Oettingen (1964) suggested that the mechanism of
hepatic changes is a functidn of the lipid solubility of the
methyl chloroform.
Signs of hepatic effects include retention of BSP
and change in SGPT activity following injection or inhalation
of methyl chloroform. Gehring (1968) found the £050 for SGPT
activity was 2.91 g/kg in mice, whereas Klaassen and Plaa
(1966) found a value of 3.34 g/kg for the same effect. The
inhalation EV$Q for SGPT activity in mice was 13,662 ppm for
approximately 10 hours (Gehring, 1968).
Plaa and Larson (1965) reported that only one of
the nine mice given methyl chloroform (3,400 mg i.p./kg)
exhibited significant proteinurea. In another trial, mice
exhibited swelling of the convoluted tubules of the kidney
after a similar dose of methyl chloroform. However, no
necrosis was observed in these studies. Renal toxicity
(tubular damage) in mice was also observed in another study
42
-------
111-33
(Klaassen and Plaa, 1966). These authors studied renal
function patterns in dogs exposed to methyl chloroform and
found renal changes as determined by phenolsulfonphthalein
glucose, and protein excetion data, but no histopatho-
logical changes (klaassen and Plaa, 1967). According to
these data, the kidney is less affected by methyl chloroform
than the liver.
Stewart (1971) reported several instances of apparent
kidney toxicity related to methyl chloroform exposure in
humans. According to a human ingestion study, elevated serum
bilirubin and evidence of kidney injury associated with
hematuria and proteinurea were seen. In other studies
exposures to the solvent (900 ppm for 20 minutes) produced
elevated urinary urobilinogen in one subject, and some evidence
of adverse effects on kidneys (dye clearance rate, hematuria)
was observed in six subjects after exposure to 500 ppm of
methyl chloroform for 78 minutes. Five of the seven subjects
exposed to methyl chloroform (0 to 2,650 ppm) for 15 minutes
exhibited a few erythrocytes in the urine and/or a positive
urinary urobilinogen (Steware, e_t a_l. 1961).
Summary
Various experiments using rats, dogs, and mice to
determine the influence of methyl chloroform on liver function
provide conflicting results due to variation in animal species,
43
-------
111-34
dose, and treatment schedule. For example, guinea pig
experiments have shown: 1) no organ damage following exposure
to 1,500 ppm of methyl chloroform for 7 hours/day for 3
months, and again, 2) liver damage due to 1,000 ppm of methyl
chloroform for 30 to 90 minutes/day for 3 months.
Nephrotoxicity, as measured by tubular damage, PSP,
glucose, and protein excretion data has been investigated in
animals and man with reference to exposure to methyl chloroform,
Although some kidney damage in laboratory animals has been
reported, it appears that methyl chloroform affects the liver
before it damages the kidneys.
4. Pneumotoxicity
Irritation of the lungs and respiratory tract as a
result of methyl chloroform inhalation has been observed in
industrial workers and experimental animals (Stewart, et al.
1961; 1969; Salvini, e_t a_l. 1971). Humans occupationally
exposed to methyl chloroform by inhalation and skin contact
for prolonged periods complained of irritation of the upper
respiratory tract (Weitbrecht, 1965). American industrial
workers, who were chronically exposed to the compound at low
levels also have complained of respiratory tract irritation
(Vandervort and Thoburn, 1975; Hervin, 1975). Nearly all
National Institute for Occupational Safety and Health Hazard
44
-------
111-35
Evaluation Reports on methyl chloroform, when instituted by
worker complaint, were due to strong solvent odor and throat
irritation (1978). In nearly all cases the levels in ambient
air were far below the maximum allowable concentrations.
There is no idication in the literature that the lungs of man
or animals become hypersensitive following repeated inhalation,
but the irritation is apparently a matter of concern.
In animal studies,^structural changes in the lungs
were seen in guinea pigs exposed to 1,000 ppm of methyl
chloroform for 72 minutes/day (69 exposures), and to 2,000
ppm for 12 minutes/day for 69 exposures. On the other hand,
1,000 ppm for 36 minutes/day (69 exposures) produced no lung
irritation (Torkelson, e_t al. 1958). Prendergast, e_t al.
(1967) exposed several animal species to 370 ppm of methyl
chloroform continuously for 90 days but observed only non-
specific inflammatory changes in the lungs.
MacEwen and Vernot (1974) reported that the most
significant effect seen in rats continuously exposed to methyl
chloroform by inhalation for 100 days was respiratory disease.
45
-------
111-36
Lung changes were seen in approximately half of the rats
exposed to 250 and 1,000 ppm.
Pulmonary congestion in animal inhalation experiments
has been widely reported, particularly for chronic (or high-
level) exposures to methyl chloroform (Horiguchi and Horiguchi,
1971). Pulmonary edema and congestion, however, are consistent
with cardiovascular insufficiency rather than primary lung
\
effects. The lung effects appear to be limited to irritation,
and are reported to be transitory in humans, even following
moderately high exposures to the compound (Weitbrecht, 1965).
Summary
The possibility of increased pneumotoxicity due to
"additive" exposure to various levels of methyl chloroform
from food and drinking water contamination cannot be ignored.
However, the effects of the compound through ingestion would
be less severe than effects from inhalation since the small
amount of compound is eliminated via the gastrointestinal tract
in the urine and feces.
46
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V. HEALTH EFFECTS IN ANIMALS |
1. Acute Toxicity
Lazarew (1929) exposed an unspecified number of
mice to methyl chloroform to determine the minimum concentration
_required to produce prostration, loss of reflexes and death
within 2 hours of exposure (Table V-l).
Table V-l EFFECTS OF TRICHLOROETHANE ISOMERS ON MICE
Minimum Concentration for Response
Within 2 Hours of Exposure (mg/1)
Compound Proneness Loss of Reflex Death
Methyl chloroform 40 45 65
l,l,22trichloroethane 10 15 60
Adapted from: Lazarew (1929)
Lazarew assigned toxicity ratings to the 12 compounds
based on concentrations required to produce prostration.
Higher indices meant greater toxicity. The index for methyl
chloroform was 3.5 compared to 14 for 1,1,2-trichloroethane,
meaning that the 1,1,2-isomer was 4 times as toxic as the
methyl chloroform isomer. The acute oral L£>$Q for methyl
chloroform, as determined in several species of animals, is
reported by Torkelson, e_t al. (1958) to range from 5.7 to
14.3 g/kg. Unfortunately, little other toxicological data
47
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V-2
involving oral ingestion are available. LDsg values that
were derived upon administration of methyl chloroform by routes
other than oral illustrate the difficulty in using such data
to predict consequences of ingestion of the chemical. In
contrast with an oral LDsg value of 11 g/kg in the mouse
(Torkelson, e_t a_l. , 1958), the LV$Q is approximately 16 g/kg
for subcutaneous injection (Plaa, e_t aJL. 1958) and approximately
4.9 g/kg for intraperitoneal injection (Klaassen and Plaa,
1966). By administering equivalent intraperitoneal and oral
doses of carbon tetrachloride to rats, Nadeau and Marchand
(1973) demonstrated that significantly higher hepatic
concentrations of carbon tetrachloride and more extensive
hepatotoxicity are manifested in the animals given the compound
intraperitoneally.
Despite the problems that are inherent in extrapolating
data from one route of chemical exposure to another, we may
gain qualitative insight into the toxicity of methyl chloroform
by examining information from studies in which the oral route
was not used. Plaa and his colleagues found methyl chloroform
to be the least hepatotoxic of a series of alkyl halocarbons
that were given subcutaneously (Plaa et al., 1958) and
intraperitoneally (Klaassen and Plaa, 1966) to mice and
intraperitoneally to dogs (Klaaassen and Plaa, 1967) and rats
(Klaassen and Plaa, 1969). Near-lethal quantities of methyl
48
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V-3
chloroform were generally required to produce hepatotoxicity.
The authors observed little to no evidence of nephrotoxicity.
In contrast to methyl chloroform (ED$Q = 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 (EDso =2.9 ml/kg).
In laboratory animals, as well as humans, the
primary hazard of inhalation of high concentrations of methyl
chloroform is excessive depression of the CNS. Adams e_t al .
(1950) reported the 3-hour LCso in rats to be 18,000 ppm.
They observed that recovery of several test species of animals
from marked depression of the CNS was rapid and uneventful.
