United States Office of Health and EPA-600/8-82-003
Environmental Protection Environmental Assessment January ' 982
Agency Washington OC 20460
Research and Development
Health Assessment
Document for
1,1,1 -Trichloroethane
(Methyl Chloroform)
-------
EPA-60U/8-8J-003
Review Draft
DRAFT
Do not cite or quote
HEALTH ASSESSMENT DOCUMENT
FOR
1,1,1-TRICHLOROETHANE
(METHYL CHLOROFORM)
Notice
This document is a preliminary draft. It has not
been formally released by EPA and should not at
this stage be construed to represent Agency
policy. It is being circulated for comment on
its technical accuracy and policy implications.
U.S. ENVIRONMENTAL PROTECTION AGENCY
Office of Research and Development
Environmental Criteria and Assessment Office
Research Triangle Park, North Carolina 27711
Project Coordinator: Dr. Jean C. Parker
-------
DISCLAIMER
The report Is an Internal draft for review purposes only and does not
constitute Agency policy. Mention of trade names or commercial products does
not constitute endorsement or recommendation for use.
11
-------
PREFACE
The Office of Health and Environmental Assessment, 1n consultation with
an Agency work group, has prepared this health assessment to serve as a "source
document" for Agency-wide use. Originally the health assessment was developed
for use by the Office of Air Quality Planning and Standards, however, at the
request of the Agency Work Group on Solvents, the assessment scope was expanded
to address multimedia aspects. This assessment will help insure consistency in
the Agency's consideration of the relevant scientific health data associated with
methyl chloroform.
In the development of the assessment document, the scientific literature
has been inventoried, key studies have been evaluated and summary/conclusions
have been prepared so that the chemical's toxicity and related characteristics
are qualitatively identified. Observed effect levels and other measures of
dose-response relationships are discussed, where appropriate, so that the
nature of the adverse health responses are placed in perspective with observed
environmental levels.
-------
TABLE OF CONTENTS
LIST OF TABLES vi i
LIST OF FIGURES ix
«
1. SUMMARY AND CONCLUSIONS 1-1
2. INTRODUCTION 2-1
3. GENERAL BACKGROUND INFORMATION 3-1
3.1 CHEMICAL AND PHYSICAL PROPERTIES, ANALYTICAL METHODOLOGY 3-1
3.1.1 Chemical and Physical Properties 3-1
3.1.2 Analytical Methodology 3-3
3.1.2.1 Sampling and Sources of Error 3-5
3.1.2.2 Calibration 3-8
3.1.2.3 Standard Methods 3-10
3.2 PRODUCTION, USE, AND EMISSIONS 3-10
3.2.1 Production 3-10
3.2.2 Usage 3-12
3.2.3 Emissions 3-14
3. 3 ATMOSPHERIC TRANSPORT, TRANSFORMATION AND FATE 3-14
3.3.1 Residence Time and Tropospheric Removal Mechanisms... 3-14
3.3.2 Impact Upon the Ozone Layer 3-21
3.3.3 Laboratory Studies 3-26
3.4 AMBIENT MIXING RATIOS 3-27
3.4.1 Global Atmospheric Distributions 3-27
3.5 REFERENCES 3-36
4. METABOLIC FATE AND DISPOSITION 4-1
4.1 ABSORPTION, DISTRIBUTION AND ELIMINATION 4-1
4.1.1 Oral and Dermal Absorption 4-1
4.1.2 Pulmonary Uptake and Body Burden 4-3
4.1.3 Tissue Distribution 4-13
4.1.4 Pulmonary Elimination 4-15
4.1.5 Elimination by Other Routes 4-17
4. 2 BIOTRANSFORMATION 4-17
4.2.1 Magnitude of Methyl Chloroform Metabolism 4-18
4.2.2 Kinetics of Blood and Urine Metabolites 4-21
4.2.3 Enzyme Pathways of Methyl Chloroform
Metabolism 4-26
4. 3 SUMMARY AND CONCLUSIONS 4-32
4.4 REFERENCES 4-34
5. TOXIC EFFECTS 5-1
5.1 HEALTH EFFECTS IN HUMANS 5-1
5.1.1 Experimental Studies 5-1
5.1.2 Occupational Studies 5-8
5.1.3 Accidental Exposure 5-11
-------
CONTENTS (cont.)
5.2 EFFECTS ON ANIMALS 5-15
5.2.1 Acute and Subacute Effects.; 5-15
5.2.2 Central Nervous System Effects 5-21
5.2.3 Cardiovascular Effects 5-21
5.3 TERATOGENICITY, MUTAGENICITY, AND CARCINOGENICITY 5-29
5.3.1 Teratogenicity, Embryotoxicity, and Reproductive
Effects 5-30
5.3.1.1 Overview 5-30
5.3.1.2 Human Studies 5-33
5.3.1.3 Animal Studies 5-33
5.3.1.3.1 Rats 5-33
5.3.1.3.2 Mice 5-35
5.3.1.3.3 Chicken embryos 5-35
5.3.2 Mutagenicity 5-36
5.3.3 Carcinogenicity 5-38
5.4 SUMMARY OF ADVERSE HEALTH EFFECTS AND LOWEST OBSERVED
EFFECTS LEVELS 5-43
5.4.1 Inhalation Exposure 5-43
5.4.1.1 Effects of Single Exposures 5-44
5.4.1.2 Effects of Intermittent or Prolonged
Exposures 5-50
5.4.2 Oral Exposure 5-53
5.4.3 Dermal Exposure 5-55
5. 5 REFERENCES 5-56
6. BIBLIOGRAPHY 6-1
7. APPENDIX: THE CARCINOGEN ASSESSMENT GROUP'S CARCINOGEN
ASSESSMENT OF METHYL CHLOROFORM 7-1
-------
LIST OF TABLES
3-1 Physical properties of 1,1,1-trichloroethane 3-1
3-2 Major producers of methyl chl oroform 3-11
3-3 Stabilizers used in methyl chloroform formulations 3-13
3-4 1978 emission losses to air 3-15
3-5 Relative efficiency of halocarbons in reducing
stratospheric ozone 3-24
3-6 Important atmospheric reactions that affect stratospheric
ozone 3-25
3-7 Ambient air mixing ratios of CH3CC13 measured at sites
around the world 3-33
4-1 Partition coefficients of methyl chloroform and other
sol vents at 37°C 4-2
4-2 Estimated uptake of MC during a single 4-hr exposure
(average body weight, 77 kg; 67 kg lean body mass),
estimated uptake of MC during a single 8-hr exposure
(average body weight, 74 kg) 4-8
4-3 Mean values and SEM for 12 male subjects at rest and
exercise for 30-minute periods 4-10
4-4 Tissue content (rat) of methyl chloroform (MC) after
chronic inhalation exposure at 500 ppm 4-14
4-5 Recovery Experiment with rats (3) intraperitoneally
injected with 14C-MC(700 mg/kg) 4-20
4-6 Relation between inhalation exposure and urinary metabolites
of MC 4-22
5-1 Subjective and physiological responses to a constantly
increasing methyl chloroform vapor concentration over
a period of 15 mi nutes 5-4
5-2 Subjective and physiological reponses to methyl chloroform
vapor concentrations of 900 to 1000 ppm 5-5
5-3 Number of subjective responses to methyl chloroform
exposure 5-7
5-4 Signs and symptoms of patients surviving intoxication with
methyl chloroform 5-12
5-5 Acute toxicity of methyl chloroform 5-16
5-6 The relative hepatotoxic efficacy of chlorinated solvents 5-21
5-7 Probable result of single exposure to the vapors of methyl
chloroform 5-22
5-8 Left ventricular and hemodynamic effects of
methyl chloroform 5-25
5-9 Concentration of chemicals causing cardiac sensitization
and their physical properties 5-27
5-10 Oncogenic and terotogenic testing of methyl chloroform 5-31
5-11 Summary of NCI chloroethane bioassay results as of
July 1978 5-39
vn
-------
LIST OF TABLES (cont.)
Page
5-12 Summary of neoplasms in rats and mice ingesting
methyl chloroform 5-41
5-13 Summary of neoplasms in rats inhaling methyl chloroform
for 52 weeks 5-42
5-14 Human fatalities associated with methyl chloroform
inhalation 5-45
5-15 Non-lethal effects of methyl chloroform on humans 5-47
-------
LIST OF FIGURES
Page
3-1 Global distribution of methyl chloroform 3-30
4-1 Absorption and pulmonary elimination of MC, and blood
concentration 4-6
4-2 Data from one subject exposed to 30-min periods of MC 4-11
4-3 Postulated pathways of hepatic biotransformation of MC 4-27
ix
-------
The authors of this document are:
Dr. Richard Carchman, Department of Pharmacology, The Medical College of
Virginia, Health Sciences Division, Virginia Commonwealth University,
Virginia
Dr. I. W. F. Davidson, Department of Physiology/Pharmacology, The Bowman Gray
School of Medicine, Wake Forest University, Winston Salem, North Carolina
Mr. Mark M. Greenberg, Environmental Criteria and Assessment Office, U.S.
Environmental Protection Agency, Research Triangle Park, North Carolina
Dr. Jean C. Parker, Environmental Criteria and Assessment Office, U.S. Environ-
mental Protection Agency, Research Triangle Park, North Carolina
Assistants to the Project Coordinator:
Mr. Mark M. Greenberg, Environmental Criteria and Assessment Office, U.S.
Environmental Protection Agency, Research Triangle Park, North Carolina.
Ms. Donna Sivulka, Environmental Criteria and Assessment Office, U. S.
Environmental Protection Agency, Research Triangle Park, North Carolina.
Dr. David E. Weil, Environmental Criteria and Assessment Office, U. S. Environ-
mental Protection Agency, Research Triangle Park, North Carolina.
-------
The following Individuals were asked to review an early draft of this
document and submit comments:
Or. Joseph Borzelleca
Dept. of Pharmacology
The Medical College of Virginia
Virginia Commonwealth University
Richmond, VA 23298
Dr. Benjamin Van Duuren
Institute of Environmental Medicine
New York Univeristy Medical Center
New York, NY 10016
Dr. Herbert Cornish
Dept. of Environmental and Industrial Health
University of Michigan
Ypsilanti, MI 48197
Dr. I. W. F. Davidson
Dept. of Physiology/Pharmacology
The Bowman Gray School of Medicine
Winston-Sal em, NC 27103
Dr. Lawrence Fishbein
National Center for Toxicological Research
Jefferson, AR 72079
Dr. John G. Keller
P. 0. Box 10763
Research Triangle Park, NC 27709
Dr. John L. Laseter
Director, Environmental Affairs, Inc.
New Orleans, LA 70122
All Members of the
Interagency Regulatory Liason Group
Subcommittee on Organic Solvents
x1
-------
The following individuals attended a review workshop to discuss draft
EPA documents on organic compounds which included an early draft of
this document:
Dr. Mildred Christian
Argus Laboratories
Perkasie. PA 18944
Or. Rudolf Jaeger
Institute of Environmental Medicine
New York, NY 10016
Dr. Benjamin Van Duuren
Institute of Environmental Medicine
New York University Medical Center
New York, NY 10016
Dr. Herbert Cornish
School of Public Health
University of Michigan
Ann Arbor, MI 48197
Dr. I. W. F. Davidson
Dept. of Physiology/Pharmacology
The Bowman Gray School of Medicine
Winston-Sal em, NC 27103
Dr. John Egle
Dept. of Pharmacology
Virginia Commonwealth University
Richmond, VA 23298
Dr. John Keller
P. 0. Box 10763
Research Triangle Park, NC 27709
Dr. Norman Tn'eff
Dept. of Preventive Medicine
University of Texas Medical Branch
Galveston, TX 77550
Dr. Thomas Haley
National Center for Toxicology Research
Jefferson, AK 72079
Dr. James Withey
Food Directorate
Bureau of Food Chemistry
Ottawa, Canada
xii
-------
Participating members of the Carcinogen Assessment Group
Roy E. Albert, M.D. (Chairman)
Elizabeth L. Anderson, Ph. D.
Larry D. Anderson, Ph. D.
Steven Bayard, Ph. D.
Chao W. Chen, Ph. D.
Bernard H. Haberman, D. V. M. , M.S.
Charaligayya B. Hiremath, Ph. 0.
Chang S. Lao, Ph. D.
Robert McGaughy, Ph. D.
Beverly Paigen, Ph. D.
Dharm V. Sinch, D.V.M, Ph. D.
Nancy A. Tanchel, B.A.
Todd W. Thorslund, Sc. D.
Participating members of the Reproductive Effects Assessment Group
Peter E. Voytek, Ph. D. (Chairman)
John R. Fowle III, Ph. D.
Members of the Agency Work Group on Solvents
Elizabeth L. Anderson Office of Health and Environmental Assessment
Charles H. Ris Office of Health and Environmental Assessment
Jean Parker Office of Health and Environmental Assessment
Mark Greenberg Office of Health and Environmental Assessment
Cynthia Sonich Office of Health and Environmental Assessment
Steve Lutkenhoff . Office of Health and Environmental Assessment
James A. Stewart Office of Toxic Substances
Paul Price Office of Toxic Substances
William Lappenbush Office of Drinking Water
Hugh Spitzer Consumer Product Safety Commission
David R. Patrick Office of Air Quality Planning and Standards
Lois Jacob Office of General Enforcement
Arnold Edelman Office of Toxic Integration
Josephine Breeder Office of Water Regulations and Standards
Mike Ruggiero Office of Water Regulations and Standards
Van Jablonski Office of Solid Waste
Charles Delos Office of Water Regulations and Standards
Richard Johnson Office of Pesticide Programs
Priscilla Holtzclaw Office of Emergency and Remedial Response
xin
-------
1. SUMMARY AND CONCLUSIONS
1,1,1-Trichloroethane (methyl chloroform, MC) is a chlorinated hydro-
carbon compound which is manufactured and used in large quantities. Since its
commercial introduction in the mid-1900s, it has been used increasingly as an
industrial solvent and in consumer products, such as spot removers. In recent
years, the U.S. production of MC has grown significantly; current production
is estimated to have increased from 266 million pounds (121 million kg) in
1970 to 716 million pounds (325 million kg) in 1979. The compound is produced
by three manufacturers with a total annual production capacity of 975 million
pounds. Methyl chloroform's popularity is apparently due primarily to early
studies which indicated that it had a very low toxicity in comparison to other
halogenated hydrocarbon solvent's" with similar physical properties.
It is estimated that approximately 88 percent of the MC consumed in the
United States is lost directly to the environment through dispersive use,
largely by evaporation to the atmosphere. Three-quarters of the air emissions
are attributed to metal cleaning operations which consume 66 percent of the
total production. There are no known natural sources of MC. In addition to
the workplace, ambient air and water measurements indicate that it is found in
a variety of urban and non-urban areas of the United States and other regions
of the world. Measurable amounts of MC have been reported in the atmosphere,
soil, rainwater, marine and fresh surface waters, and ground water in the low
part per billion (ppb) level. Residues of MC have been measured at similar
levels (low ppb) in the tissues of aquatic and terrestrial plants and animals,
002MC1/H 1-1 11-10-81
-------
and in food items. In addition, MC has been detected in human expired air, at
levels of 0.03-140 ug/h/ subject. Based on available information, an average
3
ambient air concentration of about I ppb (5.4 ug/m ) would be expected for
some large urban centers, while air samples from rural areas average around
100 parts per trillion (ppt).
Chlorine atoms are released from MC by photodissociation in the strato-
sphere and react with ozone (0-) thus contributing to a reduction of strato-
spheric Og. Therefore, MC may contribute to the effects of ozone depletion on
human health, i.e., an increased incidence of certain types of skin cancers
due to increased UV-B radiation reaching the earth's surface. However, the
approximate extent to which stratospheric ozone is depleted by all halocarbons
and the extent to which past, current and future emissions of MC contribute to
this depletion can only be estimated through computer modeling of the stra-
tosphere. It is not currently possible to verify by direct measurement an
ozone depletion of less than 2 percent per decade. Unlike chlorofluorocarbons,
which are not known to be removed by mechanisms in the troposphere, MC is
removed to a substantial extent through reaction with hydroxyl radicals. The
tropospheric lifetime of MC is generally assumed to be within a range of 5 to
12 years in spite of the lack of scientific agreement on the global average
concentration of hydroxyl radicals. It has been estimated that this period of
time allows from 10 to 20 percent of the MC emitted to survive tropospheric
removal mechanisms and reach the stratosphere. The National Academy of
Sciences has recently estimated that MC currently contributes one-quarter to
one-half the number of chlorine atoms reaching the stratosphere, as do either
of the chl orofl uorocarbons F-ll or F-12. Assuming the same rates of pro-
duction, MC has been calculated to be approximately 15 and 20 percent as
002MC1/H 1-2 11-10-81
-------
effective as chlorofluorocarbon F-ll and F-12, respectively, in destroying
ozone. This estimate assumes a 9-year tropospheric lifetime for MC. If it
replaces other solvents in the future, or as new uses for MC are found, it
will necessarily play a more significant role in ozone photochemistry.
Methyl chloroform production has been rising in recent years, and esti-
mates of tropospheric levels show a corresponding rate of increase of 17
percent annually. The most recent measurements indicate a global average
mixing ratio of about 110 ppt.
At levels of methyl chloroform necessary for anesthesia (10,000 to 50,000
ppm), significant cardiovascular effects have been observed in animals and
humans. Even at 1000 ppm, MC inhalation produces cardiovascular effects in
humans that include sensitization of the heart to spontaneous or catecholamine-
provoked arrhythmias and'hypotension. This cardiovascular response is, in
part, the result of MC's ability to depress the conduction system of the
heart.
More recent studies have also shown that MC is not entirely innocuous to
human health at the lower concentrations likely to be encountered in the
*
workplace (TLV-TWA = 350 ppm), although single exposures to concentrations
less than 5000 ppm are probably not potentially life threatening to humans.
The lowest observed adverse effect lever (LOAEL, 500 - 350 ppm) produces
subjective symptoms of lightheadedness, syncope, stuffiness, mild headache,
*
TLV-TWA (Threshold Limit Value - Time Weighted Average): is defined as the
time-weighted average concentration for a normal 8-hour workday and a 40-hour
workweek to which nearly all workers may be exposed repeatedly, day after day,
without adverse effect.
LOAEL: is defined as the lowest exposure level in a study or group of studies
which produces statistically significant increases in frequency or severity of
adverse effects between the exposed population and its appropriate control.
002MC1/H 1-3 11-10-81
-------
nausea, and mild irritation of eye, nose, and throat. No significant abnormal
blood chemistry or organ function tests have been noted. The most adverse
effects are neurological symptoms, which have been diagnosed by subjects'
impaired performance of cognitive and manual tasks.
The incidence of adverse health effects at low ambient air mixing ratios
(~ 100 ppt) is unknown. However, because there is evidence that MC accumu-
lates in the body, long-term or lifetime exposure to even low ambient air
concentrations might represent a health hazard. A no observed effect level
*
(NOEL ) for long term occupational exposure of humans to MC is presently
assumed to be around 53 ppm.
Methyl chloroform has been demonstrated to have mutagenic activity in the
Ames test, with and without metabolic activation, and in cultured mammalian
cell transformation systems. If the metabolism and pharmacokinetics of this
compound in humans result in metabolic products which can interact with DNA,
as is the case for bacteria, it may cause mutagenic effects in humans as well.
It may also possibly have teratogenic potential, thereby showing similarity to
other halogenated hydrocarbon t:ompounds. In tests conducted to date, MC has
not appeared to be carcinogenic; however, the fact that it is mutagenic in
Salmonella warrents further examination of its carcinogenic potential.
The pharmacokinetics and metabolism of MC have been studied in man. Like
other halogenated hydrocarbon solvents, inhalation and lung absorption of MC
vapor in the air is the most important and rapid route of absorption into the
body. It is estimated that for an 8 hour exposure at the TLV-TWA (350 ppm),
about 2 grams will be absorbed into the body of a normal 70 kg man. The total
NOEL: is defined as the exposure level at which there are no statistically
significant increases in frequency or severity of effects between the exposed
population and its appropriate control.
002MC1/H 1-4 11-10-81
-------
amount absorbed increases in direct proportion to inspired air concentration
and to length of exposure and physical activity. However, at equilibrium,
only approximately 30 percent of the inspired air concentration is retained.
Because of its lipophilic nature, MC is expected to cross membrane barriers in
the body and diffuse into the brain and the milk of nursing mothers, as well
as into the fetus during pregnancy. There is strong evidence that tissue
concentration of MC, particularly into adipose tissue, will occur with chronic
or long term exposure to even low ambient air concentrations. Methyl chloro-
form is metabolized in man to a very limited extent (about 6 percent of the
total retained dose).
The primary route of elimination of MC is via the lungs. The only iden-
tified uninary metabolites are trichloroethanol and trichloroacetic acid.
Metabolism of MC is enhanced by other chemicals and drugs such as phenobar-
bital, and there is some evidence that MC may enhance its own metabolism.
As stated above, some of the health hazards of exposure to MC concern the
»«•
possible mutagenic, teratogenic, and carcinogenic potential of the compound.
The extent to which its possible carcinogenic potential can be realized is
linked to the biochemical mechanisms of its metabolism in the liver. Methyl
chloroform may be biotransformed to "reactive intermediate" metabolites which
may contribute to tissue and organ toxicities, as well as carcinogenesis.
However, the evidence for reactive intermediate metabolites of MC is frag-
mentary at present. Methyl chloroform has been demonstrated to be mutagenic
in the Ames test, with and without metabolic activation, and in a cultured
mammalian cell transformation system. However, animal bioassays performed by
the National Cancer Institute (NCI) and others have not provided definitive
evidence of carcinogenicity. At the present time, there is inadequate evidence
to properly evaluate MC as a chemical carcinogen (see attached CAG report).
002MC1/H 1-5 11-10-81
-------
There are only a few studies on the teratogenicity and fetotoxicity of MC
and the limitations of the available data do not allow for a full assessment
of the effects. Further testing is required to determine whether this toxicity
is a health hazard to humans, particularly at low ambient concentrations.
Until there is considerably more information available on the biological
effects of MC and its role in contributing to an increased incidence of skin
cancer as a result of ozone depletion, a definitive evaluation of all the
health hazards associated with its use in the workplace and its presence in
the ambient environment is not possible. For example, there is very little
data on synergistic or antagonistic effects of MC with other compounds; e.g.,
anesthetic or vasoactive agents. In addition, a lifetime animal bioassay
under the National Toxicology Program using both rats and mice is currently
nearing completion. It should be noted that the MC being used in this study
has only a very low percent (0.002%) of dioxane, a stabilizer thought possibly
to contribute to the positive results obtained in the mutagenicity and cell
transformation tests. *
002MC1/H 1-6 11-10-81
-------
2. INTRODUCTION
1,1,1-Trichloroethane (methyl chloroform, MC) belongs to a family of
saturated chlorinated compounds widely used in industrial cold cleaning and
vapor degreasing operations, in the synthesis of vinylidene chloride, and in
consumer products. This document provides an evaluation of the health hazards
of MC and a review of the relevant scientific literature. In order to provide
a perspective in evaluating the health hazards of MC, this document contains
background chapters relating to analytical methodologies, production, sources
and emissions, ambient air concentrations, and levels of exposure.
Methyl chloroform is released into the ambient air as a result of evapo-
ration during production, storage, and manufacturing or during general con-
sumer use. It is not known to* be derived from natural sources. In recent
years, a great deal of attention has been focused upon the role of MC in the
destruction of stratospheric ozone, indirectly resulting in increased ultra-
violet radiation at the earth's surface and contributing to an increased
incidence of skin cancer. MC is one of the many atmospheric pollutants whose
reactivity is sufficiently low to allow it to be transported to the strato-
sphere; its trophospheric lifetime is estimated to be 5 to 12 years. Con-
centrations in ambient air sampled around the nation reflect methods used to
control emissions and the transport and transformation processes in the at-
mosphere.
The scientific literature on MC is limited in reference to its effects on
humans. There are relatively few epidemiological studies. What is known
002MC1/D 2-1 11-10-81
-------
about the effects of MC has been primarily learned from studies involving
individuals exposed occupationally or accidentally to it. In such exposures,
the concentrations of MC associated with adverse effects to human health were
either unknown or far in excess of the concentrations measured in ambient air.
*
Controlled exposure studies have been carried out at TLV-TWA concentrations
(350 ppm) and have been directed toward elucidation of the pharmacokinetic
parameters of MC exposure. These studies have established that vapor inhala-
tion is the principal route by which MC enters into the body; it is widely
distributed into all organ systems and is metabolized to a limited but signi-
ficant extent. MC is eliminated from the body primarily as the parent com-
pound via the lungs, but metabolites are excreted mostly in the urine. Given
evidence that MC accumulates in the body, particularly in fatty tissues,
long-term or lifetime exposure to even low ambient air concentrations may
represent significant health hazards. Epidemiological studies provide some
information about the impact of MC on human health, but it is necessary to
«.
rely on animal studies to derive indications of potential harmful effects for
chronic low exposure. These studies are reviewed in chapters 4 and 5.
Apart from the important questions of carcinogenicity and teratogenicity,
other human biological effects relate to the narcosis potential of MC and to
evidence that low ambient concentrations may have accumulative neurological
and cardiovascular effects. The full detrimental consequences to human health
of MC have not been determined at present and require further study. These
questions are discussed in chapter 5.
TLV-TWA (Threshold Unit Value - Time Weighted Average): is defined as the
time-weighted average concentration for a normal 8-hour workday and a 40-
hour workweek to which nearly all workers may be exposed repeatedly, day
after day, without adverse effect.
2-2
-------
The potential of MC or its metabolites to act as chemical carcinogens
and/or mutagens represents a most serious hazard to human health. This docu-
ment summarizes the available mutagenicity studies and the animal bioassay
studies that relate to the carcinogenic potential of MC. Methyl chloroform's
potential to cause human cancer is discussed in chapter 5. According to the
EPA Carcinogen Assessment Group and Reproductive Effects Assessment Group
Reports (January, 1981), it remains suspect at the present time; however, a
final judgment on the carcinogenicity of MC has been deferred until further
information becomes available, particularly the results of the current National
Toxicology Program bioassay in rats and mice.
Permissible levels of MC in the working environment have been established
in various countries. The U.S. Occupational Safety and Health Administration
(OSHA) health standard requires that a worker's exposure to MC at no time
exceed an 8 hr time-weighted average o
air in any work shift of a 40 hr week.
exceed an 8 hr time-weighted average of 1,900 mg/m (350 ppm) in the workplace
2-3
-------
3. GENERAL BACKGROUND INFORMATION
3.1 CHEMICAL AND PHYSICAL PROPERTIES, ANALYTICAL METHODOLOGY
3.1.1 Chemical and Physical Properties
1,1,1-Trichloroethane (CHgCCl,), also called methyl chloroform (MC), 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
Chemical Formula CpHjCl.,
Chemical Abstracts Service Registry Number 71-55-6
Synonyms and Identifiers
Aerothene TI Inhibiso]
Chloroethane NU Methyl Chloroform
Chiorotene Methyltri chloromethane
Chlorothane NU NCI-C04626
Chlorothene Alpha-T.
Chlorothene NU Trichloroethane
Chlorothene VG 1,1,1-Trichloroethane
Chlorten orTrichloroethane
Ethane, 1,1,1-Trichloro
Table 3-1 shows some of its important chemical and physical properties.
TABLE 3-1. PHYSICAL PROPERTIES OF 1,1,1,-TRICHLOROETHANE
Solubility in water @ 25°C 0.44 gm/lOOgm
Boiling point @ 760 torr 74°C
Vapor pressure @ 20°C 100 torr
Vapor density (air = 1) 4.6
Molecular weight 133.41 -
1 ppm 5.4 mg/m
002MC1/G 3-1 3-25-82
-------
In the atmosphere, MC is subject to free radical attack and reaction with
hydroxy] radicals is the principal way in which it is scavenged from the
atmosphere. Photooxidation products of MC include hydrogen chloride, carbon
oxides, phosgene, and acetyl chloride (Christiansen et al., 1972). The prin-
cipal tropospheric photooxidation product has been reported to be trichloro-
acetaldehyde (U.S. Environmental Protection Agency, 1975). Data discussed in
Section 3.3 indicate that MC is relatively stable in the troposphere and that
significant amounts are conveyed to the stratosphere.
In water, methyl chloroform is slowly hydrolyzed to predominantly acetic
and hydrochloric acids (Billing et al., 1975). Billing et al. (1975) reported
a half-life of hydrolysis of 6 months at 25°C (dark reaction).
Anhydrous MC is generally noncorrosive, but in the presence of water it
can react to form hydrochloric acid, which is a corrosive of metals (Keil,
1979). The addition of epoxides can neutralize the generated acid (Keil,
1979). Anhydrous MC, when heated to 360° to 440°C, decomposes to 1,1-dichloro-
ethylene and hydrogen chloride. When MC 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 an-
hydride. Noweir et al. (1972) have observed that when MC comes in contact
with iron, copper, zinc, or aluminum at elevated temperatures, phosgene is
produced.
Bonse and Henschler (1976) have considered the general chemical reactivity
of MC. By virtue of the electron-inductive effects of the chlorine substitu-
ents, destabilization occurs at the C-C bond. Radical reaction mechanisms
would be favored as a result of the delocalization of the unpaired electron
drawn from the C-C bond.
002MC1/G 3-2 3-25-82
-------
3.1.2 Analytical Methodology
lo detect very low levels of methyl chloroform in ambient air, sophisti-
cated analytical techniques have been employed. The two most generally useful
methods for detection and analysis of MC have been gas chromatography with
electron capture detection (GC-ECD) and gas chromatographymass spectrometry
(GC-MS). Both systems have a lower limit of detection on the order of a few
parts per trillion (ppt). Ihe utility of GC-ECD over GC-MS is that it can be
used in the field to provide nearly continuous measurements through inter-
mittent sampling (every 15 to 20 minutes).
In a comparison between GC-ECD and GC-MS, Cronn et al. (1976) judged
GC-ECD to be superior in precision. Standards for four halocarbon compounds,
measured by GC-ECD, had coefficients of variation ranging from 0.5 to 3.5
percent. Of 11 halocarbon compounds measured by GC-MS, coefficients of vari-
ation ranged from 4 to 19 percent, temperature programming or isothermal
operation of the gas chromatograph yielded comparable results (Cronn et al.,
1977). The precision with temperature-programming was 4.3 percent versus 3.5
percent with isothermal operation for MC.
A close agreement between the levels of MC and other halocarbons detected
by both GC-ECD and GC-MS (on the same ambient air samples) was obtained by
Russell and Shadoff (1977). A difference of 10 ppt was reported between the
systems. Air samples were sorbed onto Porapak N porous polymer and desorbed
onto the column by heating the collection tube rapidly to 200°C. Ambient air
mixing ratios measured by this method were in the range of 90 to 110 ppt.
Ihe electron capture detector, as well as the mass spectrometer in the
selective ion monitoring mode (Cronn and Harsch, 1979a; Pellizzari, 1974), is
specific in the detection and quantisation of many halogenated hydrocarbons,
whereas nonhalogenated hydrocarbons are not detected. Thus, a high background
002MC1/G 3-3 3-25-82
-------
level of hydrocarbons in ambient air samples does not preclude analysis of
trace quantities of MC. In the electron capture detector, MC is ionized by
primary electrons released from an internal radioactive source. The net
result is removal of electrons from the gaseous mixture with substitution by
negative ions of greater mass. The measured effect is a net decrease in ion
current because the mobility of the ions is less than that of the electrons.
Samples of tropospheric air were analyzed by Cronn and coworkers (1972)
both by preconcentrating the samples according to the method of Rasmussen et
al. (1977) and by direct injection. The detection limit was 3 ppt. The
precision of the method using preconcentration was ±4 percent. The internal
consistency between direct GC-ECD analysis of MC and using the preconcen-
tration method was reported to be good (Cronn et al., 1977).
A detection limit of 2 ppt for MC was achieved by Harsch and Cronn (1978)
with a low pressure sample-transfer technique. Precision was ±7 percent with
the Rasmussen et al. (1977) preconcentration technique. Calibration was
accomplished by use of secondary standards that were compared to static dilu-
tions of pure and commercially prepared mixtures of MC (10 ppm) in helium.
Robinson (1978) reported a detection limit of 6 ppt with a precision of ±4.2
percent with secondary standards in a system using dual GC-ECD.
Pellizzari and Bunch (1979) reported an estimated detection limit of
_c 2
12.45 ppt (66 x 10 mg/m ) using high resolution gas chromatography/mass
spectrometry. The detection limit was calculated on the basis of the break-
through volume for 2.2 grams of Tenax GC, at 21°C. Ihe accuracy of analysis
was reported at ± 30 percent. Sources of error are discussed in section
3.1.2.1. Water
The relatively high volatility of MC was used to advantage by Piet et al.
(1978) in measuring the content of MC in water samples. A direct headspace
002MC1/G 3-4 3-25-82
-------
method was used with MC volatilizing into the air above the surface of the
water sample in a sealed container. A GC-ECD system was used for separation
and quantitation. Ihe systematic error of the method was reported to be less
than 5 percent. Ihe detection limit for MC was 0.05 ug per liter. Ihe 0V 225
capillary GC column provided good separation of MC from CCK.
3.1.2.1 Sampling and Sources of Error—Ihe National Academy of Sciences
(1978) has reviewed common approaches used to sample ambient air for trace gas
analysis. These approaches include:
1. Ambient pressure samples. An evacuated chamber is opened and allowed to
fill until it has reached ambient pressure at the sampling location. If.
filling is conducted at high altitude, contamination of the low pressure
sample is likely when samples are returned to ground level.
2. Pump pressure samples. A mechanical pump is used to fill a stainless
steel or glass container to a positive pressure relative to the surround-
ing atmosphere.
3. Adsorption on molecular sieves, activated charcoal, or other materials.
Sorbents that have been used to collect MC include Porapak Q, lenax GC,
and Chromosorbs 101, 102, and 103.
4. Cryogenic sampling. Air samples are transferred to a loop held at the
temperature of liquid oxygen. Components, including MC, are concentrated
by freezeout while other gases (oxygen, nitrogen) pass through.
In the analysis of whole air samples of compounds such as MC which are
present in ambient air in the ppt range, small uncontrolled errors in the
system could result in inaccurate results. Errors in the analysis can occur
during sampling, in the gas chromatograph, in the EC detector, and in cali-
bration of the instruments.
002MC1/G 3-5 3-25-82
-------
Rasmussen and Khali! (1981) reported that, in an inter!aboratory com-
parison of two samples of MC in ambient air, a majority of the 19 partici-
pating laboratories reported values lower than those determined by the authors.
It was concluded that common standards are needed if atmospheric measurements
from different laboratories are to be pooled.
Singh and coworkers (1978a) used electrochemically-polished stainless
steel sampling vessels. The sampling vessels were flushed with ultra-pure
helium until background contamination was reduced to less than 2 to 3 percent
of the expected background concentration of a given trace constituent. Cronn
and coworkers similarly employed electropolished stainless steel containers
whose interior surfaces had been passivated by electropolishing (Cronn and
Robinson, 1978; Cronn et al., 1976; 1977).
Harsch and Cronn (1978) have evaluated sample transfer techniques. Most
analytical procedures involve the collection of pressurized air samples.
Sample transfer under positive pressure minimizes serious contamination possi-
bilities posed by laboratory air containing many times the ambient mixing
ratios of most halocarbons. However, collection of low pressure samples, such
as stratospheric air samples, is a specialized situation in which careful
precautions against sample contamination are necessary. A technique appli-
cable to collection of whole air samples at altitudes up to 21 kilometers
showed a 7 percent standard deviation when the MC mixing ratio was 105 ppt
(Harsch and Cronn, 1978). Electropolished sampling bottles were evacuated to
30 microns prior to sample collection. Transfer of contents to a freezeout
loop (Rasmussen et al., 1977) (immersed in liquid 02) was made by vacuum
assist. Preconcentration was followed by injection onto a temperature-pro-
grammed column. The detection limit for MC with the GC-ECD procedure was 2
ppt. To minimize the number of potential sources of leaks, system components
002MC1/G 3-6 3-25-82
-------
were silver soldered. Ihe technique was applicable when gross halocarbon
levels were not present in laboratory air. However, it was noted that if
laboratory air contained ppb levels of halocarbons, high-boiling halocarbons
were adsorbed onto the surfaces of the fittings of the sampling containers and
associated plumbing during times when the system was exposed to laboratory
air.
The EC detector can be a source of error because water vapor and oxygen
may cause reduced sensitivity for certain halocarbons. Lillian and Singh
(1974) used an ascarite trap between the GC column and the detector to absorb
sample moisture. Carrier gas for the GC is purified by passage through traps
containing activated charcoal, anhydrous calcium sulfate, and an ascarite or
molecular sieve (Cronn, 1980). Oxygen contamination in the detector can be
minimized by preconcentration of air samples on porous polymers (Russell and
Shadoff, 1977). Significant oxygen contamination is often caused by fitting
leaks in the GC rather than by carrier gas contamination.
A freezeout concentration method was employed by Sasmussen et al. (1977)
to determine atmospheric levels of MC in the presence of other trace vapors.
The detection limit of MC was reported to be 0.8 ppt for 500 ml aliquots of
ambient air when measured by GC-ECD. Precision was 4.3 percent. Standards
were prepared by static dilutions in helium. During the procedure, the oven
of the GC was cooled to - 10°C. When freezeout was complete, the loop con-
taining the concentrated air sample was immersed in heated water and the
carrier gas swept the contents of the sample loop onto the column.
Pellizzari and Bunch (1979) reported the use of Tenax GC, a porous polymer
based on 2,6-diphenyl-p-phenylene oxide, to absorb MC from ambient air.
Recovery was made by thermal desorption and helium purging into a freezeout
trap. Included among the inherent analytical errors were (1) the ability to
002MC1/G 3-7 3-25-82
-------
accurately determine the breakthrough volume, (2) the percent recovery from
the sampling cartridge after a period of storage, and (3) the reproducibility
of thermal desorption from the cartridge and its introduction into the analy-
tical system. To minimize loss of sample, cartridge samplers should be en-
closed in cartridge holders and placed in a second container that can be
sealed, protected from light, and stored at 0°C.
3.1.2.2 Calibration—In general, calibration of the instrumentation for
GC-ECD analysis of methyl chloroform has involved static, multiple dilutions
of pure material in the ppm range to ppt levels (Cronn et al., 1976; 1977;
Harsch and Cronn, 1978; Lillian and Singh, 1974; Singh et al., 1977a). Singh
et al. (1977b) have cautioned that, in some cases, multiple dilutions of
materials to ppt levels are tedious and prone to inaccuracies. In order to
overcome the difficulties in generating low-ppb primary standards of MC, Singh
et al., (1981) has reported that permeation tubes offer the most accurate
means. Permeation tubes were conditioned for at least two weeks and, during
standard generation, were kept in holders maintained at 70 ± 0.1°C. Error in
the permeation rate (980 mg/min) were ± 15 percent. A reproducible means of
generating low-ppb primary standards was judged essential since there are
considerable difficulties in storing long-term secondary standards. Various
investigators have used GC-ECD systems to quantitate MC in ambient air samples
(Cronn et al. , 1976; 1977; Lillian and Singh, 1974; Rasmussen et al., 1977;
Singh et al. , 1977c). An inter!aboratory calibration (Cronn et al., 1976) of
six real ambient air samples gave a precision (percent standard deviation) of
11.4 ppt. A similar comparison calibration was reported by Singh et al.,
(1981).
Rasmussen and Khali! (1981) reported that primary standards of MC (~ 139
and 52 ppt) remained stable for up to about one year, even though the pressure
in the master tanks had decreased significantly.
002MC1/G 3-8 3-25-82
-------
Because the ionization efficiency of MC in the EC detector is only 20
percent, use of dual EC detectors in series have been used to achieve higher
accuracy (Lillian and Singh, 1974). The dual detection system, as employed by
Singh et al. (1977c), enables MC to be quantitated coulometrically according
to the following equation:
Coulombs = 96,500 pW;
where
p = ionization efficiency
and W = moles of compound
Determination of the ionization efficiency can be made by use of the following
expression which relates p to the signals (X, and X2) of two identical EC
detectors in series:
X
P = I-X^
X1 = 96,500 pW
X2 = p (96.500W - 96,500 pW)
The ionization efficiency should be determined for the operating conditions
and once established, can be used in the coulometric calibration.
The accuracy of the GC-ECD approach has been reported by Singh (1977a) to
be better than 10 percent for compounds such as MC that have ambient air
1C
mixing ratios of 20 ppt or greater. An overall system accuracy of ± 10 per-
cent was reported by Singh et al. (1977a) in analyses of MC in ambient air
samples. Two gas chrotnatographs, each equipped with two EC detectors, were
employed. An ascarite trap was placed between the GC column and the EC de-
tector to prevent moisture interference. Precision was reported to be better
than 5 percent and instruments were calibrated using multiple dilutions of
pure material. Singh et al., (1981) recently reported linearity of dual
frequency-modulated ECD's over a wide concentration range for MC, down to
low-ppt levels.
002MC1/G 3-9 3-25-82
-------
3.1.2.3 Standard Methods—The analytical method S335, suggested by NIOSH for
organic solvents in air, utilizes adsorption on charcoal followed by desorp-
tion with carbon disulfide. The resulting effluent is analyzed by gas chroma-
tography. This method was recommended for the range 96 to 405 ppm. Inter-
ferences are minimal and those that do occur can be eliminated by altering
chromatographic conditions. However, one disadvantage is that the charcoal
may suffer breakthrough, thus limiting the amount of air that can be sampled.
3.2 PRODUCTION, USE, AND EMISSIONS
Methyl chloroform is principally used for the cold cleaning and vapor
degreasing of fabricated metal parts. Because of its volatility and dis-
persive use pattern, much of the MC produced worldwide is emitted into the
atmosphere. There are no identified natural sources of emissions. Once in
the atmosphere, MC is subject to atmospheric transport and transformation. To
better gauge the effects of present and future emissions of MC on human health,
this section profiles MC production, usage, and emissions.
3.2.1 Production
Methyl chloroform is produced by several manufacturing processes (Jordan,
1979; Lowenheim and Moran, 1975; U.S. Environmental Protection Agency, 1979b):
1. Hydrochlori nation of 1,1-dichloroethylene (vinyl idene chloride)
EeCi,
CH2 = CC12 + HC1 - i* CH3CC13
2. Hydrochlori nation of vinyl chloride
Fed.
CH£ = CHC1 + HC1 - i* CH3CHC12
.
CH3CHC12 g > CH3CC13 + HC1
3. Chlorination of ethane
CH3CH3 + 3C12 370° to 480°C> CH3CC13 + 3HC1 + byproducts
002MC1/G 3-10 3-25-82
-------
In order to prevent catalyst deactivation, hydrochlorination reactions
should be anhydrous (Jorden, 1979). Temperature control of thermal reactors
for chlorination must be maintained to ensure MC stability (Jordan, 1979). In
reaction (3) above, ethyl chloride and vinylidene chloride are byproducts.
Increased yields of MC can be obtained through recycling of these byproducts.
In 1975, over 60 percent of the U.S. production of MC was derived from
the hydrochlorination of vinyl chloride; derivation from vinylidene chloride
accounted for 30 percent (Lowenheim and Moran, 1975).
In 1977, the U.S. production figure for MC was 288,565 metric tons (U.S.
Environmental Protection Agency, 1979b; U.S. Internationa] Trade Commission,
1977). The major producers and their production capacities for 1977 are shown
in Table 3-2. Quoting production estimates supplied by Dow Chemical U.S.A.,
Singh and coworkers (1979a) reported that production of the chlorocarbon has
been increasing and, in recent years, this increase has been at the annual
rate of 12 percent. Estimates did not take into account production in the
TABLE 3-2. MAJOR PRODUCERS OE METHYL CHLOROFORM1". (Cogswell, 1978)
1978 capacity
Organization metric tons
Dow Chemical, Freeport, IX 204,000
PPG Industries, Inc., Lake Charles, LA 79,000
Vulcan Materials Co., Geismar, LA 29,000
Production capacity estimated to increase significantly at PPG Industries
and at Vulcan Materials facilities for 1982 (Chemical and Engineering News,
1979; Chemical Marketing Reporter, 1979; Chemical Week, 1978).
002MC1/G 3-11 3-25-82
-------
Soviet Union and other eastern European countries. The Dow Chemical estimate
for global production in 1977 was 470,000 metric tons. The annual production
growth rate through 1977 was reported to be 7 to 10 percent by trade sources
(Chemical and Engineering News, 1979). SRI Internationa] estimated an average
production growth between 5.5 and 7.5 percent annually up to 1982. Future
growth in production depends on the status of other chlorinated solvents under
regulation for which MC may be substituted.
3.2.2 Usage
In 1975, cold cleaning and vapor degreasing operations accounted for 75
percent of the total end use of MC. Approximately 12 percent was used in the
synthesis of vinylidene chloride (Lowenheim and Moran, 1975). Use in metal
cleaning operations was reported to total 67 percent of 1977 production
(Cogswell, 1978).
MC is also used as a solvent in adhesive formulations, as a spot remover,
as a film cleaner, and as an additive in metal cutting oils (Jordan, 1979;
Keil, 1979; Lowenheim and Moran, 1975). Stabilizers used in MC are shown in
Table 3-3 and protect it in the following ways (Jordan, 1979): (1) prevent or
retard oxidation, (2) chelate metal ions, (3) scavenge HC1, and (4) passivate
metal surfaces. Vapor degreasing grades of MC contain 3 to 7 percent (w/w)
stabilizers and additives (Jordan, 1979); principal stabilizers include nitro-
methane, 1,3-dioxolane, 1,4-dioxane, butylene oxide, sec-butyl alcohol, iso-
butyl alcohol, N-methy1 pyrrole, and toluene (Jordan, 1979). In film cleaning
applications, a low concentration of alcohol is used as a stabilizer (Jordan,
1979).
SRI International reported that between 11,000 and 13,000 metric tons of
MC are used annually in personal care products (Cogswell, 1978). Expected
growth in this area is 15 to 20 percent annually (Cogswell, 1978).
002MC1/G 3-12 3-25-82
-------
IABLE 3-3. STABILIZEfiS USED IN MEIHYL CHLOROFORM FORMULATIONS
(Jordan, 1979)
1,4 dioxane
1,3-dioxolane
butylene oxide
epichlorohydrin
methyl ethyl ketone
sec-butyl alcohol
isobutyl alcohol
ethyl acetate
N-methylpyrrole
ter-amylphenol
hydroquinone monomethyl-
ether
methylal
ethylene glycol mono and
dialkyl ethers
aery 3 on i *.
p-ethoxypropioni tri1e
diallylamine
di i sopropy1 ami ne
acetaldoxime
nitromethane
nitroethane
N-methylmorpholine
Thymol
002MC1/G
3-13
3-25-82
-------
3.2.3 Emissions
Emissions of MC arise during primary and end product production, during
dispersive use applications, from storage containers, and during disposal of
waste materials.
Singh et al. (1979c) have estimated global emissions in 1977 at 95 percent
of the 300,000 metric tons produced. Lovelock (1977a) estimated that 500,000
metric tons were released globally in 1975. Ihe estimate of the global emissions
rate in 1976 by the National Research Council (1979) was about 439,000 metric
tons. According to McCarthy (1975), almost all the MC produced is eventually
released to the atmosphere.
Recent estimates in a report prepared for the U.S. Environmental Protection
Agency, Office of loxic Substances, placed 1978 emission losses to air at 214,000
metric tons (Katz et al. 1980). Emission estimates by sources category are shown
in Table 3-4. Ihe WMO (World Meteorological Organization, 1982), using data
reported by Neely and Agin (U.S. E.P.A., 1980), estimated current global annual
releases at 476,000 metric tons.
3.3. ATMOSPHERIC TRANSPORT, TRANSFORMATION AND EAT.E
Ihe potential for ambient air mixing ratios of MC to pose a hazard to human
health is influenced by the many processes that occur in the troposphere and
stratosphere. Such processes include: transformation of MC into other poten-
tially harmful atmospheric components; urban transport; tropospheric chemical
reactivity; and diffusion into the stratosphere where MC participates in ozone
(0,) destruction reactions.
3.3.1 Residence Time and Iropospheric Removal Mechanisms
Scientists generally agree that the longer the tropospheric residence time
for a chemical species, the greater the likelihood of diffusion into the strato-
sphere. Concern that MC is destroying stratospheric 03 and thus increasing the
incidence of certain forms of skin cancer (Chapter 5) has intensified recently.
