HALOMETHANES
Ambient Water Quality Criteria
Criteria and Standards Division
Office of Water Planning and Standards
U.S. Environmental Protection Agency
Washington, D.C.
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For methylene chloride the criterion ,to protect sal twater
aquatic life as derived using procedures o,ther than the Guide-
lines is 1,900 ug/1 as a 24-hour average and the concentration
should never exceed 4,400 ug/1 at any time.
Bromoform
For bromoform the criterion to protect freshwater aquatic
life as derived using procedures other than the Guidelines is
840 ug/1 as a 24-hour average and the concentration sho ild
never exceed 1,900 ug/1 at any time.
For bromoform the criterion to protect saltwater aquatic
life as derived using the Guidelines is 180 ug/1 as a 24-hour
average and the concentration should never exceed 420 ug/1 at
any time.
Human Health
For the protection of human health from the toxic proper-
ties of halomethanes ingested through water and through con-
taminated aquatic organisms, the ambient water criteria for
the halomethanes discussed in this document are:
Compound Criterion Level (ug/D
Chloromethane (Methyl Chloride) 2
Bromomethane (Methyl Bromide) 2
Dichloromethane (Methylene Chloride) 2
Bromodichloromethane 2
Tribromomethane (Bromoform) 2
Dichlorodifluoromethane 3,000
Trichlorofluoromethane 32,000
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CRITERION DOCUMENT
HALOMETHANES
Criteria
Aquatic Life
Methyl Chloride
For methyl chloride the criterion to~ protect - freshwater ""
aquatic life as derived using procedures other than the Guide-
lines is 7,000 ug/1 as a 24-hour average and the concentration
should never exceed 16,000 ug/1 at any time.
For methyl chloride the criterion to protect saltwater
aquatic life as derived using procedures other than the Guide-
lines is 3,700 ug/1 as a 24-hour average and the concentration
should never exceed 8,400 ug/1 at any time.
Methyl Bromide
For methyl bromide the criterion to protect freshwater
aquatic life as derived using procedures other than the Guide-
lines is 140 ug/1 as a 24-hour average and the concentration
should never exceed 320 ug/1 at any time.
For methyl bromide the criterion to protect saltwater
aquatic life as derived using procedures other than the Guide-
lines is 170 ug/1 as a 24-hour average and the concentration
should never exceed 380 ug/1 at any time.
Methylene Chloride
For methylene chloride the criterion to protect fresh-
water aquatic life as derived using procedures other than the
Guidelines is 4,000 ug/1 as a 24-hour average and the concen-
tration should never exceed 9,000 ug/1 at any time.
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Introduction
The halomethanes are a subcategory of halogenated hydro-
carbons. This document reviews the following halomethanes:
chloromethane, bromomethane, methylene chloride, bromoform,
bromodichloromethane, tr ichlorof luorometha.ne, _ and dichlorodi--
fluoromethane.
Methyl chloride is also known as chloromethane (Windholz,
1976) . It is a colorless, flammable, almost odorless gas
at room temperature and pressure. It is used as a refrigerant,
a methylating agent, a dewaxing agent, and catalytic solvent
in synthetic rubber production (MacDonald, 1964). Methyl
bromide has been referred to as bromomethane, monobromomethane,
and embafume (Windholz, 1976) . It has been widely used
as a fumigant, fire extinguisher, refrigerant, and insecticide
(Kantarjian and Shaheen, 1963) . Today the major use of
methyl bromide is as a fumigating agent, and this use has
caused sporadic outbreaks of serious human poisoning.
Methylene chloride has been referred to as dichloromethane,
methylene dichloride, and methylene bichloride (Windholz,
1976). It is a common industrial solvent found in insecticides,
metal cleaners, paints, and paint and varnish removers (Balmer,
et al. 1976). In 1976, 244,129 metric tons (538,304,000
Ibs) were produced in the United States with an additional
19,128 metric tons (42,177,000 Ibs) imported (U.S. EPA,
1977a).
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Trichlorofluoromethane is also known as trichloromono-
fluoromethane, fluorotrichloromethane, Frigen 11, Freon
11, and Arcton 9. Dichlorodifluoromethane has been referred
to as difluorodichloromethane, Freon 12, Frigen 12, Arcton
6, Genetron 12, Halon, and Isotron 2. Freon compounds are
organic compounds which contain fluorine. They have many
desirable characteristics which include a high degree of
chemical stability and relatively low toxicity, and they
are nonflammable. Freon compounds have found many applications
ranging from use as propellants to refrigerants and solvents
(Van Auken, et al. 1975).
Bromoform is also known as tribromomethane (Windholz,
1976). It is used in pharmaceutical manufacturing, as an
ingredient in fire resistant chemicals and gauge fluid,
and as a solvent for waxes, grease, and oils (U.S. EPA,
1975a). Bromodichlcromethane is used as a reagent in research
(Natl. Acad. Sci. 1978).
The physical characteristics of the halomethanes are
listed in Table 1. Monohalomethanes can be hydrolyzed slowly
in neutral waters forming methanol and hydrogen halide.
The rate of hydrolysis increases with size of the halogen
moiety (Boggs and Mosher, 1960). Zafiriou (1975) has indicated
that in seawater iodomethane can react with chloride ion
to yield chloromethane and this reaction occurs as fast
as the exchange of iodomethane into the atmosphere (exchange
rate, 4 x 10~'/sec). The monohalomethanes are not oxidized
readily under ordinary conditions. Bromomethane at 14.5
percent concentrations in air and intense heat will produce
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TABLE 1
Physical Characteristics of Hale-methanes
Compound Molecular
weight
chloromethane 50.493
bromomethane 94.94a
dichloromethane 84.93a
tnchlorofluoro- 137. 37a
methane
dichlorodifluoro- 120. 913
methane
tribromomethane 252. 753
bromodichloro- 163. 83a
methane
Physical state mo. bp. Specific Vapor Solubility
under ambient ( C) (°C) gravity pressure in water
conditions (ram Hg) (ug/1)
colorless gasa -97.73a -24. 2a 0.973 (-10°C) b 5.38xl06
colorless gasa -93. 6a 3.56a 1.737 (-10°C) b IxlO6
colorless liquid3 -95. I3 40a 1.327(20°C)a 362.4(20°C)C 13.2xl06 c
(25°C)
colorless liquid3 -1113 23.82a 1.467(25°C)a 667.4(20°C)C l.lxlO6 c
(20°C)
colorless gasa -158a -29.79a l.75(-115°C) a 4,306(20°C)C 2.8xl05 c
(25°C)
colorless liquid3 8.3a 149. 5a 2.890(20°C)a ' slightly
sol.a
colorless liquid3 -57. la 90a 1.980(20°C) ' insoluble3
Solubility
in organic
solvents
alcohol, ether
acetone, benzene,
chloroform,
acetic acid
alcohol
acetic
alcohol
alcohol
alcohol
alcohol
benzene
form,
, ether,
acid3
, ether3
, etherd
, ether3
, ether,
, chloro-
ligroin3
alcohol, ether,
acetone, benzene,
chloroform
1 > VI f i t , I '< 7 ~>
b) U.S. EPA, 1977b
c) Pearson and McConnell, 1975
d) Windholz, 1976
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a flame (Stenger and Atchison, 1964). Chloromethane in
contact with a flame will burn, producing CO2 and HC1 (Hardie,
1964) . Monohalomethanes undergo photolysis in the upper
atmostphere where ultraviolet radiation is of sufficient
energy to initiate a reaction (Basak, 1973).
Prolonged heating of dichloromethane with water at
180°C results in the formation of formic acid, methyl chloride,
methanol, hydrochloric acid and some carbon monoxide.
In contact with water at elevated temperatures, methylene
chloride corrodes iron, some stainless steels, copper, and
nickel (Hardie, 1964).
Trichlorofluoromethane is nonflammable. Decomposition
of tribromomethane is accelerated by air and light (Windholz,
1976).
Chloromethane has been demonstrated to be toxic to
aquatic organisms at levels of 270,000 to 550,000 ug/1 (96
hr. LC50 values) in controlled laboratory tests (Dawson,
et al. 1977). Corresponding acute toxicity values for bromo-
methane range from 11,000 to 12,000 ug/1 (Dawson, et al.
1977). Dichloromethane LC50 values range from 224,000 to
331,000 ug/1 (U.S. EPA, 1978) and tribromomethane LC50 values
range from 17,900 to 46,500 ug/1 (U.S. EPA, 1978). The
latter compound demonstrates aquatic organism chronic toxicity
effects at 14,000 to 24,000 ug/1 (U.S. EPA, 1978).
The toxic nature of methyl chloride on humans is thought
to act on the central nervous system. In a mild to moderate
intoxication, the symptoms consist of blurring of vision,
headache, vertigo, loss of coordination, slurring of speech,
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staggering, mental confusion, nausea, and vomiting. A sever?
exposure involves rapid loss of consciousness leading to
death (MacDonald, 1964).
Chloromethane is highly mutagenic to the bacteria,
Salmonella typhimurium TA 1535 (Andrews, et al. 1976) and
to the bacteria, Salmonella typhimurium TA 100 (Simmon,
et al. 1977).
Inhalation of bromomethane is the usual route of systemic
poisoning, but gastrointestinal absorption is a possibility
(Collins, 1965). Following exposure, irritation of eyes
and mucous membranes may be noticeable. Within a few hours,
malaise, headache, and nausea develop. After 2 to 16 hours,
the more serious symptoms develop, including visual disturbance,
speech disturbance, irrational behavior, drunkenness, and
drowsiness. Under serious exposure, neurologic and psychiatric
abnormalities may persist for months or years (Collins,
1965) .
As with chloromethane, bromomethane has been reported
to be mutagenic in Salmonella bacterial test systems (Simmon,
et al. 1977).
In non-human mammals, methylene chloride inhalation
at levels of 1,000 and 5,000 ppm (3,477 and 17,383 mg/m3)
for not more than 14 hours resulted in severe weight losses,
liver injury, hepatic failures, and death (Haun, et al.
1971). In humans, methylene chloride is a central nervous
system depressant resulting in narcosis at high concentrations
(Berger and Fodor, 1969). Inhalation levels of 500 to 1,000
ppm (1,738 to 3,477 mg/m ) resulted in elevated carboxyhemo-
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globin saturation levels as well as signs and symptoms of
central nervous system depression (Stewart, et al. 1972).
Dichloromethane demonstrated mutagenic properties in
Salmonella typhimurmm TA 100 and in immunosuppressed mice
(Simmon, et al. 1977). The compound also demonstrated a
carcinogenic response in mice (Theiss; et~al.-1977 rTheiss,
1978) but the significance of results from,this test are
open to question. The carcinogenicity of dichloromethane
was reported to be under study by the National Cancer Institute
(1977).