The lowest and shortest exposure that elicited histological
change in tissues of the rat was 8,000 ppm for 7 hours. This
treatment produced an increase in liver weight and fatty
vacuolation of hepatocytes. Dis-turbance of vestibular function
in rabbits infused intravenously with methyl chloroform was
observed by Larsby e_t al . (1978) when blood levels exceeded
75 ppm of methyl chloroform. Also, levels of methyl chloroform
in the cerebrospinal fluid were approximately one-third of
that in the blood. Although this vestibular disturbance is
physiologically significant, it should be noted that Gamberale
and Hultengren (1973) observed inhibition of psychophysiological
function in humans with blood levels of only 3-5 ppm of methyl
chloroform.
49
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V-4
A second hazard associated with acute exposure to
vapor containing high concentrations of methyl chloroform is
cardiovascular toxicity. The aforementioned accounts of
cardiotoxic effects of methyl chloroform in humans (Bass,
1970; Dornette and Jones, 1960) have been confirmed in studies
of dogs. Reinhardt e_t al. (1973) found methyl chloroform to
be more potent than trichloroethylene in inducing arrhymias
in dogs given epinephrine concomitantly. The lowest effective
concentration of methyl chloroform was 5,000 ppm. However,
Egle et al. (1976) did not detect adverse cardiovascular
effect in dogs that had been exposed to 5,000 and 10,000 ppm
methyl chloroform in a Freon propellant. They attributed the
disparity between their own findings and those of Reinhardt et
al. (1973) to differences in the experimental design. Herd ejt al.
(1974) found methyl chloroform to exert a biphasic action
on the 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 methyl chloroform'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
50
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V-5
exposure to methyl chloroform may be injurious to the
cardiovascular system.
In constrast to previous findings of microsomal
enzyme induction in mice (Lai and Shah, 1970) and rats (Fuller,
1970) that inhaled 3,000 ppm methyl chloroform for 24 hours,
inhibition of microsomal drug metabolism was observed in rats
given approximately 1.4 g/kg orally (Vaino e_t al. , 1976) and
in mice 1.0 ml/kg of undiluted methyl chloroform intraperitoneally
\
(Shah and Lai, 1976). The animals were sacrificed 24 hours
following administration of methyl chloroform. Shah and Lai
(1976) further demonstrated that dilution of methyl chloroform
with dimethylsulfoxide (DMSO) potentiated the effect, while
methyl chloroform, diluted with olive oil, reduced the inhibitory
effect. Shah and Lai suggested two factors that may be
important are (a) the augmentation (or retardation) of absorption
of chemicals by the use of different vehicles and (b) whether
the chemical enters the systemic circulation directly (via
inhalation) or is taken at once to the liver by way of the
portal circulation (after intraperitoneal circulation).
2. Subacute Toxicity
MacEwen, e_t al. (1974) exposed monkeys to 250 ppm
and 1,000 ppm methyl chloroform for 14 weeks via inhalation.
51
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V-6
There were no significant changes in hemoglobin, red blood cell
(RBC) and white blood cell (WBC) counts, Na K alkaline phosphatase,
SCOT, SGPT, creatinine, chloride, glucose, blood urea nitrogen,
albumin, globulin, total protein, calcium, cholesterol, total
bilirubin, and serum triglycerides. Additionally, no pathol-
ogical changes were detected at these concentrations.
Adams, et al. (1950) exposed one female monkey
to 3,000 ppm of methyl chloroform for 7 hr/day (53 exposures)
over 74 days via inhalatioA. The monkey was necropsied and
no pathological changes were found in the lungs, heart,
liver, kidneys, lymph nodes, spleen, adrenals, pancreas,
stomach, small and large intestines, bladder, thyroid gland,
and skeletal muscles.
Prendergast, e_t a_l_. (1967) exposed squirrel monkeys
to methyl chloroform by inhalation as follows: 2,700 ppm (8
hr/day) for 6 weeks, 450 ppm (continuously) for 90 days; and
165 ppm (continuously) for 90 days. The monkeys exposed to
2,700 ppm lost 3% of their body weight, but no microscopic
pathological changes were seen, whereas the animals given 450
ppm exhibited a weight loss equalling 4% and lung inflammation.
The monkeys exposed to 165 ppm gained weight but showed signs
of lung congestion.
52
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V-7
Prendergast, e_t al. (1967) exposed beagle dogs to
methyl chloroform by inhalation as follows: 2,700 ppm (8
hr/day) for 6 weeks; 450 ppm (continuously) for 90 days; and
165 ppm (continuously) for 90 days. Dogs given 2,700 ppm
lost 2% of their body weight and showed blood leukopenia, but
no changes in the lungs; whereas dogs exposed to 450 ppm
gained weight (5% less controls) but exhibited lung inflammation
Dogs given 165 ppm gained weight normally, but showed sporadic
lung congestion.
\
Adams, e_t al. (1950) exposed female albino rabbits
to 5,000 ppm of methyl chloroform by inhalation (7 hr/day)
for a total of 44 days. The animals manifested a slight
depression of growth rate but no other pathological changes
were reported.
Prendergast, et al. (1967) exposed guinea pigs to
methyl chloroform by inhalation as follows: 2,700 ppm (8
hr/day) for 6 weeks; 450 ppm (continuously) for 90 days; and
165 ppm (continuously) for 90 days. Guinea pigs exposed to
2,700 at dose fl were all normal. Dose #2 animals had non-
specific lung inflammation, but clinical chemistry and blood
were normal; dose #3 animals showed sporadic lung congestion,
but, as with dose #2, clinical chemistry and blood were normal.
All animals at all doses survived.
53
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V-8
Adams, et al. (1950) exposed 71 mixed strain, mixed
sex, guinea pigs (roughly divided into male/female dose
groups) to methyl chloroform as follows:
Dose fl: 45 days, 5,000 ppm, 7 hr/day, 5 days/week,
32 exposures
Dose |2: 29 days, 3,000 ppm, 7 hr/day, 5 days/week,
20 exposures
Dose #3: 60 days, 1,500 ppm, 7 hr/day, 5 days/week,
44 exposures
Dose .#4: 92 to 93 days, 650 ppm, 7 hr/day, 5 days/
week, 65 to 66 exposures
Dose #5: 57 to 58 days, 650 ppm, 7 hr/day, 5 days/
week, 40 to 41 exposures
Significant decreases in growth rate occurred at all doses.
Organ weights and clinical chemistry were normal at all dose
levels. Microscopic pathology was normal at 1,500 ppm or
less (doses #3, #4, and #5). At 5,000 ppm (dose #1), there
was slight centrilobular fatty infiltration in the livers but
no necrosis; slight testicular degeneration also occurred.
At 3,000 ppm (dose #2), the livers showed slight centrilobular
fatty infiltration, with small fat-staining globules in the
central hepatocytes.
54
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v V-9
Summary
The studies discussed above present strong evidence
that laboratory animals (dogs, rabbits, monkeys) under a wide
variety of dosage and treatment schedules presented symptoms
such as weight losses/or depressed growth rate, and lung
inflammations, etc., but no pathological changes were detected
at the subacute toxic levels of methyl chloroform used in the
various studies. As acute toxicity levels of methyl chloroform
\
were approached for specific animal models, hepatotoxicity
increased significantly.
3. Chronic Effects
McNutt e_t al . (1975) exposed mice continuously to
250 and 1,000 ppm methyl chloroform for up to 14 weeks.
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 animals exposed to 1,000 ppm. After weeks of exposure
to 1,000 ppm methyl chloroform, 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, ejt al.
55
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(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. Mild or moderate ultrastructural alterations
and increases in liver weight and triglycerides were occasionally
observed in the animals that were exposed to 250 ppm during a
14-week study. Thus, this exposure level might be considered
a threshold for a biological effect of methyl chloroform in
the mouse. Platt and Cockrill (1969) studied biochemical
changes in rat livers in response to a series of aliphatic
halocarbons. The authors found that seven daily oral doses
of 1.65 g/kg enhanced the cytoplasmic and microsomal protein
content without producing any hepatotoxic effects. Savolainen,
et al. (1977) recently reported slight decreases in brain
ribonucleic acid (RNA)and liver microsomal P-450 in rats
inhaling 500 ppm of methyl chloroform (6 hours daily) for 4
or 5 days. The significance of these latter findings is
uncertain.