002MC1/G 3-14 3-25-82
-------
TABLE 3-4. 1978 EMISSION LOSSES TO AIR
Source
1978 emission losses to air in
million pounds (kkg) and
percentage of total released to air
Production
1. From Vinyl Chloride 0.21
2. From Vinylidene Chloride 0.15
3. From Ethane 0.03
Metal Cleaning 351.70
Aerosols 39.90
Adhesives 38.37
Textiles 6.44
Paints 10.91
Inks 6.13
Drain Cleaners 0.61
Pharmaceuticals 0.27
Film Cleaning 0.48
Leather Tanning 0.23
Catalyst Preparation 0.06
Miscellaneous 14.82
Total released to the air* 470
(95)
(67)
(14)
(159,500)
(18,100)
(17,400)
(2,920)
(4,950)
(2,780)
(278)
(124)
(218)
(104)
(28)
(16,730)
0.04%
0.03%
0.01%
75%
8%
8%
1%
2%
1%
0.1%
0.06%
0.1%
0.05%
0.01%
3%
(213,300) (100%)
*An additional 63 million "pounds (28,602 kkg) are released to the
environment via solid waste and water.
Adapted from Katz et al. (1980).
002MC1/G
3-15
3-25-82
-------
A recent conference convened by the U.S. Environmental Protection Agency
(1980) met to establish the facts about the distribution and persistence of
MC. The results of research in atmospheric chemistry related to the question
of stratospheric 0, depletion by MC were discussed. Presentations from the
various perspectives of those involved in, or concerned with, regulatory
decision-making were also made.
Mass budget and other modeling estimates suggest a longer residence time
than was previously predicted. Before 1977, it was commonly believed that the
residence time was in the range of 1 to 2 years (National Research Council,
1976). Such a time span suggested a tropospheric reactivity great enough to
preclude any serious impact on 03 levels. The "short" lifetime for MC was
predicated a global average tropospheric hydroxyl radical (OH) concentration
55 -3
in the range 10 x 10 to 30 x 10 molecules cm . Reaction with OH is the
principal tropospheric removal mechanism by which many compounds are scavenged
from the atmosphere. The following reactions, occurring in the troposphere,
would serve as a sink for MC, thus reducing the levels prior to its diffusion
to the stratosphere:
CH3CC13 + -OH • > -CH2CC13 + H20 (1)
CH3CC13 + 0(1D) -CH2CC13 + -OH (2)
[0(1D) = atomic oxygen in its singlet state ]
Indications of the extent to which MC is calculated to deplete strato-
spheric 0, are predominantly derived from one- and two-dimensional modeling
•3
studies. The following scenarios consider projections of atmospheric loading,
residence time and photochemical processes in the atmosphere.
002MC1/G 3-16 3-25-82
-------
Campbell (U.S. Environmental Protection Agency, 1980) has calculated the
rate of consumption of MC via oxidation by OH as a function of altitude and
latitude. One-half of the oxidation occurs below 2.4 km. Most of the oxi-
dation also takes place in the tropics, i.e., half the removal of MC occurs
between 16°N and 16°S. These modeling efforts agreed with measured hemi-
spheric ratios and suggested a mean lifetime for MC of 6.4 years.
Logan et al., (1981) modeled MC concentrations over time and latitude,
using altitude profiles of OH averaged over an annual cycle. The model results
lend support to the findings of Campbell (U.S. Environmental Protection Agency,
1980) in that MC removal is particularly sensitive to OH levels in the tropics,
a region that accounts for about 70 percent of the global sink. Approximately
50 percent of the global sink occurs over the tropical ocean. By integrating
MC loss over altitude and latitude, using current reaction rate constants for
key reactions, Logan et al., (1981) calculated a global lifetime for MC of 5
years. It was emphasized that one-dimensional models are inappropriate for
calculating the lifetime of a compound such as MC. The model of Logan et al.,
(1981) predicted a mean OH level in the northern hemisphere of 1 x 10 per cm .
5 3
This value is somewhat higher than the level (2.5 x 10 per cm ) calculated
by Crutzen and Fishman (1977). In the model studies of Derwent and Eggleton
(1981), a global lifetime for MC was calculated at 4.8 years, using a two -
dimensional model. These investigations found that global or hemispheric
models were inapproriate; in the case of MC, a lifetime of 12 years was calcu-
lated when OH was averaged over all altitudes, latitudes, and seasons. It was
concluded that neglect of the variations of OH destruction with altitude,
latitude, and season may lead to an under - or overestimation of the impact of MC
on stratospheric 03. Global and box models, as evaluated by Derwent and Eggleton,
gave larger 0- depletion estimates; 1-D models underestimate such impact.
002MC1/G 3-17 3-25-82
-------
The mass balance studies of Singh (1977a; 1977b) had predicted reduced OH
levels (3 x 10 molecules cm ) to account for observed ambient levels of MC.
c
These OH levels are in reasonable agreement with the OH values (3 x 10 to 4 x
10 ) determined by Campbell and coworkers (1979) during monitoring studies.
From the hemispheric distribution of MC, OH abundance in the northern hemi-
sphere was 1.5 to 3 times lower than in the southern hemisphere. Carbon
monoxide (CO) levels were believed primarily responsible for the lower north-
ern hemisphere levels of OH. However, Campbell (U.S. Environmental Protection
Agency, 1980) has cautioned that, because of the combination of MC oxidation
in the tropics and CO reduction in the northern hemisphere, there is a dif-
ficulty with using the N/S ratio of MC to obtain hemispheric means of OH. For
example, a southern hemisphere OH concentration several times higher than
northern hemisphere values requires the transition from the southern hemi-
sphere value to the lower northern hemisphere value to occur within a few
degrees of the equator. Based upon the observed tropospheric distribution of
MC, atmospheric loading, and its rate of reaction (National Aeronautics and
Space Administration, 1977) with OH, Singh (1977a; 1977b) computed a global
average residence time between 8 and 11 years. This time span would be suffi-
cient to allow 15 to 22 percent of the MC. emitted to reach the stratosphere
(National Aeronautics and Space Administration, 1977; Singh et al., 1979a).
The National Research Council (1979a), using 1976 global release rates, esti-
mated that about 12 percent reaches the stratosphere.
Singh and coworkers (1979b) have found that field measurements support a
6 to 8 year global average residence time. Measurements of MC between latitudes
35°N and 35°S indicated a global average concentration of 95 ppt. When esti-
mates of other investigators are taken into account, the suggested range is 6
to 12 years (Singh et al., 1979b). This range would allow an estimated 12 to
25 percent of all MC emissions to enter the stratosphere (Singh et al., 1979b).
002MC1/G 3-18 3-25-82
-------
Ihese latter estimates agree with McConnell and Schiff (1978), who used a
one-dimensional model to compute a global average MC mixing ratio of 90 ppt, a
value consistent with observed ambient levels at the time. The average tropo-
spheric OH level needed to account for this computed MC level was 5 x 10
molecules cm .
Based upon a MC residence time of 5.4 years, Derwent and Eggleton (1978)
calculated that approximately 10 percent survives tropospheric removal pro-
cesses to reach the stratosphere. Lovelock (1977b) estimated a 5 to 10 year
residence time based on ambient measurements from 1971 to 1976.
Support for an 8 to 12 year residence time for MC can be found in the
modeling results of Chang and Penner (1978). They computed an average resi-
dence time of 11.3 years (10 to 12.8 years) from a two-box model interrelating
hemispheric abundance, release rates and interhemispheric transport time
through continuity equations.
Neely and Plonka (1978), in contrast to Singh and coworkers (1977a;
1977b) and Crutzen and Eishman (1977), who compute an average tropospheric OH
5 5-3
concentration of 2 x 10 to 4 x 10 cm , find their computed time-averaged OH
5 -3
concentration of. 4.8 x 10 molecules cm compatible with a residence time for
MC of 2.6 to 4.0 years. In their mass budget model, this OH concentration was
required to reconcile emissions (based on Dow Chemical production data) with
observed ambient MC levels. In contrast to Singh, who used a global ambient
MC mixing ratio of 90 ppt, Neely and Plonka (1978) used 76 ppt. The emissions
data were significantly higher than those data calculated by Singh.
In a recent review, Altshuller (1980) suggested an average OH concen-
tration of 3 x 10 molecules cm as the most reliable value at present. He
cautioned, however, that uncertainty still exists about the extent to which MC
reacts with OH. Ihe residence time for MC was calculated to fall in the 8 to
002MC1/G 3-19 3-25-82
-------
13 year range. For example, a residence time of 13 years was calculated from
the rate constant expression of Watson et al. (1977) at 265°K. With the rate
constant expression derived by Chang and Kaufman (1977), a MC residence time
of 8 years was computed.
Basmussen and Khali! (1981b) reported that trospheric measurements of MC
made at six locations in the northern and southern hemispheres, between January
1979 and June 1980 were consistent with an estimated lifetime in the range of
6 to 10 years. Average concentrations over both hemispheres were calculated
from latitudinal profiles and indicated that the global atmospheric concen-
tration (from January 1979 to January 1981) increased at 6.7 ± 2.0 percent per
year. In a report submitted for publication, Khali 1 and Ramussen (1981)
determined that the increase in concentration was smaller during 1980 than
during 1979. It was concluded that a decrease in the emissions rate has occur-
red since 1975.
The World Meteorological Organization (1982) recently reviewed that data
base and found that, given the uncertainties in release rates and absolute
concentrations of MC, as discussed by Logan et al. (1981), the measurements of
MC appear to be consistent with a lifetime of 5 to 10 years, and with globally
(- _ O
averaged OH concentrations of ~ 7 x 10 molecules cm . This estimate was, in
part, based on redetermi nations of the rate constant for reaction of HO with
MC (Kurylo et al., 1979; Jeong and Kaufman, 1979) and the knowledge that
release rates as given by Neely and Plonka (1978) do not account for release
in Eastern Bloc countries.
Since distribution of OH has only been estimated through use of models,
estimates for the atmospheric lifetime of MC should be cautiously viewed.
002MCD/G 3-20 3-25-82
-------
3.3.2 Impact Upon the Ozone Layer
As stratospheric ozone levels decrease, changes in the amount of light in
the solar spectrum around 300 urn that reach the earth's surface may forecast
an increased incidence of skin cancer (National Research Council, 1979b,
1982). Reduction in 03 levels also increases the likelihood of adverse changes
in weather and climate (National Research Council, 1979b, 1982). Reduced
ozone concentrations could result from the following reaction mechanisms:
hv
CH3CC13 — > CH3CC12-+ Cl- (1)
Cl- + 03 * CIO + 02 (2)
CIO- + 0 > Cl- + 0£ (3)
CIO- + NO » Cl- + N0£ (4)
The atomic chlorine produced in reaction (1) would react with 03 to yield
chlorine oxide. The subsequent chain reaction would result in a continual
depletion of 0^. The importance of this cycle and other cycles in the strato-
sphere have recently been evaluated by Wuebbles and Chang (1981) and the NRC
(National Research Council, 1982). These evaluations indicate that the effi-
ciency of the chlorine oxide cycle is closely coupled with other cycles,
principally the nitrogen oxides and hydroxyl radical cycles.
In a study (National Research Council, 1979a) of the impact of chloro and
chloroflouro compounds on stratospheric 0-, the National Research Council
(NRC) concluded that emissions of halocarbons represented the most immediate
and serious threat to 0,. Based upon atmospheric measurement data available
at that time, the NRC concluded that MC contributes one-quarter to one-half
the number of chlorine atoms on a molecule-per-molecule basis that chlorofluoro-
carbons 11 and 12 contribute to the stratosphere. At the estimated 1976
global emissions rate of approximately 400,000 metric tons, MC was estimated
002MC1/G 3-21 3-25-82
-------
to destroy about 10 percent (Table 3-5) as much 03 as both chlorof1uorocarbons
11 and 12. The magnitude of the impact of MC was not delineated further due
to a lack of reliable measurement data on OH abundance in the troposphere.
The NRC cautioned, however, that continued increased usage of MC could result
in the halocarbon becoming the largest source of stratospheric chlorine and,
thus, the most serious threat to stratospheric 0_.
Preliminary results obtained using the Lawrence Livermore Laboratory
one-dimensional vertical transport-kinetics model suggest that the relative
efficiency of MC in destroying ozone is much less than chlorof1uorocarbons
(U.S. Environmental Protection Agency, 1980). Table 3-5 shows this relative
efficiency.
The "best estimate" of the NRC for the eventual steady-state 0, decrease
due to chlorof1uorocarbons 11 and 12 at 1977 release rates was 16.5 percent
(National Research Council, 1979a). This estimate was about twice as high as
the estimate reported by the NRC in 1976 (National Research Council, 1976).
Due to the uncertainties in the modeling approach and data base, it was re-
ported that there was a 95 percent probability that the true value of eventual
0^ reduction would be somewhere between 5 and 28 percent.
In their most recent report, the NRC (1982) revised their 03 depletion
estimates downward, principally due to refinements of the values of important
reaction rates. The NRC now estimates that the steady-state (~ 100 years)
reduction in total global ozone, in the absence of other pertubations, could
be between 5 and 9 percent. These estimates only considered release of chloro-
fluorocarbons 11 and 12 at the 1977 release rates.
The World Meteorological Organization (1982) assuming continued release
at the current estimated emissions rate for MC and using the model of Wuebbles
002MC1/G 3-22 3-25-82
-------
(1981) and revised reaction rate kinetics, calculated an estimated steady-state
depletion of the total 0, column of 0.8 percent (Table 3-5). If other strato-
spherically -important halocarbons are considered (particularly chlorofluoro-
carbon 113, carbon tetrachloride, and methyl chloroform) at current release
rates, the WHO estimates that the predicted column 03 depletion of from 5 to 9
percent would be increased about one-third. In scenarios more representative
of real-time conditions for example, considering variations in carbon dioxide
and nitrogen oxides, the WMO derived other estimates of steady-state 0- deple-
tion. In each scenario, a continued increase in upper stratosphere 0, deple-
tion is predicted. As noted by the WMO the 5 to 9
percent depletion estimate due to FC-11 and FC-12, if correct, suggests that
less than a 1 percent decrease in global average stratospheric 0, should have
occurred to date. This estimated 1 percent decrease is not estimable be-
cause state-of-the-art instrumentation and statistical methodology indicate
that detection of global average stratospheric 0- trends is limited to about a
2 percent change per decade.
In addition to the uncertainties and limitations of the models used to
estimate the impact of MC on 0-, the complexity of rapidly-changing knowledge
in atmospheric chemistry make it difficult to assess with confidence such
impact in quantitative terms. Among the atmospheric reactions that can act to
enhance or restrict 03 depletion due to MC, the NRC (National Research Council,
1979a) cited those described in Table 3-6 as important determinants. An
evaluation of the impact of MC upon stratospheric 0~ must take into account
these and other atmospheric processes if realistic estimates of 0, depletion
are to be made.
002MC1/G 3-23 3-25-82
-------
TABLE 3-5. RELATIVE EFFICIENCY OF HALOCARBONS IN
REDUCING STRATOSPHERIC OZONE
(U.S. Environmental Protection Agency, 1980)
Percent ozone depletion
Compound after 320 years*
F-ll -10.7
F-12 -8.5
F-113 -8.25
F-114 -5.38
MC -0.933
-1.6b
*production rate assumed, for each species individually, at 1,000 million
pounds annually
abased on 4.5 year lifetime
based on 9 year lifetime
002MC1/G 3-24 3-25-82
-------
TABLE 3-6. IMPORTANT ATMOSPHERIC REACTIONS THAI AEFECT STRATOSPHERIC OZONE
(National Research Council, 1979a)
Cl + 03 » CIO + 02
CIO + 0 » Cl + 02
CIO + NO > Cl + N0£
Cl + CH4 > HC1 + CH3
HC1 + OH » Cl + H20
CIO + N02 + M »• C10N02 + M
C10N02 + hv » Cl + N03
CIO + H02 » HOC! + 02
HOC! + hv »• Cl + OH, CIO + H
002MC1/G 3-25 3-25-82
-------
The British Department of the Environment (1979) also released a
report on the effect of chl orof 1 uorocarbons on stratospheric ozone. Based on
annual production of 450,000 metric tons and an OH + MC rate constant of 19 x
10 cm molecule sec, the estimated steady state ozone depletion was 1.0
percent, due to MC (Table 3-5).
3.3.3 Laboratory Studies
In experiments designed to characterize the UV absorption spectrum for MC
in the wavelength and pressure ranges associated with the stratosphere, Van-
^
1 aethem-Meuree et al. (1979) found that photo-dissociation was the dominant
sink process at altitudes above 25 kilometers.
In Spence and Hanst's (1978) photooxidation studies, when MC was irradi-
o o
ated at maximum intensities of 3100 A and 3650 A, one-fifth of the initial
amount (10 ppm) was consumed after 6 minutes. The principal products observed
were carbon monoxide (1.5 ppm), hydrochloric acid (6 ppm), and phosgene (2
ppm):
Cl
hv
1
Cl
H. C-C-C1 - = - > CO + HC1 COC1
3 i U~
Of the halocarbons evaluated, methyl chloroform was the least reactive.
The recent reaction rate studies, involving MC and OH, by Jeong and
Kaufman (1981) and by Kurylo et al. (1981), indicate that the rate of this
key reaction is slower and more temperature sensitive than previously had
been indicated. Jeong and Kaufman (1981) measured reaction rates using the
discharge-flow method and MC which had been extensively purified. A reaction
-14 3 -1
rate at 293°K was determined at 1.06 ± 0.09 x 10 cm sec . The Arrhenius
expression, within 95 percent confidence limits but not including systematic
errors, was 5.49 ± 1.40 x ID*12 exp [ - (1832 ± 98/T] cm3 sec"1. The authors
002MC1/G 3-26 3-25-82
-------
indicated that the most recent rate (at 298°K) reported by JPL (Jet Propulsion
-14 3 -1
Laboratory, 1979), 1.9 x 10 cm sec is too high by a factor of about 1.7
at this temperature, and by a factor of 1.9 at 265°K, the temperature used by
Singh (1977) in deriving average OH concentrations.
The Arrhenius expression determined by Kurylo et al., (1979) was in close
agreement with that determined by Jeong and Kaufman (1981). Kurylo et al.
(1979) used the flash-photolysis method and also extensively purified the MC
prior to use.
3.4 AMBIENT MIXING RATIOS
Modeling approaches for reconciling emissions of MC to ambient air mixing
55 -3
ratios have implied low (3 x 10 to 6 x 10 molecules cm ) atmospheric levels
of hydroxyl radicals (OH), the principal scavenging species for MC. If veri-
fied, these OH levels would strongly suggest that MC and many other chemical
species have a tropospheric lifetime sufficiently long to allow their signi-
ficant transport to the stratosphere. These models, however, have relied on
point measurements of MC mixing ratios determined at disparate sites, pri-
marily in the northern hemisphere. Before 1977, reliable estimates of glob-
ally averaged MC concentration were not available. Recent measurements,
however, indicate that the global average concentration is consistent with a
long (5 to 11 years) tropospheric lifetime and that MC remains a serious
threat to stratospheric 03 levels.
3.4.1 Global Atmospheric Distributions
The global average background mixing ratio of MC has been determined by
several laboratories, including SRI International and Washington State Univer-
sity. The field studies of Singh and co-workers at SRI have been reported in
a number of publications (Singh, 1977a; Singh et al., 1977c; 1978a; 1978b;
1978c; 1979a; 1981). The global average for late 1977 was reported as 95 ppt
(Singh et al., 1979a). This average was derived from measurements made in the
002MC1/G 3-27 3-25-82
-------
northern (average = 113 ppt) and southern (average = 77 ppt) hemispheres.
Based on data collected at latitudes 30°N to 40°N from 1975 to 1978, MC pre-
sence in the atmosphere was increasing at the rate of 15 ppt (or 17 percent)
per year.
Field studies by Singh et al. (1979a) were conducted during two oceano-
graphic cruises between latitudes 64°N and 40°S (15 September to 30 October
1977; 20 November to 13 December 1977). Samples were collected in electro-
polished stainless steel and glass vessels and analyzed by GC-ECD, operated
coulometrically. Samples were analyzed ui situ as well as after storage. Ihe
northern temperate average mixing ratio was reported as 123 ppt. Ihe latitu-
dinal distribution is shown in Eigure 3-1.
Ihe vertical profile and latitudinal gradients of MC in the troposphere
and lower stratosphere have been investigated by Cronn and coworkers in a
series of high-altitude studies (Cronn and Robinson, 1979; Cronn et al.; 1976;
1977a; 1977b). Most recently, experiments conducted at the Panama Canal Zone
(9°N latitude) and at 37°N indicated that MC tropospheric abundance was 18
percent lower at 9°N (Cronn and Rqbinson, 1979). Singh et al. (1979a) re-
corded a 17 percent difference between these latitudes (Eigure 3-1). For July
1977, the average tropospheric background concentration (139 whole air samples
were collected between ground level and 13.7 kilometers) was 97.3 ± 4.6 ppt at
9°N. At 37°N (Pacific Ocean west of San Francisco), an average mixing ratio
of 116 ± 14 ppt was measured. Tropopause height at the Canal Zone was 15.7
kilometers. Methyl chloroform tropospheric mixing ratios did not vary signi-
ficantly with increasing altitude at 9°N but there was a precipitous drop in
the mixing ratio across the tropopause.
Analysis of pressurized tropospheric samples was performed by a dual
GC-ECD. Ihe detection limit for MC was 6 ppt and the precision of analysis
002MC1/G 3-28 3-25-82
-------
was ±4.2 percent. Analyses were performed on 5-ml aliquots. For the low-
pressure stratospheric air samples, precision was ±7 percent with a detection
limit of 2 ppt. Methyl chloroform was preconcentrated with a freezeout sample
loop. Overall accuracy of analysis was estimated at about 10 percent.
In experiments conducted at 37°N (Cronn et al., 1977a), samples were
collected at altitudes ranging from 6.1 to 14.3 kilometers with the tropopause
height between 11 and 12 kilometers. Samples were analyzed by GC-ECD utiliz-
ing the freezeout concentration method. The average trospheric background
mixing ratio for MC in April 1977 (excluding samples within 0.8 kilometer of
the tropopause) was 116 ± 14 ppt. This value is consistent with the results
of Singh et al., (1979a), who obtained a value of 117 ppt at this latitude
during the fourth quarter of 1977 (Figure 3-1).
When this observed mixing ratio (116 ppt) was compared with that obtained
in March 1976 at 48°N (Pacific Northwest), an annual atmospheric increase in
MC of 23.7 percent was calculated. Cronn et al. (1976; 1977a) collected whole
air samples at altitudes ranging from 4.6 to 14.6 kilometers (average tropo-
pause height was 10.8 kilometers) during March 1976 over Western Montana and
Idaho. The average tropospheric background mixing ratio for MC was 94.5 ±8.2
ppt. Samples were analyzed by GC-ECD both isothermally with a 5-ml aliquot
and with the freezeout concentration method. Precision of the overall method
was ±4 percent.
The Washington State University (WSU) group has made several studies by
aircraft of the latitudinal distribution of MC (Cronn, 1980a; Robinson, 1978;
Robinson and Harsch, 1978). Interhemispheric differences of MC in the tropo-
sphere in June, 1976, were reported, with northern levels of 96 ppt and south-
ern levels of 88 ppt (Robinson and Harsch, 1978). Lower stratospheric levels
were 80 and 67 ppt, respectively. Work begun at WSU in 1976, and continuing
002MC1/G 3-29 3-25-82
-------
200
150
«•
ft
a
p>
d 100
o
ۥ>
I '
U
BO
.<
I
i
77ppt 113ppt
1 0
Aa _ ^. . .A .
^8v — t *
DO ,-*^; *
* Q og £ . v i
u • 0° °of. .-•"f'So
* * " * *^tf^^ft^
1
1
)0 -70 -50 -30 -10 0 10 30 BO 70 9
5 LATITUDE, degrees f
Figure 3-1. Global distribution of methyl chloroform (Singh et al., 1979a)
002MC1/G
3-30
3-25-82
-------
at both WSU and the Oregon Graduate Center, has provided annual measurements
of interhemispheric differences of MC of 1.67, 1.72, 1.56, 1.40, and 1.45 for
1975, 1976, 1977, 1978, and 1979, respectively (Khali! and Rasmussen, 1980;
Robinson, 1978). Time-trend monitoring has been conducted nearly continuously
at a ground station in eastern Washington state since July 1977 (Cronn, 1980a).
Increases have exceeded 12 percent per year since that time.
Rasmussen and Khali! (1981b), from 1979 to early 1981, measured tropo-
spheric levels of MC at six locations, ranging from 70°N to 42°S, including
several measurements at the south pole (90°S). Analysis was made by EC/GC.
From these measurements, a global average concentration of 115 ppt was cal-
culated along with an annual increase of 6.7 ± 2.0 percent. This global
average is consistent with the values reported by others for previous years.
In contrast, however, to the rate of increase reported by Singh et al. (1979a)
for the period 1975 to 1978, the rate of increase appears to be declining, which
Rasmussen and Khali 1 (1981b) attribute to an overall reduction in the rate of
emissions. The hemispheric difference in concentration reported by Rasmussen
and Khalil (1981b) is consistent with that reported by Singh et al., (1979b).
During the period from January 1979 to December 1980, the northern hemisphere
average was 130 ppt compared to the southern hemisphere average of 99 ppt
(Rasmussen and Khalil, 1981b).
Intermittent monitoring of MC at various urban, nonbackground and rural
locations has also been conducted by Cronn and coworkers (Cronn, 1980b; Cronn
and Harsch, 1979b; Cronn et al., 1979; Harsch and Cronn, 1979). Levels greater
than 5 ppb have been measured in Claremont, California, with an average of 1.2
ppb during September 1978 (Cronn et al., 1979; Harsch and Cronn, 1979).
Evidence of regional pollution buildup was observed in the Smoky Mountains of
Tennessee in September 1978, with levels averaging 50 percent greater than
002MC1/G 3-31 3-25-82
-------
background tropospheric levels typical at that time (Cronn and Harsch, 1979;
Cronn et al., 1979). Values in the Caucasus Mountains of the Republic of
Georgia, USSR, in July 1979, were identical to levels measured in rural east-
ern Washington (Cronn, 1980b).
A series of studies on the distribution and levels of MC and other
halogenated hydrocarbons at various sites has been conducted by Pellizzari and
coworkers (Pellizzari, 1977; 1978; Pellizzari and Bunch, 1979; Pellizzari et
al., 1979). Methyl chloroform was detected in the ambient air at sites in New
Jersey, New York, California, Louisiana, and Texas. Levels are included in
Table 3-7.
Point measurements made by Lovelock (1977b) during 1972 to 1977 resulted
in a lower global average background mixing ratio (73 ppt). Air samples
collected at rural sites in the British Isles indicated that, during the 5
year period, MC mixing ratios increased from 31 ppt to 97 ppt. In the south-
ern hemisphere (Africa and Antarctica), it increased from 12 ppt to 50 ppt.
Absolute accuracy of the GC-ECD method was reported as ±30 percent.
In field measurements of ambient MC levels over North America (18°N to
65°N) from October 4 to 13, 1976, Pierotti and co-workers (1980) determined an
average tropospheric mixing ratio of 145 ± 25 ppt for this region. The mixing
ratio dropped sharply across the tropopause and in their stratosphere, suggest-
ing a large sink at these altitudes. These investigators suggested that the
data were consistent with a northern hemisphere background mixing ratio of
about 100 ppt. Other point measurements of MC atmospheric mixing ratios in
the troposhere are shown in Table 3-7.
002MC1/G 3-32 3-25-82
-------
TABLE 3-7. AMBIENT AIR MIXING RATIOS OF METHYL CHLOROFORM MEASURED
AT SITES AROUND THE WORLD
Location
Type of site
Date
Maximum
(ppb)
Minimum
(ppb)
Average
(ppb)
Reference
Alaska (70°N)
CO
i
CO
CO
Antarctica
South Pole
South Pole
South Pole
South Pole
South Pole
South Pole
South Pole
South Pole
Arizona
Phoenix
Arkansas
Helena
California
Los Angeles
Oakland
San Jose'
Point Arena
Claremont
Point Arena
Badger Pass
San Francisco
Riverside
Mill Valley
Yosemite
Palm Springs
Los Angeles
Badger Pass
Los Reyes
Stanford Hills
Los Angeles
Basin
Delaware
Delaware City
Remote
Remote
Remote
Remote
Remote
Remote
Remote
Remote
Urban
Remote
Urban
Urban
Urban
Marine
Urban
Marine
High altitude
Free tropo-
sphere
Urban
Background sub-
ject to urban
transport
High altitude
Suburban
Urban
High altitude
Marine
Background sub-
ject to urban
transport
Urban-suburban
Urban
Aug. 1979 -Jan. 1981 ~ 0.155
1/75 0.054
1/76 0.057
1/77 0.070
10/77 - 11/77 0.082
1/78 0.083
1/79 0.095
Jan. 1979 - Jan. 1981 -0.12 ~ 0.094
1/80 0.103
4/23-5/6, 1979 2.8136
11/30/76 < 1 < 1
4/9-4/21, 1979 5.143
6/28-7/10, 1979 0.9672
8/21-8/27, 1978 2.931
8/30-9/5, 1978 0.158
9/78 5
5/23-5/30, 1977 0.150
5/5-5/13, 1977 0.342
4/77
4/25-5/4. 1977 3.012
1/11-1/27, 1977 0.895
5/12-5/18, 1976 0.126
5/5-5/11, 1976 0.545
4/28-5/4, 1976 7.663
May 1976
12/1-12/12, 1975 0.212
11/23-11/30, 1975 0.565
4/9-4/21, 1974 2.14
7/8-7/10, 1974 0.30 0.03
Rasmussen and Khalil, 1981b
Robinson, 1978
Ibid.
Ibid.
Ibid.
Ibid.
Khalil and Rasmussen
Rasmussen and Khalil, 1981b
Ibid.
0.1978 0.8235 ± 0.5974 Singh, et al., 1981
< 1
Battelle, 1977
0.224
0.1429
0.150
0.115
0.3
0.083
0.130
0.282
0.107
0.073
0.075
0.100
—
0.061
0.070
0.01
1.028 t 0.646
0.2909 ± 0.1606
0.789 t 0.649
0.132 t 0.011
1.2
0.111 ± 0.018
0.231 t 0.056
0.12 ± 0.01
0.834 ± 0.560
0.313 ± 0.130
0.104 ± 0.009
0.159 ± 0.075
1.545 ± 1.538
0.988 ± 0.0097
0.111 ± 0.027
0.141 ± 0.117
0.37 ± 0.05
(24-hour)
Singh et al.
Ibid.
Singh, et al
Ibid.
Cronn, et al
Ibid.
Ibid.
Cronn, et al
Ibid.
Ibid.
Ibid.
Ibid.
Ibid.
Singh, et al
Singh, et al
Ibid.
Simmonds et
, 1981
. . 1979a
. , 1979
. , 1977a
.. 1978c
. , 1979a
a)., 197-
0.10
Lillian et al., 1975
-------
• TABLE 3-7. (continued)
oo
I
Location Type of site
Hawai i
Cape Kumakahi Remote
Ireland
Western Ireland Remote
Japan
Tokyo Urban
Tokyo
Kansas
Jetmar Remote
Louisiana
Baton Rouge, Urban
Geisinar, Plaquemine
Maryland
Baltimore Urban
New Jersey
Seagirt Marine
Sandy Hook Marine
Bayonne Urban
Pathway/ Urban
Woodbridge,
Boundbrook, Passaic
New York
New York City Urban
Niagara/Falls/ Urban
Buffalo
White Face High altitude
Mountains
Ohio
Wilmington Urban
Oregon
Cape Meares Remote
Panama Remote tropo-
sphere
Maximum
Date (ppb)
Nov. 1979 - Jan. 1981
June/July 1974
9/10 - 10/27, 1975 20.60
May 1974-Apr 1974
6/1-6/7, 1978 0.159
Jan/March 1977 1.6
7/11-7/12, 1974 0.21
6/18-6/19, 1974 0.20
7/2-7/5, 1974 0.33
March-December, 1973 14.4
Sept. 1978 20.5
6/27-6/28, 1974 1.6
July 1978 1.0
9/16-9/19, 1974 0.13
7/16-7/26, 1974 0.35
Jan. 1979 - Jan. 1981
7/77
Minimum Average
(ppb) (ppb)
~ 0.14
0.048 t 0.0172
0.20 1.70 ± 1.70
0.800
0.106 0.130 ± 0.016
trace 0.11
0.044 0.12
0.044 0.10
0.030 0.15
0.075 1.59
trace 11.4
0.10 0.61
0.26 0.66
0.032 0.067
0.030 0.097
~ 0.155
0.97 ± 0.05
Reference
Rasmussen
Lovelock,
Tada et al
Ohta et al
Singh, et
Pellizzari
Singh, et
Lillian et
Ibid.
Ibid.
Pellizzari
Lillian et
Pellizzari
Lillian et
Ibid.
Rasmussen
Cronn and
1979
and Khalil, 19816
1974
. , 1976
. . 1977
al., 1979a
et al., 1979
al.. 1979a
al., 1975
et al., 1979
al., 1975
et al., 1979
al., 1975
and Khalil, 1981b
Robinson,
Samoa (14°S)
Remote
Feb. 1980 - Jan. 1981
~ 0.155
Rasmussen and Khalil, 1981b
-------
TABLE 3-7. (continued)
Location Type of site
Soviet Union
Caucasus
Mountains
Tasmania
Cape Grin
Tennessee
Smoky
Mountains
to
w Texas
Houston,
Deer Park,
Pasadena
Northern Mid-
Latitudes
Washington
Pull nan
Pullman
Pullman
Pullman
Pullman
Pullman
Pullman
Pul Iman
Spokane
Remote
Remote
Regionally
polluted
Urban
Remote tropo-
sphere
Remote
Remote
Remote
Remote
Remote
Remote
Remote
Remote tropo-
sphere
Urban
Maximum
Date (ppb)
7/79 0. 12
Oct. 1976 - March 1977
Jan. 1979 - June 1980
9/78 0.32
July 1976 5.1
6/76 0. 11
1/75
1/76
1/77
10/77 - 11/77
1/78
1/79
1/80
3/76
4/78
Minimum Average
(ppb) (ppb)
0.15 0.13 ± 0.06
0.012 ± 0.003
- 0.1
0.11 0.19 t 0.03
trace 0.44
0.07 0.095 t 13
0.090
0.098
0.109
0.115
0.120
0.135
0.157
0. 095 i 0. 008
0.5
Reference
Cronn, 1980b
,
Fraser and Pearman,
Rasmussen and Khali 1
Cronn and Harsch
1979b
Pellizzari, et al.,
Robinson and Harsch,
1978
Robinson, 1978
Ibid
Ibid
Ibid
Ibid
1978
. 19816
1979
Khali] and Rasmussen,
1980
Ibid
Cronn et al., 1976
Cronn et al., 1979
-------
3.5 REFERENCES
Altshuller, A. P. Lifetimes of organic molecules in the troposphere and lower
stratosphere. Adv. Environ. Sci. Technol. 10:181-219, 1980.
Battelle Columbus Laboratories. Environmental Monitoring Near Industrial
Sites-Methyl chloroform. PB-273204. August 1977. EPA 560/6-77-025.
Bellar, T. A., J. J. Lichtenberg, and R. C. Kroner. The occurrence of organo
halides in chlorinated drinking waters. J. Amer. Water Works Assoc.
12:703-706, 1974.
Bonse, G., and H. Henschler. Chemical reactivity, biotransformation, and
toxicity of polychlorinated aliphatic compounds. CRC Critical Rev.
Toxicol. 4(4):395-409, 1976.
British Department of the Environment. Chlorofluorocarbons and their effect
on stratospheric ozone (second report). Pollution Paper No. 15, Her
Majesty's Stationary Office, Great Britain, 1979.
Campbell, M. J. , J. C. Sheppard, and B. F. Au. Measurement of hydroxyl radi
concentration in boundary layer air by monitoring CO oxidations. Geophys.
Res. Lett. 6:175-178, 1979.
Chang, J. S., and F. Kaufman. Kinetics of the reactions of hydroxyl radicals
with some halocarbons: CHFC12, CHF-C1, CH.CCK, C9HCU, and C?C1... J.
Chem. Phys. 66:4989-4994, 1977. * J * * J * 4
Chang, J. S. , and J. E. Penner. Analysis of global budgets of halocarbons.
Atmos. Environ. 12:1867-1873, 1978.
Chemical and Engineering News. 1,1,1-trichloroethane, pg. 13, October 29,
1979.
Chemical Marketing Reporter, 22 January 1979.
Chemical Week. 8 February 1978, pg. 13.
Christiansen, V. 0. , J. A. Dahlberg, and H. F. Andersson. On the nonsensi-
tized photo-oxidation of 1,1,1-trichloroethane vapour in air. Acta Chem.
Scand. Series A. 26:3319-3324, 1972.
Cogswell, S. A. Methylchloroform. Chemical Economics Handbook Marketing
Research Report on C, Chlorinated Solvents, SRI International, December
1978. *
Coleman, W. E. , R. D. Lingg, R. G. Melton, and F. C. Kopfler. The Occurrence
of Volatile Organics in Five Drinking Water Supplies Using Gas Chromato-
graphy/ Mass Spectrometry. Chapter 21. Jji: Identification and Analysis
of Organic Pollutants in Water, L. H. Keith, ed., Ann Arbor Science,
1976.
Correia, Y. , G. J. Martens, F. H. Van Mensch, and B. P. Whim. The occurrence
of trichloroethylene, tetrachloroethylene, and 1,1,1-trichloroethane in
western Europe in air and water. Atmos. Environ. 11:1113-1116, 1977.
002MC4/B 3-36 3/25/82
-------
Cronn, D. R. Measurements of atmospheric methyl chloroform by Washington
State University. In: Proceedings of the Conference on Methyl Chloro-
form and Other Halocarbon Pollutants. Final Report. Envr. Sciences
Research Lab., RTP, NC, EPA-600/9-80-003, January, 1980a.
Cronn, D. R. Comparison of halocarbon and nitrous oxide measurements at
non-urban sites—A preliminary data report. Report for EPA Grant
R0804033-03-6, Washington State University, 1980b.
Cronn, D. R. Personal communication, 1980c.
Cronn, D. R. , and 0. E. Harsch. Determination of atmospheric halocarbon
concentrations by gas chromatography-mass spectrometry. Anal. Lett.
12(B14): 1489-1496, 1979a.
Cronn, D. R., and D. E. Harsch. Smoky mountain ambient halocarbon and hydro-
carbon monitoring, September 21-26, 1978. Report for EPA Grant R0804033-
03-2, Washington State University, 1979b.
Cronn, D. R., and E. Robinson. Determination of trace gases in Learjet and
U-Z whole air samples collected during the Intertropical Convergence Zone
Study, ^n: 1977 Intertropical Convergence Zone Experiment, I. G. Poppoff,
W. A. Page, and A. P. Margozzi, eds. NASA TMX 78577, 1979.
Cronn, D. R., R. A. Rasmussen, and E. Robinson. Measurement of tropospheric
halocarbons by gas chromatography-mass spectrometry. Report for Phase I.
EPA Grant R0804033-01. Washington State University, 23 August 1976.
Cronn, D. R., R. A. Rasmussen, and E. Robinson. Measurement of tropospheric
halocarbons by gas chromatography-mass spectrometry. Report for 1977a.
Cronn, D. R., R. A. Rasmussen, E. Robinson, and D. E. Harsch. Halogenated
compound identification and measurement in the troposphere and lower
stratosphere. J. Geophy. Res. 82(37):5935-5944, 1977b.
Cronn, D. R. , M. J. Campbell, and D. E. Harsch. Measurement of tropospheric
halocarbons by gas chromatography-mass spectrometry. Report for Phase
III. EPA Grant R0804033-03. Washington State University, September,
1979.
Crutzen, P. J., and J. Fishman. Average concentrations of OH in the tropo-
sphere, and the budgets of CH., CO, H~ and CH-CC1,. Geophy. Res. Lett.
4(8):321-324, 1977. * * d J
Davis, D. D. Investigations of important hydroxyl radical reactions in the
perturbed troposphere. (Georgia Institute of Tech. Atlanta, Ga., Engineer
Exp. Station), EPA-600/3-77-111, October 1977.
Derwent, R. G., and A. E. J. Eggleton. Two-dimensional model studies of methyl
chloroform in the troposphere. Quart. J. R. Met. Soc. 102:231-242, 1981.
Derwent, R. G., and A. E. J. Eggleton. Halocarbon lifetimes and concentration
distributions calculated using a two-dimensional tropospheric model.
Atmos. Environ. 12:1261-1267, 1978.
002MC4/B 3-37 3/25/82
-------
Dilling, W. L. , N. B. Tefertiller, and G. J. Kallos. Evaporation rates and
reactivities of methylene chloride, chloroform, 1,1,1-trichloroethane,
trichloroethylene, tetrachloroethylene, and other chlorinated compounds
in dilute aqueous solutions. Environ. Sci. Technol. 9(9):833-838, 1975.
Dowty, B., D. Carlisle, and J. L. Laseter. Halogenated hydrocarbons in New
Orleans Drinking Water and Blood Plasma. Science 187:75-77, 1975a.
Dowty, B. J., D. R. Carlisle, and J. L. Laseter. New Orleans drinking water
sources tested by gas chromatography-mass spectrometry. Occurrence and
origin of aromatics and halogenated aliphatic hydrocarbons. Environ.
Sci. Technol. 9(8):762-765, 1975b.
Eimutis, E. C. and R. P. Quill. Source Assessment: Noncriteria Pollutant
Emissions, Monsanto Res. Corp., Dayton, OH, EPA-600/2-77-107e, U.S.
Environmental Protection Agency, July 1977.
Ewing, B. B., E. S. K. Chian, J. C. Cook, C. A. Evans, P. V. Hopke, and E. G.
Perkins. Monitoring to Detect Previously Unrecognized Pollutants in
Surface Waters. Institute for Environmental Studies, University of
Illinois at Urbana-Champaign, EPA 560/6-77-015, July 1977.
Fraser, P. J. B. , and G. I. Pearman. Atmospheric halocarbons in the Southern
Hemisphere. Atmos. Environ. 12:839-844, 1978.
Hardie, D. W. F. Chlorocarbons and Chlorohydrocarbons. In: Kirk-Othmer
Encyclopedia of Chemical Technology. Second Edition, Volume 5, New York-,
Interscience Pub., 1963.
Harsch, D. E., and D. R. Cronn. Low-pressure sample-transfer technique for
analysis of stratospheric air samples. J. Chromat. Sci. 16:363-367,
1978.
Harsch, D. E. , and D. R. Cronn. Continuous atmospheric monitoring of urban,
semi-rural and rural N20 and the halocarbons. Unpublished manuscript,
Washington State University, June, 1979.
Jeong, K. M., and F. Kaufman. Rates of the reactions of 1,1,1-trichloroethane
and 1,1,2-trichloroethane with OH. Geophy. Res. Lett. 6:757-759, 1979'.
Jorden, J. I. Jr., Encyclopedia of Chemical Processing and Design. Vol. 10,
Chapter 8. J. J. McKetta and W. A. Cunningham, eds. , Marcel Deker Inc.,
1979.
Katz, M. A., P. T. Lee, T. McCartin and K. Wagoner. Level II materials balance:
methyl chloroform. Final Report--JRB Assoc., Inc., Mclean, VA. (EPA
Contract No. 68-01-5793).
Keil, S. L. Chlorocarbons and Chlorohydrocarbons. Jji: Kirk-Othmer Encyclo-
pedia of Chemical Technology, Third Edition, Volume 5, New York, Inter-
science Pub., 1979.
Khalil, M. A. K., and R. A. Rasmussen. Decline in the atmospheric accumulation
rates of CC1..F (F-ll). CC19F9 (F-12) and CH~ CC1,. Submitted for publi-
cation, 1981? * L * J
002MC4/B 3-38 3/25/82
-------
Khalil, M. A. K. , and R. A. Rasmussen. Methyl Chloroform (CH3CC13): Accumula-
tion in the Earth's Atmosphere. Submitted to Science, 1980.
Kurylo, M. J., P. C. Anderson, and 0. Klais. A flash photolysis, resonance
fluorescence investigation of the reaction OH + CH^CCK -» H?0 + CH?CC1V
Geophy. Res. Lett. 6:760-762, 1979
Lillian, D. , and H. B. Singh. Absolute determination of atmospheric halo-
carbons by gas phase coulometry. Anal. Chem. 46:1060-1063, 1974.
Lillian, D. , H. B. Singh, A. Appleby, L. Lobban, R. Arnts, R. Gumpert, R.
Hague, J. Toomey, J. Kazazis, M. Antell, D. Hansen, and B. Scott. Atmos-
pheric fates of halogenated compounds. Environ. Sci. Techno!. 9(12):
1042-1048, 1975.
Logan, J. A. , M. J. Prather, S. C. Wofsy, and M. B. McElroy. Tropospheric
chemistry: A global perspective. J. Geophy. Res. 86 (C8): 7210-7254,
1981.
Lovelock, J. E. Atmospheric halocarbons and stratospheric ozone. Nature
252:292-294, 1974.
Lovelock, J. E. Halogenated hydrocarbons in the atmosphere. Ecotoxic. Environ.
Safety 1:399-406, 1977a.
Lovelock, J. E. Methyl chloroform in the troposphere as an indicator of OH
radical abundance. Nature 267:32, 1977b.
Lowenheim, F. A., and M. K. Moran, eds. Faith, Keyes, and Clark's Industrial
Chemicals. Fourth edition. Wiley-Interscience, 1975, pp. 836-843.
McCarthy. Possible impact of flurocarbons, ICAS, 1975.
McConnell, J. C., and H. I. Schiff. Methyl Chloroform: Impact on strato-
spheric ozone. Science 199-'174-177, 1978.
National Research Council. National Academy of Sciences. Halocarbons. Effects
on Stratospheric Ozone. Panel on Atmospheric Chemistry. Washington, DC,
1976.
National Research Council. National Academy of Sciences. Non-Fluorinated
Halomethanes in the Environment. Panel on Low Molecular Weight-Halo-
genated Hydrocarbons. Coordinating Committee for Scientific and Technical
Assessments of Environmental Pollutants, 1978.
National Research Council. National Academy of Sciences. Stratospheric Ozone
Depletion by Halocarbons: Chemistry and Transport. Panel on Stratospheric
Chemistry and Transport. Washington, DC, 1979a.
National Research Council. National Academy of Sciences. Protection Against
Depletion of Stratospheric Ozone by Chlorofluorocarbons. Committee on
Impacts of Stratospheric Change, 1979b.
National Research Council. National Academy of Sciences. Causes and Effects
of Stratospheric Ozone Reduction: An Update, 1982.
National Aeronautics and Space Administration. Chlorofluoromethane. Assess-
ment Workshop Report, NASA Goddard Space Flight Center, March 1977.
002MC4/B 3-39 3/25/82
-------
Neely, W. B., and J. H. Plonka. Estimation of time-averaged hydroxyl radical
concentration in the troposphere. Environ. Sci. Techno!. 12(3): 317-321,
1978.
Noweir, M. H. , E. A. Pfitzer, and T. F. Hatch. Decomposition of chlorinated
hydrocarbons: a review, J. Amer. Ind. Hyg. Assoc. 3_3(7): 454-460, 1972.
Ohta, T., M. Morita, I. Mizoguchi, and T. Tada. Washout effect and diurnal
variation for chlorinated hydrocarbons in ambient air. Atmos. Environ.
11:985-987, 1977.
Pellizzari, E. D. Electron capture detection in gas chromatography. J. Chromat.
98:323-361, 1974.
Pellizzari, E. D. Measurement of Carcinogenic Vapors in Ambient Atmospheres.
EPA-600/7-78-062, 1978.
Pellizzari, E. D. and J. E. Bunch. Ambient Air Carcinogenic Vapors: Improved
Sampling and Analytical Techniques and Field Studies, EPA-600/2-79-081,
1979.
Pellizzari, E. D. , M. D. Erickson, and R. A. Zweidinger. Formulation of a
Preliminary Assessment of Halogenated Organic Compounds in Man and Environ-
mental Media. EPA-560/13-79-006, 1979.
Pierotti, D., R. A. Rasmussen, and R. Dalluge. Measurements of N20, CF2C12,
CFC13, CH3CC13, CC14, and CH3C1 in the troposphere and lower stratosphere
over North America. J. Geomagn. Geoelect. 32:1-2, 1980.
Piet, G. J., P. Slingerland, F. E. de Grunt, M. P. M. v.d. Heuvel, and B. C.
J. Zoeteman. Determination of very volatile halogenated organic compounds
in water by means of direct head-space analysis. Anal. Lett. All(5):437-
448, 1978.
Rasmussen, R. A. and M. A. K. Khalil. Global atmospheric distribution and
trend of methyl chloroform (CH-CCK). Geophy. Res. Lett. 8 (9):
1005-1007, 1981b. J J
Rasmussen, R. A. and M. A. K. Khalil. Interlaboratory comparison of fluro-
carbons -11, -12, methyl chloroform and nitrous oxide measurements.