Trichlorofluoromethane has completely inhibited the
growth of several species of microorganisms at vapor concen-
trations of 5.62 x 104 to 5.62 x 106 mg/m3 (Van Auken, et
al. 1975). In atmospheric ambient conditions of a 1:1 mixture
of oxygen and dichlorodifluoromethane, a significant increase
in the mutation rate of the yeast, Neurospora crassa, was
noted (Stephens, et al. 1971). Slater (1965) administered
trichlorofluoromethane to the stomach of rats and noted
no effect on serum-^-glucuronidase activity or liver NADPH
levels. Taylor (1975) noted that exposure to 7 percent
oxygen-15 percent trichlorofluoromethane caused cardiac
arrhythmias in all rabbits exposed. Only a slight hyperglycemia
with hyperlactacidema was noted in rats, rabbits, and dogs
exposed to ambient atmospheric conditions of 5 percent trichloro-
fluoromethane (Paulet, et al. 1975). In dogs, trichlorofluoro-
methane caused a depression of myocardial function (Aviado
and Belej, 1975) and in the upper respiratory tract lead
to an initial apnea, bradycardia, and a fall in aortic blood
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pressure (Aviado, 1971). Azar, et al. (1972), noted that
*
human inhalation of 1,000 ppm (4,949 mg/m ) dichlorodifluoro-
methane did not reveal any adverse effect, while exposure
to 10,000 ppm (49,489 mg/m3) resulted only in a 7 percent
reduction in a standardized psychomotor test score.
Tnbromomethane is considered to~be highly" toxic to
both non-human mammalian species and humans. The compound
has been shown to be mutagenic in the Salmonella typhimur ium
TA 100 and Ta 1535 test systems (Simmon, et al. 1977) and
carcinogenic in mice (Theiss, et al. 1977; Theiss, 1978)
with the same qualifications for result significance as
for dichloromethane noted. Cantor, et al. (1977), have
reported positive correlations between cancer mortality
rates and levels of brominated trihalomethanes in drinking
water in epidemiological studies.
Bromodichloromethane is acutely toxic to mice (Bosman,
et al. 1978). It was mutagenic in the Salmonella typhimurium
TA 100 bacterial test system (Simmon, et al. 1977) and carcino-
genic in mice (Theiss, et al. 1977; Theiss, 1978) with the
same qualification for result significance as for dichloro-
methane noted. Cantor, et al. (1977), have reported positive
correlations between cancer mortality rates and levels of
brominated trihalomethanes in drinking water in epidemiological
studies.
The relatively high water solubilities of chloromethane
and bromomethane and their relatively high vapor pressures
indicate that they have a low potential to bioconcentrate
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in aquatic species. By using the equation of Metcalf and
Lu (1973) , the predicted bioconcentration factors are 2
and 6, respectively.
Methylene chloride is a major halogenated pollutant
with a large potential for delivery of chlor.ine.to the strato-.
sphere. The photooxidation of the compound in the troposphere
probably proceeds with a half-life of several months, similar
to the case of methyl chloride. The principal oxidation
product of methylene chloride is phosgene which results
from the two hydrogens being abstracted from the molecule.
It is conceivable that this phosgene may be photolyzed to
yield chlorine atoms in the ozone-rich region of the strato-
sphere. It thus appears that there is some potential for
ozone destruction by methylene chloride since the generated
chlorine atoms will attack ozone (U.S. EPA, 1975b).
Similarly, fully halogenated substances such as trichloro-
fluoromethane and dichlorodifluoromethane migrate to the
stratosphere where they are photodissociated, adversely
affecting the ozone balance (U.S. EPA, 1975b). Trichloro-
fluoromethane does not significantly bioconcentrate in aquatic
organims (Dickson and Riley, 1976).
There are few data in the literature relating to the
environmental fate or degradation of bromodichloromethane
and tribromomethane.
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REFERENCES
Andrews, A.W., et al. 1976. A comparison of the mutagenic
properties of vinyl chloride and methyl chloride. Mutat.
Res. 40: 273.
Aviado, D.M. 1971. Cardiopulmonary effects of fluorocarbon
compounds. Aerospace Med. Res. Lab. Wright Patterson Air
Force Base, Ohio.
Aviado, D.M., and M.A. Bele}. 1975. Toxicity of. aerosol
N
propellants in the respiratory and circulatory systems.
Ventricular function in the dog. Toxicology 3: 79.
Azar, A., et al. 1972. Experimental human exposure to fluoro-
carbon 12 (dichlorodifluoromethane). Am. Ind. Hyg. Assoc.
Jour. 33: 207.
Balmer, M.F., et al. 1976. Effects in the liver of methyleae
t
chloride inhaled alone and with ethyl alcohol. Am. Ind.
Hyg. Assoc. Jour. 37: 345.
Basak, A.K. 1973. The photolytic decomposition of methyl
chloride. Jour. Ind. Chem. Soc. 50: 767.
Berger, M., and G.G. Fodor. 1969. Zentralrervose storunger
inter Einfluso dichloromethanhaltiger Luftgemische-2bl.
Bakt., Abt. 1, Ref. 215, 1963, 503.
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Boggs, J.E., and H.P. Mosher. 1960. Effect of fluorine substi-
tution on the rate of hydrolysis of chloromethane. Jour.
Am. Chem. Soc. 82: 3517.
Bowman, F.G., et al. 1978. The toxicity of some halomethanes
in mice. Toxicol. Appl. Pharmacol. 44: 213.
Cantor, K.P., et al. 1977. Associations of halomethanes
in drinking water with cancer mortality. Jour. Natl. Cancer
Inst. (In press.)
Collins, R.P. 1965. Methyl bromide poisoning. Calif. Med.
103: 112.
Dawson, G.W., et al. 1977. The acute toxicity of 47 industrial
chemicals to fresh and saltwater fishes. Jour. Hazard.
Mater. 1: 303.
Dickson,.A.G., and J.p. Riley. 1976. The distribution of
short-chain halogenated aliphatic hydrocarbons in some marine
organisms. Mar. Pollut. Bull 7: 167.
Bardie, D.W.F. 1964. Methyl chloride. Kirk-Othmer Encyclopedia
of Chemical Technology. 2nd ed. Interscience Publishers,
New York.
Haun, C.C., et al. 1971. Continuous animal exposure to
methylene chloride. Aerospace Med. Res. Lab. Wright Patterson
Air Force Base, Ohio.
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Kantarjian, A.D., and A.S. Shaheen. 1963. Methyl bromide
poisoning with nervous system manifestations resembling
polyneuropathy. Neurology 13: 1054.
MacDonald, J.D.C. 1964. Methyl chloride intoxication.
Jour. Occup. Med. 6: 81.
Metcalf, R.L., and P.Y. Lu. 1973. Environmental distribution
and metabolic fate of key industrial pollutants and pesticides
in a model ecosystem. Univ. 111. Water Resour. Center,
UILU-WRC-0069. PB 225479, Natl. Tech. Inf. Serv., Springfield,
Va.
National Academy of Sciences. 1978. Nonfluorinated halomethanes
in the environment. Washington, D.C.
National Cancer Institute. 1977. Chemicals being tested
for carcinogenicity by the bioassay program. Rep. Tech.
Inf. Resour. Branch, Natl. Cancer Inst., U.S. Dep. Health
Educ. Welfare, Bethesda, Md.
Paulet, G., et al. 1975. Fluorocarbons and general metabolism
in the rat, rabbit, and dog. Toxicol. Appl. Pharmacol.
34: 197.
Pearson, C.R., and G. McConnell. 1975. Chlorinated Cl and
C2 hydrocarbons in the marine environment. Proc. R. Soc.
London B. 189: 305.
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Simmon, V.F., et al. 1977. Mutagenic activity of chemicals
identified in drinking water. Presented at 2nd Int. Conf.
Environ. Mutagens. Edinburgh, Scotland. July, 1977.
Slater, T.F. 1965. A note on the relative toxic activities
of tetrachloromethane and trichlorfluoromethane" on the rat.
Biochem. Pharmacol. 14: 178.
Stenger, V.A., and G.J. Atchison." 1964. Methyl bromide.
Kirk-Othmer Encyclopedia of Chemical Technology. 2nd ed.
Interscience Publishers, New York.
Stephens, S., et al. 1971. Phenotypic and genetic effects
of Neurospora crassa produced by selected gases and gases
mixed with oxygen. Dev. Ind. Microbiol. 12: 346.
Stewart, R.D., et al. 1972. Experimental human exposure
to methylene chloride. Arch. Environ. Health 25: 342.
Taylor, G.J. 1975. Cardiac arrhythmias in hypoxic rabbits
during aerosol propellant inhalation. Arch. Environ. Health
30: 349.
Theiss, J.C. 1978. Personal communication.
Theiss, J.C., et al. 1977. Test for carcinogenicity of
organic contaminants of United States drinking waters by
pulmonary tumor response in strain A mice. Cancer Res.
37: 2717.
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U.S. EPA. 1975a. Initial scientific and minieconomic reviev/
of folpet. Draft. Rep. Off. Pestic. Prog. Washington, D.C.
U.S. EPA. 1975b. Report on the problem of halogenated air
pollutants and stratospheric ozone. EPA 600/9-75-008. Washington,
D.C. - _-_--.--
U.S. EPA. 1977a. Area 1. Task 2. Determination of sources
of selected chemicals in waters and amounts from these sources.
Draft final rep. Contract No. 68-01-3852. Washington, D.C.
U.S. EPA. 1977b. Investigation of selected potential environ-
mental contaminants. Monohalomethanes. EPA 560/2-77-007.
Washington, D.C.
U.S. EPA. 1978. In-depth studies on health and environmental
impacts of selected water pollutants. Contract No. 68-01-
4646. Washington, D.C.
Van Auken, et al. 1975. Comparison of the effects of three
fluorocarbons on certain bacteria. Can. Jour. Microbiol.
21: 221.
Weast, R.C., ed. 1972. Handbook of chemistry and physics.
CRC Press, Cleveland, Ohio.
Windholz, M., ed. 1976. The Merck Index. Merck and Co.,
Rahway, N.J.
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Zafiriou, O.C. 1975. Reaction of methyl halides with seawater
and marine aerosols. Jour. Mar. Res. 33: 75.