Two lifetime feeding study that have been reported
were conducted as a part of the National Cancer Institute
Bioassay Program (NCI, 1977, NCI, 1983). In an initial range-
finding study, oral doses ranging from 1,000 to 10,000 mg/kg
methyl chloroform in corn oil were given to male and female
mice and rats 5 days weekly for 6 weeks. The highest "noeffect"
dose for rats was 3,160 mg/kg while that for mice was 5,620
mg/kg. Indices of toxicity that were evaluated included
56
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V-ll
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 study, male and female rats
received 750 or 1,500 mg/kg of methyl chloroform in corn oil
by gavage five times weekly for 78 weeks. Similarly, male
and female mice were given methyl chloroform 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 2,800 and 5,600 mg/kg.
Diminished body weight gain and decreased survival time were
manifested in both mice and rats. Surprisingly, the incidence
of histopathologic change was no greater for methyl chloroform
dosed than, for control animals of either species. No other
indices of toxicity were evaluated.
A repeat carcinogenesis bioassay of methyl chloro-
form was conducted by administering the test chemical in corn
oil by gavage to groups of 50 male and 50 female F344/N rats
at doses of 375 and 750 mg/kg body weight. Groups of 50 male
and 50 female B6C3F1 mice received 1,500 or 3,000 mg/kg body
weight. Methyl chloroform was administered five times per
week for 103 weeks. Groups of rats and mice of each sex
received corn oil by gavage on the same schedule and served
as vehicle controls. Rats: Mean body weights for control
and dosed rats were comparable throughout the two year study.
57
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V-12
there were no tumors in rats considered to be related to
administration of methyl chloroform. However, the large
number of accidental deaths among- dosed females (25 low dose,
17 high dose) and dosed males (14 low dose, 8 high dose) reduced
the sensitivity of this study for detecting late-appearing tumors
in these groups. Mice: Survival of high dose male mice (28/50)
was significantly (P < 0.01) less than that of the vehicle
controls (44/50). There was a significant (P < 0.05) dose
response trends and increased incidences of hepatocellular
carcinomas in low and high dose male and in high dose female
mice.
A number of long-term animal studies of the toxic
potential of inhaled methyl chloroform have been conducted
over the last 20 years. These studies have been directed
largely towards assessing potential hazards of methyl chloroform
in occupational exposure situations. Daily exposure of a
variety of species to 500 ppm of methyl chloroform over a 6-
month period elicited no recognizable adverse effect, but
1,000 ppm produced fatty and enlarged livers in guinea pigs
(Torkelson, e_t a_l. , 1958). Rowe, e_t a_l. (1963) reported
similar findings when testing a solvent mixture consisting of
approximately 75% methyl chloroform 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
58
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V-13
studies of response to even lower concentrations, Prendergast,
et a_l. (1967) exposed rats, guinea pigs, dogs, rabbits, and
monkeys to methyl chloroform vapor continuously for 90 days.
They observed depressed body weight in rabbits and dogs
inhaling 370 ppmf but no adverse effects in any species
inhaling 135 ppm. Eben and Kimerly (1974) detected no evidence
of hepatorenal injury, hematologic change, or histopathologic
alteration in rats that received 200 ppm of methyl chloroform
8 hours daily (5 days a wee)c) for 14 weeks.
Summary
Daily exposure to 500 ppm of methyl chloroform over
a 6 - month period elicited no recognizable adverse effects
in rats, guinea pigs and other animal species, however,
1000 ppm produced fatty and enlarged livers in guinea pigs.
4. Mutagenicity
The mutagenicity of methyl chloroform has been
evaluated in the B6C3F1 mouse using a host-mediated assay with
Schizosaccharomyces bombe (Lobrien e_t a1., 1979). The investi-
gators have reported that methyl chloroform administered by
gavage at 500 mg/kg did not increase the incidence of mutations
in J3. bombe measured after treatment following 3, 6, and 16
hours. No information was provided concerning whether or
not testing was conducted to determine the ability of methyl
59
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V-14
chloroform to induce mutations ^n vitro. In addition, no
data are presented concerning a determination of the toxicity
of the substance to mice after acute exposure to arrive at a
maximum tolerated dose for conducting the host mediated
assay. Therefore, it makes it difficult to assess the signi-
ficance of the results.
Two tests of the mutagenic potential of methyl
chloroform in bacteria were reported to have been conducted
using protocols designed to «prevent evaporation of methyl
chloroform and thereby ensure exposure of the indicator
organisms. Both tests were reported to yield positive results
(Simmon e_t al.1977 and Snow e_t al. 1979). The testing
performed by Simmon and coworkers was conducted using the
standard battery of Salmonella typhimurium strains TA 1535,
TA 1537, TA 1538, TA 98, and TA 100, both with and without
metabolic activation of rat liver microsome S9 fraction. The
concentrations used for testing were 0, 100, 200, 300, 400,
500, 750, and 1000 ug/g - liter desiccator. A weak dose-
related response was observed for TA 100 both with and without
metabolic activation. The exact purity of the methyl chloroform
sample tested was not given but was reported to be high.
In their studies, Snow e_t al. (1979) tested two
samples of methyl chloroform in Salmonella strain TA 100 both
with and without metabolic activation. Testing conducted with
60
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V-15
metabolic activation employed an S9 fraction obtained from
methyl chloroform induced Syrian golden hamster liver micro-
somes. Similar to the study performed by Simmon et al. (1977),
precautions were reported to have been taken to prevent evapo-
ration of methyl chloroform. Doses of 0, 500, 750, 1000, and
1500 ul/5.€ liter modular incubator chamber were employed.
Positive response was obtained for TA 100 to the two samples
of methyl chloroform tested. One of the sample was from
Aldrich (97% methyl chlorofo,rm stabilized with 3% p-dioxane)
and the other was from PPG Industries (reported to be purified
sample).
In a chronic inhalation study, 96 male and 96 female
rats were exposed to methyl chloroform at levels of 1,750 or
875 ppm for 6 hr/day, 5 days/week, for 12 months (Quast, e_t
al. 1978). Cytogenic examination of bone marrow cells from
rats sacrificed after 12 months indicated neither chromosomal
damage nor chromatid aberrations in male rats. The number
of scorable chromosome spreads for the female rats was very
low overall; consequently data on female rats were not pre-
sented.
A test of cell transformation using the Fischer rat
embryo cell line F170 was performed with methyl chloroform
and other solvents. The transformed cells produced fibrosarcomas
61
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V-16
in rats when they were inoculated. The potency of the methyl
chloroforminduced transformation was similar to that produced
by trichloroethylene (Price, e_t a_l. 1978).
Henschler e_t al. (1977) tested the mutagenic
potential of methyl chloroform by the Ames test using Salmonella
tester strain TA 100 (a highly sensitive strain). Methyl
chloroform was non-mutagenic in both activated and unactivated
tests.
\
Summary
Mutagenicity testing of methyl chloroform has proven
inconclusive. The above discussion of various test systems
evaluating the mutagenicity of methyl chloroform yielded the
following results: 2 positive (methyl chloroform is weakly
mutagenic)> 3 negative, and 1 inconclusive. The inconsistent
findings concerning the mutagenic potential of methyl chloroform
could not be thoroughly evaluated since sufficient scientific
data were not given by the various investigators in their
reports. Scientific data such as: protocol design, maximum
tolerated dose, purity of experimental compound, controls
(negative, postive), etc. were not presented in detail.
5. Carcinogenicity
Although a variety of neoplasms were observed in
methyl chloroform treated rats and mice and their respective
62
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V-17
controls, no positive correlation relationship was found
between treatment and incidence of neoplasm. The shortened
lifespans of the rats and mice made an assessment of ingested
methyl chloroform carcinogenicity impossible (National Cancer
Insititute, 1977). In the earlier studies, rats of the
Osborne-Mendel strain and B6C3F1 mice (50 of each sex of
each rodent) were given methyl chloroform orally in corn oil
at each of two dose levels 5 days/week for 78 weeks.
Rats on chronic studies received high and low doses
of 1,500 or 750 mg/kg; mice received adjusted doses averaging
5,615 or 2,807 mg/kg. The methyl chloroform used in the
carcinogenicity studies was technical grade. Male and female
weanlings were started on the test at 5 weeks of age and
sacrificed at 96 weeks of age. Initially, the doses for male
and female mice were 4,000 and 2,000 mg/kg body weight. During
the 10th week of the study, doses were increased to 5,000 and
2,500 mg/kg. During the 20th week of the study, doses were
again increased to 6,000 and 2,000 mg/kg and maintained at
these levels to the end of the study-
At death, all animals were necropsied except those
in which autolysis had occurred. Approximately 29 different
tissues were fixed informalin, sechoned, stained, and examined
microscopically. Comparison of the numbers and distribution
63
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V-18
of lesions in treated and control groups revealed no excess
of histopathological lesions that could be related to treatment,
The median survival of all groups except the female
control mice was lower than would normally be expected. This
may be due, in part, to the chronic murine pneumonia which
was prevalent and was the most probable cause for the high
incidence of natural deaths.