Atmos. Environ. 15:1559-1568, 1981a.
Rasmussen, R. A., D. E. Harsch, P. H. Sweany, J. P. Krasnec, and D. R. Cronn.
Determination of atmospheric halocarbons by a temperature-programmed gas
chromatographic freezeout concentration method. J. Air Poll. Control
Assoc. 27:579-581, 1977.
Robinson, E. Analysis of Halocarbons in Antarctica. WSU report 78/13-42 for
the National Science Foundation, December, 1978.
Robinson, E., and D. E. Harsch. A Halcarbon Survey in the Pacific Area From
80°N to 59°S, June, 1976. WSU report 78/13-24 for Manufacturing Chemists
Association, June, 1978.
Russell, J. W. , and L. A. Shadoff. The sampling and determination of halo-
carbons in ambient air using concentration on porous polymer. J.
Chromat. 134:275-284, 1977.
002MC4/B 3-40 3/25/82
-------
Sheldon, L. S., and R. A. Hites. Organic Compounds in the Delaware River.
Environ. Sci. Technol. 12(10):1188-1194, 1978.
Simmonds, P. G., S. L. Karrin, J. E. Lovelock, and F. H. Shair. Distribution
of atmospheric halocarbons in the air over the Los Angeles basin. Atmos.
Environ. 8:209-216, 1974.
Singh, H. B. Atmospheric halocarbons: Evidence in favor of reduced average
hydroxyl radical concentration in the troposphere. Geophy. Res. Lett.
4:101-104, 1977a.
Singh, H. B., L. J. Salas, and R. Stiles. Trace Chemicals in the "Clean"
Troposphere. EPA-600/3-81-055, October 1981.
Singh, H. B. Preliminary estimation of average tropospheric HO concentrations
in the Northern and Southern hemispheres. Geophy. Res. Lett. 4:453-456,
1977b.
Singh, H. B., L. J. Salas, and L. A. Cavanagh. Distribution, sources and
sinks of atmospheric halogenated compounds. J. Air Poll. Control Assoc.
27:332-376, 1977a.
Singh, H. B., L. J. Salas, D. Lillian, R. R. Arnts, and A. Appleby. Genera-
tion of accurate halocarbon primary standards with permeation tubes.
Evniron. Sci. Technol. 11(5):511-513, 1977b.
Singh, H. B. , L. J. Salas, H. Shigeishi, and A. Crawford. Urban-nonurban
relationships of halocarbons, SF6, N20 and other atmospheric trace consti-
tuents. Atmos. Environ. 11:819-828, 1977c.
Singh, H. B., L. J. Salas, H, Shigeishi, and E. Scribner. Global Distribution
of Selected Halocarbons, SF6 and N20. Phase II Interim Report, SRI
International, Menlo Park, California, May 1978a.
Singh, H. B., L. J. Salas, H. Shigeishi, and E. Scribner. Global Distribution
of Selected Halocarbons, Hydrocarbons, SF6, and N20. SRI Intern., Menlo
Pk., CA, EPA-600/3-78-100. U.S. Environmental Protection Agency, Research
Triangle Park, NC, December 1978b.
Singh, H. B., L. J. Salas, H. Shigeishi, and A. H. Smith. Fate of Halogenated
Compounds in the Atmosphere. SRI Intern., Menlo Pk., CA, EPA-600/3-78-017.
Interim Report, 1977 Environmental Monitoring Series. U.S. Environmental
Protection Agency, Research Triangle Park, NC, January 1978c.
Singh, H. B., L. J. Salas, H. Shigeishi, A. J. Smith, E. Scribner, and L. A.
Cavanagh. Atmospheric Distributions, Sources and Sinks of Selected
Halocarbons, Hydrocarbons, SF6 and N20. Final Report, SRI Intern., Menlo
Park, CA, EPA-600/3-79-107, U.S. Environmental Protection Agency, November
1979a.
Singh, H. B., L. J. Salas, H. Shigeishi, A. J. Smith and E. Serebreny. Atmos-
pheric Distributions, Sources and Sinks of Selected Halocarbons, Hydro-
carbons, SF6 and N20. Final Report, SRI International, Menlo Park,
California, October 1979b.
002MC4/B 3-41 3/25/82
-------
Singh, H. B., L. J. Salas, A. J. Smith, and H. Shigeishi. Measurements of
some potentially hazardous organic chemicals in urban environments.
Atmos. Environ. 15:601-612, 1981.
Spence, J. W., and P. L. Hanst. Oxidation of chlorinated ethanes. J. Air
Pollut. Control. Assoc. 28(3):250-255, 1978.
Tada, T., T. Ohta, and I. Mizoguchi. Behavior of chlorinated hydrocarbons in
urban air. Ann. Rep. Tokyo Metr. Res. Lab. P.H. 27(1):242-246, (transla-
tion, TR-79-0349), 1976.
U.S. Environmental Protection Agency. ESRL Report on the Problem of Halogenated
Air Pollutants and Stratospheric Ozone. EPA-600/9-75-008. U.S. Environ-
mental Protection Agency, Research Triangle Park, NC, December 1975.
U.S. Environmental Protection Agency. Unpublished data developed using the
Lawrence Livermore Laboratory 1-D model and rate constants cited in
National Academy of Sciences, 1979a.
U.S. Environmental Protection Agency. An Assessment of the Need for Limita-
tions on Trichloroethylene, Methyl Chloroform, and Perchloroethylene.
EPA-560/11-79-009. Office of Toxic Substances. July 1979b.
U.S. Environmental Protection Agency. Proceedings of the Conference on Methyl
Chloroform and Other Halocarbon Pollutants. EPA-600/9-80-003, January
1980.
U.S. International Trade Commission. Synthetic Organic Chemicals. United
States Production and Sales, 1977.
Vanlaethem-Meuree N., J. Wisemberg, and P. C. Simon. Ultraviolet absorption
spectrum of methychloroform in the vapor phase. Geophy. Res. Lett.
6(6):451-454, 1979.
Watson, R. T., G. Machado, B. Conaway, S. Wagner, and D. D. Davis. A Tempera-
ture Dependent Kinetics Study of the Reaction of OH with CH2CIF, CHC12F,
CHCIF2, CH3CC13, CH3CF2C1, and CF2CICFC12- Phys. Chem. 81:256, 1977.
World Meteorological Organization (WMO). Global Ozone Research and Monitoring
Project, Report No. 11. The Stratosphere 1981: Theory and Measurements,
World Meteorological Organization, Geneva, Switzerland, 1982.
Wuebbles, D. J. The relative efficiency of a number of halocarbons for des-
troying stratospheric ozone. Lawrence Livermore National Laboratory,
UCID 18924, 1981.
Wuebbles, D. J. and J. S. Chang. A study of the effectiveness of the C1X
catalytic ozone loss mechanisms. J. Geophy. Res. 86 (CIO): 9869-9872,
1981.
002MC4/B 3-42 3/25/82
-------
4. METABOLIC FATE AND DISPOSITION
4.1 ABSORPTION, DISTRIBUTION, AND ELIMINATION
Methyl chloroform (MC; 1,1,1-trichloroethane) is currently one of the
most widely used of the chlorinated aliphatic hydrocarbon solvents. Since the
introduction in the mid-19501s as a cold cleaning solvent substitute for
carbon tetrachloride, MC has gained recognition as being among the least toxic
of the chlorinated aliphatic hydrocarbons and is increasingly replacing other
supposedly more toxic chlorinated solvents such as trichloroethylene (Torkelson
et al., 1958; Prendergast et al., 1967; Stewart, 1968). The fact that its
isomer, 1,1,2-trichloroethane, is markedly more toxic than MC (Hardie, 1964;
Irish, 1963; Browning, 1965; CaVlson, 1973), is in agreement with the general
observation that chlorinated ethanes having chlorines on both carbon atoms are
considerably more soluble in water, blood, and lipid (Table 4-1). These
physical properties are responsible in part for the manifestations of chlori-
nated hydrocarbon toxicity (Sato and Nakajima, 1979; Clark and Tinston, 1973).
4.1.1 Oral and Dermal Absorption
While limited absorption of MC vapor through the lungs is the common
route of entry into the body, MC is also rapidly and completely absorbed from
the gastrointestinal tract (Stewart, 1971). Stewart and Andrews (1966) re-
ported an instance of non-fatal acute intoxication after oral ingestion of a
liquid ounce of MC (0.6 g/kg body weight,BW). The concentration of MC in the
expired air was measured serially and found equivalent to an inhalation exposure
002MC2/B 4-1 11-10-81
-------
TABLE 4-1. PARTITION COEFFICIENTS OF METHYL CHLOROFORM AND OTHER SOLVENTS AT 37°C
Vapor Pre
Compound torr at 2
1,1,1-Trichloroethane
1,1,2-Trichloroethane
1,1-Dichloroethane
1,2-Dichloroethane
Tri chl oroethy 1 ene
Tetrachl oroethyl ene
Dichloromethane
Chloroform
Carbon tetrachloride
125
25
250
80
436
20
400
250
100
iss Water
'5C Air
0.93
17.1
2.7
11.3
1.3
0.43
7.6
3.5
0.25
Olive Oi
Air
356
2273
187
447
718
1917
152
401
361
1 Blood
Air
3.3
38.6
4.7
19.5
9.5
13.1
9.7
10.3
2.4
Olive Oil
Blood
108
59
40
23
76
146
16
39
150
Adapted from Sato and Nakajima, 1979.
002MC2/B 4-2 11-10-81
-------
of experimental subjects to 500 ppm. On the other hand, MC vapor is poorly
absorbed through intact skin and, unless it is trapped against the skin be-
neath an impermeable barrier, it is unlikely that toxic quantities can be
absorbed (Stewart, 1971; Stewart and Dodd, 1964). Stewart and Oodd (1964)
demonstrated, with continuous immersion for 30 min of the thumbs or hands of
volunteers, that the solvent penetrates the skin, enters the blood circula-
tion, and is excreted through the lungs in exhaled air. Fukabori and co-
workers (1976, 1977) attempted a quantisation of cutaneous absorption in
humans. Systemic absorption was evaluated by measurement of MC in blood and
exhaled air and its biometabolites [trichloroethanol (TCE) and trichloroacetic
acid (TCA)} in urine. After applications of the solvent to the skin of the
o
forearm in a circumscribed area (12.5 cm) for 2 hr a day for 5 consecutive
days, or immersion of the hands 11 times a dayfor 10 min periods, the MC
concentrations in exhaled air and urinary metabolites corresponded roughly to
a 2-hr inhalation exposure to 10-20 ppm MC in ambient air. The investigators
concluded that absorption through the skin for workers in direct contact with
liquid MC may significantly (5%) add to the absorption from vapor exposure.
4.1.2 Pulmonary Uptake and Body Burden
Possibly because of its reputation as an organic solvent with low human
toxicity, few studies have been made of the pharmacokinetics of MC pulmonary
uptake, concentration in the body, and metabolism after exposure to low inha-
lation concentrations approximating the accepted TLV-TWA concentration.
Information available from these studies relate to single exposures in experi-
mentally controlled conditions with animals or human volunteers. Little
information is available regarding long-term exposure, such as may occur in
002MC2/B 4-3 11-10-81
-------
the workplace or in the environment. Recent studies have greater reliability
than earlier studies because of the availability of gas chromatographic methods
for the analytic determination of MC and its metabolites in alveolar air, body
fluids, and tissues (Monster et al., 1979b; Monster and Boersma, 1975; Astrand
et al., 1973; Eben and Kimmerle, 1974; Briemer et al., 1974; Humbert and
Fernandez, 1976, 1977; Stewart et al., 1969), although spectrophotometric
methods based on adaptations of the Fujiwara reaction are still widely used by
many investigators for determining urinary excretions of trichloroethanol
(TCE), trichloroacetic acid (TCA), or total urine chloro-derivatives of MC
(Ogata et al., 1974; Imamura and Ikeda, 1973; Tanaka and Ikeda, 1966; Ikeda
and Ohtsuji, 1972).
Inhaled MC rapidly equilibrates with arterial capillary blood across the
lung alveolar endothelium (Astrand, et al., 1973). The rate of pulmonary
uptake or absorption depends largely on the solubility of MC in blood (Ostwald
solubility coefficient) and hence the blood/air partition coefficient (Table
*.
4-1). Vapors with a high partition coefficient are absorbed into the body
readily and achieves a high level of accumulation. Conversely, vapors with a
low partition coefficient accumulate slowly because and, partition occurs more
rapidly with venous blood and alveolar air, are more rapidly eliminated into
expired air following exposure. In comparison with other common solvents in
Table 4-1, MC possesses a relatively low blood/air partition coefficient of
about 3.3 at 37°C.
The magnitude of MC uptake into the body (dose, burden) is directly
related to the following factors: 1) concentration of MC in the inspired air;
2) duration of exposure; 3) pulmonary ventilation during exposure; 4) blood/
air partition coefficient; 5) rates of diffusion into, and solubility in, the
002MC2/B 4-4 11-10-81
-------
body tissues; and 6) total body-lipid repository. Consequently, during expo-
sure at a given inspired air concentration, pulmonary uptake and retention is
initially large and gradually decreases to a minimum steady-state value as
total body equilibrium (and body burden) with inspired air concentration, is
reached. At this steady-state condition, pulmonary uptake balances the pulmo-
nary and other routes of elimination, including metabolism. For any given
breath cycle during exposure, the proportion of MC absorbed and retained by
the body is equal to the inspired air concentration (C,) minus the end alveolar
air concentration (C.) and, since pulmonary uptake is a function of inspired
air concentration, the percent retention is:
r - r
I A
% retention of inspired air concentration = x 100 (1)
CI
This value is large at the beginning of exposure, but gradually decreases to a
constant minimum value as total body equilibrium is approached (Figure 4-1).
The percent retention value at equilibrium is independent of the inspired air
concentration at equilibrium. Curing experimental exposures of subjects to 70
and 140 ppm MC for 4 and 8 hr, both Monster et al. (1979b) and Humbert and
Fernandez (1977) found retention to be 30 percent of inspired air concentra-
tion at an equilibrium reached after 4 hr of exposure.
The total amount (dose, Q) of MC retained in the body during an inhala-
tion exposure can be estimated by multiplying percent retention by the volume
of air inspired during the exposure period, or:
Q = (Cj - CA) V • T (2)
where V is ventilation rate (£/min) and T is exposure period (min). Since the
retention value decreases exponentially during the exposure until equilibrium
is reached (Figure 4-1), either experimental measurements of retention at
frequent intervals during exposure (Monster et al., 1979b) or integration over
002MC2/B 4-5 11-10-81
-------
r
o
EC
Z CC
O a
u 8j
O 2
o
LLJ
>
-J
<
100
so
EXPOSURE
I I I I I
POST EXPOSURE • MC
I 1 I
BLOOD CONC.
__ "'I ^ ^^i
10
TIME, hours
20
Figure 4-1. Absorption and pulmonary elimination of MC, and blood
concentration (see text for explanation).
Source: Davidson (1980). t
4-6
-------
the experimentally determined retention function is required (Humbert and
Fernandez, 1977). Ifce exponential nature of the retention curve is due to
first-order kinetics of saturation of body compartments with MC.
Table 4-2 shows the amounts of MC absorbed into the body during inhala-
tion exposures for volunteers from the studies of Monster et al. (1979b) and
Humbert and Fernandez (1977). Monster and his coworkers estimated pulmonary
uptake of MC by multiplying the minute volume by percent retention during
single 4-hr exposures to 70 ppm and 142 ppm. They observed a direct propor-
tionality between uptake and inspired air concentrations of MC. Similar
results were obtained by Humbert and Fernandez for volunteers exposed for 8 hr
to 72 ppm and 213 ppm. Comparison of pulmonary uptake for 4-hr and 8-hr
(Table 4-2) exposures indicates that the amount of MC retained is also propor-
tional to duration of exposure, although the values for uptake determined by
Humbert and Fernandez are 40 percent lower than those of Monster et al. This
variation can be ascribed to differences in the experimental methodologies and
t
average minute volume. Nonetheless, these experimental results indicate that
the body burden resulting from an 8-hr inhalation exposure to 350 ppm (TLV-TWA)
approximates 1.5 to 2 g of MC for a normal 70-kg man.
The body uptake of MC increases with the duration of inhalation exposure
and with physical work or exercise. Monster et al. (1979b) found that during
a 4-hr exposure to 142 ppm MC, with physical activity equivalent to light
physical work (100 watts), pulmonary uptake increased from 429 mg to 538 mg
MC, an increase of 25 percent (Table 4-2). This increase was primarily due to
an increase of ventilation from 10.7 fmin sedentary to 30.6 fmin with
work. While it might be expected from equation (2) that the increased uptake
should be directly proportional to the ventilation rate increment, an increase
002MC2/B 4-7 11-10-81
-------
TABLE 4-2. ESTIMATED UPTAKE OF MC DURING A SINGLE 4-HR INHALATION EXPOSURE
(AVERAGE BODY WEIGHT, 77 kg; 67 kg LEAN BODY MASS), MONSTER ET AL., 1979
Subject
A
B
C
D
E
F
Av.
Exposure
70 ppm (at rest*)
Uptake, mg
140
240
200
185
200
190
193
Concentration
145 ppm
305
520
465
395
425
465
429
142 ppm*, with work (100 watt)
Uptake, mg
435
610
540
560
575
505
138
"•Ventilation minute volume increased from average of 10.7 £/min. at rest to
30.6 je/min during light work.
ESTIMATED UPTAKE OF MC DURING A SINGLE 8-HR INHALATION EXPOSURE
(AVERAGE BODY WEIGHT-74 kg), HUMBERT AND FERNANDEZ, 1977
Subject
BH
JC
JO
Av.
72
293
274
277
281
Exposure Concentration*
ppm 213 ppm
Uptake, mg
921
912
—
917
*Average ventilation minute volume 5.7 £/min.
002MC2/B 4-8 11-10-81
-------
in ventilation also tends to increase alveolar elimination of MC from pulmo-
nary venous blood. Similar observations were made by Astrand et al. (1973)
with volunteers exposed to an MC inhalation concentration of 250 and 350 ppm
for 30 min at rest, alternating with identical exposure plus 50 watt of light
work. Table 4-3 shows that their subjects responded to this work with a
3-fold increase of pulmonary ventilation, nearly a 2-fold increase in cardiac
output, and a 50 percent increase in arterial blood concentration, which is an
index of pulmonary uptake. Also, end alveolar concentration of MC increased
while retention decreased from 50 to 33 percent with work. Therefore, physical
activity during MC exposure increases the uptake and body burden, but the
increase is not directly proportional to increased ventilation and is self-
limited by a compensatory increase of pulmonary elimination. For solvents
like MC, with a low blood/air partition coefficient, physical activity has a
smaller effect on net pulmonary uptake and body retention than those solvents
with a high blood/air partition coefficient (e.g., trichloroethylene, perchloro-
ethylene, dichloromethane; Tablt? 4-1; Monster, 1979).
During inhalation of MC, and in the elimination phase after exposure, the
arterial blood concentration always is directly proportional to the alveolar
concentration (Monster et al., 1979b; Humbert and Fernandez, 1977; Astrand et
al., 1973; Gamberale and Hultengren, 1973; Eben and Kimmerle, 1974). Since at
equilibrium the end alveolar air concentration is proportional to inspired air
concentration, blood concentration of MC is also related to inspired air
concentration (Monster et al., 1979b; Number and Fernandez, 1977; Astrand et
al., 1973). This fixed relationship between alveolar air and blood concen-
tration is defined by the blood/air partition coefficient for MC. Figure 4-2
illustrates this linear relationship for a volunteer exposed for 30 min to
002MC2/B 4-9 11-10-81
-------
TABLE 4-3. MEAN VALUES AND SEM FOR 12 MALE SUBJECTS
AT REST AND EXERCISE FOR 30 MINUTE PERIODS
MC
At rest
250 ppm
350 ppm
50 Watt
250 ppm
350 ppm
Ventilation
BTPS
i/min
6.6 ± 0.4
6.6 ± 0.4
22.5 ± 1.0
21.8 ± 1.1
Cardiac Alveolar
output cone
£/min ppm
5.1+0.4 125 ± 6
179 ± 13
9.7 ± 0.6 168 ± 7
239 ± 17
Blood
arterial
cone.
M9/9
3.0 ± 0.
5.0 ± 0.
4.5 ± 0.
7.2 ± 0.
2
5
2
4
From Astrand et al. (1973).
002MC2/B
4-10
11-10-81
-------
I
o
cr
z
w
o
o
u
cc
w
I
J_
100 200 300 400
ALVEOLAR CONCENTRATION, ppm
Figure 4-2. Relationship between methyl chloroform concentration
in alveolar air and arterial blood. Data from one subject. Product
moment correlation: r = 0.985. Data from one subject exposed to
30-min. periods of MC. Alveolar air samples and arterial blood sam-
ples.
Source: Gamberale and Hultengren (1973).
4-11
-------
increasing increments of MC concentration in inhaled air. The relationship
was independent of the duration of exposure over the time period studied.
Eben and Kimmerle (1974) exposed rats to 204 ppm for 8 hr daily, 5 days a wk
for 14 weeks and found that the blood concentration of MC determined immedi-
ately after daily exposure remained constant during the entire 3 mo period.
The blood/air partition coefficient, as determined from in vivo measures
of alveolar air concentration and blood concentration of MC, agrees well with
the jm vitro value of 3.3 at 37°c determined by Sato and Nakajima (1979)
(Table 4-1). Table 4-3 summarizes the data of Astrand et al. (1973) deter-
mined for sedentary men exposed to 250 and 350 ppm MC for 30-min periods
alternating with 30-min periods of physical activity. The ratios of arterial
blood concentration (ug/g) to alveolar MC concentration remain nearly constant
over a 2-fold range of alveolar concentrations, with an average value of 5.
Monster et al. (1979b) estimated from their study of men exposed to 70 and 142
ppm MC a blood/alveolar air concentration ratio of 6. In comparison to other
solvents (Table 4-1), MC has a relatively small blood/air partition coefficient,
and hence for equivalent ambient air exposure concentrations the blood concen-
tration of MC is proportionally lower than for other solvents.
The amount of MC pulmonary uptake is influenced by total body weight and
also by the total fat content of the body (average body fat = 8 percent of
body weight). The capacity of adipose tissue to absorb MC ni vivo is de-
termined by the product of adipose tissue volume and the lipid solubility of
MC. The lipid/blood partition coefficient for MC (108 at 37°C) is higher than
for most other structurally related solvents (Table 4-1) and, therefore, the
capacity of adipose tissue for MC is relatively high. However, because of the
low rate of perfusion (5 percent cardiac output), the time needed to saturate
002MC2/B 4-12 11-10-81
-------
adipose tissue is large in comparison with that for other tissues. Also,
since the blood/air partition coefficient for MC is lower than that of other
solvents, the amount of MC in adipose tissue (concentration) at the end of an
exposure of similar duration will be relatively lower. Monster (1979) suggests
that because of the high solubility of MC in adipose tissue, accumulation may
occur with repeated daily exposures, particularly in obese persons. This
speculation is supported by the observations of Savolainen, Vainio and co-
workers (1977, 1978), who exposed rats to MC (500 ppm) 6 hr daily for 5 days
and determined MC concentrations in perirenal adipose tissue and in other body
tissues. Their data, shown in Table 4-4, indicate that measureable amounts of
MC remained in perirenal fat tissue 18 hr after the previous exposure of day
4, and markedly increased further with a 6-hr exposure on day 5. The adipose
tissue/blood partition coefficient calculated from these data was 21, as
compared to 1.6 for brain and liver tissues. On the other hand, Eben and
Kimmerle (1974) exposed rats for 14 weeks (8 hr daily, 5 day per wk) to 204
«.
ppm MC but failed to find MC in*adipose or other tissues and concluded that MC
did not accumulate with chronic exposure. However, the average exposure concen-
tration for their rats was lower than that used by Savolainen et al. (500 ppm
vs. 204 ppm).
4.1.3 Tissue Distribution
During exposure to MC, distribution of the compound throughout the body
and the amount concentrated by each tissue is primarily governed by the blood
concentration, the blood perfusion rate, and the affinity of MC for respective
tissues, as determined by individual tissue/ blood partition coefficients. In
comparison with other chlorinated hydrocarbon solvents that are known to be
distributed widely in the body, MC has one of the highest lipid/ blood par-
tition coefficients (108 at 37°C, Table 4-1) and would distribute into all
002MC2/8 4-13 11-10-81
-------
TABLE 4-4. TISSUE CONTENT (RAT) OF METHYL CHLOROFORM (MC) AFTER CHRONIC INHALATION EXPOSURE OF 500 ppm
Exposure on
5th day
hr. Cerebrum Cerebellum Liver Perirenal fat Blood
nmolMC/g wet weight + range
0 0.15 + .03 0.17+ .03 0.15 + .01 16.9+ .5 0.08+ .01
*. 2 146 +1.1 14.0 + 2.2 14.7 + .04 183.5+ 10.7 11.5 + 2.0
M
* 3 13.4 + .60 13.2 + .8 15.7 +3.3 218.9+ 63.4 8.5 + 1.0
4 12.2 + .40 15.9 + 1.5 16.2 +2.8 261.2+ 19.1 12.7 + 2.9
6 15.6 +4.6 21.3 + 9.6 21.3 + .4 276.0+ 30.1 13.1 + 1.9
Measurements were performed on the 5th day of exposure after 4 previous daily exposures, 6 hr daily.
From Savolainen et al. (1977).
-------
body tissues, particularly those high in lipid content, such as brain and
adipose tissue (Holmberg et al., 1977). Table 4-4 shows the concentrations of
MC In liver, brain, and adipose tissue of rats exposed to 500 ppm in their
inspired air for 6 hr daily for 5 days (Savolainen et al., 1977). Adipose
tissue appears to have a partition coefficient with blood of approximately 20,
and brain tissue levels are also greater than blood concentration. In man, MC
readily passes the blood-brain barrier, resulting in high concentrations in
the brain (Caplan et al., 1976) and in the cerebrospinal fluid (Larsby et al.,
1978). While it has not been demonstrated directly to cross the placenta!
barrier into the fetus, it may be expected to do so (Laseter and Dowty, 1977)
like other highly lipid-soluble haloalkanes. Trichloroethanol (TCE), a major
metabolite of MC, is known to cross readily into the fetus (Bernstine, 1954,
1957). While there is no report of MC occurring in colostrum or milk of
nursing mothers, it may be expected to distribute readily into these compart-
ments because of their high lipid content.
*
4.1.4 Pulmonary Elimination »
Figure 4-1 shows schematically the time-course of pulmonary elimination
of MC after exposure. At termination of exposure, MC immediately begins to be
eliminated from the body into the lungs with blood concentration and alveolar
air concentration describing parallel exponential decay curves with three
major components. These components represent first-order passive diffusions
of MC from three major body compartments: (1) most rapidly from a vessel-rich
group of tissues (VRG) with high blood flow and high diffusion rate constant
(VRG: brain, heart, kidneys, liver, endocrine, and digestive system), (2) more
slowly from the lean body mass (MG; muscle and skin) and (3) from adipose
tissue (FG) (Fiserova-Bergerova and Holaday, 1979). The rate constants for
002MC2/B 4-15 11-10-81
-------
the passive diffusion from VRG, MG and FG compartments are dependent on both
the arterial blood flow/tissue mass and the relative solubilities of HC in the
tissues of these compartments (tissue/ blood partition coefficients). However,
the ranking of half-times (t,,-) of elimination of MC is VRG < MG <
-------
(1979b) and Humbert and Fernandez (1977) observed that, after single controlled
inhalation exposures, pulmonary elimination was not complete for 6 to 10 days
as determined by the continued presence of MC in alveolar air. The possi-
bility of significant accumulation with repeated daily exposures to this
solvent (Laseter and Oowty, 1977), however, is offset in part by the low
blood/air partition coefficient (Table 4-1), which for a given exposure con-
centration limits pulmonary absorption and body dose.
4.1.5 Elimination by Other Routes
There is no report in the literature of significant elimination of MC by
any route other than pulmonary. MC is poorly soluble in water, even when
compared with other chlorinated hydrocarbons (Table 4-1), and with its high
lipid/water partition coefficient MC is unlikely to be excreted unchanged in
the urine in any significant amounts. Studies of chlorinated compounds in the
urine after exposure of animals and humans to MC have not reported its appear-
ance in urine (Monster et al., 1979; Eben and Kimmerle, 1974; Humbert and
Fernandez, 1977; Seki et al., J975; Stewart et al., 1961; Hake et al., 1960).
Since highly lipid soluble substances like MC readily cross into the intestinal
lumen, some fecal and flatus excretion can be expected during inhalation
exposures. After controlled inhalation exposures, Humbert and Fernandez
(1977) were able to account for 88 to 100 percent of an estimated retained
dose as unchanged MC in postexposure exhaled air and as metabolites of MC in
urine. However, Monster et al. (1979b) could account for only 60 to 80 percent;
furthermore, they noted that the percentage recovered decreased with higher
exposure doses.
4.2 BIOTRANSFORHATION
MC has long been known to be metabolized to only a very limited extent by
mammals. The generally accepted metabolites of MC — trichloroethanol (TCE),
002MC2/B 4-17 11-10-81
-------
TCE-glucuronide, and trichloroacetic acid (TCA) •- are excreted primarily by
the kidney, but very small amounts of TCE (<1 percent) are excreted by the
lungs (Monster et al., 1979b). TCE-glucuronide is also excreted to an unknown
extent in bile (Owens and Marshall, 1955). No other metabolites have been
reported.
4.2.1 Magnitude of MC Metabolism
Only one balance study with isotopically labeled MC has ever been carried
out. More than 20 years ago, Hake and his coworkers (1960), using C-labeled
MC, determined that less than 3 percent of MC is metabolized by rats. More
recently, estimates of the extent of metabolism in man have been made from
controlled inhalation exposures with unlabeled MC (Seki et al., 1975; Monster
et al., 1979b; Humbert and Fernandez, 1977). From the experimentally deter-
mined retained dose and the amounts of MC metabolites excreted into the urine,
the percent of the dose metabolized in man is estimated to be about 6 percent.
Hake' et al. (1960) found that 98.7 percent of a dose of MC given to rats
»•. 14
was eliminated unchanged via the lungs. These investigators injected C-
14
labeled 1,1,1-trichloroethane-l- C (700 mg/kg) intraperitoneally into 3 rats
(170-183 g), which were then placed individually in a Roth metabolism unit
with air traps for 14C-MC (cold toluene), 14CO« (NaOH solution) and finally a
trap for "metabolites" (quartz-tube furnace and halogen absorber that con-
verted any halogenated hydrocarbon to inorganic halogen and C0_, and absorbed
the halogen). Each rat was kept in the unit for 25 hours, during which time
urine and feces were collected. At necropsy at 25 hr, blood and tissue samples
14 14
were analyzed for total C-activity. The C-MC used in the experiments was
synthesized by the investigators and was determined by paper chromatography to
be 99 percent pure, with possible contamination by 0.4 percent 1,1,2-trichloro-
ethane isomer and 0.5 percent 1,1-dichloroethane. Their findings, summarized
002MC2/B 4-18 11-10-81
-------
in Table 4-5, Indicate that metabolism of MC in the rat is limited to about 2
percent of a very large dose. However, only TCE-glucuronide was identified as
14
a metabolite in the urine, and the source of the C02 in expired air could
14
not be defined because of the presence of small amounts of C-l,l,2-isomer
14
and C-dichloroethane in the dose.
Man also appears to possess a very limited capacity for metabolism of MC.
Table 4-6 summarizes data taken from several investigative studies showing the
amount of urinary metabolites excreted after exposure to various concentra-
tions (4.3 to 213 ppm) of MC in inspired air. Seki et al. (1975) surveyed
workers in 4 printing plants where MC was the sole organic solvent in use.
The workers were exposed 8 hr daily, 5 1/2 days per wk, over a period of at
4
least 5 years. Urine samples were collected in the latter half of the work
week. Their data in Table 4-6 show a proportional increase of both TCE (as
glucuronide) and TCA, and also total trichlorinated compounds (TTC) with
increased ambient air concentrations of MC. Seki et al. expressed their data
as a linear relationship between inspired MC concentration and urinary metabo-
lite excretion, with an added constant increment presumably due to continued
excretion from the previous day's exposure. From this observation and from
evidence of continued excretion during exposure-free weekends, they suggested
that MC accumulates in the body to a steady-state body burden defined by the
air concentration of each daily exposure. Seki et al. also noted that the
amounts of metabolites excreted daily in the urine of these workers were less
than 5 percent of that observed with comparable exposures to trichloroethylene,
of which 60 to 80 percent is metabolically degraded to TCE and TCA (Monster,
1979). This comparison suggests that about 5 percent or less MC is metabo-
lized.
002MC2/B 4-19 11-10-81
-------
TABLE 4-5. HAKE ET AL. (1960) RECOVERY EXPERIMENT WITH RATS (3)
INTRAPERITONEALLY INJECTED WITH J«C-MC (700 »g/kg)
Average % dose
Expired Air
Unchanged MC (by isotopic dilution) 97.6
Unknown compound detected by
furnace (assumed to be unchanged MC) 1.1
14C02 (in NaOH) 70% within 4 hr; 100% within 12 hr 0.5
Urine
TCE-glucuronide •+• other volatile compounds but
no detectable TCA 0.85
Feces
Uncharacterized - 0.03
%
Tissues
Uncharacterized except skin (90% unchanged MC) 0.18
002MC2/B 4-20 11-10-81
-------
The data (Table 4-6) of Monster et al. (1979b) and of Humbert and Fernandez
(1977) were obtained from subjects given single 4-hr and 8-hr exposures to 70
and 145 ppm, and 72 and 213 ppm MC, respectively. Total urinary excretion of
TCE (glucuronide) and TCA is observed to be proportional to the inspired air
concentration of MC and to the expected body burden from these exposures (with
duration of exposure also taken into account). Both these research groups
attempted a balance study by estimating the retained body dose of MC either by
measuring lung clearance during exposure (Monster et al., 1979b), or by inte-
grating over the MC alveolar air decay curve to infinite time postexposure
(Humbert and Fernandez, 1977). The percentages of the retained dose metabo-
lized to TCE and TCA were 2.5 and 6.3 percent, respectively. The difference
can be ascribed to the different methodologies used for estimating body dose
and their inherent imprecisions. In both studies, the percentages of MC
metabolized were found to be independent of the retained dose (Table 4-6). A
similar observation with rats was made by Eben and Kimmerle (1974), who
i
measured urinary excretion of TCE and TCA for 3 days after a 4-hr inhalation
of MC at 221 and 443 ppm. The amounts of the metabolites excreted were" propor-
tional to the inspired concentration of MC. In rats, the urinary ratio of
TCE/TCA was 20/1 rather than the 3/1 observed in humans (Table 4-6).
A reasonable conclusion from these studies is that MC is minimally metabo-
lized by man on the order of 3 to 6 percent of the inhaled dose. The percent-
age of the dose metabolized is constant and independent of the body dose (at
least up to 213 ppm), which suggests that some factor other than the capacity
of the metabolizing system is the limiting one (e.g., hepatic extraction).
4.2.2 Kinetics of Blood and Urine Metabolites
The blood and urinary metabolites of MC (total amount, excretion ratios,
and excretion time-course) are of interest as quantitative indices of exposure
002MC2/B 4-21 11-10-81
-------
TABLE 4-6. RELATION BETWEEN INHALATION EXPOSURE AND URINARY METABOLITES OF MC
Sekl et al.. 1975
Average concentration of metabolites in urine samples from workers daily
exposed to MC.
Plant Air cone. No. TCE* TCA TTC/g
MC, ppm Subjects mg/£ creatinine
A 0 30 0 0 0
B 4.3 10 1.2 0.6 2.1
C 24.6 26 5.5 2.4 6.8
D 53.4 10 9.9 3.6 15.0
Monster et al.. 1979b
Averaged amounts of metabolites in total urine collected 70-hr post single
exposure (4 hr).
Air Cone. No.
MC. ppm Subjects TCE* TCA
mg mg
72 6 5.5 1.5
*
145 * 6 11.5 2.8
Estimated as % retained dose 2% 0.5%
Humbert and Fernandez, 1977
Averaged amounts of metabolites in total urine collected for 12 days post
single exposure (8 hr).
Air cond. No.
MC, ppm Subjects TCE* TCA
mg mg
72 3 15.2 5.2
213 2 30.7 13.0
Estimated as % retained dose 4.6* 1.75»
MCE found as glucuronide.
002MC2/B 4-22 11-10-81
-------
and body burden. However, the known metabolites of MC--TCE, TCE-glucuronide,
and TCA -- are not pathognomonic of MC, but are also metabolites of other
chlorinated hydrocarbons, e.g., trichloroethylene.
From studies of men exposed to 70 and 145 ppm MC inhaled for 4 hr, Monster
et al. (1979b) found that the TCE concentration in blood was proportional to
both the inspired concentration and the blood concentration of MC. TCE blood
concentration was about 4 percent that of MC (0.2 mg £ and 0.09 mg £ TCE
for 145 and 70 ppm MC inspired, respectively). After termination of exposure,
blood TCE concentration declined exponentially with a half-life of 10 to 12
hr. Urinary appearance of TCE and TCE-glucuronide paralleled the disappear-
ance of blood TCE, and daily excretion decreased with a half-time of renal
elimination of 10 to 12 hr. This value is in agreement with that observed
after ingestion of TCE itself (Briemer et al., 1974; Muller et al., 1974). In
contrast to the first-order blood decay kinetics of TCE, blood concentrations
of TCA progressively increased after the end of MC exposure for about 40 hr
*
before declining exponentially with a half-life of 70 to 85 hr. Consequently,
TCA appeared in the urine in almost equal daily amounts for 3 days before
decreasing. Exogenous TCA administered to men has a similarly long half-time
of renal elimination of 50 to 82 hr, presumably because of very tight non-
covalent binding to plasma proteins (Paykoc and Powell, 1945; Muller et al.,
1974). Therefore, the rise in plasma concentration of TCA during the 24 to 48
hr period following exposure is due to a rate of formation of TCA from TCE
greater than the rate of renal elimination of TCA. Similar observations on
daily urinary excretion of TCE, TCE-glucuronide, and TCA following acute MC
inhalation exposure have been made in man by Humbert and Fernandez (1977), and
in rats by Eben and Kimmerle (1974).
002MC2/B 4-23 11-10-81
-------
Stewart et al. (1969) investigated urinary metabolite excretion in men
repeatedly exposed to MC inhalation (500 ppm, 7 hr per day for 5 days). The
daily ratio TCE/TCA during exposure remained relatively constant (about 2.8),
but rapidly decreased within several days after exposure (5th day, 0.4),
indicating that the daily urinary TCE excretion decreased while the TCA excre-
tion decreased at a lesser rate or may have gradually increased. Eben and
Kimmerle (1974) also chronically exposed rats for 14 wk (8 hr daily, 5 days
per week) and measured blood levels of MC, TCE, and TCA, as well as daily
urinary excretion. Blood concentrations of MC and TCE (determined immediately
after daily exposure) remained essentially constant during the entire 14 week
period, with a concentration ratio of MC:TCE of 10:1. Weekly urinary excre-
tion of TCE reached a plateau within 3 to 4 wk, whereas TCA weekly excretion
was constant throughout the entire 14-wk period. The urinary excretion ratio
TCE/TCA was thus initially low, but after 3 to 4 wk exposure reached a constant
value of approximately 18.
«,
These findings show that the daily urinary ratio of TCE/TCA (mg/day)
during chronic MC exposure of both man and rats is determined by the relative
rates of metabolic formation and by the differences in renal elimination of
TCE (rapid, half-time 10 to 12 hr) and TCA (slow, half-time 50 to 70 hr). In
blood, both metabolites achieve steady-state plateau concentrations (TCE more
rapidly than TCA) related to the inspired air concentration of MC and its
metabolites. In urine, the TCE/TCA ratio, initially low, rises to a constant
daily value. After termination of either acute or chronic exposure, the ratio
of the amounts of daily urinary metabolites, TCE/TCA (mg/day), is highest 24
hr after exposure. Thereafter, its progressively decreases daily to less than
unity by the 5th or 6th day postexposure because of the relatively rapid renal
002MC2/B 4-24 11-10-81
-------
elimination of TCE and the slow renal elimination of TCA (Stewart, 1969; Eben
and Kimmerle, 1974; Monster, 1979).
The profile of TCE and TCA urinary excretion during and after MC exposure
is similar to that observed for trichloroethylene (Nomiyama and Nomiyama,
1971; Muller et al., 1974; Sato et al., 1977; Monster et al., 1976, 1979a;
Fernandez et al., 1977). However, the ratio of TCE/TCA excreted is 2-fold
greater for MC than for trichloroethylene, suggesting differences in the
pathways and rates of metabolism to TCE and TCA for these two chlorinated
hydrocarbons. Trichloroethylene, a chlorinated olefin, is metabolized by
hepatic microsomes to an epoxide, then to chloral hydrate, and thence to TCE
and TCA (Liebman and Ortiz, 1977; Henschler, 1977; Van Duuren, 1977). However,
neither epoxide nor chloral hydrate have been identified as metabolites of MC. •
Comparison of the percentage of the body dose metabolized to TCE and TCA (MC,
3-6 percent vs. trichloroethylene, 80-90 percent) explains the 25- to 30-fold
difference in the total amounts of these metabolites (mg/day) excreted into
urine for comparable body doses retained after inhalation exposure (Seki et
al., 1975; Stewart, 1968; Stewart et al., 1969; Monster, 1979; Ikeda and
Ohtsuji, 1972; Ikeda et al., 1972). In a comparative study of rats exposed to
200 ppm MC or its 1,1,2-isomer, Ikeda and Ohtsuji (1972) reported that the
urinary excretion of total chlorinated metabolites was substantially less for
the 1,1,2-isomer, indicating that the 1,1,2-isomer is metabolized to an even
smaller extent than MC. These workers determined the urinary metabolites of
the 1,1,2-isomer as TCE and TCA by a spectrophotometric method based on the
Fujiwara reaction. However, the MC isomer requires a shift of a chlorine atom
from one carbon to the other in order to form TCA or TCE, an unlikely reaction
HI vivo for a saturated aliphatic, and it is probable that dichlorometabolites
were actually measured.
002MC2/B 4-25 11-10-81
-------
4.2.3 Enzyme Pathways of Methyl Chloroform Metabolism
The metabolic pathways and enzyme mechanisms for the aetabolism of halo-
genated hydrocarbons assume considerable importance for understanding and
assessing cellular toxicity. Compounds that in the course of their metabolism
form intermediates reactive with cellular macromolecules, e.g., epoxides or
free radicals, are associated with enhanced cellular toxicity and carcinogenic
potential (Van Duuren, 1977). In comparison with other halogenated hydro-
carbons, MC is not extensively metabolized by mammalian systems; this may
explain in part its lower toxicity and carcinogenic potential (Weisburger,
1977). Unfortunately, these same attributes may also have contributed to the
current inadequate state of knowledge of the pathways of MC biotransformation
and the enzyme systems involved.
Figure 4-3 summarizes the presently postulated enzyme steps in the bio-
transformation of MC to TCE and TCA, the only known metabolites appearing in
the plasma and urine of animals and man (Table 4-6). It is assumed that
c
metabolism occurs principally iti the liver, although uj vitro experiments that
directly demonstrate and evaluate MC metabolism by the liver have only been
reported for TCE production (Ivanetich and Van Den Honert, 1981).
In view of the absence of MC-labeled or unlabeled balance studies with
methodologies of current sophistication, the possibility of the existence of
unknown minor metabolites of secondary pathways is real. Hake et al. (1960),
in the only reported study using labeled MC, found that about 0.5 percent of
14
the dose (of the 2 percent metabolized; see Table 4-7) was converted to CO-,
following 1,1,1-trichloroethane-l- C administration (intraperitoneal) to
rats, suggesting carbon-carbon cleavage to chloroform. Chloroform is exten-
sively metabolized to COp in man (50 percent) and to glutathione-conjugatpd
002MC2/B 4-26 11-10-81
-------
TCA
«o
CUC - C
3 NOH
"CHLORAL HYDRATE" \^N
7 DEHYDROGENASE
^
Cl - C - CH,
x . 3
Cl I VV MICROSOMAL
| \\ P450 SYSTEM
i \\ NADPH, r
• \\
I
PEROXISOME
OXIDASE,
CATALASE
SYSTEM
MICROSOMAL
DEHYDROGENASE.
NADP
CI3C-CH2OH GLUCURONIYL
/XMICROSOMAX™™5""*"
/ ETHANOL ^
f _....__...._ Trc.ftinriior
ETHANOL ^
OXYGENASE TCE•6LUCURONIDE
NADPH O-
NADPH, 0
'ALCOHOL
trj ALCOHOL
* DEHYDROGENASE?
O
ci3c - c
CHLORAL
Figure 4-3. Postulated pathways of hepatic biotransformation of MC.
Source: Davidson (1980) and Ivanetich and Van Den Honen (1981).
4-27
-------
chloromethyl derivatives (Fry et al., 1972). During these conversions, free
radicals or reactive intermediates are produced which contribute to chloroform
14
toxicity (Brown et al., 1974). However, the origin of the CO- is an open
question since Hake et al. did not identify chloroform as a metabolite of MC;
14
also, the C-MC used was contaminated with trace amounts of the MC isomer
l,l,2-trichloroethane-l-14C (0.4 percent) and l,l-dichloroethane-l-14C (0.5
percent). Both of these compounds were reported by Van Dyke (1971, 1977) to
be readily dechlorinated by the rat liver microsomal P450 system. The optimal
configuration for dechlorination was a dichloromethyl group. Hence, 1,1,2-
trichloroethane, the more toxic isomer, was readily dechlorinated but 1,1,1-
trichloroethane was not. For the isomer 1,1,2-trichloroethane, the products
were identified as mono-and dichloroethanol and mono- and dichloroacetic acid
(Van Dyke and Wineman, 1971), which are known to be metabolized to CO- or to
form glutathione conjugates (Yllner, 1971a,b). Carlson (1973) found that pre-
treatment of rats with phenobarbital, but not methylcholanthrene, potentiated
^
hepatotoxicity (measured as serum SCOT and SGPT) of both inhaled MC and its
1,1,2-isomer, but the toxicity of the isomer was increased to a far greater
extent. These several observations suggest that 1,1,2-trichloroethane, but
not MC, may be extensively metabolized by the oxidative dechlorination system
of Van Dyke and Wineman (1971).
Figure 4-3 shows that the initial pathway of MC transformation is hy-
droxylation of MC to TCE by the microsomal P450 mixed function oxidase system
(Ivanetich and Van Den Honert, 1981). There are several other observations
which support this finding.
First, when MC is incubated aerobically with rat liver microsomes plus
NADPH, it produces a P450 type I binding spectrum with peaks at 452 nm and 420
nm, and a reduced spectrum with a peak at 420 nm only (Cox et al. 1976; Pelkonen
and Vainio, 1975).
002MC2/B 4-28 11-10-81
-------
Secondly, MC inhalation induces the P450 drug metabolizing system (Fuller
et al., 1970; Lai and Shah, 1970). Rats exposed to inhaled MC (2500 to 3000
ppm) for 24 hr exhibited decreased hexobarbital sleeping time, and decreased
duration of effect of meprobamate and zoxazolamine. Furthermore, liver micro-
somes from MC-pretreated rats exhibited increased u> vHro metabolism of
hexobarbital, zoxazolamine, and aminopyrine, type I substrates. Livers from
pretreated rats had increased cytochrome P450 and NADPH cytochrome C reductase
activity, preventable by cycloheximide or actinomycin D. This induction of
hepatic microsomal drug metabolism in the reports of Fuller et al. (1970) and
Lai and Shah (1970), suggests the possibility that MC might induce its own
metabolism with repeated daily exposure. Stewart et al. (1969) observed that
men experimentally exposed to 500 ppm MC 7 hr for 5 days excreted in their
urine progressively increased daily amounts of TCE and TCA although the daily
ratio TCE/TCA remained relatively constant (2.8). Eben and Kimmerle (1974)
found that rats exposed daily to 204 ppm MC (8 hr/day 5 day/wk) for 14 weeks
excreted progressively increasing amounts of TCE for the first few weeks. The
TCE/TCA ratio increased to a maximum (about 20) that was maintained for the
remainder of the 14-wk exposure period.
Thirdly, MC can interact with pathways of drug metabolism. Plaa et al.
(1958) and Shah and Lai (1976) found that MC given intraperitoneally to mice
(1 mg/kg) potentiates pentobarbital sleeping time and reduces hexobarbital
metabolism by liver microsomes. This observation, in contrast to induction of
metabolizing enzymes by inhalation exposure or by intraperitoneal administra-
tion in oil, is explained on the basis of different amounts of MC reaching the
liver by the various routes and methods of administration. Van Dyke and
Rikans (1970) added MC directly to rat liver microsomes incubated in vitro.