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AQUATIC LIFE TOXICOLOGY*
FRESHWATER ORGANISMS
Introduction
Although the aquatic toxicity data base for halomethanes
is limited, it allows some generalization concerning trends
within the class. Data on chloroform and" carbon te^ra-
chloride are included for discussion and are also treated in
separate criterion documents. Methylene chloride, methyl
chloride, bromoform, and methyl bromide are the only other
halomethanes for which appropriate data are available.
Acute Toxicity
Apparently, the brominated compounds are more toxic to
fish than the chlorinated analogs (Table 1). This pattern is
repeated for the saltwater fish (Table 4). The unadjusted
96-hour LC50 values for bluegill are 11,000 u.g/1, and 550,000
ug/1 for methyl bromide and methyl chloride, respectively,
under static (renewal) test conditions (Dawson, et al. 1977).
For bromoform and chloroform the 96-hour LC50 values are
*The reader is referred to the Guidelines for Deriving Water
Quality Criteria for the Protection of Aquatic Life [43 FR
21506 (May 18, 1978) and 43 FR 29028 (July 5, 1978)] in order
to better understand the following discussion and recommenda-
tion. The following tables contain the appropriate data that
were found in the literature, and at the bottom of each table
are the calculations for deriving various measures of toxic-
ity as described in the Guidelines.
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29,300 ug/1 (U.S. EPA, 1978) and 115,000 ug/1 to 100,000 v.g/1,
respectively. The data on acute static tests with bluegill
show a correlation between increasing chlorination and toxic-
ity. The 96-hour LC50 values are 550,000 ug/1 (Dawson, et al.
1977) for methyl chloride, 244,000 U9/1 for methylene chloride
(U.S. EPA, 1978), 100,000 to 115, 000-ug/lr for chloifoform
(Bentley, et al. 1975), and 125,000 ug/1 (Dawson, et al. 1977)
and 27,300 ug/1 (U.S. EPA, 1978) for carbon tetrachloride.
Alexander, et al. (1978) compared the effect of test proce-
dures on the toxicity of methylene chloride to the fathead
minnow. The flow-through test result was 193,000 ug/1 and the
static test result was 310,000 U9/1 (Table 1). After adjust-
ment according to the Guidelines the latter LC50 value becomes
169,477 ug/1/ very similar to the flow-through result, sup-
porting the appropriateness of the adjustment factors for test
conditions and methylene chloride. The Final Fish Acute
Values for bromoform, methylene chloride, methyl bromide, and
methyl chloride are 4,100, 38,000, and 1.500, and 77,000 ug/1r
respectively.
The 48-hour EC50 values are 224,000, 28,900, and 35,200
ug/1 for methylene chloride (Table 2), chloroform, and carbon
tetrachloride, respectively (U.S. EPA, 1978). The result
with chloroform (28,900 ug/1) does not support any conclusion
about the correlation of toxicity and amount of chlorination
for the data with Daphnia magna. For bromoform and methylene
chloride, there appears to be little difference is sensitiv-
ity between Daphnia magna and the bluegill. The LC50 and EC50
values are both 224,000 ug/1 for methylene chloride and 29,300
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and 46,500 ug/1 respectively, for bromoform. The Final In/erte-
brate Acute Values for bromoform and methylene chloride arc 1,900
and 9,000 ug/1/ respectively (Table 2).
The data indicate that the Final Invertebrate Acute Values
for halomethanes are lower than the comparable values for fish.
The Final Fish and Final Invertebrate Acute Value -comparisons-are:
bromoform - 4,100 and 1,900 ug/1/ respectively, methylene chloride
- 38,000 and 9,000 ug/1, respectively; chloroform - 11,000 and
1,200 ug/1/ respectively; and carbon tetrachloride - 8,200 and
1,400 ug/lf respectively. Thus, when a Final Invertebrate Acute
Value exists, it becomes the Final Acute Value.
Chronic Toxicity
No life cycle or embryo-larval tests have been conducted with
freshwater organisms and any halomethane other than chloroiorm and
carbon tetrachloride. In those tests, the concentration at which
no adverse effects of chloroform were observed for Daphnia magna
was between 1,800 and 3,600 ug/1, and no adverse effects of car-
bon tetrachloride were observed on the fathead minnow at the high-
est test concentration of 3,400 ug/1. Details of these tests may
be found in the criterion documents for those chemicals.
Plant Effects
The 96-hour EC50 values for bromoform (Table 3), based on
chlorophyll a_ and cell numbers of the alga, Selenastrum
capricornutum, are 112,000 and 116,000 ug/lf respectively. The
same tests with methylene chloride showed the EC50 values were
above the highest test concentration, 662,000 ug/1 (U.S. EPA,
1978).
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Residues
No residue data for freshwater fish are available for
halomethanes other than for chloroform and carbon tetrachloride,
for which the bioconcentration factors (U.S. EPA, 1978) were 6 and
30, respectively. Details of these tests may be found in the
criterion documents for those chemicals. -"-•'--
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CRITERION FORMULATION
Freshwater-Aquatic Life
Summary of Available Data
The concentrations below have been rounded to two signi L icart
figures.
Bromoform
Final Fish Acute Value = 4,100 ug/1
Final Invertebrate Acute Value = 1,900 ug/1
Final Acute Value = 1,900 y.g/1
Final Fish Chronic Value = not available
Final Invertebrate Chronic Value = not. available
Final Plant Value = 110,000 ug/1
Residue Limited Toxicant Concentration = not available
Final Chronic Value = 110,000 ug/1
0.44 x Final Acute Value = 840 ug/1
Methylene Chloride
Final Fish Acute Value = 38,000 ug/1
Final Invertebrate Acute Value = 9,000 ug/1
Final Acute Value = 9,000 ug/1
Final Fish Chronic Value = not available
Final Invertebrate Chronic Value = not available
Final Plant Value = greater than 660,000 ug/1
Residue Limited Toxicant Concentration = not available
Final Chronic Value = greater than 660,000 ug/1
0.44 x Final Acute Value = 4,000 ug/1
Methyl Bromide
Final Fish Acute Value = 1,500 ug/1
Final Invertebrate Acute Value = not available
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Final Acute Value = 1,500 ug/1
Final Fish Chronic Value = not available
Final Invertebrate Chronic Value = not available
Final Plant Value = not available
Residue Limited Toxicant Concentration = not available
Final Chronic Value = not a~vaitable ~ " -
0.44 x Final Acute Value = 660 ug/1
Methyl Chloride
Final Fish Acute Value = 77",000 ug/1
Final Invertebrate Acute Value = not available
Final Acute Value = 77,000 ug/1
Final Fish Chronic Value = not available
Final Invertebrate Chronic Value = not available
Final Plant Value = not available
Residue Limited Toxicant Concentration = not available
Final Chronic Value = not available
0.44 x Final Acute Value = 34,000 ug/1
No freshwater criterion can be derived for any halome~hane
using the Guidelines because no Final Chronic Value for either
fish or invertebrate species or a good substitute for either
value is available.
However, results obtained with halomethanes and freshwater
and saltwater fish and invertebrate species indicate how criteria
may be estimated.
For bromoform and methylene chloride with freshwater and
saltwater organisms and for chloroform and carbon tetrachloride
with freshwater organisms, the Final Invertebrate Acute Value
divided by the Final Fish Acute Value is 0.46, 0.24, 0.16, 0.090,
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0.11, and 0.17 respectively, for an average of 0.21. Multiplying
this value times the Final Acute Values for methyl chloride and
methyl bromide with freshwater fish results in estimated fresh-
water Final Invertebrate Acute Values of 0.21 x 77,000 ug/1 =
16r000 ug/1 and 0.21 x 1,500 ug/1 = 320 ug/1 respectively. Thus
the Final Acute Values for methyl chloride -and-methyl bromide
would be based on these estimated values and are 16,000 ug/1 and
320 ug/lf respectively.
For chloroform and freshwater organisms the Final Chronic
Value is about the same as 0.44 times the Final Acute Value, and
for bromoform and saltwater organisms the Final Chronic Value is
greater than 0.44 times the Final Acute Value, even though a
chronic value is available for fish or invertebrates in both
other halomethanes and freshwater organisms using 0.44 times the
Final Acute Value.
The maximum concentration of bromoform is the Final Acute
Value of 1,900 ug/1 and the 24-hour average concentration is 0.44
times the Final Acute Value. No important adverse effects on
freshwater aquatic organisms have been reported to be caused by
concentrations lower than the 24-hour average concentration.
CRITERION: For bromoform the criterion to protect freshwater
aquatic life as derived using procedures other than the Guidelines
is 840 ug/1 as a 24-hour average and the concentration should
never exceed 1,900 ug/1 at any time.
The maximum concentration of methylene chloride is the Final
Acute Value of 9,000 ug/1 and the 24-hour average concentration is
0.44 times the Final Acute Value. No important adverse effects on
B-7
-------
freshwater aquatic organisms have been reported to be caused by
concentrations lower than the 24-hour average concentration.
CRITERION: For methylene chloride the criterion to protect
freshwater' aquatic life as derived using procedures other than the
Guidelines is 4,000 ug/1 as a 24-hour average and the concentra-
tion should never exceed 9,000 ug/1 at any time." -:~
The estimated maximum concentration of methyl bromide is the
Final Acute Value of 320 ug/1 and the 24-hour average concentra-
tion is 0.44 times the Final Acute Value. No important adverse
effects on freshwater aquatic organisms have been reported to be
caused by concentrations lower than the 24-hour average concentra-
tion.
CRITERION: For methyl bromide the criterion to protect
freshwater aquatic life as derived using procedures other than the
Guidelines is 140 ug/1 as a 24-hour average and the concentration
should never exceed 320 ug/1 at any time.
The estimated maximum concentration of methyl chloride is the
Final Acute Value of 16,000 ug/1 and the 24-hour average concen-
tration is 0.44 times the Final Acute Value. No important adverse
effects on freshwater aquatic organisms have been reported to be
caused by concentrations lower than the 24-hour average concentra-
tion.
CRITERION: For methyl chloride the criterion to protect
freshwater aquatic life as derived using procedures other than the
Guidelines is 7,000 ug/1 as a 24-hour average and the concentra-
tion should never exceed 16,000 ug/1 at any time.
B-8
-------
Table 1. Freshwater fish acute values for lialomethanes
Bioaaeay Teat Time LC50
Cpnc.** Jhraj (uq/lt
Brorooform
09
1
Bluegill.
Lepomla macrochirua
Bluegill.
lepomla macrochirua
Fathead minnow,
Pimephalea promelaa
Fathead minnow,
Pimephalea promelaa
Bluegill.