In the repeat NCI bioassay study (1983), Fischer
344/N rats and B6C3F1 mice were gavaged with daily doses of
375 or 750 mg/kg body weight (rats) and 1,500 or 3,000 mg/kg
body weight of methyl chloroform in corn oil, respectively.
The compound was administered to groups of 50 rats and 50
mice (each sex) five times per week for 103 weeks. There was
no change in mean body weights for control and dosed rats,
however, mean body weights of dosed male and female mice were
slightly lower than those of the vehicle controls. No methyl
chloroform related tumors were observed in rats, but the
large number of accidental deaths among dosed females (25 low
dose; 17 high dose) and dosed males (14 low dose; 8 high
dose) reduced the sensitivity of this study for detecting
late-appearing tumors in those groups.
In mice, (NCI, 1983), there was an increase in
hepatocellular carcinomas occurrence in low and high dosed
male and in high dosed female mice: males - vehicle control
64
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V-19
16/50, low dose 24/50, high dose 20/50; females - vehicle
control 3/49, low dose 5/49, high dose 10/49. NCI
concluded that: (1) methyl chloroform was not carcinogenic for
male F344/N rats (2) the study was considered inadequate for
carcinogenesis evaluation in female P344/N rats, (3) the
association between the administration of methyl chloroform
and the increased incidences of hepatocellular carcinomas in
male B6C3fl mice was considered equivocal, and (4) methyl
chloroform was carcinogenic for female B6C3F1 mice, causing
an increased incidence of hepatocellular carcinomas.
Price, e_t al. (1978) demonstrated the _in vitro
transforming potential of methyl chloroform (99.9 percent
pure) using the Fischer rat embryo cell system (F1706). Rat
embryo cell cultures were treated with methyl chloroform,
diluted in growth medium, for 48 hours. After nine subcultures,
the transformed cells (characterized by morphology and
formation of macroscopic foci in semi-soft agar) were inoculated
into newborn Fischer rats. After 68 days, the transformed
cells had grown as undifferentiated fibrosarcomas at the
inoculation sites in all tested animals. Acetone, the negative
control, did not induce tumors after 82 days of inoculation
(Price, et al. 1978).
Summary
In the repeat NCI bioassay in rats and mice, there was an increase
in hepatocellular carcinomas occurrence in low and high dose males
and high dose females. NCI concluded that (1) methyl chloroform
65
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V-20
was not carcinogenic for male rats, (2) the study was considered
inadequate for carcinogenesis evaluation in female rats, (3)
the association between the administration of methyl chloroform
and the increased incidences of hepatocellular carcinomas
in male mice was considered equivocal, and (4) methyl chloroform
was carcinogenic for female mice, causing an increased incidence
of hepatocellular carcinomas.
\
6. Teratogenicity
Schwetz, e_t a_l. (1975) assayed for reproductive and
teratogenic effects in Sprague-Dawley rats (250 g) and Swiss
Webster mice (25 to 30 g) exposed to 875 ppm of methyl
chloroform by inhalation for 7 hr/day from gestation day 6 to
gestation day 15. The compound was a commercial grade
preparation and contained 5.5% or about 50 ppm inhibitors.
Caesarian sections were performed on gestation day 21 (rats)
and 18 (mice). Livers in treated maternal rats were heavier
than those in the controls (p < 0.05), but no significant
changes in hepatic weights were reported in mice. No
teratogenic effects were seen in all exposed rats and mice
for the following parameters: weight gain; percent fetal
resorptions; average litter size; fetal body measurements;
fetal gross anomalies; skeletal anomalies; microscopic
examination and maternal carboxyhemoglobin content.
66
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V-21
Lane et al. (1982) studied the effects of methyl
chloroform in drinking water on teratogenicity and reproduction
in mice. Male and female ICR Swiss mice received methyl
chloroform at concentrations of 0, 0.58, 1.75 or 5.83 mg/ml.
These concentrations were designed to yield daily methyl
chloroform doses of 0, 100, 300 or 1,000 mg/kg. The
investigators stated that: (1) there appeared to be no dose-
dependent effects on fertility, gestation, viability, or
v
lactation indices, (2) pup survival and weight gain were not
adversely affected, and (3) methyl chloroform failed to
produce significant dominant lethal mutations or terata in
either of the two generations tested.
Summary
Rats and mice have been studied for the teratogenic
potential of methyl chloroform. No effects were evident in
exposed animals for the following parameters: weight gain,
percentage fetal reabsorption, average litter size, fetal
body measurements, gross skeletal anomalies, and maternal
carboxyhemoglobin content. There are some indications that
mating and fertility indices of exposed animals were lower,
and some abnormalities appeared, but were not statistically
significant. Thus, methyl chloroform-induced teratogenicity
has not been established.
67
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VI. HEALTH EFFECTS IN HUMANS
1. Acute Toxicity
The primary toxic effects of short-term, high-level
exposure to methyl chloroform in humans are characterized by
depression of the CNS. In the majority of reports of human
fatalities resulting from methyl chloroform inhalation,
death is attributed to a functional depression of the CNS.
Levels of methyl chloroform in the victims' blood varied
considerably, ranging from 60 (Hatfield and Maykoski, 1970;
Stahl e_t al., 1969) to 720 ppm (Hall and Hine, 1966). The
highest concentrations of methyl chloroform were found in the
brains of victims (Caplan e_t al., 1976; Stahl e_t al., 1969).
Due to problems that are inherent in analyses of volatile
toxicants in autopsy samples, it is difficult to establish
lethal methyl chloroform concentrations in blood or tissues.
Inhalation of high concentrations of methyl chloroform
can cause irritation of the respiratory tract and minimal
organ damage, as well as depression of the CNS. Acute
pulmonary congestion, an edema typically found in fatalities
result from inhalation of methyl chloroform (Bonventre e_t
al., 1977; Caplan et al_., 1976). There are also scattered
reports of modest fatty vacuolation in the liver (Caplan, e_t
al. 1976; Hall and Hine, 1966; Stahl, et al.1969). In most
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VI-2
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 methyl chloroform 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 hepatotoxfcity. These studies indicate that
methyl chloroform possesses a limited capacity to exert
hepatic injury in cases of acute, high-level inhalation exposure
Clinical experience and scientific investigations
suggest that acute high-level inhalation of methyl chloroform
can adversely affect the cardiovascular system of humans.
Dornette and Jones (1960) used concentrations of 10,000-26,000
ppm methyl chloroform 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. Positive urinary urobilinogen was found
ranging from 7 hours to 20 hours after exposure.
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VI-3
Bass (1970) reported a syndrome called "sudden sniffing
death" in persons dying abruptly while inhaling volatile
solvents for self-intoxication. Methyl chloroform was one of
the most suspect solvents in such incidents. The fatalities
were attributed to cardiac arrhythmias that resulted from a
combined action of the solvent and endogenous biogenic amines.
A single account of methyl chloroform ingestion by
a human has appeared in the literature (Stewart and Andrews,
1966). A 47-year-old male Mistakenly drank 1 oz. of methyl
chloroform (approximately 0.6 g/kg). He became nauseated
within 30 minutes and developed progressively severe vomiting
and diarrhea over the next few hours. Urinalysis and clinical
chemistry tests revealed evidence of only minimal hepatorenal
injury early in the course of hospitalization. After treating
the vomiting and diarrhea symptoms, the patient was asymptomatic
during a 2-week observation period.
Since depression of the CNS is the predominant
effect of methyl chloroform on humans, certain manifestations
of the depression should be the most sensitive index of the
pathophysiological action of small quantities of the solvent.
Early studies with volunteers indicate that inhalation of 500
ppm of methyl chloroform for several hours has no significant
effect other than transient, mild eye irritation (Stewart, e_t al.