002MC2/B 4-29 11-10-81
-------
They observed no effect on N-demethylation of aminopyn'ne, but a 50 percent
increase of aniline 4-hydroxylation, a type II substrate. The 1,1,2-isomer
produced similar results.
The origin of TCA as a plasma and urinary metabolite of MC is postulated
to occur from enzymic oxidation of TCE. TCE-glucuronide, also present in
plasma and urine, is presumed to be formed by glucuronyl transferase. TCE,
exogenously administered to man, yields TCA as a metabolite (Marshall and
Owens, 1954; Owens and Marshall, 1955a,b; Muller et al., 1974). Marshall and
Owens (1954) also observed TCA formation during TCE incubation with rat or dog
liver slices. The most likely reaction for the oxidation of TCE to TCA would
involve the enzyme alcohol dehydrogenase (Figure 4-3). However, ijri vitro
studies with alcohol dehydrogenase purified from horse liver, and with rat
liver cytosol fractions, have shown that TCE is a poor substrate for alcohol
dehydrogenase and that significant conversion to trichloroacetaldehyde (chloral)
does not occur (Sellers et al., 1972; Friedman and Cooper, 1960; Marshall and
*
Owens, 1954). The reverse reaction —reduction of chloral to TCE — proceeds
rapidly with a Km of 2.7 x 10~3M for horse liver enzyme (Butler, 1948, 1949;
Marshall and Owens, 1954, 1955a,b; Friedman and Cooper, 1960; Sellers et al.,
1972). Also, chloral hydrate has been sought, but not detected, as an inter-
mediate metabolite in plasma of rats and man exposed by inhalation to MC
(Monster et al., 1979; Eben and Kmmerle, 1974). On the other hand, chloral
hydrate exogenously administered is very rapidly metabolized jjn vivo with a
half-life of only a few minutes, yielding both TCE and TCA as metabolites in
plasma and urine (Butler, 1948; Marshall and Owens, 1954, 1955a,b; Breimer et
al., 1974; Muller et al., 1974; Cole et al., 1975).
002MC2/B 4-30 11-10-81
-------
The conversion of chloral to TCA is usually ascribed to so-called "chloral
hydrate dehydrogenase," a substrate-specific NAD-dependent enzyme described by
Cooper and Friedman (1958). This enzyme was obtained from rabbit liver acetone
powders. Cooper and Friedman reported that acetaldehyde was not a substrate,
but rather a markedly effective inhibitor; they did not demonstrate a normal
endogenous substrate. Human cytosolic acetaldehyde dehydrogenase does not
convert chloral hydrate to TCA (Kraemer and Deitrick, 1968; Blair and Bodley,
1969; Sellers et al., 1972). Grunnet (1973) reported that chloral hydrate is
not a substrate for mitochondrial NAD-dependent acetaldehyde dehydrogenase.
Microsomal NADP-dependent acetaldehyde dehydrogenases with broad substrate
specificity have been described, but whether chloral hydrate is a substrate
has not been determined (Tottmar et al., 1973).
In short, there is little evidence which precisely defines the enzymatic
pathways for the metabolism of MC to TCE by P450 mixed function oxidase system,
and TCE to TCA by classical alcohol dehydrogenase and acetaldehyde dehydrogenase
enzymes. Although as yet unintestigated, it is possible that TCE may be a
substrate for the microsomal P450 ethanol oxidative system (MEOS) described by
Lieber and his coworkers for ethanol and other alcohols (Lieber and De Carli,
1969; Teschke et al., 1977). TCE has been shown by Uehleke et al. (1976) to
give a binding spectrum with rat microsomes. An alternative pathway also
uninvestigated is afforded by the peroxisomal oxidase-catalase system (Figure
4-3), which is known to readily oxidize ethanol and a broad spectrum of other
substrates (Masters and Holmes, 1979; Chance et al., 1977). Indeed, peroxi-
somes may perhaps be involved in the initial oxidation of MC to TCE and other
halogenated hydrocarbons as well.
002MC2/B 4-31 11-10-81
-------
4.3 SUMMARY AND CONCLUSIONS
The pharmacokinetics and metabolism of MC in man have been studied less
than other chlorinated aliphatic solvents, both in controlled experimental
conditions and in the workplace. Like other solvents of this group, inhala-
tion and lung absorption of MC vapor in the air is the most important and
rapid route of absorption into the body. Absorption through the skin by
direct liquid contact is slow and adds less than 5 percent to total body dose.
At the accepted TWA value (350 ppm) for an 8-hr exposure, less than 2 g may be
expected to be absorbed into the body of a normal 70 kg man. This is because
pulmonary absorption is directly related to the blood/air partition coeffi-
cient, which for MC is less than that of most other structurally related
solvents. MC total body dose increases in direct proportion to inspired air
concentration and duration of exposure; it is also increased by physical
activity during exposure. MC distributes throughout the body, readily cross-
ing the blood-brain barrier and probably the placenta! barrier as well. It
*
can be assumed that MC also distributes into the colostrum or milk of nursing
mothers, although no specific data are available. Relative body tissue con-
centrations are not known, but there is a high affinity for adipose tissue due
to the higher lipid/ blood partition coefficient of MC compared with that of
other related solvents. Blood and tissue concentrations achieved during
exposure are directly proportional to inspired air concentration and total
body dose.
MC is metabolized in man to a very limited extent—about 6 percent of the
'total body dose. Metabolism appears to occur principally in the liver, and to
an unknown extent in other tissues, yielding only trichloroethanol (ICE.) and
trichloroacetic acid (TCA) as identified metabolites. Urinary excretion of
these metabolites is proportional to inspired air concentration and the total
002MC2/B 4-32 11-10-81
-------
body dose of MC. Detailed information concerning the enzymatic pathways of
metabolism is lacking. The importance of greater knowledge of the biochemical
mechanisms and pathways of metabolism relates to awareness that "reactive
intermediate" metabolites may contribute to tissue and organ toxicities as
well as carcinogenic potential. The mechanism(s) of the initial biotransfor-
mation of MC to TCE, where "reactive intermediates" may occur, are specula-
tive, although present evidence suggests a microsomal cytochrome P450 oxida-
tive reaction. However, specific covalent binding studies which would confirm
reactive intermediates have not been carried out. Also, other minor pathways
and unidentified metabolites cannot be excluded because of the lack of defini-
tive studies. Metabolism is enhanced by microsomal inducers such as phenobar-
bital and possibly MC itself. The interaction of MC metabolism and toxicity
with other common drugs, including ethanol, has not been adequately investi-
gated.
During post-exposure, more than 80 percent of MC is excreted unchanged by
the lungs. Alveolar air concentration and blood concentration decline in a
parallel exponential fashion exhibiting three major components of elimination
with half-times of approximately 1, 9, and 30 hr. The long half-time of
elimination (30 hr) is associated with elimination from adipose tissue and
indicates that accumulation may occur with repeated daily exposures, particu-
larly in obese persons. Further research on the disposition and fate of MC
after low chronic vapor exposures would be helpful, particularly with respect
to bioaccumulation, enzyme mechanisms of biotransformation, and interactions
with common drugs.
002MC2/B 4-33 11-10-81
-------
4.4 REFERENCES
American Conference of Governmental Industrial Hygienists (1976 TLV Airborne
Contaminants Committee). Threshold Limit Values for Chemical Substances
in workroom air adopted by ACGIH for 1976. Cincinnati: ACGIH, 1976.
American Industrial Hygiene Association, Toxicology Committee: Emergency
exposure limits, Am. Ind. Hyg. Assoc. J. 25:578-586, 1964.
Astrand, I., A. Kilbom, I. Wahlberg, and P. Ovrum. Methyl chloroform exposure:
I. Concentration in alveolar air and blood at rest and during exercies.
Work Environ. Hlth. 10:69-81, 1973.
Aviado, D. , S. Zakhari, J. Simaan, and A. Ulsamer. Methyl Chloroform and
Trichloroethylene in the Environment. Cleveland, CRC Press, Inc., 1976.
Bernstine, J. B. , A. E. Meyer, and H. B. Hayman. Maternal and foetal blood
estimation following the administration of chloral hydrate during labour.
J. Obst. Gyn. Brit. Emp. 61:683-685, 1954.
Bernstine, J. B., A. E. Meyer, and R. L. Bernstine. Maternal blood and cerebral
spinal fluid estimation following the administration of chloral hydrate
during the puerperium. Am. J. Obst. Gyn. 73:801-804, 1957.
Blair, A. H. , and F. H. Bodley. Human liver aldehyde dehydrogenase: partial
purification and properties. Can. J. Biochem. 47:265-271, 1969.
Breimer, D. D., H. C. J. Ketelaars, and J. M. van Rossum. Gas chromatographic
determination of chloral hydrate, trichloroethanol and trichloroacetic
acid in blood and in urine employing head-space analysis. J. Chromatogr.
88:55-63, 1974.
Brodman, K., A. J. Erdmann, I. Lorge, and H. G. Wolff. The Cornell Medical
Index: An adjunct to medical interview. J. Am. Med. Assoc. 140: 530-534,
1949.
Brown, B. R. , I. G. Sipes, and A. M. Sagalyn. Mechanisms of acute hepatic
toxicity: Chloroform, Halothane, and Glutathione Anesthesiology 41:554-
561, 1974.
Browning, E. Toxicity and Metabolism of Industrial Solvents. Amsterdam,
Elsevier, 1965.
Butler, T. C. The metabolic fate of chloral hydrate. J. Pharmacol. Exptl.
Therap. 92:49-57, 1948.
Butler, T. C. Metabolic transformations of trichloroethylene. J. Pharmacol.
Exptl. Therap. 97:84-92, 1949.
Caplan, Y. H. , R. C. Backer, and J. W. Whitaker. 1,1,1-Trichloroethane:
Report of a fatal intoxication. Clin. Toxicol. 9:69-74, 1976.
Carlson, G. P. Effect of phenobarbital and 3-methylcholanthrene pretreatment
on the hepatotoxicity of 1,1,1-trichloroethane and 1,1,2-trichloroethane.
Life Sciences 13:67-72, 1973.
002MC4/C 4-34 11-10-81
-------
Chance, B., A. Boveris, and N. Oshino. I_n: Alcohol and Aldehyde Metabolizing
Systems, Vol. 2, R. G. Thurman, 0. R. Williamson, H. R. Drott, and B.
Chance, eds., New York, Academic Press, pp. 261-274, 1977.
Clark, D. G. , and D. J. Tinston. Correlation of the cardiac sensitizing
potential of halogenated hydrocarbons with their physicochemical proper-
ties. Brit. J. Pharmacol. 49:355-357, 1973.
Cole, W. J. , R. G. Mitchell, and R. E. Salamonsen. Isolation, characteriza-
tion and quantitation of chloral hydrate as a transient metabolite of
trichloroethylene in wan using electron capture gas chromatography and
mass fragmentography. J. Pharm. Pharmacol. 27:167, 1975.
Cooper, J. R., and P. J. Friedman. The enzyme oxidation of chloral hydrate to
trichloroacetic acid. Biochem. Pharmacol. 1:76-82, 1958.
Cox, P. J., L. J. King, and D. V. Parke. The binding of trichlorofluoromethane
and other haloalkanes to cytochrome P-450 under aerobic and anaerobic
conditions. Xenobiotica 6:363-375, 1976.
Davidson, I. W. F. (personal communication), 1980.
Dornette, W. H. L., and J. P. Jones. Clinical experiences with 1,1,1-trichloro-
ethane. Anesth. Analg. 39:249-253, 1960.
Eben, A., and G. Kimmerle. Metabolism, excretion and toxicology of methyl-
chloroform in acute and subacute exposed rats. Arch. Toxikol. 31:233-242,
1974.
Eger, E. 1. , B. Brandstater, L. J. Saidman, J. J. Regan, J. W. Severinghaus,
and E. S. Munson. Equipot?ent alveolar concentrations of methoxyflurane,
halothane, diethyl ether, fluroxene, cyclopropane, xenon, and nitrous
oxide in the dog. Anesthesiology 26:771-777, 1965.
Elovaara, E. , K. Hemminki, and H. Vainio. Effects of methylene chloride,
trichloroethane, trichloroethylene, tetrachloroethylene and toluene on
development of chick embryos. Toxicol. 12:111-119, 1979.
Fernandez, J. G. , P. 0. Droz, B. E. Humbert, and J. R. Caperos. Trichloro-
ethylene exposure. Simulation of uptake, excretion, and metabolism using
a mathematical model. Brit. J. Ind. Med. 34:43-55, 1977.
Fiserova-Bergerova, V., and D. A. Holaday. Uptake and clearance of inhalation
anesthetics in man. Drug Met. Rev. 9:43-60, 1979.
Friedman, P. J. , and J. R. Cooper. The role of alcohol dehydrogenase in the
metabolism of chloral hydrate. J. Pharmacol. Exptl. Therap. 129:373-376,
1960.
Fry, B. J., T. Taylor, and D. E. Hathway. Pulmonary elimination of chlorofor
and its metabolite in man. Arch. Int. Pharmacodyn. Ther. 196: 98-101,
1972.
•m
002MC4/C 4-35 11-10-81
-------
Fukabori, S., K. Nakaaki, J. Yonemoto, and 0. Tada. On the cutaneous absorption
of methyl chloroform. J. Sci. Labour 52:67-80, 1976.
Fukabori, S., K. Nakaaki, J. Yonemoto, and 0. Tada. On the cutaneous absorption
of 1,1,1-trichloroethane. J. Sci. Labour 53:89-95, 1977.
Fuller, G. C. , A. Olshan, S. K. Puri, and H. Lai. Induction of hepatic drug
metabolism in rats by methylchloroform inhalation. J. Pharmacol. Exp.
Ther. 175:311-317, 1970.
Gamberale, F., and M. Hultengren. Methyl chloroform exposure. II. Psychol-
physiological functions. Work Environ. Hlth. 10:82-92, 1973.
Grunnet, N. Oxidation of acetaldehyde by rat-liver mitochondria in relation
to ethanol oxidation and the transport of reducing equivalents across the
mitochondrial membrane. Eur. J. Biochem. 35:236-243, 1973.
Hake, C. L. , T. B. Waggoner, D. N. Robertson, and V. K. Rowe. The metabolism
of 1,1,1-trichloroethane by the rat. Arch. Environ. Hlth. 1:101, 1960.
Hall, F. B., and C. H. Hine. Trichloroethane intoxication: A report of two
cases. J. Forensic Sci. 11:404-413, 1966.
Hardie, D. W. F. Chlorocarbons and Chlorohydrocarbons. In: Kirk-Othmer
Encyclopedia of Chemical Technology, Vol. 5, 2nd ed. , NY, Interscience
Pub., pp. 154-157, 1964.
Hatfield, T. R., and R. T. Maykoski. A fatal methychloroform (trichloroethane)
poisoning. Arch. Environ. Hlth. 20:279-281, 1970.
Henschler, D. Metabolism and mutagenicity of halogenated olefins--A comparison
of structure and activity. Environ. Hlth. Persp. 21:61-65, 1977.
Holmberg, B., I. Jakobsen, and K. Sigvardsson. A study on the distribution of
methylchloroform and n-octane in the mouse during and after inhalaton.
Scand. J. Work Environ. Hlth. 3:43-52, 1977.
Humbert, B. E. , and J. G. Fernandez. Exposure to 1,1,1-trichloroethane:
contribution to the study of absorption, excretion and metabolism in
human subjects. Arch. Mai. Prof. 38:415-425, 1977.
Humbert, B. E., and J. G. Fernandez. Simultaneous determination of trichloracetic
acid and trichlorethanol by gas chromatography. Int. Arch. Occup. Environ.
Hlth. 36:235-241, 1976.
Ikeda, M. , and H. Ohtsuji. A comparative study of the excretion of Fujiwara
reaction-positive substances in urine of humans and given trichloro-or
tetrachloro-derivatives of ethane and ethylene. Brit. J. Ind. Med.
29:99-104, 1972.
Ikeda, M., H. Ohtsuji, T. Intamura, and Y. Komoike. Urinary excretion of total
trichloro-compounds, trichloroethanol and trichloroacetic acid as a
measure of exposure to trichloroethylene and tetrachloroethylene. Brit.
J. Ind. Med. 29:328-333, 1972.
002MC4/C 4-36 11-10-81
-------
Imamura, T. , and M. Ikeda. A time-saving procedure for the determination of
total trichloro-compounds in human urine samples. Int. Arch. Arbeitsmed.
31:333-338, 1973.
Irish, D. D. Aliphatic hydrocarbons. Industrial Hygiene and Toxicology. 2nd
ed. Vol. 2. F. A. Patty ed. , New York, Interscience, 1963, p.
Ivanetich, K. M. and L. H. Van Den Honert. Chloroethanes: their metabolism
by hepatic cytochromes P-450 j_n vitro. Carcinogenesis 2:697-702, 1961.
Kramer, C. G. , M. G. Ott, J. E. Fulkerson, N. Hicks, and H. R. Imbus. Health
of workers exposed to 1,1,1-trichloroethane: a matched-pair study.
Arch. Environ. Hlth. 33:331-342, 1978.
Kraemer, R. J. , and R. A. Deitrich. Isolation and characterization of human
liver aldehyde dehydrogenase. J. Biol. Chem. 243:6402-6408, 1968.
Krantz, J. C. Jr., C. S. Park, and J. S. Ling. Anesthesia LX: the anesthetic
properties of 1,1,1-trichloroethane. Anesthesiology 20:635-640, 1959.
Lai, H. , and H. C. Shah. Effect of methyl chloroform inhalation on barbiturate
hypnosis and hepatic drug metabolism in male mice. Toxicol. Appl.
Pharmacol. 17:625-633, 1970.
Larsby, B. , R. Tham, L. M. Odkvist, B. Norlander, D. Hyden, G. Aschan, and A.
Rubin. Exposure of rabbits to methyl chloroform. Vestibular disturbances
correlated to blood and cerebrospinal fluid levels. Int. Arch. Occup.
Environ. Hlth. 41:7-15, 1978.
Laseter, 0. L. , and B. J. Dowty. Association of biorefractories in drinking
water and body burden in people. Ann. N.Y. Acad. Sci. 298:547-556, 1977.
Leibman, K. C. , and E. Ortiz. Metabolism of halogenated ethylenes. Environ.
Hlth. Persp. 21:91-99, 1977.
Lieber, C. S. , and L. M. DeCarli. Hepatic microsomes, a new site for ethanol
oxidation. J. Clin. Invest. 47:62a(abst), 1968.
Maroni, M. , C. Bulgheroni , M. G. Cassitto, F. Merluzzi, R. Gilioli, and V.
Foa. A clinical, neurophysiological and behavioral study of female
workers exposed to 1,1,1-trichloroethane. Scand. J. Work Environ. Hlth.
3:16-22, 1977.
Marshall, E. K. , Jr., and A. H. Owens, Jr. Absorption, excretion and metabolic
fate of chloral hydrate and trichloroethanol. Bull. Johns Hopkins Hosp.
95:1-18, 1954.
Masters, C. J. , and R. S. Holmes. Peroxisomes—their metabolic roles in
mammalian tissues. Trends. Biochem. Sci. 4:233-236, 1979.
Miller, K. W. , W. D. M. Paton, E. B. Smith, and R. A. Smith. Physicochemical
approaches to the mode of action of general anesthetics. Anesthesiology
36:339-351, 1972.
002MC4/C 4-37 11-10-81
-------
Monster, A. C. Difference in uptake, elimination and metabolism in exposure
to trichloroethylene, 1,1,1-trichloroethane and tetrachloroethylene.
Int. Arch. Occup. Environ. Hlth. 42:311-317, 1979.
Monster, A. C., and G. Boersma. Simultaneous determination of trichloro-
ethylene and metabolites in blood and exhaled air by gas chromatography.
Int. Arch. Occup. Environ. Hlth. 35:155-163, 1975.
Monster, A. C. , and J. M. Houtkooper. Estimation of individual uptake of
trichloroethylene, 1,1,1-trichloroethane and tetrachloroethylene from
biological parameters. Int. Arch. Occup. Environ. Hlth. 42.319-323,
1979.
Monster, A. C. , G. Boersma, and W. C. Duba. Pharmacokinetics of trichloro-
ethylene in volunteers; influence of workload and exposure concentration.
Int. Arch. Occup. Environ. Hlth. 38:87-102, 1976.
Monster, A. C., G. Boersma, and W. C. Duba. Kinetics of trichloroethylene in
repeated exposure of volunteers. Int. Arch. Occup. Environ. Hlth. 42:283-
292, 1979a.
Monster, A. C., G. Boersma, and H. Steenweg. Kinetics of 1,1,1-trichloroethane
in volunteers; influence of exposure concentration and work load. Int.
Arch. Occup. Environ. Hlth. 42:293-301, 1979b.
Morgan, A., A. Black, and D. R. Belcher. Studies on the absorption of halo-
genated hydrocarbons and their excretion in breath using 3&C1 tracer
techniques. Ann. Occup. Hyg. 15:273-283, 1972.
Miiller, G., M. Spassovski, and p. Henschler. Metabolism of trichloroethylene
in man. II. Pharmacokinetics of metabolites. Arch. Toxicol. 32:283-295,
1974.
Nomiyama, K. , and H. Nomiyama. Metabolism of trichloroethylene in human.
Int. Arch. Arbeitsmed. 28:37-48, 1971.
Ogata, M. , K. Tomokuni, and H. Asahara. Simple microdetermination of tri-
chloroethanol glucuronide and trichloroacetic acid in urine. Int. Arch.
Arbeitsmed. 32:203-215, 1974.
Owens, A. H., Jr., and E. K. Marshall, Jr. A comparison of the metabolism of
ethanol and trichloroethanol. Bull. Johns Hopkins Hosp. 9_7:395-404,
1955a.
Owens, A. H. , Jr., and E. K. Marshall, Jr. Further studies on the metabolic
fate of chloral hydrate and trichloroethanol. Bull. Johns Hopkins Hosp.
97:320-326, 1955b.
Paykoc, 2. and J. F. Powell. The excretion of sodium trichloracetatc. J.
Pharmacol. Expt. Ther. 85:289-293, 1945.
Pelkonen, 0., and H. Vainio. Spectral interactions of a series of chlorinated
hydrocarbons with cytochrome P-450 of liver microsomes from variously-
treated rats. FEBS Letters 51:11-14, 1975.
002MC4/C 4-38 11-10-81
-------
Plaa, G. L. , E. A. Evans, and C. H. Hine. Relative hepatotoxicity of seven
halogenated hydrocarbons. 0. Pharmacol. Exp. Ther. 123:224-229, 1956.
Prendergast, J. A., R. A. Jones, L. J. Jenkins, Jr., and J. Siegel. Effects
on experimental animals of long-term inhalation of trichloroethylene,
carbon tetrachloride, 1,1,1-trichloroethane, dichlorodifluoromethane, and
1,1-dichloroethylene. Toxicol. Appl. Pharmacol. 10:270-289, 1967.
Rowe, V. K., T. Wujkowski, M. A. Wolf, S. E. Sadek, and R. D. Stewart. Toxicity
of a solvent mixture of 1,1,1-trichloroethane and tetra chloroethylene as
determined by experiments on laboratory animals and human subjects. Am.
Ind. Hyg. Assoc. J. 24:541-554, 1963.
Salvini, M. Psychological Effects of Trichloroethylene and 1,1,1-Trichloro-
ethane Upon Man. Behavioral Toxicology, U.S. Dept. HEW, Publ. No. (N10SH)
74-126, 1974.
Salvini, M. , S. Binaschi, and M. Riva. Evaluation of the psychophysiological
functions in humans exposed to the "threshold limit value" of 1,1,1-
trichloroethane. Brit. J. Ind. Med. 28:286-292, 1971.
Sato, A. , and T. Nakajima. A structure-activity relationship of some chlori-
nated hydrocarbons. Arch. Environ. Hlth. 34:69-75, 1979.
Sato, A., T. Nakajima, Y. Fugiwara, and N. Murayama. A pharmacokinetic model
to study the excretion of trichloroethylene and its metabolits after
inhalation exposure. Brit. J. Ind. Med. 34:56-63, 1977.
Savolainen, H. , Pfaffli, P., Tengen, M. and Vainio, H. Trichloroethylene and
1,1,1-trichloroethane: effects on brain and liver after five days inter-
mittent inhalation. Arch.*Toxicol. 38:229-237, 1977.
Schwetz, B. A., B. K. J. Leong, and P. J. Gehring. The effect of maternally
inhaled trichloroethylene, perchloroethylene, methyl chloroform, and
methylene chloride on embryonal and fetal development in mice and rats.
Toxicol. Appl. Pharmacol. 32:84-96, 1975.
Seki, Y. , Y. Urashima, H. Aikawa, H. Matsumura, Y. Ichikawa, F. Hiratsuka, Y.
Yoshioka, S. Shimbo, and M. Ikeda. Trichloro-compounds in the urine of
humans exposed to methyl chloroform at sub-threshold levels. Int. Arch.
Arbeitsmed. 34:39-49, 1975.
Sellers, E. M. , M. Lang, J. Koch-Weser, E. LeBlanc, and H. Kalant. Interac-
tion of chloral hydrate and ethanol in man. I. Metabolism. Clin.
Pharmacol. Therap. 13:37-49, 1972.
Shah, H. C. , and H. Lai. Effects of 1,1,1-trichloroethane administered by
different routes and in different solvents on barbiturate hypnosis and
metabolism in mice. J. Toxicol. Environ. Hlth. 1:807-816, 1976.
Stahl, C. J. , A. V. Fatteh, and A. M. Dominguez. Trichloroethane poisoning:
observations on the pathology and toxicology in six fatal cases. J.
Foren. Sci. 14:393-397, 1969.
002MC4/C 4-39 11-10-81
-------
Stewart, R. D. Methyl chloroform intoxication: diagnosis and treatment.
JAMA 215:1789-1792, 1971.
Stewart, R. D. The toxicology of 1,1,1-trichloroethane. Amer. Occup. Hyg.
11:71-79, 1968.
Stewart, R. D., and J. T. Andrews. Acute intoxication with nethyl chloroform.
JAMA 195:904-906, 1966.
Stewart, R. D. and H. C. Dodd. Absorption of carbon tetrachloride, trichloro-
ethane, tetrachloroethylene, methylene chloride, and 1,1,1-trichloro-
ethane through the human skin. Am. Ind. Hyg. Assoc. J. 25:439-446, 1964.
Stewart, R. D., H. H. Gay, D. S. Erley, C. L. Hake, and A. W. Schaffer. Human
exposure to 1,1,1-trichloroethane vapor: relationship of expired air and
blood concentrations to exposure and toxicity. Am. Ind. Hyg. Assoc. J.
22:252-262, 1961.
Stewart, R. D. , H. H. Gay, A. W. Schaffer, D. S. Erley, and V. K. Rowe.
Experimental human exposure to methyl chloroform vapor. Arch. Environ.
Hlth. 19:467-472, 1969.
Tanaka, S., and M. Ikeda. A method for determination of trichloroethanol and
trichloroacetic acid in urine. Brit. J. Ind. Med. 25:214-219, 1968.
Teschke, R., K. Ohnishi, Y. Hasumura, and C. S. Lieber. Hepatic microsomal
ethanol oxidizing system: Isolation and reconstitution. In: Microsomes
and Drug Oxidations., Proc. 3rd Int. Symp. Berlin, 1976, Suppl. Biochem.
Pharmacol. Pergammon, Oxford, pp. 103-110, 1977.
*
Torkelson, T. R. , F. Oyen, D. «0. McCollister, and V. K. Rowe. Toxicity of
1,1,1-trichloroethane as determined on laboratory animals and human
subjects. Am. Ind. Hyg. Assoc. J. 19:353-362, 1958.
Tottmar, S. 0., H. Pettersson, and K. H. Kiessling. The subcellular dis-
tribution and properties of aldehyde dehydrogenases in rat liver. Biochem.
J. 135:577-586, 1973.
Uehleke, H. , S. Tabarelli-Poplawski, G. Bonse, and D. Henschler. Spectral
evidence for 2,2,3-trichlorooxirane formation during microsomal tri-
chloroethylene oxidation. Arch. Toxicol. 37:95-105, 1977.
Vainio, H. , H. Savolainen and P. Pfaffli. Biochemical and toxicological
effects of combined exposure to 1,1,1-trichloroethane and trichloro-
ethylene on rat liver and brain. Xenobiotica 8:191-196, 1978.
Van Duuren, B. L. Chemical structure, reactivity and carcinogenicity of
halohydrocarbons. Environ. Hlth. Persp. 21:17-23, 1977.
Van Dyke, R. A. Dechlorination mechanisms of chlorinated olefins. Environ.
Hlth. Persp. 21:121-124, 1977.
Van Dyke, R. A., and L. E. Rikans. Effect of the volatile anesthetics on
aniline hydroxylase and aminopyrine demethylase. Biochem. Pharmacol.
19:1501-1502, 1970.
002MC4/C 4-40 11-10-81
-------
Van Dyke, R. A., and C. G. Wineman. Enzymatic dechlorination: dechlorination
of chloroethanes and propanes £n vitro. Biochem. Pharmacol. 20:463-470,
1971.
Weisburger, E. K. Careinogenicity studies on halogenated hydrocarbons.
Environ. Hlth. Persp. 21:7-16, 1977.
14
Yllner, S. Metabolism of 1,2-dichloromethane- C in the House. Acta.
Pharmacol. et Toxicol. 30:257-265, 1971a.
?r, S. Metabolism of chloro<
et Toxicol. 30:69-80, 1971b.
14
Yllner, S. Metabolism of chloroacetate-1- C in the mouse. Acta Pharmacol.
002MC4/C 4-41 11-10-81
-------
5. TOXIC EFFECTS
Since its commercial introduction in 1954, methyl chloroform has been
used increasingly as an industrial solvent and in consumer products. Usually
the most important path of entry into the body is by inhalation. The health
hazards of MC inhalation in the work place or public environment, as well as
exposure by other routes, are pointed out by human and animal studies indicat-
ing that MC has significant adverse biological effects on the central nervous
(CNS) and cardiovascular systems. In addition, MC may cause organ tissue
damage generally associated with chlorinated hydrocarbon solvent toxicity.
Like some of these other structurally related compounds, it may also have a
%
teratogenic, mutagenic, and/or'carcinogenic potential. The available litera-
ture on the possible toxic effects of MC is reviewed in this chapter.
5.1 HEALTH EFFECTS IN HUMANS
5.1.1 Experimental Studies
Experimental studies in humans have centered around three general areas:
clinical experiences with MC as an anesthetic; the kinetics of MC absorption
and excretion after exposure via the inhalation and cutaneous routes; and the
impairment of psychophysiological functions in humans exposed to MC.
Dornette and Jones (1960) administered MC to 50 patients undergoing
elective surgery. Nitrous oxide-oxygen (4:1) was used as the vehicle and as a
supplemental anesthetic agent. The concentration of MC required for induction
002MC3/A 5-1 11-10-81
-------
of surgical plane anesthesia varied from 10,000 to 26,000 ppm, and for mainten-
ance of light anesthesia from 6,000 to 22,500 ppm. Rapid induction and re-
covery, analgesia, and the absence of disagreeable odor, respiratory depres-
sion, postoperative depression, nausea and vomiting were listed as advantages
in the use of MC. A definite disadvantage was depression of blood pressure
during anesthesia of moderate depth. The tendency to develop ventricular
arrhythmias during hypoxia was also observed. (This effect was reversed when
effective oxygenation was reestablished).
Cardiac sensitization by halogenated hydrocarbons, with resultant in-
creased susceptibility of the heart to catecholamine-produced arrhythmias,
e.g., ventricular fibrillation or ventricular tachycardia, is a well-known
phenomenon recently reviewed by Aviado et al (1976). Clark and Tinston (1973)
believe that cardiac sensitization caused by these relatively inert, lipid
soluble hydrocarbons is very likely to be a structurally non-specific action
on myocardial membranes by solution and distribution within these membranes,
and is, therefore, an example or "physical toxicity" (see Sect. 5.2.3). From
an evaluation of 14 halogenated hydrocarbons in dogs, Clark and Tinston (1973)
found that the cardiac sensitizing potencies, as determined by the partial
pressure in inhaled air needed to sensitize the heart to epinephrine, was
directly related to their saturated vapor pressures. In a similar way, the
anesthetic potency or narcotic action of the halogenated hydrocarbons, a
structurally nonspecific action, is directly related to the blood/air or
lipid/air partition coefficient for these compounds (Table 4-1) (Miller et al.,
1972; Eger et al., 1965; Sato and Nakajima, 1979).
Siebecker et al. (1960) reported that electroencephalographic patterns
during MC anesthesia showed little change before circulatory depression and
that the changes were similar to those during halothane anesthesia. The
002MC3/A 5-2 11-10-81
-------
investigators found MC to be less potent clinically than either chloroform or
halothane in supplementing nitrous oxide-oxygen for anesthesia.
Stewart et al. (1961) evaluated the acute effects of increasing concen-
trations (0 to 2,600 ppm) of MC over a 15 min exposure period. The commercial
grade of MC used was chlorothane. Table 5-1 shows the subjective and physio-
logical responses during exposure to MC. In another experiment in which 6
subjects were exposed to MC at 500 ppm for 78 min or 186 min, no eye irrita-
tions or dizziness occurred, nor were balance or coordination affected.
Exposure at 900 to 955 ppm for 73, 35, and 20 min produced a number of psycho-
physiological effects which are listed in Table 5-2.
In another study, Torkelson et al. (1958) exposed humans to MC (Chloro-
thane) vapors. Exposure to 550 ppm for 90 minutes had no measureable effect
on the vital signs being monitored. Exposure to 500 ppm for 450 minutes
produced no significant changes in pulse, respiration, blood pressure, reflexes,
or equilibrium; liver function tests were also negative. Exposure to 1000 ppm
for 30 minutes was also without*effect. However, exposure to 900 to 1000 ppm
for 75 min resulted in slight eye irritation and a feeling of lightheadedness,
and the Flanagan and Romberg tests revealed a slight but definite loss of
coordination and equilibrium. ECG and liver, function tests were normal.
Exposure to 1900 ppm for 5 minutes resulted in an obvious disturbance of
equilibrium and a positive Romberg test.
In 1969, Stewart et al. reported that exposure to 500 ppm for periods of
6.5 to 7 hours/day for 5 consecutive days resulted in mild subjective re-
sponses (sleepiness, eye irritation, and mild headache). The only untoward
physiological response was an abnormal Romberg test. None of the clinical
tests performed during or following the exposure were abnormal.
002MC3/A 5-3 11-10-81
-------
TABLE 5-1. SUBJECTIVE AND PHYSIOLOGICAL RESPONSES TO A
CONSTANTLY INCREASING METHYL CHLOROFORM VAPOR
CONCENTRATION OVER A PERIOD OF 15 MINUTES
Concentration
(ppm) Responses to Exposure
0 to 1000 Increasing awareness of a slightly sweet, not unpleasant
odor.
1000 to 1100 Mild eye irritation noted in 6 of 7 subjects.
1900 to 2000 6 of 7 subjects aware of throat irritation.
2600 1 subject very lightheaded.
2650 2 subjects unable to stand. 3 subjects very lightheaded,
but able to stand. 2 subjects were not lightheaded, and
one of these was able to demonstrate a normal Romberg
test.
Source: Stewart et al. (1961).
002MC3/A 5-4 11-10-61
-------
TABLE 5-2. SUBJECTIVE AND PHYSIOLOGICAL RESPONSES TO
METHYL CHLOROFORM VAPOR CONCENTRATIONS
OF 900 TO 1000 PPM
Average
Concentration
Responses to Exposure*
900 ppm for 20
minutes
(3 subjects)
910 ppm for 35
minutes
(2 subjects)
951 ppm for 73
minutes
(3 subjects)
Positive Romberg in one subject. Greater effort re-
quired to perform a normal Romberg in two subjects
after 10 minutes of exposure. Heel-to-toe walking
normal. Two subjects experienced lightheadedness
above 900 ppm.
Greater mental efforts required to perform a normal
Romberg test after 10 minutes of exposure. All
heel-to-toe walking performed well. One subject
experienced persistent lightheadedness above
900 ppm.
Greater mental effort required to perform a normal
Romberg test after 10 minutes of exposure. After
15 minutes of exposure one subject had consistently
positive Romberg. Heel-to-toe walking performed
well by all during exposure. No lightheadedness.
aMild eye irritation was noted by all subjects when vapor concentrations rose
above 1000 ppm.
Source: Stewart et al. (1961).
002MC3/A
5-5
11-10-81
-------
In 1975, Stewart et al. reported an experiment in which 20 subjects were
exposed to 500 ppm MC or less for 7.5 hours per day, 5 days per week for 3
weeks. No serious deleterious effects upon health or performance were de-
tected, and the health of the subjects remained unimpaired during the in-
halation studies. The blood chemistries, hematologies, urinalyses, electro-
cardiograms, and pulmonary function tests remained normal. There was a slight
increase in the number of reported negative subjective responses (Table 5-3).
Twelve subjects were exposed to 250, 350, 450, and 550 ppm of MC in
inspired air during four continuous 30 minute periods in an experiment re-
ported by Gamborale and Hultengren (1973). The air-gas mixture was supplied
via a breathing valve and a mouthpiece with very low resistance. The effects
of the introduction of the breathing tube were not assessed. In the final 20
minutes of each exposure period, five performance tests were made. Two of the
tests were of perceptual speed and the others were tests of simple reaction
time, choice reaction time, and manual dexterity. The same subjects were also
studied under control conditions in which inspired air contained no MC but in
which all operations and measurements were the same as during exposure to the
solvent. The presence or absence of MC was completely disguised by the use of
menthol crystals. To balance the training effects between experimental and
control conditions, the order of conditions was reversed for half the subjects.
The change in mean performance level during exposure to the increasing
concentrations of MC differed systematically from the change in performance
under control conditions. The level of performance in the manual dexterity
test and two perceptual tests were affected by training; however, the training
effect was less pronounced during exposure to MC. The tests of reaction time
were less sensitive to training and, with these, there was an absolute decline
in performance capability as the exposure concentration increased. However,
002MC3/A 5-6 11-10-81
-------
TABLE 5-3. NUMBER OF SUBJECTIVE RESPONSES TO METHYL CHLOROFORM EXPOSURE
in
i
i— •
i
o
i
00
Lightheadedness
Syncope
Mild sleepiness
Mild eye irritation
Mild nose or throat
irritation
Mild headache
Nausea
Fatigue
Objectionable odor
Source: Stewart et
0
0
0
0
0
0
0
0
1
0
al.
10 Males
ppm 100 ppm 350 ppm 350 ppm 500 ppm
0
0
0
0
0
0
0
0
0
001000011000000000000
000000000000000000000
011100130002000001000
oooooooo o''o oiooooooooo
011000000001200000000
001001011001000000000
000000000000000000000
000000000000000000000
000000000000000000000
10 Females
0 ppm 350 ppm
00 10000
00 00000
00 00000
00 00000
10 10000
20 01110
00 00000
00 00000
00 99999
(1975).
-------
this study contained several drawbacks: e.g., the substance used to disguise
the MC odor may itself have had a toxic effect, and the introduction of a
breathing tube may have induced stress in the subjects. Nevertheless, statis-
tically significant performance differences between experimental and control
conditions were obtained for all tests with exposures at 350 ppm or more.
Salvini et al. (1971) evaluated psychophysiological effects after ex-
posing six male university students to an average vapor concentration of 450
ppm MC for two periods of 4 hours, separated by a 1.5 hour interval. Each
subject was examined on two different days using a crossed-scheme analysis.
The psychophysiological tests included a perception test with tachistoscopic
presentation, the Wechsler Memory Scale test, a complex reaction time test,
and a manual dexterity test. After two exposures, no disturbances in motor
function, coordination, equilibrium, or behavior patterns were observed in any
of the subjects. However, there were some complaints about eye irritation.
The only factor that was reported to be statistically significant was the
association between exposure to MC and perception of mental strain. Under
stress conditions, exposure to 450 ppm MC decreased perceptive capabilities.
A small reduction in performance was also observed but was not statistically
significant.
Savolainen et al. (1981) evaluated various psychophysiological functions
in 9 male students exposed for 4 hours/day, at 6-day intervals, to MC (200 and
400 ppm) and m-xylene (200 ppm) and MC (400 ppm) in combination. Exposure to
MC or MC and xylene together were without effect on reaction time, body
balance, and critical flicker fusion thresholds.
5.1.2 Occupational Studies
Chronic occupational exposure to other chlorinated solvents has been
associated with adverse neurological and behavioral effects. However, it has
002MC3/A 5-8 11-10-81
-------
not been specifically determined whether relatively low level exposures to MC
are clearly associated with such effects.
A recent attempt to assess the central and peripheral nervous system
effects of MC in occupational situations was undertaken by Maroni and co-
workers (1977). They studied a very small group (22 subjects) of female
workers exposed to MC vapors at concentrations ranging from 110 to 990 ppm.
When compared to workers who were reportedly unexposed, no differences were
found in clinical symptoms or measures of nerve conduction velocity and psycho-
metric function.
In another study, Seki et al. (1975) surveyed 196 male workers employed
in four Japanese printing factories where MC was the sole organic solvent in
use. The four groups of workers were exposed to average concentrations of
4, 25, 28, and 53 ppm. The workers participated in a medical interview coupled
with a test for sense of vibration (studied at the distal joints of the thumbs
and great toes using a 128 Hz tuning fork) as well as routine laboratory
examinations, including peripheral hemograms, determination of blood specific
gravity, and urinalysis for urobilinogen and protein. These examinations
revealed no consistent dose-related adverse effects among the four groups of
workers.
In the most recent study, Kramer et al. (1978) measured numerous physio-
logical parameters of workers in two adjacent textile plants. Detailed blood
chemistry and hematology studies were conducted for 151 matched pairs of
employees to compare the exposed and unexposed partners. All employees in the
exposed group had been exposed to MC (and other solvents), in varying concen-
trations, for up to 6 years. The concentration range was 11 to 838 ppm, with
a mean of 115 ppm MC. It is questionable whether this period of exposure
would result in toxic symptoms. Because only healthy, active workers were
selected, and the average length of exposure for the study population was less
002MC3/A 5-9 11-10-81
-------
than 1 year at the stated TWA, no conclusions can be drawn about accumulative,
long term effects. The control group was only minimally exposed to nonchlori-
nated solvents.
Pairs were matched with regard to age, race, sex, work shift, job des-
cription and socioeconomic status, and examined within a 10 week period.
Subject height, weight, blood pressure and pulse were obtained, and electro-
cardiograms were recorded. Laboratory blood determinations included hema-
tocrit, hemoglobin, red blood cell count (RBC), white blood cell count (WBC),
mean corpuscular hemoglobin (MCH), mean corpuscular volume (MCV) alkaline
phosphatase, SGOT, SGPT, gamma glutamyl transpeptidase, total bilirubin, urea
nitrogen, LDH, uric acid, total protein, A/G ratio, albumin, calcium, and
phosphorus. For quantitative variables, t tests and tests of homogeneity of
variables were made. Multiple regression analysis was performed on paired
differences with respect to environmental variables and on the combined matched
exposed and control populations with respect to demographic variables.
Breathing zone samples were collected in charcoal tubes, except in a few
locations where area sampling was more practical, and analyzed on a portable
gas chromatograph equipped with a flame ionization detector. Samples of
expired air were analyzed immediately after collection by gas chromatography.
After explaining that some data were eliminated on the basis of subjects'
smoking habits, high blood pressure, or prior illness, the authors presented
statistical findings but no individual data. MC concentrations in the breath
ranged from "less than 5 ppm" to "greater than 30 ppm," with the majority
(127/151) between 5 and 29 ppm. Comparison of the health test data between
exposed and control subjects revealed no statistically significant differences
except in SGPT and albumin. These differences were not discussed at length
and the authors concluded that no health impairment was suffered by workers
exposed to an average daily concentration of 115 ppm MC.
002MC3/A 5-10 11-10-81
-------
Nine women washing brass frames in open containers of pure MC were studied
from the onset of their exposure and were the subject of a report in 1965 by
Weitbrecht. Air measurements were made during the summer with methyl bromide
indicator tubes (of questionable validity for measuring MC). An average of 10
ppm of MC was found in the general room air and 20 ppm in the worksite air.
In addition to vapor exposures, the women's hands were immersed in liquid MC
for varying periods of time. Breathing zone samples were not collected. It
seems likely that breathing zone concentrations would have been considerably
higher if the women were working directly over the solvent containers.
The women experienced transient irritation of the conjunctiva and/or
upper respiratory passages and a characteristic burning sensation of the
tongue. They also reported that their teeth felt dull (rhubarb effect). They
did not experience a burning sensation or initial swelling when their hands
were placed in liquid MC; however, they did have a feeling of ice-cold fingers.
A sustained paleness of the fingers occurred only at the beginning of the
work, otherwise it appeared only when the exposure was continuous.
After the windows were closed in the fall, the women complained of loss
of appetite, pressure sensation in the stomach, vomiting, tiredness, headache,
and insomnia. The author considered that these complaints were neurotic chain
reactions influenced, in part, by safety signs in the shop. He did not differ-
entiate the effects of the MC exposure from the possible suggestive effect of
the safety signs, and did not comment upon the lack of the safety sign effect
in the summer.
Clinically, he found hypertension in six of the women and positive urobi-
linogen in two; in addition, he reported what he described as autonomic
dystrophy in two, circulatory dystrophy in one, and psychasthenia in one.
5.1.3 Accidental Exposure
Accidental exposure to MC can lead to death. Table 5-4 lists the signs
and symptoms of a number of cases in which the patients survived. These
002MC3/A 5-11 11-10-a
-------
§
f\>
o
to
en
i
TARIE 5-1. SIGNS AND SYMPTOMS Of PAIMNIS SURVIVING
INIOXJCrtUON WJfll rlfimri MHOHmORM
Reference
Patient
Amount
BP* imb sr,Pic SOOT APP BUN'
ECG"
Comments
Stewart and 17 M
Andrews, 19r«<>
SlPwart, 1P71
44 WM
Stewart. 1971 55 WM
Stewart, 1971 47 WM
lilt and Cohen, 5 torn-
19
-------
results suggest that MC has only a minimal potential for producing liver or
kidney injury in man. The primary toxic effect appears to be a reversible
depression of the CNS, typical of an anesthetic agent. In addition, cardio-
\
vascular parameters may be altered by exposure to MC.
Two fatal cases in which the subjects intentionally inhaled cleaning
fluids containing MC were reported by Hall and Mine (1966). A 19-year-old
woman who was observed sniffing cleaning fluid over several days and acting
irrationally was later found dead. Pathologic findings on autopsy were con-
fined to the respiratory system, stomach, and brain. The vessels of the
bronchi were congested, and the bronchi contained thick, yellowish-brown
secretions. There was passive congestion throughout the lungs, and the
parenchyma showed considerable amounts of thick, dark red blood and thin
frothy fluid in the congested areas. The mucosa of the stomach was hyperemic;
the leptomeninges were thin, glistening, transparent and markedly congested;
brain ventricles contained clear cerebrospinal fluid; vascular markings were
«,
prominent, and there was acute", passive congestion throughout the brain.
There were indications of chronic, intentional inhalation of a cleaning
fluid containing MC in the other fatal case studied by Hall and Hine (1966).
On autopsy, pathologic findings were confined to the respiratory system and
the kidneys. The lungs were congested and edematous, the vessels dilated, and
small hemorrhagic areas were present. The kidneys showed marked vascular
congestion around the pyramids, especially on the periphery.
In neither of these cases were drugs or solvents detected in the stomach
contents, and no barbiturates were found in the blood. Blood levels of MC were
72.0 and 13.0 mg percent, respectively.
Twenty-nine cases of sudden death from sniffing MC during 1964 to 1969
were reported by Bas (1970). These were among 110 cases of sudden death
002MC3/A 5-13 11-10-81
-------
attributed to sniffing volatile hydrocarbons and halocarbons summarized by the
author. In 18 of the 110 cases, death followed sniffing coupled with some
form of exercise. No anatomical abnormalities were found from gross or micro-
scopic post mortem examinations that could explain the sudden deaths. The
author discussed the possibility that resulted from cardiac sensitization to
endogenous catecholamine.
Six fatal cases were reported by Stahl et al. (1969). In the first case,
a 20-year-old man was found dead in a closed space in which he had been work-
ing with a "paint remover." Gas chromatographic analysis revealed MC in all
tissues. Upon autopsy, the lungs were found to be congested and moderately
edamatous; the liver, spleen, kidneys, and brain were also congested. Micro-
scopic examination of the brain suggested anoxia as the cause of death.
In the second case, a 17-year-old man was found dead in a room in which
he was cleaning an air vent with MC. Gas chromatographic analysis revealed
the presence of MC although blood levels were only 0.15 mg percent. At autopsy,
i
the skin was moderately cyanotic, the brain, liver, kidneys, and spleen were
moderately congested, and the lungs were markedly edematous with evidence of
aspiration of gastric contents. Blood lactic acid levels were high. The
authors concluded that death was probably due to 0^ deprivation.