S
S
FT
S
R
U
MeLhylene
U
M
U
Methyl-
U
96
chloride
96
96
96
chloride
96
Leporals macrochirua
Bluegill.
l.epomts macrochirua
Methyl bromide
U 96
, TT = riow-Lhrough, K - rcrewal
** U = unmeasured, M » meaaured
Adjusted
LCbO
(uq/ll Deference
29,300 16,018 U.S. EPA. 1978
224,000 122,461 U.S, EPA, 1978
193,000 193,000 Alexander, et al. 1978
310,000 169,477 Alexander, et al. 1978
550,000 300,685 Dawson, et A!. 1977
11,000 6,014 Dawson, et al. 1977
16.018
Geometric mean of adjusted values - Bromofortn = 16,018 |ig/l —$-$- " 4.100 |.g/l
Methlyene chloride - 148,822 ug/1 *4B,B22 = 38.000 ng/l
3.9
Methyl chloride - 300.685 ng/l 300'683 » 77.000 Mg/1
3.9
Mechyl bromide = 6,014 pg/1 ^3^9 c :
-------
2, Freshwater invertebrate acule values foe haloroethanes (U S EPA, 1978)
iuoassa Test fine
**
LC50
Adtuttted
LCbO
Bromoform
OJ
1
(-•
o
Cladoceran. S U 48 46,500 39.386
Daplmia magna
Methylene chloride
Cladoceran. S U 48 224,000 189,728
Dciphnia magna
* S » static
** U » unmeasured
Geometric mean of adjusted values - Bromoforin ° 39,386 iig/1 — $T~ " * *'^ fg/1
«• u»>k..i _ui jj_ _ ion T>O ..-it 189,728 _ n ftft,
- 9.000 ug/1
-------
Table 3 Freshwater plane effects for halomethanes (U S EPA. 1978)
Ettect
Concentration
tug/U
Bromoform
Alga.
Selenabtrum
capricomutum
Alga.
Selenaatrum
capricornutum
Chlorophyll a
EC50 96-hr ~
Cell number
ECSO 96-hr
112.000
116,000
Hethylene chloride
00
I
Alga.
Selenaatrum
caprfcornutum
Alga,
Selenaatrum
capricornutum
Chlorophyll a .>662.QOO
ECSO 96-hr ~
Cell number
ECSO 96-hr
>662.000
Lowest plant value Bromoform «• 112,000 |)g/l
Methylene chloride - >662.000 pg/1
-------
SALTWATER ORGANISMS
Introduction
Although the aquatic toxicity data base for halomethanes is
limited, it allows some generalizations concerning trends within
the class. Data on chloroform and carbon tetrachloride are in-
cluded for discussion and are also treated "in separate criterion -
documents. Methylene chloride, methyl chloride, bromoform, and
methyl bromide are the only other halomethanes for which appro-
priate data are available.
Acute Toxicity
Apparently, the brominated compounds are more toxic to fish
than the chlorinated analogs, (Table 4) as is true for the fresh-
water-fish (Table 1). The unadjusted 96-hour LC50 values for the
tidewater silversides (Dawson, et al. 1977) and methyl bromide and
methyl chloride are 12,000 and 270,000 ug/1^ respectively. The
Final Pish Acute Values for bromoform, methylene chloride, methyl
bromide, and methyl chloride are 2,600, 49,000, 1,800, and 40,000
ug/1, respectively (Table 4).
The mysid shrimp has been tested with bromoform and methylene
chloride (U.S. EPA, 1978) and the unadjusted 96-hour LC50 values
are 24,400 and 256,000 ug/l» respectively (Table 5). The Final
Invertebrate Acute Values, obtained after adjusting the data for
test conditions and species sensitivity according to the Guidelines
are 420 ug/1 for bromoform and 4,400 ug/1 for methylene chloride.
These concentrations are below the comparable values for fish
(Table 4) and, therefore, become the Final Acute Values for
bromoform and methylene chloride.
B-12
-------
Chronic Toxicity
An embryo-larval test has been conducted with the sheepshead
minnow and bromoform (U.S. EPA, 1978) and the chronic value
derived from this test is 9,165 ug/1 (Table 6). There are ro
other chronic data for any halomethane. The Final Fish Chronic
Value, and Final Chronic Value, for bromoform is" 1,400 ug/1
Plant Effects
The 96-hour EC50 values for bromoform (Table 7), based on
chlorophyll a. and cell numbers of the alga, Skeletonema costatum,
are 12,300 and 11,500, respectively. The same tests with
methylene chloride showed the EC50 values were above the highest
test concentration, 662,000 ug/1 (U.S. EPA, 1978).
Residues
No residue data for saltwater aquatic organisms are available
for any halomethane.
B-13
-------
CRITERION FORMULATION
Saltwater-Aquatic Life
Summary of Available Data
The concentrations below have been rounded to two significant
figures.
Bromoform
Final Fish Acute Value = 2,600 ug/1
Final Invertebrate Acute Value = 420 ug/1
Final Acute Value = 420 ug/1
Final Fish Chronic Value = 1,400 ug/1
Final Invertebrate Chronic Value = not available
Final Plant Value = 12,000 ug/1
Residue Limited Toxicant Concentration = not available
Final Chronic Value = 1,400 ug/1
0.44 x Final Acute Value = 180 ug/1
Methylene Chloride
Final Fish Acute Value = 49,000 ug/1
Final Invertebrate Acute Value = 4,400 ug/1
Final Acute Value = 4,400 ug/1
Final Fish Chronic Value = not available
Final Invertebrate Chronic Value = not available
Final Plant Value = greater than 660,000 ug/1
Residue Limited Toxicant Concentration = not available
Final Chronic Value = greater than 660,000 ug/1
0.44 x Final Acute Value = 1,900 ug/1
Methyl Bromide
Final Fish Acute Value = 1,800 ug/1
Final Invertebrate Acute Value = not available
B-14
-------
Final Acute Value = 1,800 ug/1
Final Fish Chronic Value = not available
Final Invertebrate Chronic Value = not available
Final Plant Value = not available
Residue Limited Toxicant Concentration = not available
Final Chronic Value - not available
0.44 x Final Acute Value = 790 ug/1
Methyl Chloride
Final Fish Acute Value = 40,000 ug/1
Final Invertebrate Acute Value = not available
Final Acute Value = 40,000 ug/1
Final Fish Chronic Value = not available
Final Invertebrate Chronic Value = not available
Final Plant Value = not available
Residue Limited Toxicant Concentration = not available
Final Chronic Value = not available
0.44 x Final Acute Value = 18,000 ug/1
The maximum concentration of bromoform is the Final Acute
Value of 420 ug/1 end. the 24-hour average concentration is 0.44
times the Final Acute Value. No important adverse effects on
saltwater aquatic organisms have been reported to be caused by
concentrations lower then the 24-hour average concentration.
CRITERION: For bromoform the criterion to protect saltwater
aquatic life as derived using the Guidelines is 180 ug/1 as a
24-hour average and the concentration should never exceed 420 ug/1
at any time.
No saltwater criterion can be derived for methylene chloride,
methyl bromide, or methyl chloride using the Guidelines because no
B-15
-------
Final Chronic Value for either fish or invertebrate species or a
good substitute for either value is available.
However, results obtained with halomethanes and freshwater
and saltwater fish and invertebrate species indicate how criteria
may be derived.
For bromoform and methylene chloride- with'freshwater and"
saltwater organisms and for chloroform and carbon te trachlonde
with freshwater organisms, the Final Invertebrate Acute Value
divided by the Final Fish Acute Value is 0.46, 0.24, 0.16, 0.090,
0.11, and 0.17 respectively, for an average of 0.21. Multiplying
this value times the Final Acute Values for methyl chloride and
methyl bromide with saltwater fish results in estimated saltwater
Final Invertebrate Acute Values of 0.21 x 40,000 y.g/1 = 8,400 ug/1
and 0.21 x 1,800 ug/1 = 380 ug/l» respectively. Thus the Final
Acute Values for methyl chloride and methyl bromide would be based
on these estimated values and are 8,400 ug/1 and 380 ug/lr respec-
tively.
For chloroform and freshwater organisms the Final Chronic
Value is about the same as 0.44 times the Final Acute Value, and
for bromoform and saltwater organisms the Final Chronic Value is
greater than 0.44 times the Final Acute Value, even though a
chronic value is available for fish or invertebrate species in
both cases. Therefore, it seems reasonable to estimate criteria
for other halomethanes and saltwater organisms using 0.44 times
the Final Acute Value.
The maximum concentration for methylene chloride is the Final
Acute Value of 4,400 ug/1 and the 24-hour average concentration is
0.44 times the Final Acute Value. No important adverse effects on
B-16
-------
saltwater aquatic organisms have been reported to be caused by
concentrations lower than the 24-hour average concentration.
CRITERION: For methylene chloride the criterion to protect
saltwater aquatic life as derived using procedures other than the
Guidelines is 1,900 ug/1 as a 24-hour average and the concen-
tration should never exceed 4,400 ug/1 at any time.
The estimated maximum concentration of methyl bromide is the
Final Acute Value of 380 ug/1 and the 24-hour average concen-
tration is 0.44 times the Final Acute Value. No important adverse
effects on saltwater aquatic organisms have been reported to be
caused by concentrations lower than the 24-hour average
concentration.
CRITERION: For methyl bromide the criterion to protect
saltwater aquatic life as derived using procedures other than the
Guidelines is 170 ug/1 as a 24-hour average and the concentration
should never exceed 380 ug/1 at any time.
The estimated maximum concentration of methyl chloride is the
Final Acute Value of 8,400 ug/1 and the 24-hour average concentra-
tion is 0.44 times the Final Acute Value. No important adverse
effects on saltwater aquatic organisms have been reported to be
caused by concentrations lower than the 24-hour average concentra-
tion.
CRITERION: For methyl chloride the criterion to protect
saltwater aquatic life as derived using procedures other than the
Guidelines is 3,700 ug/1 as a 24-hour average and the concentra-
tion should never exceed 8,400 ug/1 at any time.