1961 Torkelson, e_t a_l. 1958). Stewart and his co-workers
70
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VI-4
(1969) concluded in a later study that 500 ppm of the chemical
may be excessive for persons who are particularly susceptible
to the chemical's depressant effects on the CNS. In a recent
investigation, inhalation of 350 ppm of methyl chloroform for
4 hours was not effective, whereas 450 ppm elicited subjective
complaints of transient eye irritation and dizziness (Salvini,
e_t a_l. 1971). Although a number of psychophysiological tests
did not reveal a statistically significant degree of functional
\
inhibition, lower scores resulted when tests were conducted
during methyl chloroform exposure than when under control
conditions. Results of an investigation by Gamberale and
Hultengren (1973) indicated that inhalation of 350 ppm of
methyl chloroform can significantly inhibit psychophysiological
functions in humans. Five performance tests were used, 2
were tests of perceptual speed and the others were tests of
simple reaction time, choice reaction time, and manual
desterity. Blood levels in the "inhibited" subjects averaged
approximately 3-4 ppm, although the investigators noted wide
intersubject differences in blood and alveolar air concentrations,
Gamberale and Hultengren concluded that it would be difficult,
with any degree of accuracy, to set a threshold for the vapor
concentration of methyl chloroform that would not alter function
of the central nervous system. Their tests of psychophysio-
logical function are certainly more sensitive and objective
than the indices used in the earlier studies of Torkelson, e_t al.
71
-------
VI-5
(1958) and Stewart, et al. (1961, 1969). Nevertheless, the
current U.S. threshold limit value for occupational exposure
to methyl chloroform remains at 350 ppm. This standard is
designed to protect the majority of workers from raucous
membrane irritation and performance inhibition.
2. Subacute Toxicity
Short-term exposure to methyl chloroform 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 methyl chloroform 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 upon examination for neurological,
respiratory, and hepatorenal function. There were also a
small accumulation of methyl chloroform and an increase in
urinary trichloroethanol levels.
3. Epidemiology
Seki and his colleagues (1975) surveyed four Japanese
printing factories where methyl chloroform, the sole organic
solvent in the entire process, was used to remove excess ink.
Duration of workday/workweek and operational procedures were
essentially uniform. Enclosure of vapor sources and installation
of exhaust systems were, in the authors' opinion, mainly responsible
72
-------
VI-6
for variation in vapor concentration. The subjects were
23-53 year-old men and had been exposed to methyl chloroform
vapor for at least 5 years. Laboratory tests, including
peripheral hemograms, blood specific gravity and urinalysis
for urobilinogen and protein, were not described. A Japanese
version of the Cornell Medical Index health questionnaire
was answered by all subjects. A test of vibrational sense
was performed as well as urinalysis for trichloracetic acid
and methyl chloroform. Decrease in urinary metabolite levels
\
provided the basis for calculation of biologic half-life.
The vapor concentration of methyl chloroform in the workroom
air was determined by gas-liquid chromotography. A preliminary
study revealed a fairly constant vapor concentration regardless
of time and location of sampling. The respective data are
presented in Tables VI-1, VI-2, and VI-3.
The authors found, through regression analysis, a
linear relationship between the vapor concentration of methyl
chloroform and level of urinary metabolites (trichloroacetic
acid and methyl chloroform), and for this reason they concluded
that the urinary metabolite level was a good index of methyl
chloroform exposure. The biological half-life of methyl
chloroform was found to be 8.7 + 1.8 hours.
In a detailed study of one worker, a steady increase
in urinary metabolite concentrations toward the weekend as
73
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VI-7
well as significant metabolite excretion on Sunday, suggested
that methyl chloroform accumulated in the body. Total
metabolite increase was primarily attributed to methyl chloroform,
No dose-dependent difference in health, as reflected
by the medical questionnaire, was found in any of the workers.
The authors recommended, based on accumulation of methyl
chloroform in the body, a subtraction from the maximum "no
adverse effect" level for short-term exposures to establish a
threshold limit value (TLV)1, for repeated exposures (Seki, e_t
al. 1975). The odor threshold has been reported to be as
high as 700 ppm or as low as 16 ppm.
TABLE VI-1
Urinary Metabolite Concentration in
Workers Exposed to Methyl Chloroform
Exposure Concentration Metabolite Concentration No. Examined
(ppm) (mg/1)*
Trichloroacetic acid Trichloroethanol
4
25
53
(0.
(1.
(2.
0.6
5-1.1)
2.4
3-4.6)
3.6
4-5.5)
(0
(3
(6
1.2
.5-2.6)
5.5
.6-8.6)
9.9
.8-14.5)
10
26
10
* Geometric mean with SD in parenthesis
Adapted from: Seki et al. (1975)
74
-------
VI-8
TABLE VI-2
Results of Physical Examinations
of Workers Exposed to Methyl Chloroform
Exposure
Concentration
(ppm)
4
25
28
53
No.
Examined
,66
33
55
42
No. of Healthy
Subjects*
60
30
48
36
Percentage
91
91
87
86
* Adapted from Seki et al. (1975).
75
-------
VI-9
TABLE VI-3
Exclusions from Healthy Category
By Class of Disorder
Class of Disorder
Cardiovascular
Hepatic
Gastrointestinal
Renal
Bone
CNS
No. Percent Affected
10 5
3 1
4 2
2 1
1 <1
1 <1
Adapted from Seki et al. (1975)
76
-------
Hervin (1975) determined that the total daily
exposure to methyl chloroform was not at a personally hazardous
level after an evaluation of 35 employees in a textile dye plant,
Breath and area air were sampled and the highest level found
was 220 mg/3 (40.5 ppm) in a 1.3-liter breath sample.
Giles and Rostand (1975) measured air levels,
interviewed 15 employees, and studied the plant insurance
records in another evaluation of an industrial site. The
breathing zone and area samples obtained were 7-18 ppm and 14
\
ppm, respectively. No hazard was seen with this exposure.
NIOSH has investigated additional workplace sites to evaluate
worker exposure to methyl chloroform and adverse action.
Methyl chloroform levels were below those allowed in the
workplace (Giles and Philbim, 1978; Markel, 1978; Gilles, 1977).
Maroni e_t al. (1977) studied 29 women working at a
factory manufacturing platinic and steel spinerets. Twenty-
two of the women were exposed to methyl chloroform in a work-
place where it was the only solvent used. Seven were employed
in the same factory with no known exposure to methyl chloroform.
Air concentrations in the exposed areas ranged from 110 to 990
ppm with only one worker in the area with the higher
concentrations (720-990 ppm). Women were subdivided into
three groups according to extent of exposure: I (7 workers)
77
-------
VI-11
110 ppm, II (7 workers) 140-160 ppm, and III (8 workers)
990 ppm. The mean length of employment was 6 years.
No significant differences were observed between
the exposed and unexposed females with respect to clinical
features, maximal motor conduction velocity, conduction
velocity of slow fibers and psychometric data. However,
since the study group was so small and had a wide range in
age, and the methods of data collection may not have been
adequately standardized, the negative results of this study
may not be conclusive and do not provide information on the
population risks associated with exposure to methyl chloroform.
Kramer, et. al. (1978) conducted a study of textile
workers at., a plant using methyl chloroform and compared them
with a group of workers at an adjacent plant not using methyl
chloroform matched by age (5 years), race, sex, job description,
shift, and socio-economic status. Most exposures were from 1
to 5 years at time weighted average levels of 100-250 ppm,
determined from work histories and industrials hygiene surveys.
The methyl chloroform contained 4% stabilizers; small quantities
of fluorocarbon 113 were used in 1973. Primary emphasis was
on cardiovascular effects via nurse administered questionnaires,
blood parameters including enzyme assays, blood pressures, and
78
-------
VI-12
electrocardiograms. No evidence of adverse effects on the
cardiovascular system, CNS, or liver was found in this study.
Collection of data does not appea'r to have been standardized
to avoid bias.
The limitations of this study in terms of design,
duration of exposure, and non-specificity of endpoint variables
make the results difficult to apply to determinations of risk
of exposure to methyl chloroform.
Summary
Transient eye irritation and upper respiratory
irritation from exposure to methyl chloroform vapors have
been reported at concentrations in excess of 500 ppm.
Regression analysis has indicated a linear relationship between
vapor concentration of methyl chloroform and the levels of
urinary metabolites (trichloroacetic acid and methyl chloroform).
The odor threshold of methyl chloroform covered a wide range
(16-700 ppm) indicating that individual sensitivity may play
a part in determining irritation and other health effects.
79
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VII-1
VII HUMAN RISK ASSESSMENT
1. Current Levels of Exposure
Exstimates of human exposure to chloroethanes via
ingestion are not available. NIOSH (1978) estimated that of
over five million workers exposed to chloroethanes by
inhalation and dermally, 4.5 million are exposed to 1,2-
dichloroethane or methyl chloroform (Table VII-1).