In the third case, an obese 24-year-old man was found dead in bed after
having cleaned electrical equipment with MC. At necropsy, marked cyanosis of
the head and neck were noted; the lungs were congested and edematous. The
brain, spleen, and kidneys were also congested.
In the fourth, fifth, and sixth cases, three males were found dead in an
unventilated 4 x 5 ft. compartment where they had been cleaning electrical
equipment with MC. Autopsies revealed congestion and edema of the lungs.
Blood levels of MC were 12.0 mg percent, 6.2 mg percent, and 6.0 mg percent in
these victims.
002MC3/A 5-14 11-10-81
-------
Hatfield and Maykoski (1970) reported on a 27-year-old who was found dead
in an aircraft tank that he had been cleaning with MC. Upon autopsy, the
lungs showed some passive congestion and some edema. The kidneys showed some
passsive congestion and there appeared to be some slight edema of the brain.
Microscopic examination disclosed a pulmonary parenchyma with considerable
acute passive congestion and focal extravasations of red blood cells into
alveolar spaces. Upon section, the renal parenchyma was intensely congested
and of a dark red color. Microscopically, there was intense, acute passive
congestion. There appeared to be marked congestion of the small vessels
within the white matter of the brain. The diagnosis was acute passive conges-
tion of the viscera with petechial hemorrhages in the lung and brain. Hatfield
and Maykoski estimated the concentration level of MC to which this worker was
exposed at 62,000 ppm.
Caplan et al. (1976) reported a fatal intoxication in which a 40-year-old
female was apparently overcome while painting a bathroom. On external examina-
«.
4
tion, the only significant abnormality was in the respiratory system. The
bronchi contained frothy fluid. On section, the lungs exuded moderate aimounts
of frothy fluid. Histologically, the lungs showed acute edema and congestion,
and the liver showed a mild fatty change. MC was identified in tissue s.amples.
Twenty-one deaths from abuse or gross misuse of decongestant aerosol
sprays containing MC in the solvent resulted in removal of several such pro-
ducts from the market (Federal Register 38:21935-36, 1973).
5.2 EFFECTS ON ANIMALS
5.2.1 Acute and Subacute Effects
The LD 's Of MC for various species are found in Table 5-5. Admini-
stration of single oral doses yielded LDcn'5 ^or laDorat-ory animals ranging
from 8.6 gm/kg for guinea pigs to 14.3 gm/kg for rats (Torkelson et al.,
002MC3/A 5-15 11-10-81
-------
TABLE 5-5. ACUTE TOXICITY OF METHYL CHLOROFORM
Reference
Torkelson et al. ,
1958
Torkelson et al. ,
1958
Torkelson et al. ,
1958
Torkelson et al. ,
1958
Torkelson et al. ,
1958
Takeuchi
1966
Priestly and Plaa
1976
Klaass'en and Plaa
1969
Torkelson et al. ,
1958
Adams et al. ,
1950
Plaa et al. ,
1958
Klaassen and Plaa
1967
Klaassen and Plaa
1967
Gehring
1968
Species
rats
rats
mice
albino
rabbits
guinea
pigs
SM mice
CF-1 Swiss
mice
Sprague-Oawley
rats
albino
rabbits
rats
Princeton
mice
Swiss-Webster
mice
dog
Swiss-Webster
mice
Route
oral
oral
oral
oral
oral
i.p.
i.p.
i.p.
dermal
inhalation
i.p.
i.p.
i.p.
i.p.
Sex
M
F
F
mixed
mixed
?
M
M
mixed
mixed
M
M
M
F
LD50
»g/kg
14,300
11,000
9,700
10,500
8,600
2,568
4,008
5,054
15,800
18.0001
16,000
5,080
4,140
4,700
95% confidence
limits
12,100 to 17,000
9,500 to 13,000
9,700 to 11,300
6,100 to 12,200
3,558 to 4,522
4,389 to 5,586
12,700 to 21,400
4,140 to 6,010
4,320 to 5,110
LC50 in ppm for 3 hr exposure; 7 hr exposure resulted in a LC,0 of 14,250 ppm (12,950 to
15,675). 50
002MC3/A
5-16
11-10-81
-------
1958). The solvent caused slight transitory irritation in the eyes. The
toxicity from skin absorption was found to be low, as doses of 4 gin/kg failed
to kill any rabbits exposed for 24 hrs. Repeated multiple daily application
of 500 mg/kg to the skin of rabbits caused no effect other than reversible
local irritation. In other experiments, laboratory animals were exposed
repeatedly to 500, 1000, 2000, and 10,000 ppm in order to establish conditions
safe for repeated exposure. Rats, guinea pigs, rabbits, and monkeys were
unaffected after 6 months of repeated 7 hr exposures 5 days/wk to 500 ppm.
Female guinea pigs, which were found to be the most sensitive in previous
experiments, were able to tolerate 1000 ppm for 0.6 hr/day for 3 months and
2000 ppm for 0.1 hr/day with no detectable adverse effects. Male rats tolerated
exposure to 10,000 ppm for 0.5 hr per day with no organic injury. The effects
of MC were shown to be primarily anesthetic, with only a slight capacity to
cause reversible injury to the lungs and liver. Based on this work, Torkelson
et al. (1958) suggested that the maximum allowable concentration for MC be 500
«,
ppm.
In another study, Eben and Kimmerle (1974) exposed rats acutely (4 hr)
and subacutely (8 hr/day, 5 times/wk for 3 months) to 220 and 440 ppm and 200
ppm, respectively. During the periods of exposure, the animals did not differ
in any way from their controls in behavior, appearance, or body weight gain.
Hematologic examination performed at the end of the exposure period did not
reveal any pathologic abnormalities. Liver and renal function tests and blood
glucose were normal. At autopsy, the organs of the exposed rats were normal;
organ weights did not deviate significantly from those of the control animals.
Prendergast et al. (1967) repeatedly exposed 15 Sprague-Dawley rats, 15
Hartley guinea pigs, 3 squirrel monkeys, 3 New Zealand albino rabbits, and 2
beagle dogs (8 hr/day, 5 days/wk for 6 weeks) to 2200 ppm MC. The same number
002MC3/A 5-17 11-10-81
-------
of animals were exposed continuously for 90 days to 135 ppm and 370 ppm. The
repeated exposure to 2200 ppm did not result in any deaths or visible signs of
toxicity, although weight loss was observed in rabbits and dogs. The con-
tinuous exposure at 370 ppm did not cause any deaths, visible toxic signs,
significant growth depression or biochemical, hematologic or pathologic changes.
Continuous exposure to 135 ppm resulted in three deaths but no visible toxic
signs or impaired growth in any of the survivors. Autopsy and subsequent
histopathologic examination of the experimental animals revealed lung conges-
tion and pneumonitis which may have been severe enough to have caused the
deaths of the two rats and the rabbit, but which were not attributed to the
exposure.
Because chlorinated hydrocarbons are known to produce a specific hepato-
toxicity, the effects of MC on hepatic function have been studied by a number
of different investigators. Lai and Shah (1970) exposed Swiss-albino, random-
bred male mice to 3000 ppm for either 24 hr or for 4 or 8 hr/day for several
days. Hexobarbital (80 mg/kg)1^, barbital sodium (275 mg/kg)- or chloral
hydrate (350 mg/kg)-induced sleeping time was measured at predetermined times
after exposure. In addition, hexobarbital oxidizing activity, nitro-group
reducing activity, and the protein content of the liver supernatant fraction
were also determined. Inhalation of MC at a concentration of 3000 ppm for 24
hr produced a maximum reduction in the duration of hexobarbital sleeping time
but had no effect on hypnosis produced by barbital or chloral hydrate. Hypnosis
returned to the control level at 48 hr after the termination of exposure.
Repeated short exposures, 4 or 8 hr/day for several days, had a cumulative
effect, but a single 8 hr exposure did not. The supernatant fraction isolated
(9000 g) from livers of mice previously exposed to MC oxidized hexobarbital
more efficiently, but the ability to reduce p-nitrobenzoic acid remained
002MC3/A 5-18 11-10-81
-------
unaffected. The protein content of this liver supernatant fraction was also
unaltered.
Fuller et al. (1970) made further observations on Lai and Shah's in-
vestigations of the inductive effect of MC on hepatic drug Metabolism. Male
Sprague-Dawley rats and Swiss-albino, random-bred mice were exposed to MC
(2500 to 3000 ppm) in a dynamic chamber for 24 hr. Loss of righting reflex
due to hexobarbital (120 mg/kg), meprobamate (300 mg/kg), or zoxazolamine (80
mg/kg) administration and iji vitro activity of hexobarbital oxidase, zoxazo-
lamine hydroxylase, aminopyrine demethylase, reduced nicotinamide adenine
dinucleotide phosphate (NADPH) cytochrome c reductase, and CO-binding pigment
(cytochrome P-450) were then measured. Pretreatment with inhibitors of pro-
tein synthesis (cycloheximide and actinomycin D) were used to block the effect
of MC on the hepatic drug-metabolizing system. Inhalation of MC (2500 to
3000 ppm) for 24 hr decreased the duration of action of hexobarbital, meproba-
mate, and zoxazolamine. This was accompanied by an increase in the metabolism
*
of hexobarbital, zoxazolamine find aminopyrine uj vitro by hepatic microsomal
enzymes. Cytochrome P-450 and cytochrome c reductase were also increased;
however, liver weight and liver microsomal protein were not enhanced. Pre-
treatment of rats with protein synthesis inhibitors prevented the MC induced
decrease in hexobarbital sleeping time and the increase in hepatic drug meta-
bolism. The authors concluded that MC may be inducing the production of a new
enzyme protein and that this protein may be used as a "prepathologic" measure
of MC toxicity.
Savolainin et al. (1977) investigated the effects of MC on rat brain and
liver after intermittent inhalation. Ten male Sprague-Dawley rats were exposed
to 500 ppm MC for 4 days, 6 hr daily. The right cerebral hemispheres were
homogenized and analyzed for protein, RNA, glutathione, and for the activity
002MC3/A 5-19 11-10-81
-------
of acid proteinases. Liver microsomes were analyzed for the amount of protein
and for cytochrome P-450 content. During exposure, the behavior of the exposed
animals was analyzed In an open field test and did not differ significantly
from that of the controls. Brain protein content was not affected; however,
the amount of RNA was lower than in the controls. MC decreased the liver
microsomal cytochrome P-450 content after cumulative exposure to the material
for 5 days. The authors explained the decrease in cytochrome P-450 by the
previously observed (Pelkonen and Vainio, 1975) affinity of MC for the type I
binding site.
McNutt et al. (1975) demonstrated hepatic lesions in mice after continu-
ous inhalation exposure to MC. CF-1 mice were exposed to 0, 250, or 1000 ppm
MC continuously for up to 14 weeks with a weekly serial sacrifice. At 1000
ppm, from 1 to 14 weeks, significant changes in centrilobular hepatocytes were
observed. Moderate liver triglyceride accumulation was evident in the 1000
ppm group and peaked at 40 mg/gm of tissue after 7 weeks of exposure (by 14
v
weeks the triglyceride level hSd not decreased to 16 gm). Electron micro-
scopic evaluation revealed that cytoplasmic alterations were most severe in
centrilobular hepatocytes in the 1000 ppm group and were mild to few in the
250 ppm group. The alterations consisted of vesticulation of the rough endo-
plasmic reticulum, with loss of attached polyribosomes, and increased smooth
endoplasrm'c reticulum, microbodies, and triglyceride droplets. Necrosis of
individual hepatocytes occurred in 40 percent of the mice exposed to 1000 ppm
for 12 weeks. This necrosis was associated with an acute inflammatory infil-
trate and hypertrophy of Kupffer cells. This study concluded that the effects
of MC were similar to carbon tetrachloride, but they appeared to be much less
severe.
002MC3/A 5-20 11-10-81
-------
TABLE 5-6. THE RELATIVE HEPATOTOX1C EFFICACY OF
CHLORINATED SOLVENTS
Relative hepatotoxic
Compound efficacy
1,1,1-trichloroethane 1
Tetrachloroethylene 3
Trichloroethylene 8
Sym-tetrachloroethane 12
1,1,2-trichloroethane 40
Chloroform 60
Carbon tetrachloride 190
Adapted from Plaa et al., (1958).
Table 5-6 shows the relative hepatotoxic effect of MC in comparison to
b
other chlorinated solvents. MC, according to Plaa et al., (1958), was judged
to be the least hepatotoxic of the seven solvents investigated.
5.2.2 Central Nervous System Effects
The most notable pharmacologic effect of methyl chloroform following
pulmonary vapor absorption is its action upon the central nervous syteir,.
Table 5-7 shows the occurrence of neurological signs of toxicity associated
with progressively increasing inhalant concentrations of MC in a variety of
species. At higher than anesthetic concentrations (approx. 10,000 pprc),
severe respiratory depression develops and cardiac arrest may occur.
5.2.3 Cardiovascular Effects
The cardiovascular effects produced by exposure to MC have been exten-
sively studied in recent years. Halogenated alkanes have been shown to sensitize
the heart to catecholamines and at the same time produce cardiac depression.
002MC3/A 5-21 11-10-81
-------
TABLE 5-7. PROBABLE RESULT OF SINGLE EXPOSURE
TO THE VAPORS OF METHYL CHLOROFORM
Exposure Concentration
time in air Expected effect in humans
(min) (ppm)
5 20,000 Complete incoordination and helplessness (R)
10,000 Pronounced loss of coordination (R)
5,000 Definite incoordination (R, M)
2,000 Disturbance of equilibrium. Odor is unpleasant
but tolerable (H)
15 10,000 Pronounced loss of coordination (R)
2,000 Loss of equilbrium (H)
1,000 Possible beginning loss of equilibrium (H)
30 10,000 Pronounced loss of coordination (R)
5,000 Incoordination (R, M)
2,000 Loss of equilibrium (H)
1,000 Mild eye and nasal discomfort; possible
slight loss of equilibrium (H)
60 20,000 Surgical anesthesia, possible death (R)
10,000 Pronounced loss of coordination (R)
5,000 Ofivious loss of coordination (R, M)
2,000 Loss of coordination (H)
1,000 Very slight loss of equilibrium (H)
500 No detectable effect, but odor is
obvious (R, H)
100 Apparent odor threshold (H)
(H) Expected effects are based on human data.
(M) Expected effects are based on monkey data.
(R) Expected effects are based on rat data.
From Stewart, (1968, 1971), Torkelson et al. (1958), and Toxicology
Committee, Am. Ind. Hgy. Assoc., 1964.
002MC3/A 5-22 11-10-81
-------
Krantz et al. (1959) were the first to observe the cardiac depression
produced by MC. Rats were deeply anesthetized with MC for 1 hr, at which time
the hearts were immediately removed. Cardiac ventricular slices were promptly
prepared and the oxygen uptake over the 1 hour period was Measured. MC
anesthesia was associated with a significant diminution (33.3 percent) in
oxygen uptake of the myocardium. Blood pressure studies in dogs also revealed
that anesthesia with MC elicited a depressed response. At the point of respi-
ratory arrest, the blood pressure was reduced to approximately one-half its
normal value. Ether anesthesia under similar conditions results in only a
slightly depressed blood pressure. Six dogs and two rhesus monkeys were
anesthetized and electrocardiograms recorded. The pattern of the electro-
cardiogram was essentially unaltered; the heart rate was increased and the
T-wave was either flattened or inverted. At the point of respiratory arrest,
a depressed S-T segment was observed; however, tachycardia was absent.
Herd and co-workers (1973, 1974) confirmed the initial observations of
Krantz et al. (1959). They exposed dogs to MC (104-4 x 10 ppm/min) and
observed a dose-dependent biphasic decline in arterial blood pressure. Since
cardiac output increased initially, the initial decline in pressure (within 10
to 15 seconds after introduction of MC) was due to a decrease in total
peripheral resistance (TPR). Injection of phenylephrine (pure alphaagonist)
reversed the peripheral vascular effects, indicating that MC does not act
directly on the vascular musculature. The second phase of blood pressure
decline was found to be associated with a decrease in myocardial contracti-
lity, reflected by a decline in both heart rate and stroke volume. Exogenous
Ca** reversed the MC induced decline in myocardial contractility, but had no
effect on the initial phase of peripheral vasodilation.
002MC3/A 5-23 11-10-81
-------
Taylor et al. (1976) exposed New Zealand white rabbits to a series of
haloalkane chemicals. The animals were first anesthetized with sodium pento-
barbital, then fitted with various cannulas allowing for the measurement of
mean arterial pressure, left ventricular pressure, left ventricle dP/dt,
cardiac output, stroke volume, heart rate, left ventricular end-diastolic
pressure, central venous pressure, and peripheral vascular resistance.
Table 5-8 lists the left ventricular and hemodynamic effects of 50,000 pprr MC.
There was no effect on heart rate, left ventricular end-diastolic pressure,
central venous pressure, or peripheral vascular resistance. During exposure,
no cardiac arrhythmias were observed nor was there a significant change in pH,
oxygen, or carbon dioxide tensions. As a cardiac depressant, MC appeared to
be as potent as halothane and fluorocarbon 11.
Numerous hydrocarbon compounds have been shown to sensitize the myo-
cardium to catecholamines. In humans, for example, several unexplained deaths
have been associated with solvent abuse or overexposure; ventricular fibrilla-
»
tion due to cardiac sensitization has been suggested as the underlying
mechanism. The cardiac sensitization potential of MC has been investigated
under various circumstances. In an early study, Rennick et al. (1949) re-
ported MC and epinephrine induction of idioventricular rhythms in dogs.
Attempts to induce MC anesthesia resulted in the sudden death, presumably of
cardiac origin, of two animals. Ventricular extrasystoles and ventricular
tachycardia were seen in five dogs under barbital anesthesia when epinephrine
was injected after "repeated small doses" of MC. Maximum sensitization of the
heart to epinephrine occurred after the administration of 0.25 to 0.4 ml/kg of
MC. Further administration of this compound produced severe hypotension.
Somani and Lum (1965), Lucchesi (1965), and Hermansen (1970) administered MC
002MC3/A 5-24 11-10-81
-------
o
o
ro
3
n
OJ
ro
tn
TABLE 5-8. LEFT VENTRICULAR AND HEMODYNAMIC EFFECTS OF METHYL CHLOROFORM
a
Pre-exposure
1 minute post
exposure
Mean
Arterial
Pressure
(mmHg)
69±5
45+4
Left
Ventricular
Pressure
(mmHg)
97±3
7*0+5
Left
Ventricle
dP/dt
(mmHg/sec)
3792+325
1433+163
Cardiac
Output
(ml/min)
423+31
266+26
Stroke
Vo 1 ume
(ml)
1.47+0.09
0.92+0.07
All values at 1 minute exposure are significantly different from pre-exposure values at p <0.05.
Source: Taylor et al. (1976).
I
«—"
o
oo
-------
to dogs or mice as a method for induction of cardiac arrhythmias in studying
and characterizing the sensitivity and specificity of adrenergic blocking
agents.
Clark and Tinston (1973) evaluated the cardiac sensitizing potencies of
14 halogenated hydrocarbons in conscious beagle dogs. During the last 10
seconds of a 5 min exposure, epinephrine (5 mg/kg) was injected intravenously
(bolus). As a control, epinephrine was given prior to exposure and also 10
min after the end of exposure. The electrocardiogram (lead II) was monitored
continuously during this procedure. Several dose levels of the chemical being
tested were used, each differing by a factor of two. The concentration at
which 50% (EC50) of the animals could be sensitized was calculated by a moving
average interpolation. The mean concentration of MC which produced cardiac
sensitization in 50% of the animals tested was 7,500 ppm (4,000 to 11,000).
The authors found that they could directly predict the ECrQ for cardiac sensi-
tization by knowing the vapor pressure at 37°C and the partial pressure at the
EC^Q. Table 5-9 lists the EC^Q for a number of different halogenated hydro-
carbons. MC appears to be a highly potent sensitizing agent, with tetrachloro-
difluoromethane being the most potent in the series. The authors concluded
that cardiac sensitization was probably a structurally nonspecific action and
that it was physically toxic.
Reinhardt et al. (1973) investigated five commonly used industrial and
household solvents, including MC, to assess their cardiac-sensitization poten-
tial. The investigators conducted experiments on unanesthetized, healthy male
beagle dogs that had been trained to breathe through a one-way face mask while
supported in a standing position by a sling. The dog inhaled house air for 7
minutes and the test compound for 10 minutes. Epinephrine (8 ug/kg in 1 ml of
normal saline) was injected i.v. in 9 seconds as a control dose after 2 minutes
002MC3/A 5-26 11-10-81
-------
TABLE 5-9. CONCENTRATION OF CHEMICALS CAUSING CARDIAC
SENSITIZATION AND THEIR PHYSICAL PROPERTIES (IN PPM)
hemical
etrachl orodi f 1 uoromethane
arbon tetrachloride
richloroethane
alothane
richlorotrif luoroethane
ethylene chloride
richlorof luoromethane
ichlorof luoromethane
ich-lorotetraf luoroethane
inyl chloride
ropane
romotr i f 1 uoromethane
hlorotrif luoromethane
EC50
1,200
5,000
7,500
20,000
10,000
24,000
12,500
25,000
100,000
50,000
200,000
200,000
800,000
Vapor pressure
at 37 C (mmHg)
Ps
99
190
210
480
524
661
1,186
2,052
2,310
4,218
9,538
15,276
40,698
Partial
pressure at
EC50(mmHg)
Pcs
2
4
6
15
8
18
10
19
76
38
153
153
610
Relative
saturation
for cardiac
sensitization
Pcs/Ps
0.02
0.02
0.03
0.03
0.02
0.03
0.01
0.01
0.03
0.01
0.02
0.01
0.02
ource: Clark and Tinston (1973).
002MC3/A
5-27
11-10-81
-------
of breathing air, and as a challenge dose after 5 minutes of breathing the
test compound. The 10-minute interval between the two doses was found to be
adequate to prevent additive effects when tested in 13 control dogs subjected
to the same procedures, but with air substituted for the test compound. A
positive response was considered to be either cessation of cardiac output
(ventricular fibrillation) or the development of an arrhythmia that was not
observed following the control dose and that was considered to pose a serious
threat to life (multiple, consecutive beats of ventricular origin). The
concentration of the test compound being delivered to the animal was deter-
mined by gas chromatography at 2-minute intervals.
The results obtained for MC indicated no response in 12 dogs at a nominal
concentration of 0.25 percent (V/V) and a marked response in 3 of 18 dogs
exposed at a nominal concentration of 0.5 percent (V/V); 12 of 12 responded at
a nominal concentration of 1.0 percent (V/V). However, unlike the other
substances, MC-induced ventricular fibrillation in the animals from the 1.0
percent group reverted to multiple consecutive ventricular beats within a
matter of seconds and eventually recovered to a normal cardiac rhythm. The
results confirm earlier reports that MC is capable of sensitizing the dog
heart to epinephrine.
Trochimowicz and co-workers (1976) were concerned with the problem of
haloalkane-induced cardiac sensitization in patients who had survived myo-
cardial infarction. They induced myocardial infarction in beagle dogs and
tested for cardiac sensitization to epinephrine after exposure to MC (2500,
3700, and 5000 ppm). Myocardial infarction failed to significantly lower the
threshold for cardiac sensitization. There was no greater potential for
cardiac sensitization among dogs having recovered from myocardial infarction
as compared to normal healthy animals.
002MC3/A 5-28 11-10-81
-------
At sufficiently high levels (in the thousands of ppm, for durations of
exposure of the order of minutes), MC can cause significant alterations in
cardiovascular function in a variety of experimental animals, including mice,
rabbits, dogs, and possibly monkeys. The concentration levels reported for
these effects are generally more than an order of magnitude greater than the
current TLV for humans of 350 ppm (0.035 percent) and are likely to be lethal
to the experimental animals if the exposure is continued for more than several
minutes. Indeed, some experimenters appeared to find it necessary to increase
the oxygen content of the inspired gas/air mixture to 40 percent to prevent
asphyxia of the exposed animals. That they appeared unable to find effects at
lower exposure levels is noteworthy. Also noteworthy is the fact that many of
the investigators reported complete recovery of the animals if the exposure
was stopped. This was the case, for example, with the dog experiments of
Reinhardt et al. (1973), and Trochimowicz et al. (1976). At necropsy follow-
ing sacrifice of several of the animals several months after exposure, there
t
was no pathology attributable t*o the exposure per se. Delayed cardiotoxicity
from acute exposure has not yet been demonstrated or ruled out.
5.3 TERATOGENICITY, MUTAGENICITY, AND CARCINOGENICITY
It has been proposed that the susceptibility of individuals to cancer is
related to their ability to metabolize carcinogenic compounds to benign mole-
cules and, conversely, to their capacity to metabolize benign compounds to
carcinogens (Kellerman et al., 1973). Susceptibility may be partly explained
by genetic differences involving enzymatic pathways, repair mechanisms, and
immune response mechanisms. An assessment of the carcinogenic potential of MC
must therefore take into account tissue concentrations of MC during typical
exposures (e.g., TLV-TWA, 350 ppm), as well as the extent and nature of MC
002MC3/A 5-29 11-10-81
-------
metabolism. Both these aspects have been extensively reviewed in Chapter 4.
While our knowledge is still limited in these areas, it can be concluded that
MC is metabolized in humans to a very small extent. About 6 percent of the
body dose is converted by a hepatic microsomal oxidase system to trichloro-
ethanol. The mechanism of this overall reaction is unknown, as is the poten-
tial for generation of "reactive intermediate compounds" which may contribute
to organ toxicity and/or carcinogenesis. Until further research is done,
particularly studies to determine how and whether intermediate reactive com-
pounds from MC metabolism bind to cellular macromolecules, an evaluation of
mutagenicity and carcinogenicity roust be made solely on the biological effects
of MC in various direct mutagen and carcinogen tests. Unfortunately, MC has
not been subjected to extensive and thorough testing. The available studies
are summarized in Table 5-10.
5.3.1 Teratogenicity, Embryotoxicity,and Reproductive Effects
5.3.1.1 Overview—This review subscribes to the basic viewpoints and defini-
tions of the terms "teratogeni£" and "fetotoxic" as summarized and stated by
Chernoff (1980):
Generally, the term "teratogenic" is defined as the tendency to produce
physical and/or functional defects in offspring n\ utero. The term "fetotoxic"
has traditionally been used to describe a wide variety of embryonic and/or
fetal divergences from the normal which cannot be classified as gross terata
(birth defects) -- or which are of unknown or doubtful significance. Types of
effects which fall under the very broad category of fetotoxic effects are
death, reductions in fetal weight, enlarged renal pelvis edema, and increased
incidence of supernumary ribs. It should be emphasized, however, that the
phenomena of terata and fetal toxicity as currently defined are not separable
into precise categories. Rather, the spectrum of adverse embryonic/fetal
effects is continuous, and all deviations from the normal must be considered
as examples of developmental toxicity. Gross morphological terata represent
but one aspect of this spectrum, and while the significance of such structural
changes is more readily evaluated, such effects are not necessarily more
serious than certain effects which are ordinarily classified as fetotoxic--
fetal death being the most obvious example.
In view of the spectrum of effects at issue, the Agency suggests that it
might be useful to consider developmental toxicity in terms of three basic
subcategories. The first subcategory would be embryo or fetal lethality.
002MC3/A 5-30 11-10-81
-------
TABLE 5-10. ONCOGENIC TERATOGENIC TESTING OF METHYL CHLOROFORM
Test System
Species
Reference
Results
Teratogem'city
Organogenesis
Mammalian gestation
Carcinogenicity
NCI bioassay - 2 yr
NTP bioassay - 2 yr
Industry bioassay -
1.5 yr
Chick embryo
S/0 rat, S-W mice
Elovaara et al., 1979
Schwetz et al., 1975
Osborne-mendel rats, and' NCI, 1977; NCI Clearinghouse on
BfiC3F| mice and oral Environmental Carcinogens, 1977
gavage; 750 and 1500
mg/kg (rat)
Rat and mouse gavage
S/D rats, inhalation 875
and 1750 ppm
Positive; high toxic dose,
skeletal abnormalities
Negative
Inconclusive; high animal
mortality
In progress
Negative
NOTE: See appendix for discussion of chemical purity.
-------
This is, of course, an irreversible effect and may occur with or without the
occurrence of gross terata. The second subcategory would be teratogenesis and
would encompass those changes (structural and/or functional) which are induced
prenatally, and which are Irreversible. Teratogenesis includes structural
defects apparent in the fetus, functional deficits which nay become apparent
only after birth, and any other long-term effects (such as carcinogenicity)
which are attributable to ui utero exposure. The third category would be
embryo or fetal toxicity as comprised of those effects which are potentially
reversible. This subcategory would therefore include such effects as weight
reductions, reduction in the degree of skeletal ossification, and delays in
organ maturation.
Two major problems with a definitional scheme of this nature must be
pointed out, however. The first is that the reversibility of any phenomenon
is extremely difficult to prove. An organ such as the kidney, for example,
may be delayed in development and then appear to "catch up". Unless a series
of specific kidney function tests are performed on the neonate, however, no
conclusion may be drawn concerning permanent organ function changes. This
same uncertainty as to possible long-lasting after effects from developmental
deviations is true for all examples of fetotoxicity. The second problem is
that the reversible nature of an embryonic/fetal effect is one species might,
under a given agent, react in another species in a more serious and irrever-
sible manner.
It is not possible, on the basis of limited available data, to define the
full potential of MC to produce adverse teratogenic or reproductive effects.
Human epidemiology studies have not been conducted to evaluate the effects of
MC on the exposed population. 'The available mammalian studies were not pro-
perly designed to evaluate the ability of MC to produce a teratogenic response
over a wide range of doses, which should include doses high enough to produce
signs of maternal toxicity and lower doses which do not produce this effect.
The teratology studies which were performed with laboratory animals used rats
and mice and only single doses of MC which produced signs of maternal toxicity.
Other studies in chicken embryos have indicated that MC disrupts embryogenesis
in a dose-related manner. However, since administration of MC directly into
the air space of chicken embryo is not comparable to administration of a dose
to animals with a placenta, it is not possible to interpret this result in
relationship to the potential of MC to cause adverse human reproductive effects.
002MC3/A 5-32 11-10-81
-------
In summary, although several studies have been conducted to evaluate the
ability of MC to cause adverse teratogenic, embryotoxic and reproductive
effects, the limitations of the available data does not allow for a full
assessment of these effects. A better assessment of these effects could be
performed if the available studies met criteria similar to those suggested for
teratogenicity and reproductive testing (U.S. EPA, 1978).
5.3.1.2 Human Studies—No clinical reports associate maternal exposure to
methyl chloroform with congenital malformations in offspring. No epidemic-
logical studies have been performed.
5.3.1.3 Animal Studies—All studies performed to date in mammals have been
done in rats and mice. On the basis of these studies, it does not appear that
short- or long-term exposure to MC results in teratogenic effects in rats, or
that short-term exposure to MC results in such effects in mice. Delays in
fetal development have been observed in both species, but this may be a rever-
sible effect. It should be noted, however, that these studies evaluated only
one dosage level per animal spe'cies, which included dosages twice the maximum
excursion limit for short-term exposures of rats and mice and six times the
maximum excursion limit for long-term exposures of rats. Another study in
chicken embryos indicates that MC may have teratogenic potential in this
species. However, since it is not known how comparative studies in chicken
embryos are to those in other mammalian species, the teratogenic potential of
MC in chickens cannot be related to other animals without additional data. In
addition, no multi-generational studies of mammalian reproductive performance
have been performed.
5.3.1.3.1 Rats--Schwetz et al. (1975) report results from Sprague-Dawley rats
exposed via inhalation to 875 ppm of MC for 7 hours daily on days 6 through 15
of gestation (Day 0 = the day sperm were observed in smears of vaginal contents).
002MC3/A 5-33 11-10-81
-------
Control rats were exposed to filtered air. Dams were evaluated for body
weight gain, food consumption and various organ weights. Maternal carboxy-
hemoglobin level determinations were performed on blood samples collected via
orbital sinus puncture immediately following the third and tenth (last) ex-
posure. One-half of the fetuses in each litter were examined for soft-tissue
malformations (free-hand sectioning), and one-haIf were stained and examined
for skeletal malformations. One fetus in each litter was randomly selected
and evaluated using histological techniques following serial sectioning.
Twenty-three litters from dams exposed to 875 ppm of methyl chloroform
were evaluated. No effect was observed on maternal body weight or food con-
sumption. The mean absolute liver weight was increased as compared with
control, however the mean relative liver weight was unchanged. No embryotoxic
or teratogenic effects were observed which were attributable to maternal MC
exposure.
York et al. (1981) exposed Long-Evans rats by inhalation to dosages of
2100 ± 200 ppm MC for 6 hours da'ily, 5 days per week, in the following regime:
(1) two weeks prior to mating through day 20 of gestation; (2) two weeks prior
to mating only; (3) throughout gestation only; (4) controls which were exposed
to filtered air before and during pregnancy. Day 1 of pregnancy was designated
as the day spermatozoa were observed in smears of vaginal contents. One-half
of each group was sacrificed on day 21 and assessed for signs of maternal
toxicity, embryotoxicity or teratogenicity. The other one-half were allowed
to deliver young naturally. When possible, litters were culled to four pups
of each sex on day 4 postparturition and to two pups of each sex at 21 days
postpartum. Pups were evaluated for behavioral effects (open field activity,
running wheel activity, amphetamine challenge) and carcinogenicity. Surviving
rats were sacrificed and necropsied at 12 months of age.
002MC3/A 5-34 11-10-81
-------
York et al. (1981) reported that both total fetal body weight and male
fetal body weight were significantly depressed in litters exposed during
pregnancy. Delayed ossification was more frequent in fetuses which had been
exposed before and during pregnancy, and a delay in the development of the
kidney was a more frequent observation in fetuses in all exposed groups.
These effects are thought to be indicative of a slight, but possibly rever-
sible delay in development. No treatment-related behavioral effects were
observed in the pups, nor were significant signs of maternal toxicity observed.
5.3.1.3.2 Mice--Schwetz et al. (1975) exposed Swiss-Webster mice to 875 ppm
of MC, twice the maximum excursion limit, for 7 hours daily, on days 6 through
15 of gestation (day 0 = day a vaginal plug was observed). Dams were Caesarean
sectioned on day 18 of gestation and thirteen litters were evaluated. Methodo-
logy similar to that described previously (Schwetz et al. 1979) in rats was
used, with the exception that food consumption was not monitored.
Mean and relative maternal liver weights in the exposed rats were slightly
4.
but not statistically decreased. Also, fetuses from the exposed group were
slightly but not statistically smaller (both the crown-rump length and the
body weight). This type of observation is thought to indicate a slight, but
perhaps reversible delay in fetal development. No increased soft tissue or
skeletal variations of the fetuses were attributable to maternal exposure to
MC.
5.3.1.3.3 Chicken embryos—Elovaara et al. (1979) evaluated the effects of a
number of aliphatic hydrocarbons on the development of chick embryos and
reported the toxicity and teratogenic potential of MC in relationship to those
of other aliphatic chlorinated hydrocarbons. MC was injected into the air
space of fertilized chicken eggs at 2, 3, and 6 days of incubation and the
rate of survival or death after 14 days of incubation was used as a measure of
002MC3/A 5-35 11-10-81
-------
embryotoxicity. The approximate LD5Q value of MC varied between 50 and 100
uM/egg, depending upon time of injection. The types of abnormalities reported
were absence of eye(s), upper beak deformations, exencephaly, brain hemorrhages,
paleness (anemia), profound edemas either in the rump sacs or other areas,
defects in external viscera and musculoskeletal defects of lower extremities.
The spontaneous background level of malformations in vehicle-injected controls
included only eye and skeletal abnormalities. This study indicates that MC
has possible teratogenic potential when evaluated in chicken embryos, and that
additional experiments should be performed for further evaluation. A scienti-
fic basis for the comparison of developmental toxic effects in various animal
species is needed before results in chickens can be compared with other
mammalian animal species.
5.3.2 Mutagenicity
Methyl chloroform has been tested for its mutagenic potential in several
systems (bacteria, yeast, and rats), but sufficient data are not presented for
evaluating the results presented in three papers (the Dow 1978 rat cytogenetic
study, the Henschler et al. 1977 testing in Salmonclla, and the Loprieno el
al. 1980 testing in yeast). Of the remaining papers, only two described the
results of mutagenicity testing conducted in such a manner as to prevent
evaporation of MC and to ensure exposure of the indicator organisms. Both of
these tests (Simmon et al. 1977 and Snow et al. 1979) were conducted in
Salmonclla and a weak positive response was reported for both.
On the basis of the available evidence, it is concluded that MC is muta-
genic in bacteria. If the metabolism and pharmacokinetics of this compound in
humans results in metabolic products which can interact with DNA as is the
case for bacteria, it may cause mutagenic effects in humans as well. However,
additional testing in other organisms (e.g., mammalian cells in culture) is
002MC3/A 5-36 11-10-81
-------
necessary to confirm the mutagenicity observed in bacteria. Careful attention
should be given to the design and conduct of these studies to prevent the
evaporation of MC, overcome its low solubility in aqueous media, and to ensure
exposure of the indicator organisms.
Results from a joint study sponsored by Imperial Chemical Industries and
the Medical Research Council in the United Kingdom and the National Institute
of Environmental Health Sciences in the USA, conducted to assess the ability of
short-term tests to predict carcinogenicity, have recently been published
(8/6/81). EPA has not received a copy of this report to evaluate these data.
Although preliminary indications are that MC tested negative, no information
was available concerning which, if any, precautions were taken to ensure
exposure of the organisms to the compound in these preliminary reports. These
data will be evaluated critically in the near future when the Agency receives
a copy of the final report.
Price et al. (1978) exposed Fischer rat embryo cell cultures (F1706,
•. i
subculture 108) to 1,1,1-trichlbroethane liquid at concentrations of 9.9 x 10
and 9.9 x 10 uM for 48 hours. 1,1,1-trichloroethane was diluted with growth
medium to yield the appropriate doses. The 1,1,1-trichloroethane sample
obtained from the Fisher Scientific Company was purportedly > 99.9 percent
pure, but a personal communication from Carlson of the Fisher Scientific
Company revealed that methyl chloroform supplied by them to Dr. Price was
really the product of the Dow Chemical Company which is about 95 percent pure.
The cells were grown in Eagles minimum essential medium in Earle's salts
supplemented with 10 percent fetal bovine serum, 2 mM L-glutamine, 0.1 mM
nonessential amino acids, 100 ug pencillin, and 100 ug streptomycin per ml.
Quadruplicate cultures were treated at 50 percent confluency with each dose.
002MC3/A 5-37 11-10-81
-------
After treatment, cells were cultured in growth medium alone at 37°C. Trans-
formation of cells treated with either dose level of 1,1,1-trichloroethane was
observed by 23 and 44 days of incubation and was characterized by progres-
sively growing foci composed of cells lacking contact inhibition and orienta-
tion. There was no transformation of cells grown in medium alone or in the
presence of a 1:100 acetone concentration. Fifty-two and 55 microscopic foci
per three dishes with low and high 1,1,1-trichloroethane dose, respectively,
were found in dishes inoculated with 50,000 cells from cultures treated four
subcultures earlier and held for four weeks at 37°C in a humidified CO^ incu-
bator prior to staining.
5.3.3 Carcinogenicity
[NOTE: Refer to Carcinogen Assessment Group's assessment of MC attached
to this document as Appendix I.]
At this time, direct animal bioassays for MC carcinogenicity have been
carried out but are inconclusive. Table 5-11 gives the results of National
Cancer Institute (NCI) animal bioassays of congeners of MC. The isomer 1,1,2-
trichloroethane is carcinogenic in mice, inducing liver cancer and pheochromo-
cytoma in both sexes. Oi- and tetrachloroethanes and hexachloroethane also
produce liver carcinomas in mice.
The initial NCI bioassay of MC (1977) was carried out in both sexes of
Osborne-Mendel rats and BgC.Fj mice by oral gavage at two dose levels (rats,
750 and 1,500 mg/kg, 5 days/wk; mice, 2,807 and 5,615 mg/kg time weighed
average) for 78 weeks. Animals were observed for another 12 weeks for a total
of 90 weeks in the experiment. In male rats, 64 percent given the low dose
and 72 percent given the high dose died within the first year, while 48 per-
cent of females given the low dose and 42 percent given the high dose died
002MC3/A 5-38 11-10-81
-------
o
o
ro
3
O
TABLE 5-11. SUMMARY OF NCI CHLOROETHANE BIOASSAY RESULTS AS OF JULY 1978 (Parker, et al., 1979)
Compound
Species/sex Tumor site
Statistically significant tumors
monochloroethane
no testing planned
1,1-dichloroethane
retesting recommended because initial results inconclusive
1,2-dichloroethane
rats/female
rats/male
mice/female
mice/male
mammary gland
forestomach
circulatory system
subcutaneous tissue
mammary gland
endometrium
lungs
adenocarcinomas
squamous cell carcinomas
hemangi ocarci nomas
fibromas
adenocarcinomas
stomal sarcomas
adenomas
adenomas
1,1,1-trichloroethane
retesting in progress
1,1,2-trichloroethane
mice/female
mice/male
mice
1 iver
1 iver
adrenal glands
hepatocellular carcinomas
hepatocellular carcinomas
pheoc h romocy toma s
1,1,1,2-tetrachloroethane
testing in progress, no report available
1,1,2,2,-tetrachloroethane
mice/male
mice/male
liver
liver
hepatocellular carcinomas
hepatocellular carcinomas
pentachloroethane
testing in progress, no report available
I
I—I
o
oo
hexachloroethane
mice/female liver
mice/male liver
hepatocellular carcinomas
hepatocellular carcinomas
-------
within a year. Similar mortality was observed in mice. The high mortality
and symptoms of other toxic effects indicate that the maximum tolerated dose
may have been exceeded. These high doses may also alter metabolism.
However, mortality was also high in untreated control rats (30 percent)
and control mice (50 percent). It should be noted that MC bioassay animals
were housed with animals receiving a variety of other chlorinated hydrocarbons.
Although a variety of neoplasms were found in both treated and control rats
and mice (Table 5-12), there was no dose-related increased incidence of tumors
in either sex or species. The NCI Report (1977) does not comment on whether
the failure to demonstrate careinogenicity for MC is due to lack of carci-
nogenic potential for this compound or due to the bioassay design and obviously
poor experimental conditions. NCI is currently testing MC in rats and mice by
gavage at lower doses.
Table 5-13 summarizes the results of an industry sponsored chronic bio-
assay (Quast et al., 1978; Rampy et al., 1977) by inhalation exposure to MC.
Male and female rats were exposed 6 hours/day, 5 days/week to 875 ppm and
1,750 ppm over a period of 52 weeks or about one-half their lifetime. The
actual amount of MC absorbed via the lungs by the rat and by the tissues was
not determined and cannot be estimated without metabolism and pharmacokinetic
data for the rat. Based on the tumor incidence in the treated rats, which was
similar in classification to those of the control animals, MC exposure did not
result in a carcinogenic outcome. On the other hand, the inhalation dose of
MC was only two- to threefold higher than that allowed in the workplace and
only one species was tested.
In recent years, a great deal of attention has been focused on the role
of MC in the destruction of stratospheric ozone (0,). Because 03 absorbs most
of the ultraviolet (UV) radiation in the 290 to 320 nm wavelength range before
002MC3/A ' 5-40 11-10-81
-------
o
o
f\>
o
to
3>
TABLE 5-12. SUMMARY OF NEOPLASMS IN RATS AND MICE INGESTING
METHYL CHLOROFORM
Number of
Species Sex Animals
Rat Male 20
50
50
Female 20
50
50
in
i. Mouse Male 20
- 50
50
Female 20
50
50
3
Dose3
_
750
1500
_
750
1500
-
2807
5615
-
2807
5615
Total number
of tumors
3
6
4
14
6
12
5
2
9
5
2
3
Liver,
spleen
1
1
-
.
-'
1
2
1
8
2
1
"
Number of tumors observed
Lung
_
-
-
_
-
-
1
1
1
.
-
1
Kidney, Integumentary
bladder system
1
-
1
_ -
-
1
-
-
-
2
1
1
Heart,
vasculature
_
1
1
_
-
1
-
-
-
-
-
™
Brain,
pituitary
—
1
-
3
2
1
-
-
-
1
-
™
Other
1
3
3
11
4
8
2
-
—
5
-
1
Compound administered in corn oil by stomach tube five days per/week.
Concentration is a time-weighted average expressed in mg/kg/day.
Source: National Cancer Institute, 1977.
o
oo
-------
o
o
ro
TABLE 5-13. SUMMARY OF NEOPLASMS IN RATS INHALING
METHYL CHLOROFORM
en
i
rvj
Number of tumors
Number of
Sex Animals
Male 189
94
92
Female 189
94
92
Concentration
(PPM)
875
1750
_
875
1750
Total number
of tumors
200
77
103
561
264
300
Liver,
spleen
2
1
-
\
1
3
Kidney,
Lung bladder
1 2
2
1
1 2
1
1
Integumentary
system
36
11
21
328
177
223
observed
Heart,
vasculature
-
1
2
-
Brain,
putuitary
39
13
21
102
28
35
Other
120
50
60
124
57
38
Source: Quast et al., 1978.
CO
-------
it reaches the earth's surface, a decrease in 0- concentration could be dele-
terious to biological processes. It is known that nucleic acids and proteins
absorb significantly in this wavelength range, with molecular disruption that
results in genetic mutations. Alteration of nucleic acids by UV irradiation
of tissues leads to an increased prevalence of skin cancer (National Research
Council 1976, 1979).
Depletion of stratospheric 0, levels have been correlated with an in-
crease in the incidence of skin cancer (National Research Council, 1976; 1979;
1982). Accelerated usage of MC would be expected to cause a further increase
in O^ depletion, thus resulting in higher incidence of skin cancer. Prelimi-
nary information from an ongoing epidemiological study of skin cancer suggest
that the incidence of nonmelanoma skin cancer in the United States may even be
greater (NCI, unpublished results, August 1979).
5.4 SUMMARY OF ADVERSE HEALTH EFFECTS AND LOWEST OBSERVED EFFECTS LEVELS
5.4.1 Inhalation Exposure
The high volatility of methyl chloroform (MC), the extensive use of this
compound as an industrial solvent, and the early interest in MC as an anesthetic
has resulted in many reports in the scientific literature of human exposure to
MC. Human experimental studies have been performed using acute and subchronic
exposures to MC. Although these studies provide precise information on ex-
posure levels, they are limited by the small numbers of subjects employed in
the studies and the restricted number of physiological and behavioral para-
meters which were assessed. While information on human chronic inhalation
exposure to MC is available from studies of occupationally exposed groups,
there is uncertainty in these studies as to the exact extent of exposure; some
studies are complicated by simultaneous exposure to other chemicals used in
the workplace. Although these human studies have deficiencies which preclude
002MC3/A 5-43 11-10-81
-------
any individual study from being used for human risk assessment, the combined
information presented in these studies does provide dose-response relation-
ships which give a relatively clear description of the toxic effects of MC.
Studies in experimental animals are available for acute and subchronic ex-
posure to MC, but the uncertainty of extrapolation from animals to humans and
the relatively large number of controlled human studies of acute exposure
makes this animal data useful only in a supportive role for human risk assess-
ment. No adequate chronic studies using experimental animals are available
and although the reports of human occupational experience with MC are not
ideal, they provide the best information on the effects of chronic exposure to
MC.