B-17
-------
Tabl« 4. Marine fish acute values for haloroethanea
00
M
co
Organise
Adjusted
Bloaaaay Teat Tima LC60 LC60
flethod.* Cone.** (hra) (uq/^l jug/lt {teferunce
Sheepshead minnow, S
Cyprlnodon variegatus
Sheepehead minnow, S
Cyprtnodon variegotua
Tidewater ailveraidea, R
Hcntdia beryllina
Tidewater silveraidea, R
Mcnidla beryllina
Bromoform
U 96 17,900 9,786 U.S. EPA, 1978
Methylene chloride
U 96 331,000 180.958 U.S. EPA. 1978
Methyl bromide
U 96 12,000 6,560 Dawaon, et al, 1977
Methyl chloride
U 96 270,000 147,610 Dawson, et al. 1977
* S = static, R » renewal
** U = unmeasured
9.786
Geometric mean of adjusted values: Br onto form - 9,786 pg/1 ~JT~7~ " 2-600
Methylene chloride - 180,958 Mg/1 37 " 49.000 gg/1
Methyl bromide = 6.560 ng/l ~^j~ = 1,800 yg/1
Methyl chloride - 147.610 |ig/l lj7^-0 - 40.000
-------
* S = static
03 ** u = unmeasured
S. Marine invertebrate acute values for halomechanea (U S EPA, 1978)
Adjusted
biddssay Teat Time 1X50 LCbO
ttslUSili- £2ii£i** IfiiS) fM'i/M ton/U
Bromoform
Hysld shrimp. S U 96 24.400 20,667
Hysidopaia bahla
Methylene chloride
Mysld shrimp. S U 96 256,000 216,832
Hyaldopais Lahia
Geometric mean of adjusted valuesi Bromoform - 20,667 wg/1 • tg •= 420 tig/1
Methylene chloride - 216.8J2 ug/1 21^i83- = 4,400 ng/1
-------
00
N)
O
Table 6. Marine fieh chronic values for haloroethane (U.S. EPA, 1978)
Chronic
Units Value
Organism feec* (u<[/i) («J1/U
bromoform
Sheepshead minnow, E-L 14,000- 9,165
Cyprinodon varlegatus 24,000
E-L *> embryo-larval
Geometric mean chror
Lowest chronic value for bromoforro «• 9,165 iig/1
Q 1 £ C
Geometric mean chronic value for bromoform •» 9,165 Mg/1 "A'7" " 1.^00 |ig/l
-------
&tolo I', Marine plane eCfecta for haioaethanee (U S EPA. 1978)
Kf feet
«Uge, Ch1 crept*)-' j. a 12.300
SkelaConeina ccsEaEum EG5G
Alga. Cpll number
Skeletonema coacacum ECiO
11.500
DO
I
K)
Alga.
Skeletonepia costatua
Alga.
SkeleConema coscaCurn
Mathylene chloride
Chlorophyll a >662.000
EC50
Cell number >662,000
ECSO
Lowest plant value. Broraofono = 11,500 yg/1
Methylene chloride = >662,000
-------
REFERENCES
Alexander, H.C. , et al. 1978. Toxicity of perchloroethylene,
trichloroethylene, 1,1,1-trichloroethane, and methylene
chloride to fathead minnows. Bull- Environ." €ontam.~~ Tox-icol.
20: 344.
Bentley, R.E., et al. 1975. Acute toxicity of chloroform
to bluegill (Lepomis macrochiras), rainbow trout, (Salmo
gairdneri), and pink shrimp (Penaeus duorarum). Contract
No. WA-6-99-1414-B. U.S. Environ. Prot. Agency.
Dawson, G.W., et al. 1977. The acute toxicity of 47 indus-
trial chemicals to fresh and saltwater fishes. Jour. Hazard
Mater. 1: 303.
U.S. EPA. 1978. In-depth studies on health and environmental
impacts of selected water pollutants. Contract No. 68-
01-4646. Washington, D.C.
B-22
-------
Mammalian Toxicology and Human Health Effects
EXPOSURE
Irtroduction
The halomethanes are a subclass of halogenated aliphatic
hydrocarbon compounds, some of whose members constitute
important or potentially hazardous environmental contaminants.
The seven halomethane compounds selected for discussion
in this document are listed in Table 1. Many other halo-
genated methane derivative chemicals exist, including various
combinations of halogen (bromine, chlorine, fluorine, iodine)
substitutions on one, two, three, or all four of the hydrogen
positions of methane. Of these, two other particularly
important halomethanes, trichloromethane (chloroform) and
tetrachloromethane (carbon tetrachloride) are subjects of
separate criteria documents. Several recent reviews are
available which present extensive discussions of health
effects related to halomethane exposure (Natl. Acad. Sci.,
1978; Davis, et al. 1977; Howard, et al. 1974).
Humans are exposed to halomethanes by any of three
primary routes: (a) intake in water or other fluids, (b)
ingestion in food; and (c) inhalation. In certain circum-
stances (e.g., occupational), exposure by skin absorption
may be significant. Halomethanes have been identified in
air (Grimsrud and Rasmussen, 1975; Lovelock, et al. 1973;
Lovelock, 1975; Singh, et al. 1977; Lillian and Singh, 1974),
water (Shackelford and Keith, 1976; Lovelock, 1975; Symons,
et al. 1975; Morris and McKay, 1975; Kleopfer, 1976) and
food (McConnell, et al. 1975; Monro, et al. 1955), but infor-
C-l
-------
TABLE 1
Halomethanes*
Names and CAS Registry Number - - ~ ~
Bromomethane, methyl bromide, monobromo-
methane, Embafume, Iscobrome, Rotox; 74-83-9
Chloromethane, methyl chloride,
monochloromathane; 74-87-3
Dichloromethane, methylene chloride/
methane dichloride, methylene dichloride,
methylene bichloride; 75-09-2
Tribromomethane, bromoform, methyl
tribromide; 75-25-2
Bromodichloromethane, dichloromethyl
bromide; 75-25-4
Dichlorodifluoromethane, fluorocarbon 12,
P-12, Arcton 6, Freon 12, Frigen 12,
Genetron 12, Halon, Isotron 12,
difluorodichloromethane; 75-71-8
Trichlorofluoromethane, fluorocarbon 11,
F-ll, Arcton 9, Freon 11, Frigen 11,
Algofrene type 1, trichloromonofluoro-
methane, fluorotrichloromethane; 75-69-4
Formula
CH3Br
CH3C1
CHBr3
BrCHCl-
CC12F2
CC13F
*Chemical names, common names (underlined), some trade names
(capitalized) and synonyms are provided. References:
Int. Agency Res. Cancer (1978), Natl. Cancer Inst. (1977),
Stecher, et al. (1968), Natl. Library Med. (1978b).
C-2
-------
mation concerning relative exposure for specific compounds
via the different media is incomplete. Inhalation and/or
ingestion of fluids are probably the most important routes
of human exposure (Natl. Acad. Sci., 1978).
Presence of the halomethanes in the environment is
generally the result of natural, anthropogenic, or secondary
sources. The monohalomethanes (bromo-, chloro-, iodomethane)
are believed natural in origin with the oceans as a priirary
source (Lovelock, 1975); natural sources have also been
proposed for dichloromethane, tribromomethane, and certain
other halomethanes (Natl. Acad. Sci., 1978).
Anthropogenic sources of environmental contamination,
such as manufacturing and use emissions are important for
several halomethanes. These include: chloromethane (chemical
intermediate in production of silicone, gasoline antiknock,
rubber, herbicides, plastics, and other materials); bromo-
methane (soil, seed, feed, and space fumigant agents); dichlo-
romethane (paint remover, solvent, aerosol sprays, plastics
processing); tribromomethane (chemical intermediate); bromodi-
chloromethane (used as a reagent in research); dichlorodi-
fluoro methane and trichlorofluoromethane (refrigerant and
aerosol propellant uses) (Natl. Acad. Sci., 1978; Davis,
et al. 1977; Stecher, et al. 1968).
Secondary sources of halomethanes include such processes
as the use of chlorine to treat municipal drinking water
and some industrial wastes, and the combustion and thermal
degradation of products or waste materials, wherein secondary
formation reactions or incidental contamination occur (Natl.
Acad. Sci., 1978).
C-3
-------
Ingestion from Water
The U.S. Environmental Protection Agency has identified
at least ten halogenated methanes in finished drinking waters
in the U.S. as of 1975: chloromethane, bromometnane, dichloro-
methane, dibromomethane, trichloromethane, tribromomethane,
bromodichloromethane, dibromochloromethane, dichloroiodo-
methane, and tetrachloromethane (U.S. EPA, 1975). In the
National Organics Reconnaissance Survey in 80 cities, halo-
genated hydrocarbons were found in finished waters at greater
concentrations than in raw waters (Symons, et al. 1975).
It was concluded by Symons, et al. (1975) that trihalomethanes
(THM) result from chlorination and are widespread in chlori-
nated drinking waters; concentrations are related to organic
content of raw water. Incidence and levels of halomethanes
found in the survey are summarized in Table 2.
TABLE 2
Kalomethanes in the National Organics
Reconnaissance Survey (80 Cities)
Number of
Cities with Concentration, mg/1
Compound Positive
Tr ichloromethane
Bromodichlorome thane
Dibromochlor ome thane
Tr ibroraome thane
Tetrachloromethane
Results
80
78
72
26
10
Minimum
0,
0,
0.
0,
0,
.0001
.0003
.0004
.0008
.002
Median
0
0
0
.021
.006
.0012
(a)
"•" ^
Maximum
0
0
0
0
0
.311
.116
.110
.092
.003
(a) 98.3 percent of 80 cities had 0.005 mg/1 tribromo-
methane
Source: Natl. Acad. Sci., 1978 (data from Symons, et
al. 1975)
C-4
-------
In its Region V Organics Survey at 83 sites U.S. SPA
reported concentrations of several halomethanes in a large
percentage of finished municipal waters, as summarized in
Table 3. Of the halomethanes detected in drinking waters,
dichloromethane, tetrachloromethane, and fully chlorinated
higher hydrocarbons probably are not products of water chlori-
nation (U.S. EPA, 1975; Morris and McKay, 1975). Because
of its solubility, dichloromethane may exist in water efflu-
ents at concentrations of up to 1,500 mg/1, depending on
process and terminal treatment factors (Natl. Acad. Sci.,
1978).
TABLE 3
Halomethanes in the U.S. EPA Region V
Organics Survey (83 Sites)
Percent of
Locations with Concentrations (mg/1)
Compound Positive Results Median
Bromodichlorome thane
Dibromochlorome thane
Tr ichloromethane
Tr ibromomethane
Tetrachloromethane
Dichloromethane
78
60
95
14
34*
8
0.006
0.001
0.020
^0.001
-<0.001*
<0.001
Maximum
0.031
0.015
0.366
0.007
0.026*
0.007
*A total of 11 samples may have been contaminated by
exposure to laboratory air containing tetrachloromethane.
Source: (U.S. EPA, 1975)
U.S. EPA's National Organic Monitoring Survey (NOMS),
conducted in 1976 and 1977 (Phases L-III), sampled 113 water
supplies representing various sources and treatments (U.S.