\
Workers, who are occupationally exposed to
chloroethanes, by inhalation and/or dermally represent a
special group at risk. Epidemiological studies have not
disclosed a relationship between exposure to chloroethanes
and cancer; however, four chloroethanes have proved to be
carcinogenic in at least one species of rodent (NCI 1978).
Those individuals who are exposed to known hepatotoxins or
have liver disease may constitute a group at risk.
2. Existing Guidelines and Standards
OSHA standards and NIOSH recommended standards are
based on exposure by inhalation (Table VII-2). Based on
information available in 1976, NIOSH recommended that
occupational exposures to 1,2-dichloroethane do not exceed 5
80
-------
VII-2
TABLE VII-1
CHLOROETHANE EXPOSURES AND PRODUCTION
Chemical
Estimated number
of
workers exposed
Annual
Production
quantities
(pounds)
monochloroe thane
1,1-dichloroe thane
1 , 2-dichloroethane
methyl chloroform
1,1, 2-trichloroe thane
1,1,1, 2-tetrachloroethane
1,1,2, 2-tetrachlorbe thane
pen tachloroe thane
hexachloroe thane
113,000
^ 4,600
1,900,000
2,900,000
112,000
a
11,000
a
1,500
670 million
b
8 billion
630 million
c
b
c
b
b,d
(1976)
(1976)
(1976)
aNIOSH estimates not available.
bDoes not appear to be commercially produced in the United States,
cDirect production information not available.
d730,000 kg were imported in 1976.
Adapted from: NIOSH (1978)
81
-------
VII-3
Table VII-2
CHLOROETHANE EXPOSURE STANDARDS
OSHA
Exposure
Standard
Chemical (ppm)
monochloroethane 1,000
1,1-dichloroethane 100
1,2-dichloroethane 50
\
methyl chloroform 350
1,1,2-trichloroethane 10
1,1,1,2-tetrachloroethane none
1,1,2,2-tetrachloroethane 5
pentachloroethane none
hexachloroethane 1
*NIOSH has tentative plans for a Criteria Document for a
Recommended Standard for this substance.
Adapted from: NIOSH (1978).
ppm (20 mg/m3) determined as a time-weighted average for up to
a 10-hour work day, 40-hour work week. Peak concentrations
should not exceed 15 ppm (60 mg/m3) as determined by a 15-minute
sample.
82
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VIII-1
VIII. Quantification of Toxicological Effects
The quantification of toxicological effects of a chemical
consists of an assessment of the non-carcinogenic and carcino-
genic effects. In the quantification of non-carcinogenic
effects, an Adjusted Acceptable Daily Intake (AADI) for the
chemical is determined. For ingestion data, this approach
is illustrated as follows:
Adjusted ADI = (NOAEL or MEL in mg/kg)(70 kg)
(Uncertainty factor)(2 liters/day)
The 70 kg adult consuming 2 liters of water per day is used
as the basis for the calculations. A "no-observed-adverse-effect-
level" or a "minimal-effect-level" is determined from animal
toxicity data or human effects data. This level is divided
by an uncertainty factor because, for these numbers which are
derived from animal studies, there is no universally acceptable
quantitative method to extrapolate from animals to humans,
and the possibility must be considered that humans are more
sensitive to the toxic effects of chemicals than are animals.
For human toxicity data, an uncertainty factor is used to
account for the heterogeneity of the human population in
which persons exhibit differing sensitivity to toxins. The
guidelines set forth by the National Academy of Sciences
(Drinking Water and Health, Vol. 1, 1977) are used in estab-
lishing uncertainty factors. These guidelines are as follows:
an uncertainty factor of 10 is used if there exist valid
experimental results on ingestion by humans, an uncertainty
-------
; VIII-2
factor of 100 is used if there exist valid results on long-
term feeding studies on experimental animals, and an uncertainty
factor of 1000 is used if only limited data are available.
In the quantification of carcinogenic effects, mathematical
models are used to calculate the estimated excess cancer
-risks associated with the consumption of a chemical through
the drinking water. EPA's Carcinogen Assessment Group has
used the multistage model, which is linear at low doses and
does not exhibit a threshold, to extrapolate from high dose
\
animal studies to low doses of the chemical expected in the
environment. This model estimates the upper bound (95%
confidence limit) of the incremental excess cancer rate that
would be projected at a specific exposure level for a 70 kg
adult, consuming 2 liters of water per day, over a 70 year
lifespan. Excess cancer risk rates also can be estimated
using other models such as the one-hit model, the Weibull
model, the logit model and the probit model. Current
understanding of the biological mechanisms involved in cancer
do not allow for choosing among the models. The estimates
of incremental risks associated with exposure to low doses
of potential carcinogens can differ by several orders of
magnitude when these models are applied. The linear, non-
threshold multi-stage model often gives one of the highest
risk estimates per dose and thus would usually be the one
most consistent with a regulatory philosophy which would
avoid underestimating potential risk.
-------
VIII-3
The scientific data base, which is used to support the
estimating of risk rate levels as well as other scientific
endeavors, has an inherent uncertainty. In addition, in
many areas, there exists only limited knowledge concerning
the health effects of contaminants at levels found in drinking
water. Thus, the dose-response data gathered at high levels of
exposure are used for extrapolation to estimate responses at
levels of exposure nearer to the range in which a standard
might be set. In most cases, data exist only for animals; thus,
uncertainty exists when the data are extrapolated to humans.
When estimating risk rate levels, several other areas of
uncertainty exist such as the effect of age, sex, species
and target organ of the test animals used in the experiment,
as well as the exposure mode and dosing rates. Additional
uncertainty exists when there is exposure to more than one
contaminant due to the lack of information about possible
additive, synergistic or antagonistic interactions.
A. Non-carcinogenic Effects
The toxic effects of 1,1,1-trichloroethane (methyl
chloroform) in animals and humans following acute and chronic
exposure at high doses are (1) fatty vacuolation and increase
in liver weight; (2) manifestations of depression of the
central nervous system; (3) transient eye irritation and
dizziness? and (4) cardiovascular changes including increase
in systolic pressure and premature ventricular contractions.
Effects of acute exposure to methyl chloroform in rats
were reported by Adams et al. (1950). The investigators
-------
VIII-4
stated that the 3-hour LCso in rats was 18,000 ppm. The
lowest and shortest exposure that elicited histological
change in tissues of rats was 8,000 ppm for 7 hours. This
produced an increase in liver weight and fatty vacuolation
of hepatocytes.
McNutt et al. (1975) exposed mice continuously (inhalation)
to 250 and 1,000 ppm methyl chloroform for 14 weeks. Control
mice were exposed to room airy Serial sacrifice of exposed
and control mice from 1 to 14 weeks demonstrated significant
changes in the centrilobular hepatocytes of animals in the
1000 ppm group. There was also an evidence of liver
triglyceride accumulation in the 1000 ppm. Findings
are summarized in Table VIII-1.
Electron microscopic evaluation of mice liver in the
above study (McNutt et al., 1975) revealed that cytoplasmic
alterations were most severe in centrilobular hepatocytes in
the 1000 ppm group and were mild to minimal in the 250 ppm
group. These alterations consisted of vesiculation of the
rough endoplasmic reticulum, with loss of attached polyri-
bosomes, increased smooth endoplasmic reticulum, microbodies,
and' triglyceride droplets. There was also present necrosis
of individual hepatocyes which was associated with an acute
inflammatory infiltrate and hypertrophy of Kupfler cells.
The investigators stated that the comparison of these findings
to the results obtained by other investigators studying
-------
VIII-5
dichloromethane indicates that the pathologic changes observed
TABLE VIII-1
SUMMARY OF EFFECTS IN MICE AFTER CONTINUOUS INHALATION
EXPOSURE TO METHYL CHLOROFORM3
Parameter
Food/water intake
Liver wt/100 gm. b.w.
250 ppm
Not significantly
different from
control
Not significantly
different from
control except at
8 and 9 week intervals
Light microscopic observation;
Lipid contents
Significantly different
at 13-week interval
Electron microscopic observations;
1,000 ppm
Not significantly
different from
control
Significantly
different from
control
Significantly
different at
2-14 week intervals
Cytoplasmic
alterations^5
Mild to minimum in Severe in
centrilobular centrilobular
hepatocytes hepatocytes
necrotic hepatocytes
(associated with focal
infiltrates of neutro-
philic leukocytes in
the hepatic lobules)
a.
Adapted from McNutt et al. (1975) Lab. Invest. 32:642-654.
Alteration consisted of; (i) vesiculation of the rough
endoplasmic reticulum, (ii) loss of attached polyribosomes
and (iii) increased smooth endoplasmic reticulum microbodies
and triglyceride droplets.