5.4.1.1 Effects of Single Exposures—Lethal effects of acute exposure to MC
have been reported after accidental exposure and abuse, with death resulting
from CNS depression followed by respiratory and cardiac failure (Hall and Hine
1966; Bas, 1970; Stahl et al., 1969; Bonventre et al., 1977; Klienfeld and
Feiner, 1966; Halfield and MayKoski, 1970; Caplan et al., 1976). From the
levels of MC in the blood and brain of cadavers, estimates have been made of
the concentration of MC present in the air during the time the victim was
exposed. These estimates range from 200 to 102,900 ppm, with the majority of
values being between 6,700 and 18,600 ppm (Table 5-14). However, these esti-
mates are extremely crude and probably low since it is not known to what
degree the MC had dissipated from the victims' body prior to obtaining tissue
samples. Also, some of the observed deaths which occurred at relatively low
MC concentrations may have resulted from aspiration pneumonia prior to exten-
sive involvement of the CNS. A clearer indication of the levels of MC needed
to produce narcosis is available in the study of Dornette and Jones (1960)
investigating the use of MC as an anesthetic in humans. Although this study
002MC3/A 5-44 11-10-81
-------
TABLE 5-14. HUMAN FATALITIES ASSOCIATED WITH METHYL CHLOROFORM
Case
No. Sex
1
2
3
4
5
6
7
8
9
10
11
12
F
M
M
M
M
M
M
M
M
M
F
M
Material or
Product Inhaled
Energine
1,1,1-trichloro-
ethane
"degreaser"
K)
Chlorothene
1,1,1-trichloro-
ethane
n
11
"
"
"paint remover"
"paint thinner"
1,1,1-trichloro-
ethane
1,1
,1-Trichloroe thane
Concentrations
Lungs at Autopsy Blood mg%
passive congestion
no autopsy
acute congestion
and edema
heavy, edematous
heavy, edematous
heavy, edematous
heavy, edematous
heavy, edematous
moderately edematous
moderately edematous
acute edema & con-
gestion
markedly edematous
72
30.0
13
12.0
6.3*
6.2
6.0
6.0
4.7*
2.0
0.15
Air ppmx Remarks
102,900
75,000 ppm in work
space; collapsed
after leaving work
area
42,900
18,600 possible aspira-
tion, pneumonia
17,000
9,000
8,900
8,600
8,600
6,700
2,900 ethanol cone, in
blood was 0.04%
200 possible aspira-
tion, pneumonia
Source
Hall and Hine
Kleinfeld and
Bonventre et
Hall and Hine
Stahl et al. ,
Stahl et al. ,
Stahl et al. ,
Stahl et al. ,
, 1966
Feiner, 1966
al., 1977
, 1966
1969
1969
1969
1969
Hatfield and Maykoski, 1970
Stahl et al. ,
Caplan et al.
Stahl et al. ,
1969
, 1976
1969
Calculations based on assumption from Stfwart et al., 1969, of one hour exposure correlating to 0.07 mg
percent in blood per 100 ppm in air.
*flstimated from brain concentration.
-------
study gives an indication of the levels of MC which cause CNS depression,
presumably a higher concentration would be needed to cause depression severe
enough to result in respiratory or cardiac failure. From these data and the
LC50 concentrations of 14,250 ppm obtained by Adams et al. (1950) for rats, it
can be estimated that a single exposure to concentrations of MC less than
5,000 ppm are probably not potentially life threatening in humans, while
higher concentrations may produce narcosis and possibly death.
The effects of exposure of human volunteers to MC for single short term
periods were reported for MC levels far below the levels which cause narcosis
(Table 5-15). Stewart et al. (1961) exposed 7 subjects to vapors of MC which
were increased from 0 to 2,600 ppm in increments of 15 minutes each. The
progress of observed effects is presented in Table 5-1, with 6 of 7 subjects
complaining of throat irritation at 1,900 ppm and lightheadedness and incoor-
dination occurring between 2,600 and 2,650 ppm. The progressive exposure
method used in this study and the small number of subjects makes the results
difficult to interpret. However, in a second experiment in which subjects
were exposed to 900 MC for periods of 20, 35, or 73 minutes, difficulty was
observed in the performance of the Romberg tests, and some lightheadedness was
experienced. No effects were observed in subjects exposed to 500 ppm for MC
for 78 or 186 min. In both of these experiments, commercial grade MC was used
which contained the inhibitors dioxane (2.4-3.0%), butanol (0.12-0.3%) and
small amounts of 1,2-dichloroethane. These compounds may have also had some
effect on the subjects. In support of the above findings, Torkelson et al.
(1958) obtained similar results with 2 groups of 4 subjects each exposed to
900 or 500 ppm of pure MC for 75 to 90 minutes. Subtle changes in perceptive
capability were observed following exposure to 350 and 450 ppm of MC by
Gamborale and Haltengren (1973) and Salvini et al. (1971). However, these
002MC3/A 5-46 11-10-S1
-------
TABLE 5-15. NON-LETHAL EFFECTS OF METHYL CHLOROFORM ON HUMANS
Study
Dose/Species
Effect
Dornette & Jones, 1960
10,000-26,000 ppm
6,000-22,500
Siebecker et al., 1960
Stewart et al., 1961
Torkelson et al. , 1958
Torkelson et al. , 1958
Stewart, 1968; 1971
Am. Ind. Hyg. Assoc.
Stewart et al., 1969
Stewart et al., 1975
Anesthesia
0-2,650 ppm
for 15 min
500 ppm
900-1000 ppm
900-1,000 ppm
for 75 win
1,900 ppm for
5 min
Results of single
exposures
500 ppm
6.5-7 hr/day for
5 days
500 ppm
Induction of anesthesia
Maintain light anesthesia
Depressed BP during mod. an-
esthesia
Tendency to develop ventri-
cular arrhythmias during
hypoxia (reversed by oxy-
genation)
Little change in EEC-similar
halothane anesthesia
See Table 5-1
No effects
See Table 5-2
Slight eye irritation
and lightheadedness;
Flanagan and Romberg test
showed slight loss of
coordination and equili-
brium
Equilibrium disturbed,
positive Romberg test
See Table 5-7
Mild subjective
complaints; abnormal
Romberg
See Table 5-3
002MC3/A
5-47
11-10-81
-------
TABLE 5-15. (continued)
Study
Dose/Species
Effect
Gamborale and Hulten-
gren, 1973
Salvini et al, 1971
Maroni et al., 1977
Seki et al., 1975
Kramer et al., 1978
Weitbrecht, 1965
Stewart and Andrews,
1966
Stewart, 1971
Litt & Cohen, 1969
250, 350, 450, 550
ppm for 4-30 min
periods
450 ppm for 2-4 hr
periods
110-990 ppm
4, 25, 28, 53 ppm
11-838 ppm •» x = 115
10-20 ppm,
hands immersed
in MC
Change in manual dexterity
and perceptual tests in
exp. vs. control groups
Decreased perceptive
capability under stress,
eye irritation
No effects
No effects
No effects, although SGPT
and albumin were different
in exposed vs. control
group.
Transient irritation of
conjunctiva, upper respira-
tory tract; burning sensa-
tion in tongue; teeth felt
dull (rhubarb effect)
feeling of ice-cold fingers
when placed in liquid MC;
hypertension;
positive urobilinogen;
automatic dystrophy;
circulatory dystrophy;
psychasthenia
See Table 5-4
002MC3/A
5-48
11-10-81
-------
last two observations are questionable since the effects of mentol used to
mask the odor of MC in the first study wre not evaluated, and in the second
study the control subjects were not matched for all intervening variables such
as food and drinking habits.
Although a precise dose-response gradient of effects produced by MC
exposure cannot be derived, it is possible to establish a crude relationship
between exposure and effects from a compilation of the human data available.
A summary of the estimated dose-response relationships for acute effects of
single short-term exposures is presented below:
>5,000 ppm Onset of narcosis, possible life threatening
2,650-1,900 ppm Lightheadedness, irritation of the throat
1,000 ppm Disturbance of equilibrium
500-350 ppm Slight changes in perception, obvious odor
100 ppm Apparent odor threshold
The approximate concentrations of MC which elicit a particular adverse
effect have greater uncertainty at the two extremes that is, life threatening
*
levels (>5,000 ppm), and the lowest observed adverse effect level (LOAEL)
(500-350 ppm). This results from the inherent difficulties in obtaining exact
exposure values in the cases of accidental overexposure to MC, and the diffi-
culty in the acquisition of either quantitative or qualitative data on slight
behavioral changes at the lower exposure levels. Acute overexposure to MC may
be limited by the low odor threshold in humans of 100 ppm. Others report that
an obvious odor is present at 500 ppm. It also should be noted that there are
no reports of residual adverse effects from a single exposure to MC.
*
LOAEL: is defined as the lowest exposure level in a study or group of studies
which produces statistically significant increases in frequency or severity of
adverse effects between the exposed population and its appropriate control.
002MC3/A 5-49 11-10-81
-------
A major uncertainty in the dose-response relationship estimated for MC
from the compilation of the available human reports is the lack of information
on the length of exposure in accidental exposure, and the short duration (less
than 2 hours) in most of the studies in which controlled exposures of human
volunteers were used. Although inhaled MC is retained in the lungs in propor-
tion to the concentration in the air.^the time to reach pulmonary steady-state
conditions is relatively long (4 hours). Since the maximum body burden from a
given exposure to MC was probably not reached in any of these studies, it is
likely that exposures for longer times would result in a greater body burden
and more severe effects at a given concentration. In the studies of the
inhalation toxicity of MC, there are insufficient data to predict the results
of the increased body burden of MC obtained by extending the exposure until
steady-state conditions are obtained. However, from the pharmacokinetic data
presented in Figure 4-1, it can be reasonably concluded that the effects
observed in the dose-response table would not shift by more than 30%. From
t
the above discussion, it should'be evident that these approximations are crude
estimates and contain several areas of uncertainty.
5.4.1.2. Effects of Intermittent or Prolonged Exposures
There is very limited information from either animal or human studies on
the effects of subchronic or chronic inhalation exposure to MC. As discussed
below, the only experimental study of humans involved repeated exposure to MC
5 days per week for 3 weeks and is of such a short duration that no informa-
tion can be extrapolated from this study as to the long term effects of MC
exposure (Stewart et al., 1976). Observations of occupationally exposed
workers are limited to reports where the exposure estimates are imprecise and
comparable control populations were not studied. The paucity of chronic
002MC3/A 5-50 11-10-81
-------
toxicity data adds additional uncertainty in deriving human risk assessment
based upon inhalation exposure to MC.
There are, however, three subchronic experimental animal studies with
exposures continuing for approximately 90 days which provide some information
on the effects of repeated exposures to MC. The study of Torkelson et al.
(1958) using rats, guinea pigs, rabbits, and monkeys, and the study of Eben
*
and Kimmerle (1974) using rats established a no observed effect level (NOEL)
for subchronic exposure to MC for 7 to 8 hours a day, 5 days per week for 3
months at 500 and 440 ppm, respectively. Similarly, a NOEL of 370 ppm was
obtained by Pendergast et al. (1967) in a variety of species (15 guinea pigs,
3 squirrel monkeys, 3 New Zealand rabbits, and 2 beagle dogs) exposed continu-
ously to MC for 6 weeks. In this study there were 3 deaths in the low exposure
group (135 ppm), but these were attributed to lung infections. These three
studies would indicate that subchronic exposure to MC in the range of 370 to
500 ppm produces no gross signs of toxicity. However, the report of McNutt et
al. (1975) indicates that exposure below this range may alter some biochemical
parameters in the liver and brain.
McNutt et al. (1975) observed alterations in the rough endoplasmic reti-
culum, detachment of polyribosomes, microbodies, and triglyceride droplets in
the livers of mice exposed to 250 ppm of MC continusously for 24 weeks. At
1000 ppm, the extent of these changes had increased and some individual hepa-
tocyte necrosis was observed. Although it is unclear whether the early bio-
chemical and histologic changes observed at exposures of 250 ppm adversely
affected liver function, they may represent the first stages in the sequence
of events which leads to the hepatocellular necrosis observed at 1000 ppm.
*
NOEL: is defined as the exposure level at which there are no statistically
significant increases in frequency or severity of effects between the exposed
population and its appropriate control.
002MC3/A 5-51 11-10-81
-------
The NOEL of 370 to 500 ppm discussed previously may reflect the insensitivity
of the parameters Investigated in the other studies.
The only study involving multiple experimental exposures of humans was
that of Stewart et al. (1975), in which 20 subjects were exposed to 500 ppm of
MC for 7.5 hours a day, 5 days per week for 3 weeks. There were no effects on
the clinical chemistry of the blood or urine, nor on pulmonary function tests.
However, the subjects did have an increased number of subjective complaints,
including sleepiness, irritation, and headaches. Again, these tests would
probably not be sensitive enough to detect the slight changes in the liver
observed in mice at exposures to 1000 or 250 ppm by McNutt et al. (1975). The
combined evidence from the human and animal studies would indicate that only
minimal effects are produced by multiple exposure to 250 ppm of MC and that
the pathologic importance of these effects are unknown.
Reports of occupational exposure have major deficiencies which add to the
uncertainty of a NOEL derived from these studies. The study by Weitbrecht
(1965), which reported on the exposure of 9 women to MC at a workroom concen-
tration of 10 ppm, is unacceptable for human risk assessment. The number of
workers surveyed was too small to obtain an adequate data base, and the measure-
ments of MC in the general workroom air were irrelevant for establishing
individual expsoure of workers operating over open vats of a compound as
volatile as MC. Also, the workers had their hands immersed in the solvent for
varying lengths of time, and it has been determined by Fukabori et al. (1976,
1977) that significant amounts of MC can be absorbed through unbroken skin.
Therefore, while no reliable estimate of exposure concentration can be made,
it was probably considerably higher than the 10 ppm reported.
The studies of Maroni et al. (1977), Seki et al. (1975) and Kramer et al.
(1978) reported a NOEL for workers occupationally exposed to MC of between 53
002MC3/A 5-52 11-10-81
-------
and 350 ppm. The short duration of exposure, averaging less than 1 year, of
the work population in the report of Kramer et al. (1978) precludes the use of
this study in human risk assessment. The study of Seki et al. (1975) provides
information on 196 male workers exposed to MC for at least 5 years at concentra-
tions of 4, 25, 28, and 53 ppm. The number of workers exposed at each concen-
tration was relatively small, with only 42 people exposed to the highest
concentration. While no dose related effects were observed, the exposed
groups were only compared among themselves and not with a control population.
The reported details of the analytical procedures were insufficient to deter-
mine whether the analytical data represented measurements over the entire time
period (5 years) of exposure of the study population, or whether the concen-
trations reported were the concentrations in the breathing zone. Most of the
deficiences in this study would probably result in an underestimation of the
exposure levels, hence, it is reasonable to assume that 53 ppm is a NOEL
concentration for MC. Maroni et al. (1977) looked for neurophysiological
abnormalities in a population ef 21 women who had been exposed for 6.5 years
to an average concentration of MC between 110 and 345 ppm. No neurotoxicity
was observed in exposed workers, as compared to a control population of 7
unexposed women. The small size of the exposed and control populations, and
the limited number of physiological measurements made makes the NOEL obtained
from this study extremely uncertain. However, the data of Maroni et al.
(1977) do provide greater confidence that long term occupational exposure to
53 ppm of MC produces no adverse effects.
5.4.2 Oral Exposure
There is little information on the toxicity of MC by the oral route. As
summarized in Table 5-5, the acute LD5Q for MC has been determined in rats,
mice, guinea pigs, and rabbits by Torkelson et al. (1958) and the values range
002MC3/A 5-53 11-10-81
-------
from 8,600 to 14,300 mg/kg body weight. These LDrQ values could theoretically
be used to calculate an approximate human lethal dose using the cubed root of
the body weight ratios for interspecies conversion (U.S. EPA, 1980; Freireich
et al., 1966; Rail, 1969). However, the data obtained from the species studied
in the report of Torkelson et al. (1958) do not show a relationship between MC
toxicity and body weight. Therefore, without further information, it would
not be justified to place much reliance on an approximate human lethal dose
calculated using the above approach. However, as a crude indication of a
lethal oral dose of MC, the values were calculated from each species with the
range for a human lethal dose falling between 770 and 3940 mg of MC/kg. Also,
there is no information from human exposure to MC to indicate whether values
obtained from a calculated lethal dose are applicable to human toxicology.
For the above reasons it is considered inappropriate to attempt to predict an
approximate human lethal dose from the present data available.
There are no subchronic studies on oral exposure to MC, and only one
chronic study, an NCI bioassay? In the NCI (1977) bioassay, rats and mice
were treated by gavage with MC in corn oil 5 days/week for 78 weeks at a level
of 750 and 1500 mg/kg body weight for the low and high dose group rats, and
2807 and 5615 mg/kg body weight for the low and high dose group mice. Early
deaths were observed in both rats and mice, with a statistically significant
dose-related trend observed in male and female rats, and in female mice. The
control animals also had poor survival and the early mortality in this group
would suggest that MC contributed only partly to the early deaths of the
treated animals. Another difficulty with this study is that treatment of
animals by gavage is not identical to exposure through food or water since the
daily dose of the compound is administered at a single time, resulting in high
body levels immediately after treatment. As a result of the poor survival of
002MC3/A 5-54 11-10-81
-------
the control animals and the inappropriateness of the route of administration,
the relevance of this study to human risk assessment is questionable.
5.4.3 Dermal Exposure
There is insufficient information available for quantitative risk assess-
ment of dermal exposure to MC. The pharmacokinetic data of Fakabori et al.
(1976, 1977) would indicate that absorption of MC through intact skin can
contribute significantly to the levels of MC in the body. The extent of
dermal absorption was estimated to be 5 percent of respiratory absorption in
humans in direct contact with the liquid. The high vapor pressure of MC would
preclude dermal contact with this solvent for sufficient periods of time to
allow toxic quantities to be absorbed, except in some industrial situations.
Even so, the greater efficiency of absorption by inhalation would make this
the route of greatest concern.
002MC3/A 5-55 11-10-81
-------
5.5 REFERENCES
Adams, E. M. , H. C. Spencer, V. K. Rowe, and D. D. Irish. Vapor toxicity of
1,1,1-trichloroethane (methyl chloroform) determined by experiments on
laboratory animals. Arch. Ind. Hyg. Occup. Med. 1:225-236, 1950.
American Industrial Hygiene Association, Toxicology Committee: Emergency
exposure limits, Am. Ind. Hyg. Assoc. J. 25:578-586, 1964.
Argus, M. F., J. C. Arcos, and C. Hoch-Ligeti. Studies on the carcinogenic
activity of protein-denaturing agents: Hepatocarcinogenicity of dioxane.
J. Natl. Cancer Inst. 35:949-958, 1965.
Argus, M. F. , R. S. Sohal, G. M. Bryant, C. Hoch-Ligeti, and J. C. Arcos.
Dose-response and ultrastructural alterations in dioxane carcinogenesis.
Eur. J. Cancer 9:237-243, 1973.
Astrand, 1., H. Kilbom, I. Wahlberg, and P. Ovrum. Methylchloroform exposure.
I. Concentration in alveolar air and blood at rest and during exercise.
Work Environ. Health 10:69-81, 1973.
Aviado, D. , S. Zakhari, J. Simoan and A. Ulsamer. Methyl Chloroform and
Trichloroethylene in the Environment. Cleveland, CRC Press, Inc. 1976.
Bas, S. M. Sudden sniffing death. JAMA 212:2075-2079, 1970.
Bonventre, J. , 0. Brennan, D. Jason, A. Henderson and M. L. Bastos. Two
deaths following accidental inhalation of dichloromethane and 1,1,1-tri-
chloroethane. J. Analytical Tox. 4:158-160, 1977.
*
Caplan, Y. H. , R. C. Backer, and J. Q. Whitaker. 1,1,1-Trichloroethane:
Report of a fatal intoxication. Clin. Toxicol. 9:69-74, 1976.
Chernoff, N. Personal communication, and published in U.S. EPA Office of
Pesticides, Notice of Determination: Abstract of Carbaryl Decision
Document. Federal Register 45:81869, Dec. 12, 1980.
Chu, 1. H. Y., and H. V. Mailing. Chemical induction of specific locus muta-
tions in Chinese hamster cells _in vitro. Proc. Nat. Acad. Sci. 61:1306-
1312, 1968.
Chu, E. H. Y. , and H. V. Mailing. Induction of mutations in mammalian cells
implanted in heterologous hosts. 2nd Annual Meeting of the Environmental
Mutagen Society, Washington, DC, Environmental Mutagen Society Newsletter
No. 6:15, 1972.
Clark, D. G. , and D. J. Tinston. Correlation of the cardiac sensitizing
potential of halogenated hydrocarbons with their physicochemical proper-
ties. Brit. J. Pharmacol. 49:355-357, 1973.
Clive, D. , and J. F. S. Spector. Laboratory procedure for assessing specific
locus mutations at the TK locus in cultured L5178Y mouse lymphoma cells.
Mutation Res. 31:17-29, 1975.
002MC4/D 5-56 11-10-81
-------
Dornette, W. H. L., and J. P. Jones. Clinical experiences with 1,1,1-trichloro-
ethane: A preliminary report of 50 anesthetic administrations. Anesthesia
and Analgesia 39:249-253, 1960.
Eben, A., and G. Kimmerle. Metabolism, excretion and toxicology of wethylchloro-
form in acute and subacute exposed rats. Arch. Toxikol. 31:233-242,
1974.
Eger, E. 1., B. Brandstater, L. J. Saidman, J. J. Regan, J. W. Severinghaus,
and E. S. Munson. Equipotent alveolar concentrations of methoxyflurane,
halothane, diethyl ether, fluroxene, cyclopropane, xenon, and nitrous
oxide in the dog. Anesthesiology 26:771-777, 1965.
Elovaara, E. , K. Hemminki, and H. Vainio. Effects of methylene chloride,
trichloroethane, trichloroethylene, tetrachloroethylene and toluene on
the development of chick embryos. Toxicol. 12:111-119, 1979.
Federal Register 38:21935-21936, 1973.
Freireich, E. J. , E. A. Gehan, D. P. Rail, L. H. Schmidt, and H. E. Skipper.
Quantitative comparison of toxicity of anticancer agents in mouse, rat,
hamster, dog, monkey, and man. Cancer Chemother. Rep. 50:219, 1966.
Fukabori, S. , K. Nakaaki, J. Yonemoto, and 0. Tada. On the cutaneous absorp-
tion of 1,1,1-trichloroethane. J. Sci. Labour 53:89-95, 1967.
Fukabori, S. , K. Nakaaki, J. Yonemoto, and 0. Tada. On the cutaneous absorp-
tion of 1,1,1-trichloroethane. J. Sci. Labour 53:89-95, 1977.
Fuller, G. C. , A. Olshan, S. Kv Puri, and H. Lai. Induction of hepatic drug
metabolism in rats by methylchloroform inhalation. J. Pharmacol. Exp.
Ther. 175:311-317, 1970.
Gamberale, F. , and M. Hultengren. Methyl chloroform exposure. II. Psycho-
physiological functions. Work Environ. Health 10:82-92, 1973.
Gehring, P. J. Hepatotoxic potency of various chlorinated hydrocarbon vapours
relative to their narcotic and lethal potencies in mice. Toxicol. Appl.
Pharmacol. 13:287-298, 1968.
Green, T. Metabolism and mutagenicity of methylene-chloride. Abstracts Soc.
Toxicol. #312, A104, 1980.
Hake, C. L. , T. B. Waggoner, D. N. Robertson, and V. K. Rowe. The metabolism
of 1,1,1-trichloroethane by the rat. Arch. Environ. Health 1:101-105,
1960.
Hall, F. B. , and C. H. Hine. Trichloroethane intoxication: a report of two
cases. J. Forensic Sci. 11:404-413, 1966.
Hatfield, T. R., and R. T. Maykoski. A fatal methyl chloroform (trichloroethane)
poisoning. Arch. Environ. Health 20:279-281, 1970.
002MC4/D 5-57 11-10-81
-------
Henschler, D. , E. Eder, T. Neudecker, and M. Metzler. Careinogenicity of
trichloroethylene: fact or artifact? Arch. Toxicol, 37:233-236, 1977.
Herd, P. A., M. Lipsky and H. F. Martin. Cardiovascular effects of 1,1,1-tri-
chloroethane. Arch. Environ. Health 28:227-233, 1974.
Herd, P. A., H. F. Martin, and M. Lipsky. Cardiovascular alterations resulting
from inhalation of 1,1,1-trichloroethane. Toxicol. Appl. Pharmacol.
25:468, 1973 (abstract).
Hermansen, K. Antifibrillatory effect of some B-adrenergic receptor blocking
agents determined by a new procedure in mice. Acta Pharm. et Toxicol.
28:17-27, 1970.
Hoch-Ligeti, C., and M. F. Argus. Effect of carcinogens on the lung of guinea
pigs. In: Morphology of Experimental Respiratory Carcinogens. AEC
Symp. Ser. 21:267-279, 1970.
Hoch-Ligeti, C., M. F. Argus, and J. C. Arcos. Induction of carcinomas in the
nasal cavity of rats by dioxane. Brit. J. Cancer 24:164-167, 1970.
Humbert, B. E., and J. G. Fernandez. Exposure to 1,1,1-trichloroethane:
contribution to the study of absorption, excretion and metabolism in
human subjects. Arch. Mai. Prof. 38:415-425, 1977.
Ikeda, M. , and H. Ohtsuji. A comparative study of the excretion of Fujiwara
reaction-positive substances in urine of humans and rodents given trichloro-
or tetrachloro-derivatives of ethane and ethylene. Brit. J. Ind. Med.
29:99-104, 1972.
Kellermann, G. , C. R. Shaw, ami M. Luyten-Kellermann. Aryl hydrocarbon hy-
droxylase inducibility and bronchogenic carcinoma. N. Engl. J. Med.
289:934-937, 1973.
Kim, N. K. Air pollution evaluations using risk assessment methodology. Air
Pollut. Contr. Assoc. 31(2):120-122, 1981.
King, M. E. , A. M. Shefner, and R. R. Bates. Carcinogenesis bioassay of
chlorinated dibenzodioxins and related chemicals. Environ. Health Perspect.
5:163-170, 1973.
Klaassen, C. D. , and G. L. Plaa. Relative effects of various chlorinated
hydrocarbons on liver and kidney function in mice. Toxicol. Appl.
Pharmacol. 9:139-151, 1966.
Klaassen, C. D. , and G. L. Plaa. Relative effects of various chlorinated
hydrocarbons on liver and kidney function in dogs. Toxicol. Appl.
Pharmacol. H):119-131, 1967.
Kleinfeld, M. and B. Feiner. Health hazard associated with work in confined
spaces. J. Occup. Med. 8:358-364, 1966.
002MC4/0 5-58 11-10-81
-------
Kociba, R. J., S. B. McCollister, C. Park, T. R. Torkelson, and P. J. Gehring.
1,4-Dioxane. I. Results of a 2-year ingestion study in rats. Toxicol.
Appl. Pharmacol. 30:275-286, 1974.
Kramer, C. G., M. G. Ott, J. E. Fulkerson, N. Hicks, and H. R. Imbus. Health
of workers exposed to 1,1,1-trichloroethane: A matched-pair study.
Arch. Environ. Health 33:331-342, 1978.
Krantz, J. C. , Jr., C. S. Park, and J. S. L. Ling. Anesthesia LX: the
anesthetic properties of 1,1,1-trichloroethane. Anesthesiology 20:
635-640, 1959.
Lai, H., and H. C. Shah. Effect of methyl chloroform inhalation on barbiturate
hypnosis and hepatic drug metabolism in male mice. Toxicol. Appl.
Pharmacol. 17:625-633, 1970.
Leong, B. K. J., B. A. Schwetz and P. J. Gehring. Embryo and fetotoxicity of
inhaled trichloroethylene, perchloroethylene, methyl chloroform and dichloro-
methane in mice and rats. Toxicol. and Appl. Pharmacol. 33:136, 1975.
Litt, I. F., and M. I. Cohen. "Danger ... vapor harmful": Spot-remover
sniffing. N. Engl. J. Med. 281:543-544, 1969.
Litton Bionetics, Inc. Mutagenic evaluation of compound D6. LBI Project No.
2506. Submitted to Dow Chemical Co., 1975.
Loprieno, N. , R. Bangle, A. M. Rossi, S. Fumero, G. Meriggi, A. Mondino, and
S. Si 1 vest, ^n vivo mutagenicity studies with trichloroethylene and
other solvents. Preliminary results. Institute di Ricerche Biomediche.
Ivrea, Italy, 1979.
*
Lucchesi, B. R. The effects of pronethalol and its dextro isomer upon
experimental cardie arrhythmias. J. Pharmacol. Exp. Ther. 148:94-99.
1965.
Maroni, M., C. Bulgheroni, M. G. Cassitto, F. Merluzzi, R. Giliolo, and V.
Foa. A clinical, neurophysiological and behavioral study of female
workers exposured to 1,1,1-trichloroethane. Scand. J. Work Environ.
Health 3:16-22, 1977.
McNutt, N. S. , R. L. Amster, E. E. McConnell, and F. Morris. Hepatic lesions
in mice after continuous inhalation exposure to 1,1,1-trichloroethane.
Lab. Invest. 32:642-654, 1975.
Miller, K. W. , W. D. M. Paton, E. B. Smith and R. A. Smith. Physicochemical
approaches to the mode of action of general anesthetics. Anesthesiology
36:339-351, 1972.
Monster, A. C. Difference in uptake, elimination and metabolism in exposure
to trichloroethylene, 1,1,1-trichloroethane, and tetrachloroethylene.
Int. Arch. Occup. Environ. Health 42:311-317, 1979.
002MC4/D 5-59 11-10-61
-------
Monster, A. C. , and J. M. Houtkooper. Estimation of individual uptake of
trichloroethylene, trichloroethane, and tetrachloroethylene from biological
parameters. Int. Arch. Occup. Environ. Health 42:319-323, 1979.
Monster, A. C., G., Boersma, and H. Steenweg. Kinetics of 1,1,1-trichloroethane
in volunteers: Influence of exposure concentration and work load. Int.
Arch. Occup. Environ. Health 42:293-301, 1979.
National Academy of Sciences. Halocarbons. Effects on Stratospheric Ozone.
Panel on Atmospheric Chemistry. Washington, DC, 1976.
National Academy of Sciences. Drinking Water and Health. Safe Drinking Water
Committee, Washington, DC, 1977.
National Academy of Sciences. Stratospheric Ozone Depletion by Halocarbons:
Chemistry and Transport. Panel on Stratospheric Chemistry and Transport,
Washington, DC, 1979a.
National Academy of Sciences. Protection Against Depletion of Stratospheric
Ozone by Flurochlorocarbons. Committee on Impacts of Stratospheric
Change, 1979b.
National Cancer Institute. Bioassay of 1,1,1-trichloroethane for possible
carcinogenicity. Carcinog. Tech. Rep. Ser. No. 3, NCI-CG-TR-3, 70 pp. ,
1977.
National Cancer Institute. Bioassay of 1,4-dioxane for possible carci-
nogenicity. Carcinog. Tech. Rep. Ser. No. 80, NCI-CG-TR-80, 107 pp.,
1978.
National Cancer Institute Clearinghouse on Environmental Carcinogens.
Consideration of 1,1,1-trichloroethane. Minutes of the second meeting of
the risk assessment subgroup, pp. 4-5, March 25, 1977..
Parker, J. C. , G. E. Casey, L. J. Bahlman, N. A. Leidel, D.. Rose, H. P. Stein,
A. W. Thomas, and J. M. Lane. Chloroethanes: review of toxicity. NIOSH
Current Intelligence Bulletin #27. Am. Ind. Hyg. Assoc. J. 40:A46-A60,
1979.
Pelkonen, 0., and H. Vainio. Spectral interactions of a series of chlorinated
hydrocarbons with cytochrome P-450 of liver microsomes from variously-
treated rats. FEBS Letters 5_1:11-14, 1975.
Plaa, G. L. , E. A. Evans, and C. H. Hine. Relative hepatotoxicity of seven
halogenated hydrocarbons. J. Pharmacol. Exp. Ther. .123:224-229, 195S.
Prendergast, J. A., R. A. Jones, L. J. Jenkins, Jr., and J. Siegel. Effects
on experimental animals of long-term inhalation of trichloroethylene,
carbon tetrachloride, 1,1,1-trichloroethane, dichlorodif luorometliane, and
1,1-dichloroethylene. Toxicol. Appl. Pharmacol. K):270-289, 1967.
Price, P. J., C. M. Hassett, and J. I. Mansfield. Transforming activities of
trichloroethylene and proposed industrial alternatives. l_n vitro
14:290-293, 1978.
002MC4/D 5-60 11-10-81
-------
Priestly, B. G. , and G. L. Plaa. Hepatic function after acute or subchronic
nicotine administration in untreated mice and mice treated with
hepatotoxic chemicals. Arch. Int. Pharmacodyn. 223:132-141, 1976.
Quast, J. F., B. K. J. Leong, L. W. Rampy, and P. J. Gehring. Toxicologic and
carcinogenic evaluation of a methyl chloroform (1,1,1-trichloroethane)
formulation by chronic inhalation in rats -- Interim Report after 24
months. Midland, Michigan, Dow Chemical Co., 14 pp., 1978.
Rail, D. P. Difficulties in extrapolating the results of toxicity studies in
laboratory animals to man. Environ. Res. 2:360-367, 1969.
Rampy, L. W. , J. F. Quast, B. K. J. Leong, and P. J. Gehring. Results of
long-term inhalation toxicities studies on rats of 1,1,1-trichloroethane
and perchloroethylene formulations. In: Proc. Int. Cong. Toxicol.,
Toronto, p. 27, 1977 (abstract).
Reinhardt, C. F., L. S. Mullin and M. E. Maxfield. Epinephrine-induced cardie
arrhythmia potential of some common industrial solvents. J. Occup. Med.
15:953-955, 1973.
Rennick, B. R. , S. D. Malton, G. K. Mow and M. H. Seevers. Induction of
idioventricular rhythms by 1,1,1-trichloroethane and epinephrine. Fed.
Proc. 8:327, 1979.
Salvini, M. , S. Binaschi, and M. Riva. Evaluation of the psychophysiological
functions in humans exposed to the "threshold limit value" of 1,1,1-trichloro-
ethane. Brit. J. Ind. Med. 28:286-292, 1971.
Sato, A. and T. Nakajima. A structure-activity relationship of some chlorinated
hydrocarbons. Arch. Environ. Hlth. 34:69-75, 1979.
Savolainen, H., P. Pfaffli, M. Tengen, and H. Vainio. Trichloroethylene and
1,1,1-trichloroethane: effects on brain and liver after five days inter-
mittent inhalation. Arch. Toxicol. 38:229-237, 1977.
Savolainen, H. , V. Riihimaki, A. Laine, and J. Kekoni. Short-term exposure
of human subjects to m-xylene and 1,1,1-trichloroethane. Int. Arch.
Occup. Environ. Health 49:89-98, 1981.
Schlossberg, President, Dextrex Chemical Industries, Box 401, Detroit,
Michigan 48232. Letter to Bill Stewart, Executive Director, Texas Air
Control Board, Austin, Texas 78758, July 26, 1978.
Schwetz, B. A., B. K. J. Leong, and P. J. Gehring. The effect of maternally
inhaled trichloroethylene, perchloroethylene, methyl chloroform and
methylene chloride on embryonal and fetal development in mice and rats.
Toxicol. Appl. Pharmacol. 32:84-96, 1975.
Seki, Y. , Y. Urashima, H. Aikawa, H. Matsumura, Y. Ichikawa, F. Hiratsuka, Y.
Yoshioka, S. Shimbo, and M. Ikeda. Trichloro-compounds in the urine of
humans exposed to methyl chloroform at sub-threshold levels. Int. Arch.
Arbeitsmed. 34:39-49, 1975.
002MC4/D 5-61 11-10-81
-------
Siebecker, K. L., Jr., B. J. Bamforth, J. E. Steinhaus, and 0. S. Orth.
Clinical studies on new and old hydrocarbons. Anesth. Analg. (Cleve)
39:180-188, 1960.
Simmon, V. F., K. Kauhanen, and R. G. Tardiff. Mutagenic activity of chemicals
identified in drinking water. In: Progress in Genetic Toxicology, D.
Scott, B. A. Bridges and F. H. Sobels, eds. Amsterdam, Elsevier, pp.
249-258, 1977.
Singh, H. B., L. Salas, H. Shigeishi, and A. Crawford. Urban-nonurban relation-
ships of halocarbons, SFg, N?0, and other atmospheric trace constituents.
Atmos. Environ. 11:819-828, 1977.
Snow, L. P. , B. C. McNair, and B. C. Castro. Mutagenesis Testing of
1,1,1-Trichloroethane in Salmonella Strains TA-100 and TA-98. Northrop
Services, Inc., Research Triangle Park, NC. EPA Sponsored Study, 1979.
Somani, P. and B. K. B. Lum. The antiarrhythmic actions of beta adrenergic
blocking agents. J. Pharmacol. Exp. Ther. 147:194, 1965.
Stahl, C. J. , A. V. Fatteh, and A. M. Oominguez. Trichloroethane poisoning:
Observations on the pathology and toxicology in six fatal cases. J.
Forensic Sci. 14:393-397, 1969.
Stewart, R. D. The toxicology of 1,1,1-trichloroethane. Am. Occup. Hyg.
11:71-79, 1968.
Stewart, R. D. Methyl chloroform intoxication: Diagnosis and treatment.
JAMA 215:1789-1792, 1971.
Stewart, R. D., and J. T. Andrews. Acute intoxication with methyl chloroform.
JAMA 195:904-906, 1966.
Stewart, R. D., H. H. Gay, D. S. Erley, C. L. Hake, and A. W. Schaffer. Human
exposure to 1,1,1-trichloroethane vapor: relationship of expired air and
blood concentrations to exposure and toxicity. Amer. Ind. Hyg. Assoc. J.
22:252-262, 1961.
Stewart, R. D. , H. H. Gay, A. W. Schaffer, D. S. Erley, and V. K. Rowe.
Experimental human exposure to methyl chloroform vapor. Arch. Environ.
Health 19:467-472, 1969.
Stewart, R. D. , C. L. Hake, A. Wu, S. A. Graff, H. V. Forster, A. J. Lebrun,
P. E. Newton, and R. J. Soto. 1,1,1-Trichloroethane: Development of a
Biologic Standard for the Industrial Worker by Breath Analysis. The
Medical College of Wisconsin and the National Institute of Occupational
Safety and Health. NIOSH-MCOW-ENVM-l,l,l-T-75-4, 1975.
Stokinger, H. E., and R. L. Woodward. Toxicologic methods for establishing
drinking water standards. J. Amer. Water Works Assoc., April, 1958.
Su, G. , and K. A. Wurzel. A regulatory framework for setting air emission
limits for noncriteria pollutants. J. Air Pollut. Contr. Assoc.
31(2):160-162, 1981.
002MC4/D 5-62 11-10-81
-------
Takeuchi, Y. Experimental studies on the toxicity of 1,1,1,2-tetrachloroethane
compared with 1,1,2,2-tetrachloroethane and 1,1,1-trichloroethane. Jap.
J. Ind. Health 8:371-374, 1966.
Taylor, G. Mutagenicity Testing: Interoffice memo to Office/ Division
Directors, NIOSH mutagenicity task force members. Dated 12/9/77.
Taylor, G. Personal communication. NIOSH, Morgantown, West Virginia, 1978.
Taylor, G. J., R. T. Drew, E. M. Lores, Jr., and T. A. Clemmer. Cardiac
depression by haloalkane propellents, solvents, and inhalation anesthetics
in rabbits. Toxicol. Appl. Pharmacol. 38:379-387, 1976.
Torkelson, T. R., B. K. J. Leong, R. J. Kociba, W. A. Richter, and P. J.
Gehring. 1,4-Dioxane. II. Results of a two-year inhalation study in
rats. Toxicol. Appl. Pharmacol. 30:287-298, 1974.
Torkelson, T. R. , F. Oyen, D. D. McCollister, and V. K. Rowe. Toxicity of
1,1,1-trichloroethane as determined on laboratory animals and human
subjects. Am. Ind. Hyg. Assoc. J. 19:353-362, 1958.
Trochimowicz, H. J. , C. F. Reinhardt, L. S. Mullin, A. Azar, and B. W. Karrh.
The effect of myocardial infarction on the cardiac sensitization potential
of certain halocarbons. J. Occup. Med. 18:26-30, 1976.
U. S. Environmental Protection Agency. Interim procedures and guidelines for
health risk and economic impact assessments of suspected carcinogens.
Federal Register 41:21402, May 25, 1976.
U. S. Environmental Protection Agency. Guidelines and Methodology for the
Preparation of Health Effect Assessment Chapters of the Ambient Water
Quality Criteria Documents. Environmental Criteria and Assessment
Office, 1980a.
U. S. Environmental Protection Agency. Ambient Water Quality Criteria for
Chlorinated Ethanes. U. S. EPA. (NTIS PB81-117400), 1980b.
Van Dyke, R. A., and C. G. Wineman. Enzymatic dechlorination: dechlorination
of chloroethanes and propanes in vitro. Biochem. Pharmacol. 20:463-470,
1971.
Weitbrecht, U. Tri and tri-substitutes in the metal industry. Zentralb
Arbeitsmed. 15:138-146, 1965.
York, R. G., B. Sowry, L. Hastings and J. Manson. Evaluation of the prenatal
toxicity of methyl chloroform. J. Toxicol. Environ. Health. Accepted for
publication July 1981.
002MC4/D 5-63 11-10-81
-------
-------
6. BIBLIOGRAPHY
Adams, E. M. , H. C. Spencer, V. K. Rowe, and D. D. Irish. Vapor toxicity of
1,1,1-trichloroethane (methyl chloroform) determined by experiments on
laboratory animals. Arch. Ind. Hyg. Occup. Med. 1:225-236, 1950.
Altshuller, A. P. Lifetimes of organic molecules in the troposphere and lower
stratosphere. Adv. Environ. Sci. Technol, H): 181-219, 1980.
American Conference of Governmental Industrial Hygienists (1976 TLV Airborne
Contaminants Committee). Threshold Limit Values for Chemical Substances
in workroom air adopted by ACGIH for 1976. Cincinnati: ACGIH, 1976.
American Industrial Hygiene Association, Toxicology committee: emergency
exposure limits, Am. Ind. Hyg. Assoc. J. 25:578-586, 1964.
Argus, M. F. , R. S. Sohal, G. M. Bryant, C. Hoch-Ligeti, and J. C. Arcos.
Dose-response and ultrastructural alterations in dioxane carcinogenesis.
Eur. J. Cancer 9:237-243, 1973.
Astrand, I., A. Kilbom, I. Wahlberg, and P. Ovrum. Methyl chloroform exposure:
I. concentration in alveolar air and blood at rest and during exercise.
Work Environ. Hlth. 10: 69-81, 1973.
Aviado, D. , S. Zakhari, J. Simaan, and A. Ulsamer. Methyl Chloroform and
Triochloroethylene in the Environment. Cleveland, CRC Press, Inc., 1976.
Bas, S. M. Sudden sniffing death. JAMA 212:2075-2079 1970.
Battelle Columbus Laboratories':' Environmental Monitoring Near Industrial
Sites-Methyl Chloroform. PB-273204. August 1977. EPA 560/6-77-025.
Bellar, T. A., J. J. Lichtenberg, and R. C. Kroner. The occurrence of organo-
halides in chlorinated drinking waters. J. Amer. Water Works Assoc.
12:703-706, 1974.
Bernstine, J. B. , A. E. Meyer, and H. B. Hayman. Maternal and fetal blood
estimation following the administration of chloral hydrate during labour.
J. Obst. Gyn. Brit. Emp. 61:683-685, 1954.
Bernstine, J. B. , A. E. Meyer, and R. L. Bernstine. Maternal blood and cerebral
spinal fluid estimation following the administration of chloral hydrate
during the puerperium. Am. J. Obst. Gyn. 73:801-804, 1957.
Blair, A. H. , and F. H. Bodley. Human liver aldehyde dehydrogenase: partial
purification and properties. Can. J. Biochem. 47:265-271, 1969.
Bonse, G. , and H. Henschler. Chemical reactivity, biotransformation, and
toxicity of polychlorinated aliphatic compounds. CRC Critical Rev.
Toxicol. 4(4):395-409, 1976.
002MC5/F 6-1 11-10-81
-------
Bonventre, J., 0. Brennan, D. Jason, A. Henderson and M. L. Bastos. Two deaths
following accidental inhalation of dichloromethane and 1,1,1-trichloro-
ethane. J. Analytical Tox. 4:158-160, 1977.
Breimer, 0. 0., H. C. J. Ketelaars, and J. M. van Rossurn. Gas chromatographic
determination of chloral hydrate, trichloroethanol and trichloroacetic
acid in blood and in urine employing head-space analysis. J. Chromatogr.
88:55-63, 1974.
British Department of the Environment. Chlorofluorocarbons and their effect
on stratospheric ozone (second report). Pollution Paper No. 15, Her
Majesty's Stationary Office, Great Britain, 1979.
Brodman, K. , A. J. Erdmann, I. Lorge, and H. G. Wolff. The Cornell Medical
Index: an adjunct to medical interview. J. Am. Med. Assoc. 140:530-534,
1949.
Brown, B. R. , I. G. Sipes, and A. M. Sagalyn. Mechanisms of acute hepatic
toxicity: (chloroform, halothane, and glutathione). Anesthesiology 41:554-
561, 1974.
Browning, E. Toxicity and Metabolism of Industrial Solvents. Amsterdam, Elsevier,
1965.
Butler, T. C. The metabolic fate of chloral hydrate. J. Pharmacol. Exptl.
Therap. 92:49-57, 1948.
Butler, T. C. Metabolic transformations of trichloroethylene. J. Pharmacol.
Exptl. Therap. 97:84-92, 1949.
^
Campbell, M. J. , J. C. Shepparo*. and B. F. Au. Measurement of hydroxyl radical
concentration in boundary layer air by monitoring CO oxidations. Geophys.
Res. Lett. 6:175-178, 1979.
Caplan, Y. H. , R. C. Backer, and J. Q. Whitaker. 1,1,1-trichloroethane:
report of a fatal intoxication. Clin. Toxicol. 9:69-74, 1976.
Carlson, G.P. Effect of phenobarbital and 3-methylcholanthrene pretreatment
on the hepatotoxicity of 1,1,1-trichloroethane and 1,1,2-trichloroethane.
Life Sciences 13:67-72, 1973.
Chance, B. , A. Boveris, and N. Oshino. In: Alcohol and Aldehyde Metabolizing
Systems, Vol. 2, R. G. Thurman, J. R. Williamson, H. R. Orott, and 6.
Chance, eds., New York, Academic Press, pp. 261-274, 1977.
Chang, J. S., and F. Kaufman. Kinetics of the reactions of hydroxyl radicals
with some halocarbons: CHFC12, CHF2C1, CH3CC13, C2HC13, andC2C!4. J.
Chem. Phys. 66:4989-4994, 1977.
Chang, J. S. , and J. E. Penner. Analysis of global budgets of halocarbons.
Atmos. Environ. 12:1867-1873, 1978.
Chemical and Engineering News. 1,1,1-trichloroethane, pg. 13, October 29,
1979.
002MC5/F 6-2 11-10-81
-------
Chemical Marketing Reporter, 22 January 1979.
Chemical Week. 8 February 1978, pg. 13.
Chernoff, N. Personal communication and published in U.S. EPA Office of
Pesticides Notice of Determination: abstract of carbaryl decision docu-
ment. Fed. Register 45:81869, Dec. 12, 1980.
Christiansen, V. 0., J. A. Dahlberg, and H. F. Andersson. On the nonsensi-
tized photo-oxidation of 1,1,1-trichloroethane vapor in air. Acta Cheir.
Scand. Series A. 26:3319-3324, 1972.
Chu, E. H. Y., and H. V. Mailing. Chemical induction of specific locus muta-
tions in Chinese hamster cells u> vitro. Proc. Nat. Acad. Sci. 61:1306-
1312, 1968.
Chu, E. H. Y. , and H. V. Mailing. Induction of mutations in mammalian cells
implanted in heterologous hosts, 2nd Annual Meeting of the Environmental
Mutagen Society, Washington, DC, Environmental Mutagen Society Newsletter
No. 6:15, 1972.
Clark, D. G. , and D. J. Tinston. Correlation of the cardiac sensitizing
potential of halogenated hydrocarbons with their physicochemical proper-
ties. Brit. J. Pharmacol. 49:355-357, 1973.
Clive, D., and J. F. S. Spector. Laboratory procedure for assessing specific
locus mutations at the TK locus in cultured L5178Y mouse lymphoma cells.
Mutation Res. 31:17-29, 1975.
Cogswell, S. A. Methyl Chloroform. Chemical Economics Handbook .Marketing
Research Report on C2 Chlorinated Solvents, SRI International, December
1978.
Cole, W. J. , R. G. Mitchell, and R. E. Salamonsen. Isolation, characteriza-
tion and quantisation of chloral hydrate as a transient metabolite of
trichloroethylene in man using electron capture gas chromatography and
mass fragmentography. J. Pharm. Pharmacol. 27:167, 1975.
Coleman, W. E. , R. D. Lingg, R. G. Melton, and F. C. Kopfler. The Occurrence
of Volatile Organics in Five Drinking Water Supplies Using Gas Chromato-
graphy/Mass Spectrometry. Chapter 21. I_n: Identification and Analysis
of Organic Pollutants in Water, L. H. Keith, ed., Ann Arbor Science,
1976.
Cooper, J. R., and P. J. Friedman. The enzyme oxidation of chloral hydrate to
trichloroacetic acid. Biochem. Pharmacol. 1:76-82, 1958.
Correia, Y. , G. J. Martens, F. H. Van Mepsch, and B. P. Whim. The occurrence
of trichloroethylene, tetrachloroethylene, and 1,1,1-trichloroethane in
western Europe in air and water. Atmos. Environ. H:1113-1116, 1977.