EPA, 1978a, b). Incidence and concentration data for six
C-5
-------
halomethanes are summarized in Table 4. Some 63 additional
organic compounds or classes were detected, including these
halomethanes: bromomethane, dibromomethane, bromochloro-
methane, iodomethane, dichloroiodomethane, and trichloro-
fluoromethane. Mean and median total trihalomethane (TTHM)
values in 105 to 111 cities over the Ifhree" phases arid sample
modes ranged from 0.052 to 0.120 mg/1 and 0.038 to 0.087
mg/1, respectively.
Data from a Canadian national survey for halomethanes
in drinking water are in general agreement with those from
the United States (Health and Welfare Can. 1977). Samples
taken from 70 finished water distribution systems showed
the following halomethane concentrations:
Concentration
range median
Chloroform 0 - 121 13 ug/1
Bromodichloromethane 0-33 1.4 ug/1
Chlorodibromomethane 0-6.2 0.1 ug/1
Tribromomethane 0-0.2 0.01 ug/L
As would be expected, based upon previous observations,
(Symons, et al. 1975), chlorination as part of the water
treatment process led to considerable enhancement of Salome-
thane concentrations, and well sources were associated with
much lower halomethane concentrations than river or lake
sources. In addition, an unexplained increase in the concen-
tration of halomethanes occurred in the distribution system
as compared to halomethane levels in water sampled at the
treatment plant.
C-6
-------
TABLE 4
Partial summary of National Organics Monitoring Survey, 1976-1977 (U.S. EPA, I978b)
Compound
Number of Positive Analyses
per Number of Analyses
Mean Concentration,
mg/1 (Positive
Results only)
Median Concentration,
mg/1 (All Results)
0
1
Trichloro-
methane
Tribromo-
me thane
Bromodi-
chloro-
rae thane
Dlbromo-
chloro-
me thane
Tetra-
chloro-
me thane
Dichloro-
me thane
Phase
0*
T
Q
T
Q
T
Q
T
Q
T
I
102/111*
3/111*
88/111*
47/111*
3/111*
15/109
II
18/18
112/113
6/118
38/113
18/18
109/113
15/18
97/113
10/110
III
98/106
101/105
19/106
30/105
100/106
103/105
83/106
97/105
8/106
11/105
I
0.047*
0.021*
0.022*
0.017*
0.0029*
0.0061
II
0.068
.084
0.028
.012
0.016
.018
0.013
.014
0.0024
III
0.038
.073
0.013
.013
0.0092
.017
0.0075
.011
.0064
0.0043
I
0.027
<0. 003-0. 005a
0.0096
<0. 0006-0. 003a
0. 001-0. 002a
<0. 001-0. 002a
II
0.068
.059
<0.0003a
<0.0003a
0.018
.014
.0019
.0035
l
<0.0002a
i
III
0.022
.045
<0. 0002-0.
<0. 0003-0.
0.0059
.011
.0021
.0031
<0. 0002-0.
<0. 0002-0
0006a
0006a
0004a
'Samples shipped iced, stored 1-2 weeks refrigerated before analyses.
^Quenched (Q) samples preserved with sodium thiosulfate at sampling, shipped at ambient temp., stored 2.0-25°C
3-6 weeks before analyses. Terminal(T) samples treated similarly to Q except no Na thiosulfate.
aM minium Ljudnll Ciable limits.
Phases (I, II, III) refer to sampling projects and corresponding sample treatment and storage conditions.
I Collected and analyzed as in National Organics Reconnaissance Survey (earlier) (Symons, et al. 1975).
Shipped and stored refrigerated (1-8°C) 1-2 weeks before analyses.
II: S
-------
Evidence of the presence of trichlorofluoromethane in ocean
surface waters has been reported (Howard, et al. 1974; Lovelock,
et al. 1973; Wilkness, et al. 1975). None was detectable
below surface waters, indicating that the oceans are not
a significant sink (long-term pool or repository) for this
compound. As noted above, trichlorofluoromethane has been
detected, but not quantified, in finished drinking water
in the NOMS. Environmental data suggest that human exposure
to the refrigerant-propellant chlorofluoromethanes in water
is much less significant than to these compounds' presence
in air.
Ingestion from Foods
Bromomethane residues from fumigation decrease rapidly
through loss to the atmosphere and reaction with protein
to form inorganic bromide residues. With proper aeration
and product processing most residual bromomethane will rapidly
disappear due to methylatibn reactions and volatilization.
The more persistent inorganic bromide residues are products
of bromomethane degradation (Natl. Acad. Sci., 1978; Davis,
' et al. 1977). Scudamore and Heuser (1970) reported that
residues in fumigated wheat, flour, raisins, corn, sorghum,
cottonseed meal, rice, and peanut meal were reduced to less
than 1 rag/kg within a few days. Initial levels of inorganic
bromide were positively related to concentration used, and
disappearance rate was lower at low temperatures. No residual
bromomethane was found in asparagus, avocados, peppers,
or tomatoes after two-hour fumigation at 320 mg CH-,Br/m
air (Seo, et al. 1970) . Only trace amounts were present
in wheat flour and other products fumigated at 370 CHjBR
C-8
-------
mg/m after nine days of aeration (Dennis, et al. 1972).
Table 5 summarizes data on organic and inorganic bromide
residues in cheese with time after fumigation, as reported
by Roehm, et al. (1943). Table 6 summarizes specific inor-
ganic bromide residue maxima analyzed in several food commodi-
ties, according to Getzendaner, et al. (1968). Lynn, et
al. (1963) reported that cows fed grain fumigated with
bromomethane gave milk containing bromide levels proportional
to those in feed intake. Milk bromide levels of up to 20
mg/1 were noted at exposure levels up to 43 mg inorganic
bromide/kg diet, at which level milk production was not
affected. Blood total bromides correlated with milk bromides.
TABLE 5
Bromomethane Residues in Cheese (outer % inch) (mg/kg)
(Natl. Acad. Sci., 1978, data from Roehm, et al. 1943)
Hours of Longhorn Cheese A Longhorn Cheese B
Ventilation Inorganic Organic Total Inorganic Organic Total
0.5 15 62 77 23 78 101
4 21 40 61 30 54 84
24 22 20 42 38 9 47
48 25 0 25 39 4 43
96 24 0 24 38 1 39
168 25 1 26 36 2 38
C-9
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TABLE 6
Specific Residue Maxima: Inorganic Bromide
in Food Materials (NAS, 1978, data from
Getzendaner, et al. 1968)
Max. SRa ~ ---------
mg-kg Ib min Materials
0-5 Baking powder, butter, chewing gum,
dry yeast, macaroni, marshmallows,
oleomargarine, shortening, tapioca,
flour, tea, whole roasted coffee
5-10 Cake mix, candy, cheese, dried milk,
ground ginger, ground red pepper,
pancake mix, precooked breakfast
cereals, veal loaf
10-15 Cocoa, ground roasted coffee, powdered
cinnamon
15-20 Allspice, beef cuts, gelatin, noodles,
peanuts, pie crust mix
20-30 Cornmeal, cream of wheat, frankfurters,
pork cuts, rice flour.
30-40 Bacon, dry dog food, mixed cattle
feed, white and whole wheat flour
40-50 Soy flour
75-100 Grated Parmesan cheese
100-125 Powdered eggs
a
Specific Residue (SR) _ increase in bromide from fumigation(mg/kg)
rate of fumigation(Ib/min)
Chloromethane and bromomethane are considered to have
relatively low potentials for bioconcentration, judging
from their relatively high vapor pressure and water solubility.
Estimating from solubility and use of the Metcalf and Lu
(1973) equation, biomagnification factors for these compounds
are relatively low (two and six, respectively). No directly
determined bioaccumulation factors were available.
C-10
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A bioconcentration factor (ECF) relates the concert-ration
of a chemical in water to the concentration in aquatic organisms,
but BCF's are not available for the edible portions of all
four major groups of aquatic organisms consumed in the United
States. Since data indicate that the _BCF >_£or lipid-tsoluble ...
compounds is proportional to percent lipids, BCF's can be
adjusted to edible portions using data on percent lipids
and the amounts of various species consumed by Americans.
A recent survey on fish and shellfish consumption in the
United States (Cordle, et al. 1978) found that the per capita
consumption is 18.7 g/day. From the data en the nineteen
major species identified in the survey and data on the fat
content of the edible portion of these species (Sidwell,
et al. 1974), the relative consumption of the four major
groups and the weighted average percent lipids for each
group can be calculated: '
Consumption Weighted Average
Group (Percent) Percent Lipids
Freshwater fishes 12 4.8
Saltwater fishes 61 2.3
Saltwater molluscs 9 1.2
Saltwater decapods 18 1.2
Using the percentages for consumption and lipids for each
of these groups, the weighted average percent lipids is
2.3 for consumed fish and shellfish.
No measured steady-state bioconcentration factor (BCF)
is available for methylene chloride or bromoform but the
equation "Log BCF =0.76 Log P - 0.23" can be used (Vei-h,
C-ll
-------
et al. Manuscript) to estimate the BCF for aquatic organisms
that contain about eight percent lipids from the octanol-
water partition coefficient (P). Based on an octanol-water
partition coefficient of 18 for methylene chloride the steady-
state bioconcentration factor for methylene chloride is
estimated to be 5.2. The steady-state bioconcentration
factor for bromoform is estimated to be 48, based on an
octanol-water coefficient of 330. An adjustment factor
of 2.3/8.0 = 0.2875 can be used .to adjust the estimated BCF
from the 8.0 percent lipids on which the equation is based
to the 2.3 percent lipids that is the weighted average for
consumed fish and shellfish. Thus, the weighted average
bioconcentration factor for methylene chloride and the edible
portion of all aquatic organisms consumed by Americans is
calculated to be 5.2 x 0.2875 = 1.5. Similarly, for bromoform
it is calculated to be 48 x 0.2875 = 14.
Inhalation
Reported concentrations of several halomethanes in
general air masses are summarized in Table 7. For comparison,
some halomethanes other than those addressed by this docu-
ment (Table 1) are included.