-------
; VII1-6
with methyl chloroform were similar to those observed with
dichloromethane.
Exposure to 500 ppm (7 hours/day, 5 days/ week for 6
months) produced no effect on rats (#20), guinea pigs (#8),
rabbits (12) and monkeys (*2), when compared with controls
in terms of growth, organ weights, hematologic values, gross
pathology and histopathology (Torkelson et al., 1958). The
investigators reported that female guinea pigs which were
found to be the most sensitive in previous experiments were
\
able to tolerate 1,000 ppm for 0.6 hours/day with no detectable
adverse effects. Male rats tolerated exposure of 0.5 hours/day
to 10,000 ppm with no organic injury.
Epidemiological evidence cannot be related to the
exposure levels of methyl chloroform with confidence; how-
ever, exposures of workers to methyl chloroform and its
association with observed health effects - fatigue, dizzi-
ness, nervous system disorders, etc. is worth mentioning.
Two lifetime feeding or gavage studies have been
conducted as a part of the National Cancer Institute
(NCI) Bioassay Program (1977; 1983). In the first study,
male and female rats were given 750 or 1,500 mg/kg methyl
chloroform in corn oil by gavage 5 times weekly for 78
weeks. Similarly, male and female mice received approximately
2,800 and 5,600 mg/kg for 78 weeks. Diminished body weight
gain and decreased survival time were manifest in both rats
and mice. The incidence .of histopathological change was
no greater for methyl chloroform than for control animals
-------
VIII-7
of either species. No other indices of toxicity were
evaluated.
In the second NCI bioassay study (1983), Fischer 344/N
rats and B6C3F1 mice were gavaged with daily doses of 375
or 750 mg/kg body weight (rats) and 1,500 or 3,000 mg/kg
body weight (mice) of methyl chloroform in corn oil, respectively,
The compound was administered fives times per week for 103
weeks. The report stated that: (1) methyl chloroform was
not considered tumorgenic for male rats and this study
.was inadequate for tumorigenic evaluation in female rats
because of the large number of accidental deaths and because
of the high dose being toxic; (2) the association between
the administration of methyl chloroform and the increased
incidences of tumors in male B6C3F1 mice was considered
equivocal, whereas there was a significant increase in tumor
incidence in female B6C3F1 mice.
Lane et al. (1982) have reported results of methyl
chloroform in drinking water on reproduction and development
in mice. A multi-generation reproduction study was carried
out in mice in addition to screening for dominant lethal and
teratogenic effect of methyl chloroform. Male and female
Swiss mice received methyl chloroform at concentrations of 0,
0.58, 1.75 or 5.83 mg/ml to yield daily doses of 0, 100, 300,
or 1,000 mg/kg. There appeared to be no dose-dependent
effects on fertility, gestation, viability, or location
indices. Pup survival and weight gain were not adversely
-------
VIII-8
affected. Methyl chloroform also failed to produce significant
dominant lethal mutations or terata in either of the two
generations tested. The results of these studies could not
be used in the development of a QTEL because animals were
maintained only for 35 days on test solution containing
-specified concentrations of methyl chloroform and also the
study did not identify a dose-response level at which an
effect occurred.
Synergistic/additive effects and other related effects
\
such as resulting from multiple chemical exposure with
respect to methyl chloroform have not been studied in either
in vitro or in vivo systems.
B. Quantification of Non-carcinogenic Effects
The liver of the mammalian system appears to be the
sensitive endpoints with respect to the adverse health effects.
There are limited data concerning the dosage, duration of
exposure and the effects on the central nervous system.
Liver toxicity should be considered as an endpoint
for estimating Adjusted Acceptable Daily Intake (ADI) for
methyl chloroform. The compound has been shown to cause
hepatocytic vacuolation and increase in liver weight and
triglyceride content in animals. In the absence of definitive
information on the chronic toxicity of ingested methyl
chloroform, HAS (1980) had calculated the chronic Suggested
No Adverse Response Level (SNARL), 3.8 mg/1, based on the
-------
VIII-9
lowest dose used in the NCI bioassay (1977) in animals.
Similarly, U.S. EPA (AWQD, 1980) and (ODW) have also considered
the lowest dose of 750 mg/kg of methyl chloroform administered
orally in calculating ADI and Health Advisories, respectively.
These levels are shown in Table VIII-2. However, in view of
recent findings of NCI bioassay in rats and mice and lack of
chronic ingestion studies of methyl chloroform in animals for
quantifying non-carcinogenic effect, it may be prudent to
consider inhalation study in animals (McNutt et al., 1975),
in addition to data of repeat NCI bioassay (1983) even
though the inhalation studies in animals may not meet all
criteria necessary for quantifying non-carcinogenic effects.
TABLE VIII-2
HEALTH ADVISORY FOR METHYL CHLOROFORM
Non-CA
CA
NAS-SNARL
3.8 mg/la
EPA-HA
1 .07 mg/lb
AWQD- AD I
18.7 mg/lc
WHO
-
NOTE:
- Not available.
a Based on NCI bioassay study in rats - 750 mg/kg (NCI, 1977)
and ^ is calculated for an adult weighing 70 kg consuming
2 liters of water and contribution from water being 20%
(NAS, 1980) .
b Based on NCI bioassay study in rats - 750 mg/kg (NCI, 1977)
and is calculated for a 10 kg child consuming 1 liter of
water and contribution from water being 20% (U.S. EPA Health
Advisory, 1980) .
c Based on NCI bioassay study in rats - 750 mg/kg (NCI, 1977)
and is calculated for an' adult weighing 70 kg consuming 2
liters of water and assuming 100% of exposure from water
(U.S. EPA - AWQD, 1981) .
-------
VIII-10
McNutt et al. (1975) exposed male mice continuously
(inhalation) to 250 (1,365 mg/m3) or 1,000 ppm (5,460 mg/m3)
methyl chloroform for 14 weeks. Control mice were exposed
to room air. Serial sacrifice of exposed and control mice
from 1 to 14 weeks demonstrated significant changes in the
centrilobular hepatocytes of animals in the 1,000 ppm (5,460
mg/m3) group and mild to minimal in the 250 ppm (1,365
mg/m3) group. These changes consisted of vesiculation of
\
the rough endoplasmic reticulum, with loss of attached
polyribosomes, increased smooth endoplasmic reticulum, micro-
bodies, and triglyceride droplets. No no-observed-adverse-
effect-level (NOAEL) can be identified but a MEL (Minimum
Effect Level) of 250 ppm (1,365 mg/m3) can be used. An ADI
based upon these data could be derived as follows:
20.1o 1.33?
(1365 mg/m3)(l m3/hr)(6 hrs)(I3.3%) = Q^&4 mg/1 (or
(1000) (2 1/d) &,cig ^TOW mg/kg/day
for a 70 kg adult)
Where: 1,365 mg/m3 (250 ppm) = MEL
1 m3/hr = Ventilation volume for a 70 kg adult
6 hrs = Exposure assumed to be saturable and therefore
equivalent to exposure for 24-hour period
l«li*a% = Assumed percent body burden metabolized
(Schumann et al., 1982)
1000 = Uncertainty factor appropriate to. MEL in animals
with no equivalent data in the human
70 kg - Average body weight of an adult
2 I/day = Water consumption per day for an adult
hiv{
Us lie
-------
11
Strength; Serial sacrifice of exposed mice from 1 to 14 weeks
demonstrated significant changes in the centrilobular
hepatocytes of animals.
Weakness; (1) Route of exposure is inhalation and the period
of continuous exposure was for 98 days. (2) Percent body
burden of methyl chloroform following 24-hr continuous exposure
is not available. (Calculations are based on 6-hr inhalation
exposure results.)
NCI repeat ingestion study in rats
Methyl chloroform was administered in corn oil by gavage
to groups of 50 male and 50 female rats (F344/N) at doses of
375 and 750 rag/kg body weight. Methyl chloroform was given
5 times per week for 103 weeks.