Cox, P. J., L. J. King, and D. V. Parke. The binding of trichlorofluoromethane
and other haloalkanes to cytochrome P-450 under aerobic and anaerobic
conditions. Xenobiotica 6:363-375, 1976.
002MC5/F 6-3 11-10-81
-------
Cronn, D. R. Measurements of atmospheric methyl chloroform by Washington
State University. In: Proceedings of the Conference on Methyl Chloro-
form and Other Halocarbon Pollutants. Final Report. Envr. Sciences
Research Lab., RTP, NC, EPA-600/9-80-003, January, 1980a.
Cronn, D. R. Comparison of halocarbon and nitrous oxide measurements at
non-urban sites—A preliminary data report. Report for EPA Grant
R0804033-03-6, Washington State University, 1980b.
Cronn, D. R. Personal communication, 1980c.
Cronn, 0. R., and D. E. Harsch. Determination of atmospheric halocarbon
concentrations by gas chromatography-mass spectrometry. Anal. Lett.
12(814):1489-1496, 1979a.
Cronn, D. R., and D. E. Harsch. Smoky mountain ambient halocarbon and hydro-
carbon monitoring, September 21-26, 1978. Report for EPA Grant R0804033-
03-2, Washington State University, 1979b.
Cronn, D. R. , and E. Robinson. Determination of trace gases in Learjet and
U-Z whole air samples collected during the Intertropical Convergence Zone
Study. In: 1977 Intertropical Convergence Zone Experiment, I. G. Poppoff,
W. A. Page, and A. P. Margozzi, eds. NASA TMX 78577, 1979.
Cronn, D. R. , R. A. Rasmussen, and E. Robinson. Measurement of tropospheric
halocarbons by gas chromatography-mass spectrometry. Report for Phase I.
EPA Grant R0804033-01. Washington State University, 23 August 1976.
Cronn, D. R., R. A. Rasmussen, and E. Robinson. Measurement of tropospheric
halocarbons by gas chromatography-mass spectrometry. Report for 1977a.
Cronn, D. R. , R. A. Rasmussen, E. Robinson, and D. E. Harsch. Halogenated
compound identification and measurement in the troposphere and lower
stratosphere. J. Geophy. Res. 82(37):5935-5944, 1977b.
Cronn, D. R. , M. J. Campbell, and D. E. Harsch. Measurement of tropospheric
halocarbons by gas chromatography-mass spectrometry. Report for Phase
III. EPA Grant R0804033-03. Washington State University, September,
1979.
Crutzen, P. J. , and J. Fishman. Average concentrations of OH in the tropo-
sphere and the budgets of CH4, CO, H2 and CH3CC13. Geophy. Res. Lett.
4(8):321-324, 1977.
Davidson, I. W. F. (personal communication), 1980.
Davis, D. 0. Investigations of important hydroxyl radical reactions in the
perturbed troposphere. (Georgia Institute of Tech. Atlanta, Ga., Engineer
Exp. Station), EPA-600/3-77-111, October 1977.
Derwent, R. G. and A. E. J. Eggleton. Two-dimensional model studies of methyl
chloroform in the troposphere. Quart. J. R. Met. Soc. 107:231-242, 1981.
002MC5/F 6-4 11-10-81
-------
Derwent, R. G., and A. E. J. Eggleton. Halocarbon lifetimes and concentration
distributions calculated using a two-dimensional tropospheric model.
Atmos. Environ. 12:1261-1267, 1978.
Dilling, W. L. , N. B. Tefertiller, and G. J. Kallos. Evaporation rates and
reactivities of methylene chloride, chloroform, 1,1,1-trichloroethane,
trichloroethylene, tetrachloroethylene, and other chlorinated compounds
in dilute aqueous solutions. Environ. Sci. Techno!. 9(9):833-838, 1975.
Dornette, W. H. L. , and J. P. Jones. Clinical experiences with 1,1,1-tri-
chloroethane: a preliminary report of 50 anesthetic administrations.
Anesthesia and Analgesia 39:249-253, 1960.
Dowty, B. J., D. R. Carlisle, and J. L. Laseter. New Orleans drinking water
sources tested by gas chromatography-mass spectrometry. Occurrence and
origin of aromatics and halogenated aliphatic hydrocarbons. Environ.
Sci. Technol. 9(8):762-765, 1975b.
Dowty, B. , 0. Carlisle, and J. L. Laseter. Halogenated hydrocarbons in New
Orleans Drinking Water and Blood Plasma. Science 187:75-77, 1975a.
Eben, A., and G. Kimmerle. Metabolism, excretion and toxicology of methyl
chloroform in acute and subacute exposed rats. Arch. Toxicol. 31:233-242,
1974.
Eger, E. I., B. Brandstater, L. J. Saidman, J. J. Regan, J. W. Severinghaus,
and E. S. Munson. Equipotent alveolar concentrations of methoxyflurane,
halothane, diethyl ether, fluroxene, cyclopropane, xenon, and nitrous
oxide in the dog. Anesthesiology 26:771-777, 1965.
Eimutis, E. C. and R. P. Quill. Source Assessment. Noncriteria Pollutant
Emissions, (Monsanto Res. Corp., Dayton, OH), EPA-600/2-77-107e, (U.S.
Environmental Protection Agency), July 1977.
Elovaara, E., K. Hemminki, and H. Vainio. Effects of methylene chloride,
trichloroethane, trichloroethylene, tetrachloroethylene and toluene on
development of chick embryos. Toxicol. 12:111-119, 1979.
Ewing, B. B. , E. S. K. Chian, J. C. Cook, C. A. Evans, P. V. Hopke, and E. G.
Perkins. Monitoring to Detect Previously Unrecognized Pollutants in
Surface Waters. Institute for Environmental Studies, University of
Illinois at Urbana-Champaign, EPA 560/6-77-015, July 1977.
Federal Register 38:21935-21936, 1970.
Fernandez, J. G. , P. 0. Droz, B. E. Humbert, and J. R. Caperos. Trichloro-
ethylene exposure: simulation of uptake, excretion, and metabolism using
a mathematical model. Brit. J. Ind. Med. 34:43-55, 1977.
Fiserova-Bergerova, V., and D. A. Holaday. Uptake and clearance of inhalation
anesthetics in man. Drug Met. Rev. 9:43-60, 1979.
Fraser, P. J. B. , and G. I. Pearman. Atmospheric halocarbons in the southern
hemisphere. Atmos. Environ. 12:839-844, 1978.
002MC5/F 6-5 11-10-81
-------
Freireich, E. J., E. A. Gehan, 0. P. Rail, L. H. Schmidt and H. E. Skipper.
Quantitative comparison of toxicity of anticancer agents in mouse, rat,
hamster, dog, monkey and nan. Cancer Chemother. Rep. 50:219, 1966.
Friedman, P. J., and J. R. Cooper. The role of alcohol dehydrogenase in the
metabolism of chloral hydrate. J. Pharmacol. Exptl. Therap. 129:373-376.
1960.
Fry, B. J., T. Taylor, and D. E. Hathway. Pulmonary elimination of chloroform
and its metabolite in man. Arch. Int. Pharmacodyn. Ther. 196:98-101.
1972.
Fukabori, S., K. Nakaaki, J. Yonemoto, and 0. Tada. On the cutaneous absorp-
tion of methyl chloroform. J. Sci. Labour 52:67-80, 1976.
Fukabori, S. , K. Nakaaki, J. Yonemoto, and 0. Tada. On the cutaneous absorp-
tion of l.l.l.trichloroethane. J. Sci. Labour 53:89-95, 1977.
Fuller, G. C., A. Olshan, S. K. Puri, and H. Lai. Induction of hepatic drug
metabolism in rats by methylchloroform inhalation. J. Pharmacol. Exp.
Ther. 175:311-317, 1970.
Gamberale, F. , and M. Hultengren. Methyl chloroform exposure. II. Psychol-
physiological functions. Work Environ. Hlth. 10:82-92, 1973.
Gehring, P. J. Hepatotoxic potency of various chlorinated hydrocarbon vapours
relative to their narcotic and lethal potencies in mice. Toxicol. Appl.
Pharmacol. 13:287-298, 1968.
Green, T. Metabolism and mutagjsnicity of methylene-chloride. Abstracts Soc.
Toxicol. #312, A104, 1980*.
Grunett, N. Oxidation of acetaldehyde by rat-liver mitochondria in relation
to ethanol oxidation and the transport of reducing equivalents across the
mitochondria! membrane. Eur. J. Biochem. 35:236-243, 1973.
Hake, C. L., T. B. Waggoner, D. N. Robertson, and V. K. Rowe. The metabolisrr
of 1,1,1-trichloroethane by the rat. Arch. Environ. Hlth. 1:101, 1960.
Hall, F. B. , and C. H. Hine. Trichloroethane intoxication: a report of two
cases. J. Forensic Sci. 11:404-413, 1966.
Hardie, D. W. F. Chlorocarbons and Chlorohydrocarbons. I_n: Kirk-Othmer
Encyclopedia of Chemical Technology, 2nd ed., Vol. 5, NY, Interscience
Pub., pp. 154-157, 1963.
Harsch, D. E. , and D. R. Cronn. Continuous atmospheric monitoring of urban,
semi-rural and rural N20 and the halocarbons. Unpublished manuscript,
Washington State University, June, 1979.
Harsch, D. E. , and D. R. Cronn. Low-pressure sample-transfer technique for
analysis of stratospheric air samples. J. Chromat. Sci. L6:363-367,
1978.
002MC5/F 6-6 11-10-81
-------
Hatfield, T. R. , and R. T. Maykoski. A fatal methyl chloroform (trichloro-
ethane) poisoning. Arch. Environ. Health 20:279-281, 1970.
Henschler, D. Metabolism and mutagenicity of halogenated olefins—a comparison
of structure and activity. Environ. Hlth. Persp. 21:61-65, 1977.
Henschler, D., Eder, T. Neudecker, and M. Metzler. Carcinogenicity of trichloro-
ethylene: fact or artifact? Arch. Toxicol. 37:233-236, 1977.
Herd, P. A., H. F. Martin, and M. Lipsky. Cardiovascular alterations result-
ing from inhalation of 1,1,1-trichloroethane. Toxicol. Appl. Pharmacol.
25:468, 1973 (abstract).
Herd, P. A., M. Lipsky, and H. F. Martin. Cardiovascular effects of 1,1,1-
trichloroethane. Arch. Environ. Health 28:227-233, 1974.
Hermansen, K. Antifibri1latory effect of some beta-adrenergic receptor block-
ing agents determined by a new procedure in mice. Acta Pharm. et Toxicol.
28:17-27, 1970.
Hoch-Ligeti, C., and M. F. Argus. Effect of carcinogens on the lung of guinea
pigs. In: Morphology of Experimental Respiratory Carcinogens. AEC
Symp. Ser. 21:267-279, 1970.
Hoch-Ligeti, C., M. F. Argus, and J. C. Arcos. Induction of carcinomas in the
nasal cavity of rats by dioxane. Brit. J. Cancer 24:164-167, 1970
Holmberg, B., I. Jakobsen, and K. Sigvardsson. A study on the distribution of
methylchloroform and n-octane in the mouse during and after inhalation.
Scand. J. Work Environ. HHh. 3:43-52, 1977.
*
Humbert, B. E. , and J. G. Fernandez. Exposure of 1,1,1-trichloroethane:
contribution to the study of absorption, excretion and metabolism in
human subjects. Arch. Mai. Prof. 38:415-425, 1977.
Humbert, B. E. , and J. G. Fernandez. Simultaneous determination of trichlo-
racetic acid and trichlorethanol by gas chromatography. Int. Arch.
Occup. Environ. Hlth. 36:235-241, 1976.
Ikeda, M. , and H. Ohtsuji. A comparative study of the excretion of Fujiwara
reaction-positive substances in urine of humans and rodents given tri-
chloro- or tetrachloro-derivatives of ethane and ethylene. Brit. J. Ind.
Med. 29:99-104, 1972.
Ikeda, M. , H. Ohtsuji, T. Imamura, and Y. Komoike. Urinary excretion of total
trichloro-compounds, trichloroethanol and trichloroacetic acid as a
measure of exposure to trichloroethylene and tetrachloroethylene. Brit.
J. Ind. Med. 29:328-333, 1972.
Imamura, T. , and M. Ikeda. A time-saving procedure for the determination of
total trichloro-compounds in human urine samples. Int. Arch. Arbeitsnipd.
31:333-338, 1973.
002MC5/F 6-7 11-10-81
-------
Irish, D. D. Aliphatic hydrocarbons. Industrial Hygiene and Toxicology, 2nd
ed. Vol. 2. F. A. Patty ed, , New York, Interscience, 1963, p. 1291.
Ivanetich, K. M. and L. H. Van Den Honert. Chloroethanes: their metabolism
by hepatic cytochrome P-450 in vitro. Carcinogenesis 2:697-702, 1981.
Jeong, K. M. and F. Kaufuran. Rates of the reactions of 1,1,1-trichloroethane
and 1,1,2-trichloroethane with OH. Geophy. Res. Lett. 6:757-759, 1979.
Jorden, Jr., J. I. Encyclopedia of Chemical Processing and Design. Vol. 10,
Chapter 8. J. J. McKetta and W. A. Cunningham, eds., Marcel Deker
Inc., 1979.
Katz, M. A., P. T. Lee, T. McCartin and K. Wagoner. Level II materials balance:
methyl chloroform. Final Report--JRB Assoc., Inc., Mclean, Va. (EPA
Contract No. 68-01-5793).
Keil, S. L. Chlorocarbons and Chlorohydrocarbons. In: Kirk-Othmer Encyclo-
pedia of Chemical Technology, Third Edition, Volume 5, New York, Inter-
science Pub., 1979.
Kellermann, G., C. R. Shaw, and M. Luyten-Kellermann. Aryl hydrocarbon
hydroxylase inducibility and bronchogenic carcinoma. N. Engl. J. Med.
289: 934-937, 1973.
Khalil, M. A. K., and R. A. Rasmussen. Decline in the atmospheric accumula-
tion rates of CC13F (F-ll), CC12F2 (F-12) and CH3CC13. Submitted for
publication, 1981.
Khalil, M. A. K., and R. A. Rasmussen. Methyl chloroform (CH3CC13): accumula-
tion in the earth's atmosphere. Submitted to Science, 1980.
Kim, N. K. Air pollution evaluations using risk assessment methodology. J.
Air Pollut. Contr. Assoc. 31:120-122, 1981.
King, M. E. , A. M. Shefner, and R. R. Bates. Carcinogenesis bioassay of
chlorinated dibenzodioxins and related chemicals. Environ. Health Perspect.
5:163-170, 1973.
Klaassen C. D. , and G. L. Plaa. Relative effects of various chlorinated
hydrocarbons on liver and kidney function in mice. Toxicol. Appl.
Pharmacol. 9:139-151, 1966.
Klaassen, C. D., and G. L. Plaa. Relative effects of various chlorinated
hydrocarbons on liver and kidney function in dogs. Toxicol. Appl.
Pharmacol. 10:119-131, 1967.
Kleinfeld, M. and B. Feiner. Health hazard associated with work in confined
spaces. J. Occup. Med. 8:358-364, 1966.
Kociba, R. J. , S. B. McCollister, C. Park, T. R. Torkelson, and P. J. Gehring.
1,4-Dioxane. I. Results of a 2-year ingestion study in rats. Toxicol.
Appl. Pharmacol. 30:275-286, 1974.
002MC5/F 6-8 11-10-81
-------
Kraemer, R. J. , and R. A. Deitrich. Isolation and characterization of human
liver aldehyde dehydrogenase. J. Biol. Chem. 243:6402-6408, 1968.
Kramer, C. G., M. G. Ott, J. E. Fulkerson, N. Hicks, and H. R. Imbus. Health of
workers exposed to 1,1,1-trichloroethane: a matched-pair study. Arch.
Environ. Health 33:331-342, 1978.
Krantz, J. C. Jr. , C. S. Park, and J. S. Ling. Anesthesia LX: the anesthetic
properties of 1,1,1-trichloroethane. Anesthesiology 20:635-640, 1959.
Kurylo, M. J. , P. C. Anderson, and 0. Klais. A flash photolysis, resonance
fluorescence investigation of the reaction OH + CH3CCl3 •* CH2CCL3.
Geophy. Res. Lett. 6:760-762, 1979.
Lai, H., and H. C. Shah. Effect of methyl chloroform inhalation on barbiturate
hypnosis and hepatic drug metabolism in male mice. Toxicol. Appl. Pharmacol.
17:625-633, 1970.
Larsby, B. , R. Tham, L. M. Odkvist, B. Norlander, D. Hyden, G. Aschan, and A.
Rubin. Exposure of rabbits to methyl chloroform: vestibular disturbances
correlated to blood and cerebrospinal fluid levels. Int. Arch. Occup.
Environ. Hlth. 41:7-15, 1978..
Laseter, J. L. , and B. J. Dowty. Association of biorefractories in drinking
water and body burden in people. Ann. N.Y. Acad. Sci. 298:547-556, 1977.
Leibman, K. C. , and E. Ortiz. Metabolism of halogenated ethylenes. Environ.
Hlth. Persp. 21:91-99, 1977.
Leong, B. K. J., B. A. Schwetz and P. J. Gehring. Embryo and fetotoxicity of
inhaled trichloroethylene, perchloroethylene, methyl chloroform and
dichloromethane in mice and rats. Toxicol. and Appl. Pharmacol. 33:136,
1975.
Lieber, C. S., and L. M. DeCarli. Hepatic microsomes, a new site for ethanol
oxidation. J. Clin. Invest. 47:62a (abst), 1968.
Lillian, D. , and H. B. Singh. Absolute determination of atmospheric halo-
carbons by gas phase coulometry. Anal. Chem. 46:1060-1063, 1974.
Lillian, D., H. B. Singh, A. Appleby, L. Lobban, R. Arnts, R. Gumpert, R.
Hague, J. Toomey, J. Kazazis, M. Antell, D. Hansen, and B. Scott.
Atmospheric fates of halogenated compounds. Environ. Sci. Technol.
9(12):1042-1048, 1975.
Litt, I. F. , and M. I. Cohen. "Danger... vapor harmful": spot remover sniff-
ing. N. Engl. J. Med. 281:543-544, 1969.
Litton Bionetics, Inc. Mutagenic evaluation of compound D6. LBI Project No.
2506. Submitted to Dow Chemical Co., 1975.
Logan, J. A., M. J. Prather, S. C. Wofsy, and M. B. McElroy. Tropospheric
chemistry: A global perspective. J. Geophy. Res. 86(C8):7210-7254,
1981.
002MC5/F 6-9 11-10-81
-------
Loprieno, N. , R. Bangle, A. M. Rossi, S. Fumero, G. Meriggi, A. Mondino, and
S. Sllvest. Ij} vivo mutagenicity studies with trichloroethylene and
other solvents. Preliminary results. Institute di Ricerche Biomediche.
Ivrea, Italy, 1979.
Lovelock, J. E. Atmospheric halocarbons and stratospheric ozone. Nature
252:292-294, 1974.
Lovelock, J. E. Halogenated hydrocarbons in the atmosphere. Ecotoxic. Environ.
Safety 1:399-406, 1977a.
Lovelock, J. E. Methyl chloroform in the troposphere as an indicator of OH
radical abundance. Nature 267:32, 1977b.
Lowenheim, F. A., and M. K. Moran, eds. Faith, Keyes, and Clark's Industrial
Chemicals. Fourth edition. Wiley-Interscience, 1975, pp. 836-843.
Lucchesi, B. R. The effects of pronethalol and its dextro isomer upon experi-
mental cardiac arrhythmias. J. Pharmacol. Exp. Ther. 148:94-99, 1965.
Maroni, M., C. Bulgheroni, M. G. Cassitto, F. Merluzzi, R. Giliolo, and V.
Foa. A clinical, neurophysiological and behavioral study of female workers
exposed to 1,1,1-trichloroethane. Scand. J. Work Environ. Health 3:16-22,
1977.
Marshall, E. K. Jr., and A. H. Owens, Jr. Absorption, excretion and metabolic
fate of chloral hydrate and trichloroethanol. Bull. Johns Hopkins Hosp.
95:1-18, 1954.
Masters, C. J., and R. S. Holmes. Peroxisomes--their metabolic roles in
mammalian tissues. Trends. Biochem. Sci. 4:233-236, 1979.
McCarthy. Possible impact of flurocarbons, ICAS, 1975.
McConnell, J. C. , and H. I. Schiff. Methyl Chloroform: Impact on strato-
spheric ozone. Science 199:174-177, 1978.
McNutt, N. S., R. L. Amster, E. E. McConnell, and F. Morris. Hepatic lesions
in mice after continuous inhalation exposure to 1,1,1-trichloroethane.
Lab. Invest. 32:642-654, 1975.
Miller, K. W. , W. D. M. Paton, E. B. Smith, and R. A. Smith. Physicochemical
approaches to the mode of action of general anesthetics. Anesthesiology
36: 339-351, 1972.
Monster, A. C. Difference in uptake, elimination and metabolism in exposure
to trichloroethylene, 1,1,1-trichloroethane, and tetrachloroethylene.
Int. Arch. Occup. Environ. Hlth. 42:311-319, 1979.
Monster, A. C. , and G. Boersman. Simultaneous determination of trichloro-
ethylene and metabolites in blood and exhaled air by gas chromatography.
Int. Arch. Occup. Environ. Hlth. 35:155-163, 1975.
002MC5/F 6-10 11-10-81
-------
Monster, A. C. , and J. M. Houtkooper. Estimation of individual uptake of
trichloroethylene, 1,1,1-trichloroethane, and tetrachloroethylene from
biological parameters. Int. Arch. Occup. Environ. Hlth. 42:319-323,
1979.
Monster, A. C. , G. Boersma, and W. C. Duba. Pharmacokinetics of trichloro-
ethylene in volunteers; influence of workload and exposure concentration.
Int. Arch. Occup. Environ. Hlth. 38:87-102, 1976.
Monster, A. C. , G. Boersma, and W. C. Duba. Kinetics of trichloroethylene in
repeated exposure of volunteers. Int. Arch. Occup. Environ. Hlth. 42:283-
292, 1979a.
Monster, A. C., G. Boersma, and H. Steenweg. Kinetics of 1,1,1-trichloroethane
in volunteers: influence of exposure concentration and work load. Int.
Arch. Occup. Environ. Hlth. 42:293-301, 1979b.
Morgan, A. , A. Black, and D. R. Belcher. Studies on the absorption of halo-
genated hydrocarbons and their excretion in breath using 38C1 tracer
techniques. Ann. Occup. Hyg. 15:273-283, 1972.
Mu'ller, G. , M. Spassovski, and D. Henschler. Metabolism of trichloroethylene
in man. II. Pharmacokinetics of metabolites. Arch. Toxicol. 32:283-295,
1974.
National Research Council. National Academy of Sciences. Halocarbons.
Effects on Stratospheric Ozone. Panel on Atmospheric Chemistry.
Washington, DC, 1976.
National Research Council. National Academy of Sciences. Drinking Water and
Health. Safe Drinking Water Committee, Washington, D.C., 1977.
National Research Council. National Academy of Sciences. Non-Fluorinated
Halomethanes in the Environment. Panel on Low Molecular Weight-
Halogenated Hydrocarbons. Coordinating Committee for Scientific and
Technical Assessments of Environmental Pollutants, 1978.
National Research Council. National Academy of Sciences. Stratospheric Ozone
Depletion by Halocarbons: Chemistry and Transport. Panel on Strato-
spheric Chemistry and Transport. Washington, D.C., 1979a.
National Research Council. National Academy of Sciences. Protection Against
Depletion of Stratospheric Ozone by Chlorofluorocarbons. Committee on
Impacts of Stratospheric Change, 1979b.
National Research Council. National Academy of Sciences. Causes and Effects
of Stratospheric Ozone Reduction: An Update, 1982.
National Aeronautics and Space Administration. Chlorofluoromethane. Assess-
ment workshop report, NASA Goddard Space Flight Center, March 1977.
National Cancer Institute Clearinghouse on Environmental Carcinogens. Con-
sideration of 1,1,1-trichloroethane. Minutes of the second meeting of
the risk assessment subgroup, pp. 4-5, March 25, 1977.
002MC5/F 6-11 11-10-81
-------
National Cancer Institute. Bioassay of 1,1,1-trichloroethane for Possible
Carcinogenicity. Carcinog. Tech. Rep. Ser. No. 3, NCI-CG-TR-3, 70 pp.,
1977.
National Cancer Institute. Bioassay of 1,4-dioxane for Possible Carcinogeni-
city. Carcinog. Tech. Rep. Ser. No. 80, NCI-CG-TR-80, 107 pp. , 1978.
Neely, W. B., and J. H. Plonka. Estimation of time-averaged hydroxyl radical
concentration in the troposphere. Environ. Sci. Techno!. 12(3):317-321,
1978.
Nomiyama, K., and H. Nomiyama. Metabolism of trichloroethylene in humans.
Int. Arch. Arbeitsmed. 28:37-48, 1971.
Noweir, M. H., E. A. Pfitzer, and T. F. Hatch. Decomposition of chlorinated
hydrocarbons; a review, J. Amer. Ind. Hyg. Assoc. 33(7):454-460, 1972.
Ogata, M., K. Tomokumi, and H. Asahara. Simple microdetermination of trichlo-
roethanol glucuronide and trichloroacetic acid in urine. Int. Arch.
Arbeitsmed. 32:203-215, 1974.
Ohta, T. , M. Morita, I. Mizoguchi, and T. Tada. Washout effect and diurnal
variation for chlorinated hydrocarbons in ambient air. Atmos. Environ.
11:985-987, 1977.
Owens, A. H., Jr., and E. K. Marshall, Jr. A comparison of the metabolism of
ethanol and trichloroethanol. Bull. John Hopkins Hosp. 97:395-404,
1955.
Owens, A. H., Jr., and E. K. Marshall, Jr. Further studies on the metabolic
fate of chloral hydrate and trichloroethanol. Bull. Johns Hopkins Hosp.
97:320-326, 1955.
Parker, J. C., G. E. Casey, L. J. Bahlman, N. A. Leidel, D. Rose, H. P. Stein,
A. W. Thomas, and J. M. Lane. Chloroethanes: review of toxicity.
NIOSH Current Intelligence Bulletin #27. Am. Ind. Hyg. Assoc. J. 40:
A46-A60, 1979.
Paykoc, Z. and V. J. F. Powell. The excretion of sodium trichloroacetate.
J. Pharmacol. Expt. Ther. 85:289-293, 1945.
Pelkonen, 0., and H. Vainio. Spectral interactions of a series of chlorinated
hydrocarbons with cytochrome P-450 of liver microsomes from variously
treated rats. FEBS Letters 51:11-14, 1975.
Pellizzari, E. D. Electron capture detection in gas chromatography.
J. Chromat. 98:323-361, 1974.
Pellizzari, E. D. Measurement of Carcinogenic Vapors in Ambient Atmospheres.
EPA-600/7-78-062, 1978.
Pellizarri, E. D. and J. E. Bunch. Ambient Air Carcinogenic Vapors: Improved
Sampling and Analytical Techniques and Field Studies. EPA-600/2-79-081, 1979.
002MC5/F 6-12 11-10-81
-------
PeTh'zarri, E. D. , M. D. Erickson and R. A. Ziveidinger. Formulation of a
Preliminary Assessment of Halogenated Organic Compounds in Man and
Environmental Media. EPA 560/13-79-006, 1979.
Pierotti, D. , R. A. Rasmussen, and R. Dalluge. Measurements of N20,
CF2C12, CFC13, CH3CC13, CC14, and CH3C1 in the troposphere and lower
stratosphere over North America. Accepted for publication in the Journal
of Geomagnetism and Geoelectricity, Vol. 32, 1980.
Piet, G. J., P. Slingerland, F. E. de Grunt, M. P. M. v.d. Heuvel, and B.
C. J. Zoeteman. Determination of very volatile halogenated organic
compounds in water by means of direct head-space analysis. Anal. Lett.
All(5):437-448, 1978.
Plaa, G. L. , E. A. Evans, and C. H. Nine. Relative hepatotoxicity of seven
halogenated hydrocarbons. J. Pharmacol. Exp. Ther. 123:224-229, 1958.
Prendergast, J. A., R. A. Jones, L. J. Jenkins, Jr., and J. Siegel.
Effects on experimental animals of long-term inhalation of tri-
chloroethylene, carbon tetrachloride, 1,1,1-trichloroethane,
dichlorodifluoromethane, and 1,1-dichloroethylene. Toxicol. Appl.
Pharmacol. 10:270-289, 1967.
Price, P. J., C. M. Hassett, and J. I. Mansfield. Transforming activities of
trichloroethylene and proposed industrial alternatives. In vitro 14:290-
293, 1978.
Priestly, B. G., and G. L. Plaa. Hepatic function after acute or subchronic
nicotine administration in untreated mice and mice treated with hepato-
toxic chemicals. Arch. Int. Pharmacodyn. 223:132-141, 1976.
Quast, J. F., B. K. J. Leong, L. W. Rampy, and P. J. Gehring. Toxicologic and
carcinogenic evaluation of a methyl chloroform (1,1,1-trichoroethane)
formulation by chronic inhalation in rats—Interim Report after 24 months.
Midland, Michigan, Dow Chemical Co., 14 pp., 1978.
Rail, D. P. Difficulties in extrapolating the results of toxicity studies in
laboratory animals to man. Environ. Res. 2:360-367, 1969.
Rampy, L. W. , J. F. Quast, B. K. J. Leong, and P. J. Gehring. Results of
long-term inhalation toxicities studies on rats of l,l,l,trichloroethane
and perchloroethylene formulations. In: Proc. Int. Cong. Toxicol.,
Toronto, p. 27, 1977 (abstract).
Rasmussen, R. A., and M. A. K. Khalil. Interlaboratory comparison of fluoro-
carbons -11, -12, methyl chloroform and nitrous oxide measurements.
Atmos. Enviorn. 15:1559-1568, 1981a.
Rasmussen, R. A., and M. A. K. Khalil. Global atmospheric distribution
and trend of methyl chloroform (CH3CC12). Geophy. Res. Lett. 8(9):
1005-1007, 1981b.
002MC5/F 6-13 11-10-81
-------
Rasmussen, R. A., D. E. Harsch, P. H. Sweany, J. P. Krasnec, and D. R. Cronn.
Determination of atmospheric halocarbons by a temperature-programmed gas
chromatographic freezeout concentration method. J. Air Poll. Control
Assoc. 27:579-581, 1977.
Reinhardt, C. F., L. S. Mullin and M. E. Maxfield. Epinephrine-induced cardiac
arrhythmia potential of some common industrial solvents. J. Occup. Med.
15:953-955, 1973.
Rennick, B. R., S. D. Maltos, G. K. Mow and M. H. Seevers. Induction of
idioventricular rhythms by 1,1,1-trichloroethane and epinephrine. Fed.
Proc. 8:327, 1949.
Robinson, E. Analysis of Halocarbons in Antarctica. WSU report 78/13-42 for
the National Science Foundation, December, 1978.
Robinson, E., and D. E. Harsch. A Halocarbon Survey in the Pacific Area From
80°N to 59°S, June, 1976. WSU report 78/13-24 for Manufacturing Chemists
Association, June, 1978.
Rowe, V. K. , T. Wujkowski, M. A. Wolf, S. E. Sadek, and R. D. Stewart.
Toxicity of a solvent mixture of 1,1,1-trichloroethane and tetrachloro-
ethylene as determined by experiments on laboratory animals and human
subjects. Am. Ind. Hyg. Assoc. J. 24:541-554, 1963.
4
Russell, J. W., and L. A. Shadoff. The sampling and determination of halo-
carbons in ambient air using concentration on porous polymer. J. Chromat.
134:275-284, 1977.
Salvini, M. Psychological Effects of Trichloroethylene and 1,1,1-Trichloro-
ethane Upon Man. Behavioral Toxicology, U.S. Dept. HEW, Publ. No. (NIOSH)
74-126, 1974.
Salvini, M., S. Binaschi, and M. Riva. Evaluation of the psychophysiological
functions in humans exposed to the "threshold limit value" of 1,1,1-
trichloroethane. Brit. J. Ind. Med. 28:286-292, 1971.
Sato, A., and T. Nakajima. A structure-activity relationship of some chlori-
nated hydrocarbons. Arch. Environ. Hlth. 34:69-75, 1979.
Sato, R., T. Nakajima, Y. Fugiwara, and N. Murayama. A pharmacokinetic model
to study the excretion of trichloroethylene and its metabolites after
inhalation exposure. Brit. J. Ind. Med. 34:55-63, 1977.
Savolainen, H. , V. Riihimaki, A. Laine, and J. Kekoni. Short-term exposure
of human subjects to m-xylene and 1,1,1-trichloroethane. Int. Arch.
Occup. Environ. Health 49:89-98, 1981.
Savolainen, H. , P. Pfaffli, M. Tengen, and H. Vainio. Trichloroethylene and
1,1,1-trichloroethane: effects on brain and liver after five days inter-
mittent inhalation. Arch. Toxicol. 38:229-237, 1977.
Schlossberg, President, Dextrex Chemical Industries, Box 401, Detroit, Michigan
48232. Letter to Bill Stewart, Executive Director, Texas Air Control
Board, Austin, Texas 78758, July 26, 1978.
002MC5/F 6-14 11-10-81
-------
Schwetz, B. A., B. K. J. Leong, and P. J. Gehring. The effect of maternally
inhaled trichloroethylene, perch!oroethylene, methyl chloroform, and
methylene chloride on embryonal and fetal development in mice and rats.
Toxicol and Appl. Pharmacol. 32:84-96, 1975.
Seki, Y. , Y. Urashima, H. Aikawa, H. Matsumura, Y. Ichikawa, F. Hiratsuka, Y.
Yoshioka, S. Shimbo, and M Ikeda. Trichloro-compounds in the urine of
humans exposed to methyl chloroform at sub-threshold levels. Int. Arch.
Arbeitsmed. 34:39-49, 1975.
Sellers, E. M., M. Lang, J. Koch-Weser, E. LeBlanc, and H. Kalant. Interaction
of chloral hydrate and ethanol in man. I. Metabolism. Clin. Pharmacol.
and Therap. 13:37-49, 1972.
Shah, H. C. , and H. Lai. Effects of 1,1,1-trichloroethane administered by
different routes and in different solvents on barbiturate hypnosis and
metabolism in mice. J. Toxicol. Environ. Hlth. 1: 807-816, 1976.
Sheldon, L. S. , and R. A. Hites. Organic compounds in the Delaware River.
Environ. Sci. Technol. 12(10):1188-1194, 1978.
Siebecker, K. L. , Jr., B. J. Bamforth, J. E. Steinhaus, and 0. S. Orth.
Clinical studies on new and old hydrocarbons. Anesth. Analg. (Cleve)
39:180Tl88, 1960.
Simmon, V. F. , K. Kauhanen, and R. G. Tardiff. Mutagenic Activity of Chemicals
Identified in Drinking Water. In: Progress in Genetic Toxicology, D.
Scott, B. A. Bridges and F. H. Sobels, eds., Amsterdam, Elsevier, pp.
249-258, 1977.
Simmonds, P. G. , S. L. Kerrin, J. E. Lovelock, and F. H. Shair. Distribution
of atmospheric halocarbons in the air over the Los Angeles basin. Atmos.
Environ. 8:209-216, 1974.
Singh, H. B. , L. J. Salas, and R. Stiles. Trace Chemicals in the "Clean"
Troposphere. EPA-600/3-81-055, October 1981.
Singh, H. B. Atmospheric halocarbons: evidence in favor of reduced average
hydroxyl radical concentration in the troposphere. Geophy. Res. Lett.
4:101-104, 1977a.
Singh, H. B. Preliminary estimation of average tropospheric HO concentrations
in the Northern and Southern hemispheres. Geophy. Res. Lett. 4:453-456,
1977b.
Singh, H. B., L. J. Salas, and L. A. Cavanagh. Distribution, sources and sinks
of atmospheric halogenated compounds. J. Air Poll. Control Assoc. 27:332-
376, 1977a.
Singh, H. B. , L. J. Salas, D. Lillian, R. R. Arnts, and A. Appleby. Genera-
tion of accurate halocarbon primary standards with permeation tubes.
Environ. Sci. Techol. 11(5):511-513, 1977b.
002MC5/F 6-15 11-10-81
-------
Singh, H. B. , L. J. Salas, H. Shigeishi, and A. Crawford. Urban-nonurban
relationships of halocarbons, SF6, N20 and other atmospheric trace consti-
tuents. Atmos. Environ. 11:819-828, 1977c.
Singh, H. B. , L. J. Salas, H. Shigeishi, and E. Scribner. Global Distribution
of Selected Halocarbons, SF6 and N20. Phase II Interim Report, SRI
International, Menlo Park, California, May 1978a.
Singh, H. B., L. J. Salas, H. Shigeishi, and E. Scribner. Global Distribution
of Selected Halocarbons, Hydrocarbons, SF6, and N20. SRI Intern., Menlo
Park, California, EPA-600/3-78-100. U.S. Environmental Protection Agency,
Research Triangle Park, NC, December 1978b.
Singh, H. B., L. J. Salas, H. Shigeishi, and A. H. Smith. Fate of Halogenated
Compounds in the Atmosphere. SRI Intern., Menlo Park, California, EPA-
600/3-78-017. Interim Report, 1977 Environmental Monitoring Series.
U.S. Environmental Protection Agency, Research Triangle Park, NC, January
1978c.
Singh, H. B. , L. J. Salas, H. Shigeishi, A. J. Smith, E. Scribner, and L. A.
Cavanagh. Atmospheric Distributions, Sources and Sinks of Selected
Halocarbons, Hydrocarbons, SF6, N20. Final Report, SRI Intern., Menlo
Park, CA, EPA-600/3-79-107, U.S. Environmental Protection Agency, November
1979a.
Singh, H. B., L. J. Salas, H. Shigeishi, A. J. Smith and E. Serebreny. Atmos-
pheric Distributions, Sources and Sinks of Selected Halocarbons, Hydro-
carbons, SF6 and N20. Final Report, SRI International, Menlo Park,
California, 1979b.
Singh, H. B., L. J. Salas, A. J. Smith and H. Shigeishi. Measurements of some
potentially hazardous organic chemicals in urban environments. Atmos.
Environ. 15:601-612, 1981.
Snow, L. P., B. C. McNair, and B. C. Castro. Mutagenesis Testing of 1,1,1-
Trichloroethane in Salmonella Strains TA-100 and TA-98. Northrop Services,
Inc., Research Triangle Park, NC. EPA Sponsored Study, 1979.
Somani, P. and B. K. B. Lum. The antiarrhythmic actions of beta-adrenergic
blocking agents. J. Pharmacol. Exp. Ther. 147:194, 1965.
Spence, J. W. , and P. L. Hanst. Oxidation of chlorinated ethanes. J. Air
Pollut. Control. Assoc. 28(3):250-255, 1978.
Stahl, C. J., A. V. Fatten, and A. M. Dominguez. Trichloroethane poisoning:
observations on the pathology and toxicology in six fatal cases. J.
Foren. Sci. 11:393-397, 1969.
Stewart, R. D. The toxicology of 1,1,1-trichloroethane. Amer. Occup. Hyg.
11:71-79, 1968.
Stewart, R. D. Methyl chloroform intoxication: diagnosis and treatment.
JAMA 215:1789-1792, 1971.
002MC5/F 6-16 11-10-81
-------
Stewart, R. D. and H. C. Dodd. Absorption of carbon tetrachloride, trichloro-
ethane, tetrachloroethylene, methylene chloride, and 1,1,1-trichloro-
ethane through the human skin. Am. Ind. Hyg. Assoc. J. 25:439-446, 1964.
Stewart, R. D., and J. T. Andrews. Acute intoxication with methyl chloroform.
JAMA 195:904-906, 1966.
Stewart, R. D., H. H. Gay, D. S. Erley, C. L. Hake, and A. W. Schaffer. Human
exposure to 1,1,1-trichloroethane vapor: relationship of expired air and
blood concentrations to exposure and toxicity. Am. Ind. Hyg. Assoc. J.
22:252-261, 1961.
Stewart, R. D. , H. H. Gay, A. W. Schaffer, D. S. Erley, and V. K. Rowe.
Experimental human exposure to methyl chloroform vapor. Arch. Environ.
Hlth. 19:467-472, 1969.
Stewart, R. D. , C. L. Hake, A. Wu, S. A. Graff, H. V. Forster, A. J. Lebrun,
P. E. Newton, and R. J. Soto. 1,1,1-trichloroethane: Development of a
Biologic Standard for the Industrial Worker by Breath Analysis. The
Medical College of Wisconsin and The National Institute of Occupational
Safety and Health. NIOSH-MCOW-ENVM-l,l,l-T-75-4, 1975.
Stokinger, H. E. and R. L. Woodward. Toxicologic methods for establishing
drinking water standards. J. Amer. Water Works Assoc., 1958.
Su, G. and K. A. Wurzel. A regulatory framework for setting air emission
limits for noncriteria pollutants. J. Air Pollut. Cont. Assoc. 31:160-
162, 1981.
Tada, T., T. Ohta, and I. Mizoguchi. Behavior of chlorinated hydrocarbons in
urban air. Ann. Rep. Tokyo Metr. Res. Lab. P.H. 27(1):242-246, (trans-
lation, TR-79-0349), 1976.
Takeuchi, Y. Experimental studies on the toxicity of 1,1,1,2-tetrachloro-
ethane compared with 1,1,2,2-tetrachloroethane and 1,1,1-trichloroethane.
Jap. J. Ind. Health 8:371-374, 1966.
Tanaka, S., and M. Ikeda. A method for determination of trichloroethanol and
trichloroacetic acid in urine. Brit. J. Ind. Med. 25:214-219, 1968.
Taylor, G. Mutagenicity Testing: Interoffice memo to Office/Division
Directors, NIOSH mutagenicity task force members. Dated 12/9/77.
Taylor, G. Personal communication. NIOSH, Morgantown, West Virginia 1978.
Taylor, G. J. , R. T. Drew, E. M. Lores, Jr., and T. A. Clemmer. Cardiac
depression by haloalkane propellents, solvents, and inhalation anesthetics
in rabbits. Toxicol. Appl. Pharmacol. 38:379-387, 1976.
Teschke, R. , K. Ohnishi, Y. Hasumura, and C. S. Lieber. Hepatic Microsomal
Ethanol Oxidizing System: Isolation and Reconstitution. lt\: Microsomes
and Drug Oxidations., Proc. 3rd Int. Symp. Berlin, 1976, Suppl. Biochem.
Pharmacol. Pergammon, Oxford, pp. 103-110, 1977.
002MC5/F 6-17 11-10-81
-------
Torkelson, T. R., F. Oyen, D. D. McCollister, and V. K. Rowe. Toxicity of
1,1,1-trichloroethane as determined on laboratory animals and human
subjects. Am. Ind. Hyg. Assoc. J. 19:353-362, 1958.
Torkelson, T. R., B. K. J. Leong, R. J. Kociba, W. A. Richter, and P. J.
Gehring. 1,4-Dioxane. II. Results of a two-year inhalation study in
rats. Toxicol. Appl. Pharmacol. 30:287-298, 1974.
Tottmar, S. 0., H. Pettersson, and K. H. Kiessling. The subcellular distri-
bution and properties of aldehyde dehydrogenases in rat liver. Biochem. J.
135:577-586, 1973.
Trochimowicz, H. J. , C. F. Reinhardt, L. S. Mullin, A. Azar, and B. W. Karrh.
The effect of myocardial infarction on the cardiac sensitization potential
of certain halocarbons. J. Occup. Med. 18:26-30, 1976.
U.S. Environmental Protection Agency. Interim Procedures and Guidelines for
Health Risk and Economic Impact Assessments of Suspected Carcinogens.
Federal Register 41:21402, May 25, 1976.
U.S. Environmental Protection Agency. ESRL Report on the Problem of Haloge-
nated Air Pollutants and Stratospheric Ozone. EPA-600/9-75-008. U.S.
Environmental Protection Agency, Research Triangle Park, NC, December
1975.
U.S. Environmental Protection Agency. Unpublished data developed using the
Lawrence Livermore Laboratory 1-D model and rate constants cited in
National Academy of Sciences, 1979a.
U.S. Environmental Protection Agency. An Assessment of the Need for Limita-
tions on Trichloroethylene, Methyl Chloroform, and Perchloroethylene.
EPA-560/11-79-009. Office of Toxic Substances. July 1979b.
U.S. Environmental Protection Agency. Guidelines and Methodology for the Prepara-
tion of Health Effect Assessment Chapters of the Ambient Water Quality
Criteria Documents. Environmental Criteria and Assessment Office, 1980a
U.S. Environmental Protection Agency. Ambient Water Quality Criteria for
Chlorinated Ethanes. U.S. EPA (NTIS PB81-117400), 1980b.
U.S. Environmental Protection Agency. Proceedings of the Conference on Methyl
Chloroform and Other Halocarbon Pollutants. EPA-600/9-80-003, January
1980c.
U.S. International Trade Commission. Synthetic Organic Chemicals. United
States Production and Sales, 1977.
Uehleke, H. , S. Tabarelli-Poplawski, G. Bonse, and D. Henschler. Spectral
evidence for 2,2,3-trichloroxirane formation during microsomal trichloro-
ethylene oxidation. Arch. Toxicol. 37:95-105, 1977.
Vainio, H. , H. Savolainen and P. Pfaffli. Biochemical and toxicological
effects of combined exposure to 1,1,1-trichloroethane and trichloro-
ethylene on rat liver and brain. Xenobiotica 8:191-196, 1978.
002MC5/F 6-18 11-10-81
-------
Van Duuren, B. L. Chemical structure, reactivity and carcinogenicity of
halohydrocarbons. Environ. Hlth. Persp. 21:17-23, 1977.
Van Dyke, R. A. Dechlorination mechanisms of chlorinated olefins. Environ.
Hlth. Persp. 21:121-124, 1977.
Van Dyke, R. A., and C. G. Wineman. Enzymatic dechlorination: dechlorination
of chloroethanes and propanes in vitro. Biochem. Pharmacol. 20:463-470,
1971.
Van Dyke, R. A., and L. E. Rikans. Effect of the volatile anesthetics on
aniline hydroxylase and aminopyrine demethylase. Biochem. Pharmacol.
19:1501-1502, 1970.
Vanlaethem-Meuree N. , J. Wisemberg, and P. C. Simon. Ultraviolet absorption
spectrum of methyl chloroform in the vapor phase. Geophy. Res. Lett.
6(6):451-454, 1979.
Watson, R. T., G. Machado, B. Conaway, S. Wagner, and D. D. Davis. A tempera-
ture dependent kinetics study of the reaction of OH with CH2CIF, CHC12F,
CHCIF2, CH3CC13, CH3CF2C1, and CF2CICFC12. Phys. Chem. 81:256, 1977.
Weisburger, E. K. Carcinogenicity studies on halogenated hydrocarbons.
Environ. Hlth. Persp. 21:7-16, 1977.
Weitbrecht, U. Tri and tri-substitutes in the metal industry. Zentralb
Arbeitsmed 15:138-146, 1965.
World Meteorological Organization (WMO). Global Ozone Research and Monitoring
Project, Report No. 11. The Stratosphere 1981: Theory and Measurements,
World Meteorological Organization, Geneva, Switzerland, 1982.
Wuebbles, D. J. The relative efficiency of a number of halocarbons for
destroying stratospheric ozone. Lawrence Livermore National Laboratory,
UCID 18924, 1981.
Wuebbles, D. J. , and J. S. Chang. A study of the effectiveness of the C1X
catalytic ozone loss mechanisms. J. Geophy. Res. 86(C10):9869-9872,
1981.
14
Yllner, S. Metabolism of chloroacetate- C in the mouse. Acta Pharmacol. et
Toxicol. 30:69-80, 1971b.
14
Yllner, S. Metabolism of 1,2-dichloromethane- C in the mouse. Acta. Pharmacol,
et Toxicol. 30:257-265, 1971a.
York, R. G., B. Sowry, L. Hastings and J. Manson. Evaluation of the prenatal
toxicity of methyl chloroform. J. Toxicol. Environ. Health. Accepted for
publication July 1981.
002MC5/F 6-19 11-10-81
-------
7. Appendix
THE CARCINOGEN ASSESSMENT GROUP'S
CARCINOGEN ASSESSMENT OF
METHYL CHLOROFORM
7-1
-------
EXTERNAL REVIEW DRAFT
January 16, 1981
THE CARCINOGEN ASSESSMENT GROUP'S
CARCINOGEN ASSESSMENT
OF
METHYL CHLOROFORM
Roy E. Albert, M.D.
Chairman
PARTICIPATING MEMBERS
Elizabeth L. Anderson, Ph.D.
Larry D. Anderson, Ph.D.