Saltwater atmospheric background concentrations of
chloromethane averaging about 0.0025 mg/m have been reported
(Grimsrud and Rasmussen, 1975; Singh, et al. 1977; Lovelock,
et al. 1973). These are higher than reported average contin-
ental background and urban levels (ranging from 0.001 to
0.002 mg/m ) and suggest that the oceans are a major source
of global chloromethane (Natl. Acad. Sci., 1978). Localized
C-12
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TABLE 7
Ranges of Mean Concentrations (mg/m ) of
Halomethanes Measured in General Air Masses
Compound
Continental
Background
Saltwater
Background
Urban
o
i
M
CO
Chloromethane
Dichloromethane
Bromomethane
lodomethane
Tr ichloromethane
Tetrachloromethane
0.0011-0.0021a'c'd'f'k
0.0012°
0.00006d
(0.000002-0.000004)6
0.000052d
0.000044-0.000122a/C'd
0.0023; 0.0026'
0.00012f
0.00036d
0.000041
( 0.000006-0.000064)
0.000132, 0.000234
0.000126-0.000838
a,c,d,k
0.000699-0.000806
b,d,f
0.0017
+c
( 0.00007-0.0005)
0.00042d
( 0.00004-0.00085)e
0.000139d
( 0.000006-0.02204)g
0.000498
(0.000049-0.0732)g.
(0.000029-0.01464)i
0.000844d
(0,.000756-0.1134)g
. (0.00882)n
(0.000756-0.00945)1
Brackets identify individual reported values; other numerals represent reported means or range
of reported means.
a-1
Adapted from Natl. Acad. Sci., 1978, data from: (aj Cronn, et al. 1976; (b) Pierotti, et
al. 1976; (c) Pierotti and Rasmussen, 1976; (d) Singh, et al. 1977; (e) Harisch and Rasmussen,
1977; (f) Cox, et al. 1976; (g) Lillian, et al. 1975; (h) Ohta, et al. 1976; (i) Su and
Goldberg, J.976; (j) Lovelock, et al. 1973; (k) Grimsrud and Rasmussen, 1975; (1) Lovelock,
1975
-------
sources, such as burning of tobacco or other combustion
processes, may produce high indoor-air concentrations of
chloromethane (up to 0.04 mg/m ) (Natl. Acad. Sci., 1J78,
citing Palmer, 1976, and Harsch, 1977). Chlor MICthan* is
the predominant halomethane in indoor air, and is generally
in concentrations two to ten times ambient background levels
(Natl. Acad. Sci., 1978). Although direct anthropogenic
sources of chloromethane greatly influence indoor atmosphere
concentrations, they are not significant contributors to
urban and background tropospheric levels (Natl. Acad. Sci.,
1978) .
Data on atmospheric bromomethane are few (Singh, et
al. 1977; Grimsrud and Rasmussen, 1975). Its continental
background concentrations of 7.8 x 10~ mg/m or less are
much lower than saltwater background and urban air concentra-
tions (Natl. Acad. Sci., 1978). Relatively high concentra-
tions of bromo-methane reported in surface seawater suggest
that oceans are a major source of the compound (Lovelock,
et al: 1973; Lovelock, 1975), and this is supported by high
concentrations in saltwater atmosphere (Singh, et al. 1977).
There is evidence that combustion of gasoline containing
ethylene dibromide (EDB, an additive) is also a significant
source of environmental bromomethane, and this is corroborated
by urban air concentrations at least as high as those in
saltwater air masses (Natl. Acad. Sci., 1978, citing Harsch
and Rasmussen, 1977, and Singh, et al. 1977). Table 7
summarizes reported levels of bromomethane in tropospharic
air masses. Concentrations of up to 8.5 to 10~ mg/m may
occur outdoors locally with light traffic as a result of
C-14
-------
exhaust containing bromomethane as a combus :ion oreakdown
product of EDB in leaded gasoline. Similarly, indoor air
contaminated by exhaust from cars burning EJB-containing
leaded gasoline can have elevated concentra :ions of bromo-
methane (Natl. Acad. Sci., 1978, citing Barsch and Rasmussen,
1977). ~ ~
Data on concentrations of dichloromethane in tropospheric
air masses are scarce. As shown in Table 7, reported back-
ground concentrations in both continental and saltwater
atmospheres were about 1.2 x 10 mg/m , and urban air concen-
trations ranged from less than 7 x 10 to 5 x 10 mg/m
(Natl. Acad. Sci., 1978, citing Pierotti and Rasmussen,
1976, and Cox, et al. 1976). Concentrations of dichloromethane
in indoor air typically exceed tropospheric background levels
because of local sources of contamination such as the use
of aerosol hair spray or solvents (Natl. Acad. Sci., 1978,
citing Harsch, 1977) . Air sampled from various indoor loca-
tions contained dichloromethane at concentrations ranging
from a low of 2 x 10 mg/m (in a laundromat washer) to
high values of 2.5 mg/m (automobile dealer display floor),
4.9 mg/m (records and automotive section of discount store),
and even 8.1 mg/m (beauty parlor waiting area) (Natl. Acad.
Sci., 1978, citing Harsch, 1977). Indoor air has 10 to
1,000 times more dichloromethane than is present in unpolluted
tropospheric air, and sometimes dichloromethane is the pre-
dominant halomethane contaminant (Natl. Acad. Sci., 1978).
Data through 1974 indicate that dichlorodifluoromethane
is produced and used considerably more than trichlorofluoro-
C-15
-------
methane and the other major fluorocarbon refrigerants (Howard,
et al. 1974). This production and use appears to be reflected
in atmospheric analyses showing higher concentrations for
dichlorodifluoromethane than for trichlorofluoromethane.
Concentrations over urban areas are several times those
over rural areas and over oceans. This probably reflects
that the primary modes of entry to the environment, use
of refrigerants and aerosols, are greater in industrializ-
ed and populated areas (Howard, et al. 1974). Atmospheric
concentrations of trichlorofluoromethane are higher during
stagnant air conditions and decrease upon displacement or
dilution by clean air. Conversely, concentrations in off-
shore air masses increase when displaced by polluted air
masses from industrialized urban areas (Howard, et al.
1974; U.S. EPA, 1976; Wilkness, et al. 1975; Lovelock, 1971,
1972) . Average concentrations of trichlorofluoromethane
(F-ll) reported for urban atmospheres have ranged from 9
x 10 to 3 x 10 mg/m , and for ocean sites, from 2.2
—4 —4 3
x 10 to 5 x 10 mg/m . Mean urban concentrations for
dichlorodifluoromethane (F-12) ranged from 3.5 x 10 to
—2 3
2.9 x 10 mg/m , and an ocean atmosphere mean of 5.7 x
10~4 mg/m was reported (Howard, et al. 1974; Hester,
et al. 1974; Simmonds, et al. 1974; Su and Goldberg, 1976;
Wilkness, et al. 1973, 1975; Lovelock, et al. 1973; Lovelock,
1974) . Concentrations in air near fluorocarbon release
sites may be many times the average city levels. F-ll concen-
trations of 1.3 x 10~4 to 2.4 x 10~4 mg/m3, about 100 times
the city average, were measured near a polyurethane plant
C-16
-------
I
using the material as a blowing agent; near a cosmetics
plant where aerosol cans are filled, levels were three to
four times typical city readings (Howard, et al. 1974;
Hester, et al. 1974).
The F-ll and 7-12 fluorocarbons are regarded as very
stable and persistent in the environment and are without
tropospheric or oceanic sinks. Tropospheric lifetimes of
ten to more than 40 years have been asserted, and an atmos-
pheric half-life of 15 to 30 years for F-ll has been calcu-
lated (Howard, et al. 1974; U.S. EPA, 1976; Howard and Hanchett,
1975; Lovelock, et al. 1973; Wilkness, et al. 1973; Krey,
et al. 1976). Concern has developed that fluorocarbons
in the troposphere will diffuse into the stratosphere and
catalytically destroy stratospheric ozone, with possible
health and meteorologic effects, globally.
Trichlorofluoromethane and dichlorodifluoromethane
have been measured at highly varying levels indoors in homes.
F-ll concentrations of 1.7 x 10 to 2.9 mg/m have been
reported (Hester, et al. 1974). Similar levels have been
measured in public buildings. Indoor concentrations were
generally higher than in outside air. In a beauty shop,
where fluorocarbon-pressured cosmetic sprays were apt to
be used, concentrations of 0.28 and 1.8 mg/m were reported
for F-ll and F-12, respectively. Evidence of quite high
levels of propellants F-ll and F-12 after spray-product
releases indoors was presented by Bridbord, et al. (1974
cited in U.S. EPA, 1976). These data are summarized in
Table 8.
C-17
-------
TABLE 8
Dichlorodifluoromethane Concentrations in Room Air as
a Result of Release of Aerosol Can Products (U.S. EPA,
1976, data from Bridbord, et al. 1974)
Level at Periods after 60- Level -at Periods'af-ter 30-
second Release of Hair Spray second Release,of Insect ,
in 29.3m Room (mg/m ) Spray in 21.4m Room {mg/m
During: 306.8 1 min: 2,304.0
30 min: 12.4 60 min': 130.4
60 min: 0.5 150 min: 56.8
Data on environmental concentrations of halomethanes
indicate that human uptake of the trihalomethanes bromodi-
chloromethane and tribromomethane from fluids is less than
that of trichloromethane. Uptake of chloromethane, dichloro-
methane, bromomethane and the chlorofluoromethanes from
fluids is apparently minor; for these, uptake from
sources other than fluid consumption is more important (Natl.
Acad. Sci., 1978).
Human uptake of chloromethane from fluids should be
considerably less than that for bromodichloromethane and
triboromomethane. However, human exposure to chloromethane
from cigarette smoke, local in nature and affecting discrete
target populations, can be quite significant (Natl. Acad.
Sci., 1978, citing Philippe and Hobbs, 1956, Owens and Rossano,
1969, and Chopra and Sherman, 1972). Reports or estimates
of air concentrations in rooms with people smoking range
roughly from 0.03 to 0.12 mg/m . The smoker's exposure
from direct inhalation could be considerably greater still,
C-18
-------
I
since the range of reported chloromethane is 0.5 to 2 rag
per cigarette.
Dermal
Uptake of halomethanes from dermal exposure can occur
under certain circumstances. Occupational exposure stand-
ards warn of possible significant skin absorption for bromo-
methane and tribromomethane under industrial exposure condi-
tions (Occup. Safety Health Admin., 1976; Natl. Acad. Sci.,
1978). But there was no evidence in the available literature
that dermal exposure contributes significantly to total
dose of halomethanes for the general public.
PHARMACOKINETICS
Absorption, Distribution, Metabolism, and Excretion
Most of the literature regarding biological aspects
of the halomethanes has focused on the usual case with res-
pect to exposure, absorption, and intoxication. Absorption
via the lungs upon inhalation is of primary importance and
is fairly efficient for the halomethanes; absorption can
also occur via the skin and gastrointestinal (GI) tract,
although this is generally more significant for the nonfluori-
nated halomethanes than for the fluorocarbons (Natl. Acad.