No biologically significant tumor pathology was observed
in these rats. The increase in intestinal cell testicular
tumors was not considered to be related to the administration
of methyl chloroform in the high dose group. However, the
survival of high dose female rats in the present study was
significantly less (P < 0.001) than that of the vehicle
control. A large number of accidental deaths due to gavage
errors occurred among dosed female and male rats (25 low
dose and 17 high dose females and 14 low dose and 8 high
dose males). An ADI based upon low dose, 375 mg/kg, may be
derived as follows;
(375 mg/kg)(5 days)(70 kg) = 9.38 mg/1 =9.4 rag/1
(7 days)(2 I/day)(1,000)
-------
12
re: 375 mg/kg = observed adverse effect dose
5/7 = fraction converting from 5 to 7 day exposure
70 kg = average weight of an adult
1000 = uncertainty factor
2 I/day = adult consumption of water per day
•ength; The exposure is via ingestion and for a lifetime
13 weeks) .
ikness; This study suffers from one important criteria and
at is poor survival of animals at the end of 103 weeks of
posure. A large number of deaths in animals occurred over
e 103 weeks of exposure either due to gavage error or to
e toxicity of methyl chloroform administration in high
se groups of animals. The survival rate for animals at
ie end of the 103 week exposure is shown below:
Survival of Animals
Control Low Dose High Dose
Animal 0 375 mg/kg 750 mg/kg
Female 29/50 10/50 5/50
Male -36/50 20/50 26/50
Since no methyl chloroform effects were observed in the
epeat NCI bioassay in rats, the ingestion dose level of 375
g/kg would have been appropriate for the derivation of an
iDI. However, the repeat study in rats suffers from the
ligh death rate either from gavage error or toxic effects of
nethyl chloroform (in high doses) in animals. The percent
teaths in the female rats at end of the 103 week period were
42%, 80%, and 90% in the control, low dose (375 mg/kg), and
high dose (750 mg/kg), respectively. Therefore use of this
study in the derivation of an ADI is highly questionable for
-------
VIII-14
species, sex, type of neoplasm, or site of occurrence. It
was concluded that the carcinogenicity could not be determined
from this study (NCI, 1977).
A repeat carcinogenesis bioassay of methyl chloroform was
conducted by administering the test chemical in corn oil by
gavage to groups of 50 male and 50 female F344/N rats at doses
of 375 and 750 mg/kg body weight. Groups of 50 male and 50
female B6C3F1 mice received 1,500 or 3,000 mg/kg body weight.
Methyl chloroform was administered five times per week for 103
weeks. Groups of rats and mice of each sex received corn oil
by gavage on the same schedule and served as vehicle controls.
Rats; Mean body weights for control and dosed rats were
comparable throughout the two year study. There were no tumors
in rats considered to be related to administration of methyl
chloroform. However, the large number of accidental deaths
among dosed females (25 low dose, 17 high dose) and dosed
males (14 low dose, 8 high dose) reduced the sensitivity of
this study for detecting late-appearing tumors in these groups.
Mice; Survival of high dose male mice (28/50) was significantly
(P < 0.01) less than that of the vehicle controls (44/50). There
was a significant (P < 0.05)- dose response trend and increased
incidences of hepatocellular carcinomas in low and high dose
male and in high dose female mice.
Dow Chemical Co. (Quast et al. 1978) studied groups of
Sprague-Dawley rats exposed by inhalation (6 hours/day, 5
days/ week, over one-half'of a lifetime). Rats were treated
for 12 months and observed until death or until they reached
-------
VIII-15
the age of 31 months. The dose of 875 and 1,750 ppm were 2.5
and 5 times the threshold limit value of 350 ppm, respectively.
There are two shortcomings of this study: 1) the animals were
treated for only 12 months rather than a lifetime but observed
for another 12 months, and (2) it is not evident that the
maximum tolerated dose was used during the treatment period.
The only sign of toxicity was an increased incidence of
focal hepatocellular alterations in female rats at the highest
dosage.
Methyl chloroform has been tested for its ability to
cause point mutations in bacteria, point mutations and gene
conversion in yeast, and for cytogenetic abnormalities in
rats. The results of these studies are summarized in Table
VIII-3.
Henschler et al. (1977) and Taylor et al. (1977) reported
that methyl chloroform was not mutagenic in the bacterial system,
Salmonella/S9. The experimental details given in their reports
were inadequate to verify the conclusions of the investigators.
However, other investigators (Simmon et al., 1977 and Snow
et al., 1979) independently reported that methyl chloroform
was mutagenic in various Salmonella typhimurium strains
(both with and without metabolic activation).
Methyl chloroform also was tested for mutagenic potential
employing yeast as an indicator organism (Litton Bionetics,
1975 and Loprieno et al., 1979). The results of these tests
indicated that methyl chloroform was not mutagenic in the
test system Saccharomyces cerevisiae or Schizosaccharomyes
bombe.
-------
VIII-16
TABLE VII1-3
Mutagenicity Testing of Methyl Chloroform
Test
System
A. Bacteria
Activation
System
Salmonella/59 PCB induced liver,
(spot test and lung and testes S9
plate incorporation)
Salmonella/S9
Salmonella/59
Salmonella/59
(plate incor-
poration)
Salmonella/59
PCB induced rat liver
microsomes S9 mix
PCB induced rat liver
microsome S9 mix
Aroclor-activated rat
liver microsome S9 mix
Methyl chloroform
induced Syrian hamster
liver microsome S9 mix
Result
99% formulation + ive,
Other formulations - ive
- ive
+ ive for TA 100
- ive
ive
Reference
Litton, 1975
Henschler
et al. (1977)
Simmon et al.
(1977)
Taylor et al.
(1977)
Snow et al.
(1979)
B. Yeast
Saccharomyces
cerevisiae
(gene conversion)
Schizosaccharo-
myces
(forward mutation)
PCB induced rat liver - ive
S9 mix
Host mediated assay - ive
B6C3F1 mice
Litton, 1975
Loprieno et al
(1979)
-------
VIII-17
D. Quantification of Carcinogenic Effects
Using methodology described in detail elsewhere, (U.S.EPA,
1980) the EPA's Carcinogen Assessment Group (CAG, memo dated
April 29, 1983) and the National Academy of Sciences (WAS, 1983)
have calculated estimated incremental excess cancer risks associated
with exposure to methyl chloroform in drinking water, extra-
polating from data obtained in the NTP repeat Bioassay in mice
(NCI, 1983) with this compound. CAG and NAS derived their
estimates based on a statistically significant increase in
hepatocellular carcinomas in mice receiving 1500 or 3000
mg/kg methyl chloroform by gavage in corn oil. The ranges of
concentrations are summarized in Table VIII-4.
Table VIII-4
Drinking Water Concentrations and Estimated Excess Cancer Risks
Range of Concentrations (ug/1)a
Excess Lifetime
Cancer Risk CAGb •NASC
ID'4
10-5
10-6
0
2200
220
22
0.00
1680
168
16.8
0.00
a Assumes the consumption of two liters of water per day by 70
kg adult over a lifetime; number represents 95% upper bound
confidence limit
b (McGaughy, 1983)
c (NAS, 1983)
-------
VIII-18
The CAG calculated that consuming 2 liters of water per day
having a methyl chloroform concentration of 2200 ug/1, 220
ug/1 or 22 ug/1 would increase the risk of one excess cancer
per 10,000 (10~4), 100,000 (10"5) or 1,000,000 (10~6) respec-
tively, per lifetime. Similarly, the NAS also calculated
excess cancer risk values based on same NCI repeat bioassay
data using the multistage model. They stated that consuming
2 liters of water per day over a lifetime at a methyl chloroform
concentration of 1680 ug/1, 168 ug/1 or 16.8 ug/1 would
increase the risk of one excess cancer per 10,000 (10~4),
100,000 (10~5), or 1,000,000 (10~6) people exposed, respectively.
The slight difference between CAG and NAS values is due to
the fact that CAG has taken into consideration hepatocellular
carcinomas observed in the female mice whereas the NAS have
included in the derivation of risk values the results of both
male and female mice hepatocellular carcinomas.
In the quantification of toxicological effects for a
chemical, consideration should be given to subgroups within
the general population which are at greater than average risk
upon exposure to the chemical. For methyl chloroform, animal
studies have not been carried' out to characterize adverse
effects in the aged or newborn.
Methyl chloroform has also been shown to have interaction
with other chemicals. Ingestion of ethanol was shown to
increase the hepatotoxicity of methyl chloroform. However,
*
ingestion of isopropyl alcohol or acetone prior to administration
of methyl chloroform did not alter the response of enzyme activity,
-------
VIII-19
The latest bioassay data on 1,1,1-trichloroethane is
currently undergoing audit by NTP and a final report has not
been issued. Therefore, this proposal will use the non cancer
inhalation data as the basis for the proposed RMCL. This
approach will be amended if the final NTP report determines
that 1 ,1 ,1-trichloroethane was carcinogenic under the condition
of the text.
-------
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