Steven Bayard, Ph.D. -
Chao W. Chen, Ph.D.
John R. Fowle III. Ph.D.*
Bernard H. Haberman, D.Y.M., M.S.
Charalingayya B. Hiremath, Ph.D.
Chang S. Lao, Ph.D.
Robert McGaughy, Ph.D.
Beverly Paigen, Ph.D.
Dharm Y. Singh, D.V.M., Ph.D.
Nancy A. Tanchel, B.A.
Todd W. Thorslund, Sc.D.
Peter E. Yoytek, Ph.D.*
*Reproduct1ve Effects Assessment Group
DRAFT
DO NOT QUOTE OR CITE
This document has been reviewed and approved by the Chairman and staff of the
Carcinogen Assessment Group, Office of Health and Environmental Assessment, U.S.
Environmental Protection Agency. It has not been formally released by the EPA
and should not at this stage be construed to represent Agency policy. It is
being circulated for comment on its technical accuracy and policy implication.
7-2
-------
CONTENTS
I. Summary 1
II. Introduction 2
III. Metabolism 2
IV. Mutagenicity and Cell Transformation 4
Cell Transformation
V. Toxicity 14
VI. Carcinogenicity 15
Rats
Mice
Carcinogenicity of 1,4-Dioxane
VII. Unit Risk Estimate 23
VIII. References 26
7-3
-------
I. SUMMARY
There 1s no adequate basis for the evaluation of the carclnogenidty of
methyl chloroform. A lifetime animal bloassay using both rats and mice,
currently 1n progress under the National Toxicology Program (NTP), will be
completed In May 1981. An earlier National Cancer Institute (NCI) study was
Inconclusive due to the poor survival of treated animals. An Inhalation study
1n rats by the Dow Chemical Company showed no evidence of carclnogenidty, but
the doses were given for only half of the lifetime of the animals and the
highest dose did not appear to be the maximum tolerated dose.
Technical grade methyl chloroform has been shown to be weakly mutagenic and
to transform animal cells 1n vitro using Fisher rat embryo cell line F1706.
Technical grade methyl chloroform contains about 3% of the stabilizing substance
dioxane which shows evidence of being a carcinogen (Kociba et al. 1974; Argus et
al. 1965, 1973; NCI 1978).
Therefore, because of the inconclusive results of the NCI gavage bioassay
in rats and mice, the dosage Inadequacies in the negative Dow inhalation test
and the possible contribution of dioxane to the positive mutagenic and cell
transformation tests, a final judgment on the carcinogenicity of methyl
chloroform will have to be deferred until the results of the NTP bioassay, which
has a very low percentage (0.002%) of dioxane, are available.
7-4
-------
II. INTRODUCTION
Methyl chloroform (1,1,1-tHchloroethane, Cl^CCls) 1s used primarily as
a cleaning or degreaslng agent for metals. It 1s Increasingly being used as a
substitute for chlorinated ethyl enes. An estimated 630 million pounds were
produced 1n the United States 1n 1976; of this, dispersive uses of methyl
chloroform (primarily metal degreaslng and aerosols) comprise at least 300
million pounds. Methyl chloroform escapes Into the environment primarily Into
the air. It 1s soluble (2 gm 1n 100 ml) 1n water and has a boiling point of the
74°C. The National Institute for Occupational Safety and Health (NIOSH) judges
that 2.9 million workers may be exposed (Parker et al. 1979).
III. METABOLISM
Only a small percentage of methyl chloroform 1s metabolized; most 1s
excreted unchanged by the lungs. Using rodent liver In vitro, Van Dyke and
Wineman (1971) showed that dechlorf nation of chloroethanes was carried out by
the nrfcrosomal mixed- function oxldases and required molecular oxygen. However,
methyl chloroform was a poor substrate for this reaction compared to other
chloroethanes and less than 0.5% of the chlorine was enzymatlcally removed.
Metabolism was not Increased when rats were pre-exposed to methyl chloroform for
3 days.
In humans, Monster et al. (1979) have estimated that 60 to 80% of Inhaled
methyl chloroform was exhaled unchanged from the lungs. Only a small part of
the retained methyl chloroform was excreted 1n urine as trlchloroethanol (2%)
and trichloroacetlc acid (1.5%). The authors had no explanation for the
unaccounted methyl chloroform.
Hake and coworkers (1960) injected one female and two male rats (170 to
7-5
-------
IV. MUTAGENICITY* AND CELL TRANSFORMATION
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 studies presently available for review are
summarized in Table 1.
Five reports have been prepared about the mutagenicity of methyl chloroform
in bacteria; all were conducted using the Salmonella/S9 system. Two of the
reports, Henschler et al. (1977) and Taylor (1977) were reported to be negative.
The report by Henschler cannot be evaluated because no data are presented. In
the report by Taylor, actually an interoffice memo describing results generated
from testing performed by a contract laboratory, 0, 50, 100, 200, 300, and 500
ul/plate doses of methyl chloroform (source and purity not reported) were
administered in plate incorporation tests using TA 1535, TA 1537, TA 98, and TA
100. Different concentrations of S9 activation were also tested. The high
doses of methyl chloroform (300 and 500 ul/plate) were reported to be toxic for
all strains in tests conducted without activation. The 500 ul/plate dose
level was reported to be toxic for either TA 1537 or TA 98 1n the various tests
conducted with metabolic activation, but not for the other strains. The
criteria for determining toxicity were not reported. Although special
precautions were not reported to have been taken to prevent evaporation of
methyl chloroform, it appears that the test agent did enter the cells at the
highest doses because of the toxicity reported.
^Prepared by the Reproductive Effects Assessment Group.
7-6
-------
183 g) Intraperftoneally (1.p.) with 700 rag/kg of 14C-methyl chloroform.
About 50% of the urinary radioactivity occurred as 2,2,2-trichloroethanol 1n the
form of glucuronlde conjugate. The remaining urinary radioactivity volatilized
at room temperature and was probably the parent compound. It was suggested that
methyl chloroform metabolized by an Initial oxidation to trlchloroethanol and
subsequent oxidation to small quantities of trlchloroacetlc add. In this
study, 98.7% of the Injected radioactivity was exhaled unchanged, and 0.5% as
14C02. Only 0.85% of the Injected radioactivity was recovered 1n urine, and
only half of that was Identified as a metabolite (Figure 1).
METHYL
CHLOROFORM » TRICHLOROETHANOL
oxidation
CC13 - CH3 CCla - CH2OH
glucuronlde \
conjugation oxidation
/ \
CCla - CH20 - glu. TRICHLOROACETIC ACID
CClsCOOH
Figure 1. Metabolic route suggested for methyl chloroform.
Source: Hake et al. 1960, Ikeda an Ohtsuji 1972
Ikeda and Ohtsuji (1972) compared the quantities of metabolites In urine
(trlchloroethanol and trlchloroacetlc add) 1n Wlstar rats exposed by Inhalation
and by 1ntraper1toneal Injection. The quantity of metabolites was essentially
equivalent for exposure to 200 ppm for 8 hrs and 2.78 mmol/kg body weight.
These metabolites are the same metabolites formed from trlchloroethylene.
However, the concentration of trlchloroethanol 1n the blood of volunteers
exposed to methyl chloroform 1s only l/35th that found In volunteers exposed to
equivalent amounts of trlchloroethylene (Monster 1979, Monster et al. 1979,
Monster and Houtkooper 1979).
7-7
-------
TABLE 1. MJTAGENICITY TESTING OF METHYL CHLOROFORM
A. BACTERIA
Reference
Litton 1975
Henschler
et al. 1977
Simmon et al .
1977
Test System Strain
Salmonella/59: TA 1535
spot test and TA 1537
plate Incor- TA 1538
poration
Sa1mone11a/S9 TA 100
Sa1monella/S9: TA 1535
conducted In TA 1537
sealed TA 1538
desiccator TA 98
TA 100
Activation
System
PCB induced liver,
lung and testes S9
mix from adult male
animals: 1CR random
bred mice, Sprague-
Dawley rats and
Macaca mulatta monkeys,
PCB Induced rat liver
microsome S9 mix.
PCB Induced rat liver
microsome S9 mix.
Concentration
Formulation %
99+ TUT
2.5
96 2.0
1.0
95.65 1.0
0.5
93.75 0.5
0.25
Not reported.
(Extrapolated
from figure 21)
0, 100, 200, 300
400, 500, 750,
1000 ul /9-liter
desiccator.
Result
99+% formulation
reported positive
with TA 1535. Result
was reported to be
repeatable.
The other formulations
were reported to be
negative.
Reported negative.
TA 100
Dose +S9 -S9
, 0" T2T T2T
100 130 145
200 125 180
300 175 185
400 145 -
500 200 220
750 260 210
1000 280 225
Comment
1. All formulations reported
to be not soluble at test
concentrations.
2. Toxicity reported to be
variable (In many tests, 25/48,
as many or more survivors were
observed at the high dose
compared to the low dose).
3. Strains TA 98 and TA 100 not
tested (not available at time
test conducted).
4. No Information about the
Identity of the stabilizers
and other components.
5. No special precaution taken
to prevent evaporation of the
compound, but test reported to
be conducted in suspension.
1. No precautions taken to
prevent evaporation reported.
2. No data presented,
therefore, cannot evaluate.
3. Only one strain tested.
1. Results indicate ability of
methyl chloroform to mutate
bacteria when precautions are
taken to ensure exposure of test
organisms.
2. Data were presented for TA
100 only.
3. Exact purity of test compound
not given, but reported to be
high.
7-8
-------
A. BACTERIA
TABLE 1. (continued)
Reference
Taylor 1977
Test System
Salmonella/59:
plate incor-
poration tests
Strain
TA 1535
TA 1537
TA 98
TA 100
Activation
System
Aroclor-actlvated
rat liver mlcrosome
S9 mix. Different
amounts tested (0,
10, 20, 30, 40, and
50 ul/plate).
Concentration
0, 50, 100, 200,
300, and 500
ul/plate
Result Comment
Reported negative. 1. Mo precautions reported to have
been taken to prevent evaporation
of the test material.
2. Protocol not adequately
described.
3. Mo positive controls reported to
have been run.
4. The purity of the test chemical
not reported.
Snow et al.
1979
Sa1njone]la/S9: TA 100
conducted 1n
sealed chambers
Methyl chloroform
Induced Syrian
golden hamster
liver
S9 mix.
0*
500
750
1000
1500
0
500
750
1000
1500
AldHch Sample PPG Sample
(without activation)
144,115,130 144,115,150
234,251,235
271,271,274
315,270.310
355,336,340
225,232,233
263,301,262
307,283,268
398,360,336
(with activation)
122,143,119 122,143,119
324,281,312 266.291.297
359,333,348
373.372,407
365,346,351
384,402,393
485,432,430
471,467,430
Linear Regression Analysis
(y « ax +b)
1. Only one strain tested.
2. Results Indicate ability of
methyl chloroform to mutate bacteria
when precautions are taken to ensure
exposure of test organisms.
3. Linear dose responses obtained
with no significant differences found
between Aldrlch or PPG samples at any
concentration tested.
4. Protocol not completely
described.
5. Purity of Aldrlch sample not
reported. Purity of the PPG
sample reported to be high but
Information about composition
not provided.
Chemical
Source
B
Aldrlch +S9 ^1 I6F .94
-S9 .14 152 .96
PPG +S9 .22 157 .97
-S9 .15 143 .97
.6-liter B11lups-Rothenberg Modular Incubator Chamber
(continued on the following page)
7-9
-------
B. YEAST
TABLE 1. (continued)
Reference
Test System
Strain
Activation
System
Concentration
Result
Comment
Litton 1975 Saccharomyces D4
cerevlslae:
gene conversion
PCB induced Sprague-
Dawley rat liver S9
mix.
Loprleno
et al. 1979
Schlzosac-
charomyces
pombe forward
mutation
ade 6-60/ Host mediated assay
rad 10-198/ B6C3F1 mice.
h-
Formylatlon %
59? T7T~
2.25
96
95.65
93.75
2.0
1.0
2.0
1.0
5.0
2.5
0 or 5000 mg/kg
administered by
gavage to mice.
Yeast exposed for
3, 6, or 16 h.
Reported negative.
Reported negative.
1. All formulations reported to
be not soluble at the test concen-
trations employed.
2. Toxlclty reported to be
variable (In many cases as many or
more survivors observed at the high
dose as at the low dose).
3. No Information about
stabilizers or other chemical
substances In the formulations.
4. No special precautions taken to
prevent evaporation of methyl
chloroform but tests reported to be
conducted in suspension.
1. Preliminary results; protocol
not fully presented.
2. MTO may not have been employed.
3. Unclear if negative and
positive controls performed
concurrently.
4. Unclear 1f test compound was
absorbed from GI tract and exposed
test organisms.
5. No jm vitro testing performed.
C.MAMMALIAN IN VIVO UTTOGENETICS
Quast Chromosome Sprague-
et al. 1978 aberrations Dawley,
In rat marrow spartan
cells substrain
0, 875, and 1750 Reported negative.
ppm Inhalation
5 days/week 6 hr/day
for one year.
1. Protocol and data not
presented. Cannot evaluate
conclusions.
2. Reported that data from female
rats Insufficient for clear inter-
pretation of the results.
3. Treatment had no effect on body
weight of rats. MTD may not have
been employed.
7-10
-------
No special precautions were reported to have been taken to prevent
evaporation of methyl chloroform 1n the tests conduced by L1tton-B1onet1cs
(1975) for Dow Chemical Company either. Various formulations of methyl
chloroform (99+%, 96%, 95.65%, and 93.75%) were assayed for mutagenlc potential
1n Salmonella strains TA 1535, TA 1537, and TA 1538, both with and without
metabolic activation. No Information was provided concerning the stabilizers or
other components of the formulated samples tested. Preliminary toxldty testing
was conducted to determine the appropriate test doses. The test doses decided
upon differed for each formulation and are presented 1n Table 1. It was
reported by the contractor that the chemicals tested were not soluble 1n the
aqueous testing environment, and 1t was stated, for the 99+% formulation at
least, that "the toxldty from test to test was quite variable depending upon
the ability to effectively disperse the compound 1n the testing medium." The
low solubility of methyl chloroform coupled with Its high volatility raise the
concern that, In the tests conducted by L1tton-B1onet1cs, exposure of the test
organisms to 1t may have been minimal. Salmonella strain TA 1535 was reported
to exhibit a repeatable mutagenlc response to the 99+% formulation, but 1t 1s
stated 1n the report that "the mutagenlclty of this chemical for Indicator
strain TA 1535 must be considered presumptive for the following reasons:
A. The positive response 1s only evident at high dose levels which
generally result 1n low population survivals (high toxlclty). Thus
one cannot exclude some type of selection.
B. The data from activation plate tests does (sic) not Indicate any
activity. The activation plate tests were repeated and were negative
1n those tests as well."
With respect to point A, an examination of the computer print-outs
summarizing the mutagenlclty of methyl chloroform for strain TA 1535 both with
and without activation reveals that the population of cells 1n the high dose
group was equal to or greater than the cells 1n the low dose group 1n two out of
7-11
-------
four cases, Including the experiment in which the highest mutation frequency was
observed. In other words, there does not seem to be significant cytotoxicity at
the high dose level which could possibly result in a spurious positive result.
With respect to point B, the plate activation tests performed in this
experiment were spot tests. The proper conduct of a bacterial spot test
requires that the compound be soluble in an aqueous environment, dissolving
through the agar from point of placement outward, forming a concentration
gradient. Since methyl chloroform 1s volatile and was not soluble in the
testing performed by Lltton-Bionetics, the negative results of the plate tests
cannot be considered evidence supportive of the nonmutagenicity of methyl
chloroform: therefore, the study by Litton-Bionetics (1975) 1s considered to be
an inadequate assessment of the mutagenicity of methyl chloroform.
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 et al. 1977 and Snow
et al. 1979). The testing performed by Simmon and coworkers was conducted using
the standard battery of Salmonella typhlmurium strains TA 1535, TA 1537, TA
1538, TA 98, and TA 100, both with and without PCB-induced rat liver mlcrosome
S9 mix for metabolic activation. The concentrations used for testing
(extrapolated from figure 21) were 0, 100, 200, 300, 400, 500, 750, and 1000
ug/9-Hter desiccator. A weak dose-related response was observed for TA 100
both with and without metabolic activation. These results indicate that methyl
chloroform does possess mutagenic activity 1n Salmonella. The exact purity of
the methyl chloroform sample tested was not given but was reported to be high.
In their studies, Snow et al. (1979) tested two samples of methyl chloroform
1n Salmonella strain TA 100 both with and without metabolic activation. Testing
7-12
-------
conducted with metabolic activation employed an S9 mix obtained from methyl
chloroform Induced Syrian golden hamster liver microsomes. Similar to the study
performed by Simmon et al. (1977), precautions were reported to have been taken
to prevent evaporation of methyl chloroform. Doses of 0, 500, 750, 1000, and
1500 ul/5.6 liter Billups-Rothenberg Modular Incubator Chamber were employed,
and repeatable, nearly Identical, linear dose-responses were observed for TA 100
(see result column, Table 1) to the two samples of methyl chloroform tested.
One of the samples was from Aldrich (97% methyl chloroform stabilized with 3%
p-d1oxane) and the other was from PPG Industries (reported to be a purified
sample). The results of Snow and coworkers strengthen the observations by
Simmon et al. (1977) that methyl chloroform 1s a weak mutagen 1n Salmonella.
The nearly Identical responses achieved after testing these two samples of
methyl chloroform obtained from different sources support the conclusion that
methyl chloroform Is a mutagen.
Testing of methyl chloroform for mutagenldty employing yeast as Indicator
organisms has been conducted by two laboratories (L1tton-B1onet1cs 1975 and
Loprleno et al. 1979). Both reported negative results. The L1tton-B1onet1cs
yeast study was conducted at the same time as was the testing of methyl
chloroform In bacteria, and many of the deficiencies noted above concerning the
bacterial tests apply to the yeast testing as well. No special precautions were
reported to have been taken to prevent evaporation of the test compound; the
compound was not soluble under the condition of test, and the toxlclty results
were reported to be variable. In many cases (I.e., 5/11 for the various
formulations) as many or more survivors were observed at the high dose as were
observed at the low dose. As was the case for the bacterial results, the
testing by Lltton-Blonetlcs of methyl chloroform with respect to Its ability to
Induce gene conversion 1n Saccharomyces cerevlslae with and without rat liver S9
7-13
-------
mix metabolic activation is considered to have resulted in a "no-test." The
volatility and insolubility of methyl chloroform raise the likelihood that the
cells on test were simply not adequately exposed.
Based on preliminary testing using the host-mediated assay in B6C3F1 hybrid
mice, Loprieno et al. (1979) have reported that methyl chloroform administered
by gavage at 500 mg/kg did not increase the incidence of forward mutations in
Schizosaccharomyces pombe measured after treatment times of 3, 6,and 16 hours.
No Information was provided concerning the ability of methyl chloroform to be
absorbed and transported to the peritoneum, thereby effectively exposing the
yeast cells, and no information is provided concerning whether or not testing
was conducted to determine the ability of methyl chloroform to induce mutations
in vitro. Furthermore, 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. Besides the concerns
that the Indicator organisms may not have been exposed to methyl chloroform, the
report does not provide adequate information concerning the design and conduct
of the testing and this In turn, makes it Impossible to assess the significance
of the results. (It is not clear what protocol was followed to plate the yeast
after harvest; it Is not clear if concurrent positive and negative controls were
performed, etc.)
The reported lack of chromosome aberrations produced after chronic exposure
to Sprague-Dawley rats (Quast et al. 1978) also cannot be evaluated based on the
data provided to EPA at the time of writing this report. Details concerning the
protocol employed are very sketchy. The conclusions are forwarded unsupported
by the presentation of experimental data.*
*A written request has been made to Dow to obtain these data.
7-14
-------
A joint study sponsored by Imperial Chemical Industries and the Medical
Research Council in the United Kingdom, and the National Institute of
Environmental Health Sciences in the U.S.A. entitled the International Program
for Evaluating Short-Term Tests for Carcinogenicity (IPESTTC) was recently
conducted to assess the ability of short-term tests (including mutagenicity
tests) to predict carcinogenicity. Forty-two chemical substances of high purity
were tested blind in 23 different assays, (e.g., gene mutation tests in
bacteria, yeast, and mammalian cells in culture; SCE formation in vitro and jm
vivo; chromosome aberrations 1n -vitro, etc.) some of which were conducted in
more than one laboratory. The results of the IPESTTC testing have recently been
published (8/6/81). EPA has not yet received a copy of this report to evaluate
the data, but preliminary indications are that methyl chloroform tested negative
in a majority of the experiments (apparently only 9 weak positive responses were
obtained out of 38 test systems). When EPA receives these data, they will be
evaluated with respect to the mutagenicity of methyl cloroform. Since
preliminary reports of the IPESTTC study do not note which, if any, precautions
were taken to ensure exposure of the test organisms to the compound, and the
data are not yet releasable for complete review, the preliminary indication that
methyl chloroform tested negative in the IPESTTC study needs to be further
evaluated.
In summary, methyl chloroform has been tested for its mutagenic potential in
several systems (bacteria, yeast, and rats), but sufficient data are not
presented for evaluating the results presented in three papers (the Dow 1978 rat
cytogenetic study, the Henschler et al. 1977 testing in Salmonella, and the
Loprieno et al. 1980 testing in yeast). Of the remaining papers, only two
described the results of mutagenicity testing conducted in such a manner as to
prevent evaporation of methyl chloroform and to ensure exposure of the indicator
organisms. Both of these tests (Simmon et al. 1977 and Snow et al. 1979) were
conducted in Salmonella and a weak positive response was reported for both.
7-15
-------
On the basis of the available evidence, it is concluded that methyl
chloroform is mutagenlc in bacteria. If the metabolism and pharmacokinetics of
this compound in humans results in metabolic products which can interact with
DNA as is the case for bacteria, it may cause mutagenic effects in humans as
well. However, additional testing in other organisms, (e.g., mammalian cells in
culture) is necessary to confirm the mutagenicity observed in bacteria. Careful
attention should be given to the design and conduct of these studies to prevent
the evaporation of methyl chloroform, overcome its low solubility in aqueous
media, and to ensure exposure of the indicator organisms.
CELL TRANSFORMATION
Price et al. (1978) exposed Fischer rat embryo cell cultures (F1706,
subculture 108) to 1,1,1-trichloroethane liquid at concentrations of 9.9 x IQl
and 9.9 x 102 uM for 48 hours. 1,1,1-Trichloroethane was diluted with growth
medium to yield the appropriate doses. The 1,1,1-trichloroethane sample
obtained from the Fisher Scientific Company was purportedly >_ 99.94 pure, but a
personal communication from Carlson of the Fisher Scientific Company revealed
that methyl chloroform supplied by them to Dr. Price was really the product of
the Dow Chemical Company which is about 95% pure. The chemical composition of
Dow's methyl chloroform is given in Table 4, as reported by Quast et al. (1978)
of the Dow Chemical Company. The cells were grown in Eagles minimum essential
medium In Earle's salts supplemented with 10% fetal bovine serum, 2 mM
L-glutamine, 0.1 mM nonessential amino adds, 100 ug pencillin, and 100 ug
streptomycin per ml. Quadruplicate cultures were treated at 50% confluency with
each dose. After treatment, cells were cultured in growth medium alone at 37°C.
Transformation of cells treated with either dose level of 1,1,1-trichloroethane
was observed by 23 and 44 days of incubation and was characterized by
7-16
-------
progressively growing foci composed of cells lacking contact Inhibition and
orientation. There was no transformation of cells grown in medium alone or in
the presence of a 1:1000 acetone concentration. Fifty-two and 55 microscopic
foci per three dishes with low and high 1,1,1-trichloroethane dose,
respectively, were found in dishes inoculated with 50,000 cells from cultures
treated four subcultures earlier and held for four weeks at 37°C in a humidified
C02 incubator prior to staining.
Subcutaneous injection of cells treated with 9.9 x 101 uM
1,1,1-trichloroethane two subcultures earlier produced local flbrosarcomas in
8/8 newborn Fischer 344 rats within 68 days following treatment. The ability of
cells grown in growth medium alone to induce local fibrosarcomas was not
determined; however, this tumor type did not develop in rats given cells grown
in the presence of a 1:1000 concentration of acetone. Exposure of cells to 3.7
x 10~1 uM 3-methylcholanthrene produced 124 microscopic foci per three dishes
in the inoculation test described above by 37 days of incubation and local
fibrosarcoma in 12/12 rats by 27 days following subcutaneous injection of cells.
The exposure of 3-methylcholanethrene was attained by initial dilution 1n
acetone to 1 mg/ml followed by further dilution in growth medium to 0.1 ug/ml
(personal communication, Dr. Price). It is understood that this cell line
contains the genome of the Rausher leukemia virus, but there 1s no basis for
minimizing the positive results since the mode of action of
1,1,1-trichloroethane is not known i.e., due to activation of the virus.
V. TOXICITY
The toxicity of methyl chloroform has been recently reviewed (Parker et al.
1979). Experiments were performed with various species and strains of animals
at different concentrations. The most harmful effects of methyl chloroform are
7-17
-------
central nervous system problems including anesthesia, disturbed equilibrium, and
impairment of perceptual speed and dexterity. The effects of methyl chloroform
on the heart include bradycardia, hypotension, and cardiac arrhythmias.
Exposure can also cause inflammatory changes in the lungs, cellular damage and
fatty changes in the liver, and damage to the kidneys. Methyl chloroform is
reportedly teratogenic to chick embryos (Elovaara et al. 1979).
VI. CARCINOGENICITY
RATS
Two rat bioassays have been completed and one is in progress. The completed
studies include an NCI bioassay and an inhalation study by the Dow Chemical
Company. A 2-year carcinogenesis bioassay by gavage is now underway by the NTP
in the mouse and rat with 1,1,1-trichloroethane, which has a very low percentage
of dioxane. The animals will be sacrificed in May 1981. In the previous NCI
bioassay, technical grade 1,1,1-trichloroethane was used. This was purchased
from Aldrich Chemical Company, Inc., Milwaukee, Wisconsin. The purity was
checked by Hazleton Laboratories of America, Inc., Vienna, Virginia using
gas-liquid chromatograph (glc) and infrared spectrophotometry. Analyses by glc
showed that it contained 95% 1,1,1-trichloroethane and 3% p-dioxane, an
inhibitor routinely added to commercial preparations of 1,1,1-trichloroethane.
The remaining 2% of the glc peak area contained several minor impurities, two of
which may have been 1,1-dichloroethane and 1,1-dichloroethylene. In this study,
Osborne-Mendel rats were treated with 750 mg/kg and 1500 mg/kg of methyl
chloroform in corn oil 5 times a week for 78 weeks by gavage (NCI 1977). The
rats were observed an additional 32 weeks with the experiment ending at 110
weeks. Both males and females were used with 20 untreated males and 20
untreated females and 50 of each sex at each dose. The study was inadequate
because only 3% of the treated rats survived to the end of the experiment.
7-18
-------
The survival of both sexes of dosed rats was less than that of the matched
control groups, which was also inadequate in the males. In male rats 6/20 (30%)
of the controls, 32/50 (64%) of the low-dose group, and 36/50 (72%) of the
high-dose group died within a year of the start of the study. The Tarone
statistical test of survival showed a dose-related positive trend (P < 0.001) in
the proportions of deaths over the period of the experiment, although this
differential mortality is not reflected in the survival at 78 weeks. In female
rats, 1/20 (5%) of the matched controls, 24/50 (48%) of low-dose group, and
21/50 (42%) of the high-dose group died in the first year. As in male rats, the
statistical test for positive dose-related trend was significant (P < 0.04). In
both sexes, the early mortality in the 1,1,1-trichloroethane-treated rats may
have affected the incidence of late-appearing tumors; this is especially true in
the males, since none survived to the scheduled termination of the study.
Fewer of the rats receiving 1,1,1-trichloroethane survived at both 78 and
110 weeks than did the positive control rats receiving the known carcinogen
carbon tetrachloride (see Table 2).
TABLE 2. COMPARISON OF SURVIVAL OF CONTROL GROUPS,
1,1,1-TRICHLOROETHANE-TREATED, AND CARBON TETRACHLORIDE-TREATED
(POSITIVE CONTROL) RATS
1 ,1 ,1-Trichl oroethane
Group
Male
control
low dose
high dose
Femal e
control
low dose
high dose
Initial
No. of
Animals
20
50
50
20
50
50
Number
Alive at
78 Weeks
7
1
4
14
9
12
Number
Alive at
110 Weeks3
0
0
0
3
2
1
Carbon Tetrachloride
Initial
No. of
Animal s
20
50
50
20
50
50
Number
Alive at
78 Weeks
20
34
35
18
38
21
Number
Alive at
110 Weeks3
12
15
8
14
20
14
in study at last weighing.
7-19
-------
A variety of neoplasms (Table 3) were represented In 1,1,1-trichloroethane-
treated and matched-control rats. However, each type of neoplasm has been
encountered previously as a lesion 1n untreated rats. The neoplasms observed
are not believed attributable to 1,1,1-trlchloroethane exposure, since no
relationship was established between the dosage groups, the species, sex, type
of neoplasm, or the site of occurrence. Even 1f such a relationship were
Inferred, It would be Inappropriate to make an assessment of the cardnogenlcity
of 1,1,1-trlchloroethane on the basis of this test, because of the abbreviated
Hfe spans of the rats. The NCI Clearing House on Environmental Carcinogens
concluded that the cardnogenlcity could not be determined from this study (NCI
Clearing House 1977).
The Dow Chemical study (Quast et al. preprint 1978) treated groups of
Sprague-Dawley rats by Inhalation under conditions that were slmlllar to those
experienced by workers (6 hours/day, 5 days/week, over one-half of a lifetime).
Rats were treated 12 months and observed until death or until they reached the
age of 31 months. The dose of 875 and 1750 ppm was 2.5 and 5 times the
threshold limit value of 350 ppm. Composition of formulation of
1,1,1-trlchloroethane 1s given In Table 4. Total tumor Incidence In the treated
animals was similar to that of controls (Table 5).
When tumors at each site by tumor type, both benign and malignant, were
examined, there were eight differences between control and treated animals at
the P < 0.05 level (Fisher Exact Probability Test). Seven of these were
decreased tumor Incidence; one was an Increase In ovarian granulosa cell tumors
1n females at the 875 ppm dose. There were no ovarian tumors In 189 controls,
three 1n 33 treated at 875 ppm (P = 0.003), and two In 82 treated at-1750 ppm (P
= 0.14). Since ovarian granulosa cell tumors are rare and the P value was low
for the animals treated at 875 ppm, 1t will be of Interest to see whether this
result Is repeated 1n the NTP study.
7-20
-------
TABLE 3. STATISTICAL ANALYSES OF THE INCIDENCE OF TUMORS AT SPECIFIC SITES IN MATCHED CONTROLS AND
1,1,1-TRICHLOROETHANE-TREATED RATS
Topography: Morphology
Total Animals: all tumorsb
P Values0
Weeks to first observed tumor
Pituitary: Chromophobe
Adenomab
P Values0
Weeks to first observed tumor
Thyroid: Follicular-Cell
Adenomab
P Values0
Weeks to first observed tumor
Adrenal: Cortical
Adenomab
P Values0
Weeks to first observed tumor
*»• i i i i i
Matched
Control
3/20
N.S.
72
0/20
N.S.
--
0/20
N.S.
— —
0/20
N.S.
Males3
Low
Dose
6/48
N.S.
28
0/48
N.S.
--
0/48
N.S.
— -
3/49
N.S.
28
High
Dose
6/50
N.S.
50
0/48
N.S.
—
0/50
N.S.
--
1/50
N.S.
106
Matched
Control
7/20
N.S.
58
3/20
N.S.
—
2/20
N.S.
--
2/19
N.S.
85
Females3
Low
Dose
7/50
N.S.
64
2/48
N.S.
—
0/50
N.S.
--
1/48
N.S.
99
High
Dose
9/50
N.S.
56
1/48
N.S.
—
1/49
N.S.
--
2/49
N.S.
106
doses of 750 and 1,500 mg/kg body weight, respectively.
bNumber of tumor-bearing animals/number of animals examined at site.
°Beneath the incidence of the matched controls is the probability level for the Armitage test for
positive dose-related trend in proportions when it is below 0.10, otherwise N.S. = not significant.
Beneath the dosed group incidence is the probability level for the Fisher exact (conditional) test for
comparison of that dosed group with the matched control group when it is below 0.10, otherwise N.S. = not
significant.
7-21
-------
TABLE 4. COMPOSITION OF THE FORMULATION OF 1,1,1-TRICHLOROETHANE
USED IN CHRONIC INHALATION STUDIES IN RATS
(Quast et al. 1978)
Compounds3
1 , 1 , l-Tr1 chl oroethane
Nltrome thane
Butyl ene oxide
l,4-D1oxane
Liquid volume %
94.71
0.44
0.74
3.93
Calculated weight %
95.88
0.38
0.46
3.11
••Analysis of 1,1,1-trfchloroetnane Lot TA020T3B oy gas cnromatograpny.
TABLE 5. TUMOR INCIDENCE IN RATS TREATED WITH METHYL CHLOROFORM
(Quast et al. 1978)
control
875 ppm
1750 ppm
Number
male
189
91
93
of Animals
female
189
92
93
Total
male
1.06
0.85
1.11
Neopl asms/Animal
female
2.97
2.67
3.23
7-22
-------
The Dow study suffers from two drawbacks: 1) the animals were treated for
only 12 months rather than a lifetime but they were observed for another 12
months, and it is not evident that the maximum tolerated dose was used during
the treatment period. There is no evidence that a range-finding study
(subchronic) has been done before the start of experiment. The treated animals
in the Dow study were no different in body weight, terminal organ weight, or
mortality from untreated animals. The only sign of toxicity was an increased
incidence of focal hepatocellular alterations in female rats at the highest
dosage.
MICE
In the NCI bioassay (NCI 1977), B6C3F1 hybrids were used with 20 animals of
each sex in the control group and 50 animals of each sex at each treatment dose.
The time-weighted average dose was 2807 mg/kg and 5615 mg/kg. The mice were
treated by gavage 5 days a week for 78 weeks and observed for another 12 weeks
for a total of 90 weeks in the experiment.
In male mice, 10/20 (50%) of the matched-control group, 21/50 (42%) of the
low-dose group, and 25/50 (50%) of the high-dose group died within a year of the
start of the experiment. In female mice, 1/20 (5%) of the matched-control
group, 9/50 (18%) of the low-dose group, and 20/50 (40%) of the high-dose group
died within the first year of the study. The Tarone test for positive
dose-related trend in the proportions surviving had a significance level of
P = 0.002, although this differential mortality is not reflected in the survival
at 78 weeks. Table 6 shows that a few mice receiving carbon tetrachlorfde
survived until the planned termination of the test, and 25 to 40% of those
treated with 1,1,1-trichloroethane reached the planned termination date. The
7-23
-------
TABLE 6. COM>ARISON OF SURVIVAL OF CONTROL GROUPS,
1,1,1-TRICHLOROETHANE-TREATED, AND CARBON TETRACHLORIDE-TREATED
(POSITIVE CONTROL) MICE
1 ,1 ,1-THchl oroethane
Group
Male
control
low dose
high dose
Femal e
control
low dose
high dose
Initial
No. of
Animals
20
50
50
20
50
50
Number
Alive at
78 Weeks
6
21
14
12
28
14
Number
Alive at
90 Weeks
2
15
11
11
23
13
Carbon Tetrachlorlde
Initial
No. of
Animals
20
50
50
20
50
50
Number
Alive at
78 Weeks
13
11
2
18
10
3
Number
Alive at
90 Weeks
7
0
1
17
0
1
high early mortality In mice receiving 1,1,1-trlchloroethane may have lowered
the Incidence of late-appearing tumors. The treated animals gained less than
the controls.
A variety of neoplasms (Table 7) were represented 1n 1,1,1-trichloroethane-
treated and matched-control mice. However, each type of neoplasm has been
encountered previously as a lesion In untreated mice. In male mice there
appeared to be an excess of tumors In the liver with one occurring among the
controls and four among the treated, but the Increase was not statistically
significant. The neoplasms observed are not believed attributable to
1,1,1-trlchloroethane exposure, since no relationship was established between
the dosage groups, the species, sex, type of neoplasm, or the site of
occurrence. It would be Inappropriate to make an assessment of cardnogenlcity
of 1,1,1-trlchloroethane on the basis of this test, because of the abbreviated
life spans of the mice.
7-24
-------
TABLE 7. STATISTICAL ANALYSES OF THE INCIDENCE OF lUMORS AT SPECIFIC SITES IN MATCHED CONTROLS AND
1,1,1-TRICHLOROETHANE-TREATED MICE
Topography : Morphol ogy
Total Animal: All tumors^
P Values0
Weeks to first observed tumor
Hematopoletlc System:
Malignant Lymphoma^
P Values0
Weeks to first observed tumor
Liver: Hepatocellular
Adenoma or Carcinoma
or Neoplastic Nodule"
P Values0
Weeks to first observed tumor
Matched
control
2/15
N.S.
80
2/15
N.S.
80
0/15
P = 0.035
Males3
Low
Dose
2/47
N.S
89
0/47
N.S.
— —
0/47
N.S.
\
High
Dose
6/49
N.S.
50
2/49
N.S.
64
4/49
N.S.
Matched
Control
4/18
N.S.
80
3/18
N.S.
80
0/18
N.S.
Females3
Low
Dose
2/48
N.S.
54
1/48
N.S.
90
0/48
N.S.
High
Dose
3/50
N.S.
26
0/50
N.S.
»•*
0/50
N.S.
time-weighted average doses of 2,807 and 5,615 mg/kg/ body weight, respectively.
^Number of tumor-bearing animals/number of animals examined at site.
cBeneath the matched controls Incidence 1s the probability level for the Armltage test for positive
dose-related trend 1n proportions when 1t Is below 0.10, otherwise N.S. = not significant.
Beneath the dosed group Incidence 1s the probability level for the Fisher exact test for comparison of
that dosed group with the control group when It Is below 0.10, otherwise N.S. = not significant.
7-25
-------
CARCINOGENICITY OF 1,4-DIOXANE
Methyl chloroform contains a small amount of stabilizing substances. The
concentration of specific stabilizers that had been identified in various
commercial methyl chloroform products is shown below (Avlado 1977 and Detrex
1976, cited by Mazaleskl 1979).
Volume %
Nitromethane 0.4 - 1.8
Butylene oxide 0.4 - 0.8
Dioxane 2.5 - 3.5
Dloxolane 1.0 - 1.4
Methyl ethyl ketone 1.0 - 1.4
Toluene 1.0 - 1.4
2-Butyl alcohol 0.2 - 0.3
Isobutyl alcohol 1.0-1.4
Not all of these stabilizers are 1n every product, but the maximum total
Inhibitor package (combinations of stabilizers) appears to be between 7 and 8%
by volume (Aviado 1977, cited by Mazaleski 1979).
Since dioxane Is a contaminant in methyl chloroform (about 3%) the
cardnogenlcity of dioxane has been studied extensively. The results of these
studies are summarized Table 8.
It should be noted that dioxane causes liver and nasal tumors in more than
one strain of rats and hepatocellular carcinomas 1n mice. Liver tumors have
been Induced by dioxane In both male and female rats as well as In mice. These
animal results, coupled with a reported finding of nasal carcinomas in furniture
workers exposed to dioxane (NCI 1978, p. 108), suggest that dioxane 1s a
potential human carcinogen. A detailed evaluation of the cardnogenicity of
1,4-dloxane is currently being prepared by the CAG.
VII. UNIT RISK ESTIMATE
No data exist which can be used to estimate quantitatively the potential
human carcinogenicity of methyl chloroform.
7-26
-------
TABLE 8. SUMMARY OF ANIMAL CARCINOGENICITY STUDIES FOR DIOXANE
Species
Rats
Rats
Guinea
Pigs
Rats
Mice
Rats
Strain
Wlstar
Sprague-
Dawley de-
rived Charles
River CD
Sprague-
Dawley de-
rived Charles
River CD
Swiss Webster
Sherman
Route, Frequency of
Administration Sex Control
In drinking water M Untreated
for 63 weeks
In drinking water M Untreated
for 13 months
In drinking water M Untreated
for 23 months
In drinking water M Untreated
for 13 months
Applied to shaved M Acetone
skin of back 3 F Acetone
times/week for 60
weeks
In drinking water M Untreated
for 2 years 4
F
Dose
300 Rig/day
average
0.75, 1.0.
1.40, and
1.8%
588-635 g
In 23 mo.
0.75, 1.0,
1.40, and
1.80%
Unspecified
Unspecified
0.01, 0.1
and It
Tumor type
Hepatocellular carcinoma,
renal transitional cell
carcinoma, my el old leukemia
and lymphosarcoma
Hepatocellular carcinoma
(dose-response) 4/30, 9/30,
16, 30, 23/30
Gall bladder carcinoma.
hepatoma, renal adenoma
Squamous cell carcinoma (nasal
cavity), heptacellular
carcinoma and fibroma
Carcinoma, subcutaneous tumor
Hepatic tumors P * 00022
(all types)
Hepatocellular P - 00033
carcinoma
Nasal carcinoma P * 054
(these tumors are at
the U level)
Reference
Argus et al.
1965
Argus et al .
1973
Hoch-Llgetl
and Argus 1970
Hoch-Llgetl
et al. 1970
King et al.
1973
Koclba et al.
1974
(continued on following page)
7-27
-------
TABLE B. (continued)
Route, Frequency of
Species Strafn
Rats Wlstar
Administration
Inhalation 7 hrs
dally 5 day /week
Sex
M
&
F
Control Dose
Filtered 111 ppm
air
Tumor type
No hepatic or nasal carcinoma
Retlculum cell sarcoma
M 18/150 vs. 37/206 (P < 0.08)
F 18/139 vs. 30/207
Found many other types of tumor
but not significant
Reference
Torkelson et
al. 1974
Rats
Mice
Osborne-
Mendel
B6C3F1
In drinking water
for 110 weeks
In drinking water
for 90 weeks
M
t
F
N
«
F
Untreated 0.5 and Hepatocellular adenoma (P • 0.001)
l.OJ and squamous cell carcinoma
of the nasal turblnataes
(P - 0.008) (both sexes)
Untreated 0.5 and Hepatocellular carcinoma
l.OS (P * 0.001) (both sexes)
NCI Bloassay
1978
7-28
-------
VIII. REFERENCES
Argus, M.J., J.C. Arcos, and C. Hoch-L1geti. 1965. Studies on the
carcinogenic activity of protein-denaturing agents: Hepatocarcinogenicity
of dioxane. J. Nat!. Cancer Inst. 35:949-958.
Argus, M.F., R.S. Sohal, G.M. Bryant, C. Hoch-Ligeti, and J.C. Arcos. 1973.
Dose-response and ultrastructural alterations in dioxane carcinogenesis.
Eur. J. Cancer 9:237-243.
Elovaara, E., K. Hemminki, and H. Vainio. 1979. Effects of methylene
chloride, trichloroethane, trichloroethylene, tetrachloroethylene, and
toluene on the development of chick embryos. Toxicology 12:111-119.
Hake, C.L., T.B. Waggoner, D.N. Robertson, and V.K. Rowe. 1960. Metabolism
of 1,1,1-trichloroethane by rats. Arch. Environ. Health. 1:1010
Henschler, D., E. Eder, T. Neudecker, and M. Metzler. 1977. Carcinogenicity of
trichloroethylene: fact or artifact? Arch. Toxicol. 37:233-236.
Hoch-Ligeti, C., and M.F. Argus. 1970. Effect of carcinogens on the lung of
guinea pigs. In: Morphology of Experimental Respiratory Carcinogens.
AEC Symp. Ser. 21:267-279.
Hoch-Ligeti, C., M.F. Argus, and J.C. Arcos. 1970. Induction of carcinomas
in the nasal cavity of rats by dioxane. Brit. J. Cancer 24:164-170.
Ikeda, M., and H. Ohtsuji. 1972. Comparative study of the excretion of
Fujiwara reaction-positive substances in urine of humans and rodents given
trichloro- or tetrachloro-derivatives of ethane and ethylene. Brit. J.
Ind. Med. 29:99-104.
King, M.E., A.M. Shefner, and R.R. Bates. 1973. Carcinogenesis bioassay of
chlorinated dibenzodioxlns and related chemicals. Environ. Health Perspect.
5:163-170.
Kociba, R.J., S.B. McCollister, C. Park, T.R. Torkelson, and P.J. Gehrfng.
1974. 1,4-Dioxane. I. Results of a 2-year ingestlon study in rats.
Toxicol. Appl. Pharmacol. 30:275-286.
Litton Blonetics, Inc. 1975. Mutagenic evaluation of compound D6. LBI
Project No. 2506, submitted to the Dow Chemical Co.
Loprieno, N., R. Banale, A.M. Rossi, S. Fumero, G. Mer1gg1, A. Mondlno, S.
Silvestri. 1979. In vivo mutagenicity studies with trichloroethylene and
other solvents (preTTminary results). Institute di Rlcerche Biomedlche,
Ivrea, Italy.
Mazaleski, S.C. 1979. An assessment of the need for limitation on
trichloroethylene, methyl chlorofrom, and perchloroethylene. EPA
560/11-79-009 p. 3-17.
7-29
-------
Monster, A.C. 1979. Difference 1n uptake, elimination, and metabolism 1n
exposure to trichloroethylene, 1,1,1-trichloroethane and
tetrachloroethylene. Int. Arch. Occup. Environ. Health 42:311-317.
Monster, A.C., 6. Boersma, and H. Steenweg. 1979. Kinetics of
1,1,1-trichloroethane in volunteers. Influence of exposure concentration
and work load. Int. Arch. Occup. Environ. Health 42:293-301.
Monster, A.C., and J.M. Houtkooper. 1979. Estimation of Individual uptake of
trichloroethylene, 1,1,1-trichloroethane and tetrachloroethylene from
biological parameters. Int. Arch. Occup. Environ. Health 42:319-323.
NCI. 1977. Bioassay of 1,1,1-trichloroethane for possible cardnogenlcity.
Carcinogen Tech. Rep. Ser., Natl. Cancer Inst. (U.S.) NCI-C6-TR-3. 70 pp.
NCI. 1978. Bioassay of l,4-d1oxane for possible carcinogenlcity. Carcinogen
Tech. Rep. Ser., Natl. Cancer Inst. (U.S.) NCI-GG-TR-80. 107 pp.
NCI Clearinghouse on Environmental Carcinogens. March 25, 1977.
Consideration of 1,1,1-trichloroethane. Minutes of the second meeting of
the risk assessment subgroup, p. 4.
Parker, J.C., G.E. Casey, L.J. Bahlman, N.A. Leidel, D. Rose, H.P. Stein, A.VI.
Thomas, and J.M. Lane. 1979. Chloroethanes: review of toxicity. NIOSH
Current Intelligence Bulletin #27. Am. Ind. Hyg. Assoc. J. 40:A46-A60.
Price, P.J., C.M. Hassett, and J.I. Mansfield. 1978. Transforming activities
of trichloroethylene and proposed industrial alternatives. In Vitro
14:290-293.
Quast, J.F., L.W. Rampy, M.F. Balmer, B.D.J. Leong, and P.J. Gehring. 1979.
Toxicological and carcinogenic evaluation of a 1,1,1-trichloroethane
formulation by chronic inhalation in rats. Available from Dow Chemical Co.,
Midland, Michigan 48640. Preprint written 1n 1978.
Simmon, V.F., K. Kauhanen, and R.G. Tardlff. 1977. Mutagenic activity of
chemicals Identified in drinking water. Pages 249-258 in I.D. Scott, B.A.
Bridges, and F.H. Sobels, eds. Progress 1n genetic toxicology. Elsevier.
Snow, L.P., B.C. MacNair, B.C. Castro. 1979. Mutagenesls testing of
1,1,1-trichloroethane in Salmonella strains TA 100 and TA 98. Northrop
services, Inc. Research Triangle, NC 27709.
Taylor, G. 1977. Mutagen1c1ty testing: Interoffice memo to Office/Division
Directors, NIOSH mutagenidty task force members. Dated 12/9/77.
Torkelson, T.R., B.K.J. Leong, R.J. Kociba, W.A. Rlchter, and P.J. Gehring.
1974. 1,4-Dloxane. II. Results of a two-year inhalation study in rats.
Toxicol. Appl. Pharmacol. 30(2):287-298.
U.S. Environmental Protection Agency (EPA). 1976. Interim procedures and
guidelines for health risk and economic impact assessments of suspected
carcinogens. Federal Register 41:21402 (May 25).
Van Dyke, R.A., and C.G. Wineman. 1971. Enzymatic dechlorlnatlon.
Dechlorination of Chloroethanes and propanes in vitro. Biochem. Pharmacol.
20:463-470.
7-30
------- |