Sci., 1978; Davis, et al. 1977; U.S. EPA, 1976; Howard,
et al. 1974).
Bromomethane: The usual route for systemic poisoning
by bromomethane is by inhalation, and absorption commonly
occurs via the lungs; some absorption can also occur through
the skin, particularly in skin exposures to the compound
in liquid form (Davis, et al. 1977; von Oettingen, 1964).
C-19
-------
Occupational Safety and Health Administration (1976) exposure
standards warn of possible significant dermal absorption.
Significant absorption can also occur via the gastrointestinal
tract when bromomethane is ingested. Upon absorption, blood
levels of residual nonvolatile bromide increase, indicating
rapid uptake of bromomethane or its metabolites (Miller
and Haggard, 1943). Bromomethane is rapidly distributed
to various tissues and is broken down to inorganic bromide.
Storage, only as bromides, occurs mainly in lipid-rich tissues.
Blood bromide levels of 24 to 250 mg/1 were reported
in severe, and 83 to 2,116 mg/1 in fatal, bromomethane poison-
ings; normal background blood bromide levels ranged up to
15 mg/1 (Natl. Acad. Sci., 1978, citing: Clarke, et al.
1945, Benatt and Courtney, 1948). In rats fed bromomethane-
fumigated diets with residual bromide levels, higher tissue
bromide levels were in their eyes, lungs, blood, spleen,
and testes, while lowest tissu^levels were in fat, skeletal
muscle, bone, and liver. In similar bovine experiments,
bromide was secreted in milk (Williford, et al. 1974; Lynn,
et al. 1963).
Evidently the toxicity of bromomethane is mediated
by the bromomethane molecule itself and its reaction with
tissue (methylation of sulfhydryl groups in -critical cellular
proteins and enzymes), rather than by the bromide ion residue
resulting from breakdown of the parent compound (Davis,
et al. 1977). Bromomethane readily penetrates cell membranes
while the bromide ion does not. Intracellular bromomethane
reactions and decomposition result in inactivation of intra-
C-20
-------
cellular metabolic processes, disturbed function, and irrita-
tive, irreversible, or paralytic consequences (Natl. Acad.
Sci., 1978; Davis, et al. 1977; Miller and Haggard, 1943;
Lewis, 1948; Rathus and Landy, 1961; Dixon and Needham,
1946). Poisoning with bromomethane is generally associated
with lower blood bromide levels than is poisoning with inorganic
bromide (Natl. Acad. Sci., 1978, citing Collins, 1965).
Elimination of bromomethane is rapid initially, largely
through the lungs as bromomethane. The kidneys eliminate
much of the remainders as bromide in urine,. Final elimina-
tion may take longer, accounting in part for prolonged toxi-
city (Natl. Acad. Sci., 1978 citing Miller and Haggard,
1943, and Clarke, et al. 1945).
Chloromethane: As with bromomethane, chloromethane
is usually encountered as a gas and is absorbed readily
via the lungs. Skin absorption is less significant (Natl.
Acad. Sci., 1978; Davis, et al. 1977). No poisonings involving
gastrointestinal absorption have been reported. Uptake
of chloromethane by the blood is rapid but results in only
moderate blood levels with continued exposure. Signs and
pathology of intoxications suggest wide tissue (blood, nervous
tissue, liver, and kidney) distribution of absorbed chloro-
methane. Initial disappearance from the blood occurs rapidly.
Decomposition and sequestration result primarily by reaction
with sulfhydryl groups in intracellular enzymes and proteins.
Excretion via bile and urine occurs only to a minor degree
(Natl. Acad. Sci., 1978; Davis, et al. 1977; Lewis, 1948;
Morgan, et al. 1967; von Oettingen, 1964).
C-21
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Dichloromethane: Absorption occurs mainly through
the lung but also through the gastrointestinal tract and
to some extent through intact skin. Lung absorption effi-
ciencies of 31 to 75 percent have been reported, influenced
by length of exposure, concentration, and activity level
(Natl. Acad. Sci., 1978; Natl. Inst. Occup. Safety "Health,
1976a, citing: Lehmann and Schmidt-Kehl, 1936, Riley, et
al. 1966, DiVincenzo, et al. 1972, and Astrand, et al. 1975).
Upon inhalation and absorption, dichloromethane levels increase
rapidly in the blood to equilibrium levels that depend primarily
upon atmosphere concentration; fairly uniform distribution
to heart, liver, and brain is reported (Natl. Acad. Sci.,
1978, citing von Oettingen, et al. 1949, 1950). Carlsson
and Hultengren (1975) reported that dichloromethane and
its metabolites were in highest concentrations in white
adipose tissue, followed in descending order by levels in
brain and liver. Dichloromethane is excreted intact primarily
via the lungs, with some in the urine. DiVincenzo, et al.
(1972.) have reported that about 40 percent of absorbed dichlo-
romethane undergoes some reaction and decomposition process
in the body (Natl. Acad. Sci., 1978).
Some of the retained dichloromethane is metabolized
to carbon monoxide (CO). Some of this CO is exhaled, but
a significant amount is involved in the formation of carboxy-
hemoglobin (COHb). The formation of COHb leads to inter-
ference with normal oxygen transport capabilities of blood,
so relative oxygen deprivation and secondary effects ensue
(Natl. Inst. Occup. Safety Health, 1976a, citing Stewart,
et al. 1972a, Fassett, 1978, and DiVincenzo and Hamilton,
C-22
-------
1975; Natl. Acad. Sci., 1978, citing Stewart, et al. 1972a,b)
Bioconversion of CO and formation of COHb,continues after
exposure. Therefore, cardiorespiratory stress from elevated
COHb may be greater as a result of dichloromethane exposure
than from exposure to CO alone (Stewart and Hake, 1976).
Other metabolites of dichloromethane rnclude" carBori "dioxide,
formaldehyde, and formic acid (Natl. Acad. Sci., 1978).
Tribromomethane: Absorption occurs through the lungs
upon inhalation of vapors, from the GI tract upon ingestion,
and to some extent through the skin. The OSHA (1976) stand-
ard warns of possible significant skin absorption. Some
of the body burden is biotransformed in the liver to inorgan-
ic bromide. After inhalation or rectal administration of
tribromomethane bromides were found in tissues and urine
(Natl. Acad. Sci., 1977). Bioconversion of tribromomethane
and other trihalomethanes, apparently by a cytochrome P-450
dependent mixed function oxidase system, to carbon monoxide
has been reported (Ahmed, et al. 1977). Excretion occurs
partly through the lungs as tribromomethane, and complete
excretion requires considerable time (Natl. Acad. Sci.,
1978) .
Bromodichloromethane: Little information is available
on the pharmacokinetics or other biological aspects of this
compound. This reflects its very limited use, primarily
in research, and limited discharge to the environment (Natl.
Acad. Sci., 1978). Current increased environmental interest
in bromodichloromethane focuses on its presence in drinking
water (Kleopfer, 1976) along with other trihalomethanes,
as a consequence of chlorination. Absorption, distribution,
C-23
-------
metabolism, and excretion may resemble that of bromochloro-
methane (see the following) dichloromethane, or dibromomethane,
in view of close chemical similarities among these compounds
and bromodichloromethane. Further possible evidence for
similarity exists in that the mutagenic, carcinogenic, and
general toxic effects of the latter are srmirlar' to-"those
of other di-and trihalogenated (Cl and Br), methanes (Natl.
Acad. Sci., 1978; Sax, 1968).
Patty (1963) placed bromochlbromethane "roughly in
a class with methylene chloride," but "somewhat more toxic,"
among "the less toxic halomethanes." Animal experiments
have indicated that inhaled bromochloromethane is readily
absorbed intact by the blood and hydrolyzed in significant
amounts by the body to yield inorganic bromide. Tissue
concentrations of both organic and inorganic bromine increased
in dogs and rats exposed daily to bromochloromethane. After
exposure, blood levels decreased to undetectable or insignifi-
cant levels in 17 to 65 hours. Significant absorption by
the GI tract after exposure by ingestion was indicated by
hepatic and renal pathology in mice dosed by stomach tube.
Similar injury in these organs was not observed in animals
exposed to vapors. Absorption through the skin would also
seem likely in view of its irritation and solubility charac-
teristics (Patty, 1963).
If the pharmacokinetics of bromodichloromethane does
resemble that of chemically similar halomethanes, it would
be expected that bromodichloromethane would: (1) Be absorbed
readily by the inhalation and ingestion routes; (2) be distri-
C-24
-------
buted widely, preferentially to tissues with high lipid
content; (3) be eliminated in part via expired breath; and
(4) combine with cellular protein and be metabolized to
CO and inorganic halide. >
Trichlorofluoromethane (P-ll) and dichlorodifluorometh-
ane (F-12): Inhalation and absorption thrpugh the lungs
are the exposure and uptake modes of most concern; however,
when ingested, absorption of F-12 does occur via the GI
tract. Some absorption through the skin could occur also,
judging from tests with F-113 (CC12F-CC1F2) (U.S. EPA, 1976;
Howard, et al. 1974; Clark and Tinston, 1972a,b; Allen and
Hanbury, 1971; Azar, et al. 1973; Sherman, 1974; DuPont,
1968). Absorption and elimination are dynamic processes
involving equilibria among air, blood, and various tissues.
Upon absorption a biphasic blood-level pattern occurs, with
an initial rapid then slower rise in blood levels (arterial,
venous) during which the material is absorbed from blood
into tissues. After termination of exposure a similar but
inverse biphasic pattern of elimination occurs. The relative
decreasing order of several fluorocarbons with respect to
absorption into blood has been reported as F-ll, F-113, F-
12, F-114 (Shargel and Koss, 1972; Morgan, et al. 1972).
These authors agree in general with partition coefficients
for the fluorocarbons in blood, serum, and lipid (oil) (Allen
and Hanbury, 1971; Chiou and Niazi, 1973; Morgan, et al.
1972). More easily absorbed compounds are retained longer.
Under conditions of prolonged, lower-level exposure, periods
of elimination (washout) are longer. Although varying among
C-25
-------
individuals, apparently F-ll is more readily absorbed in
mammals than F-12. To what extent this reflects artifacts
involving the higher volatility of F-12 is not clear (Howard,
t
et al. 1974) .
F-ll and F-12 are distributed by blood and stored tempo-
rarily by various tissues. Measured tissue levels in rats
after pulse inhalation exposure in one report were: adrenals
greater than fat greater than heart (Allen and Hanbury,
1971). Chemically related fluorocarbons have been found
primarily in tissues of high lipid content (fat, brain,
liver, heart), but elimination following pulse exposure
was rapid, and there was no evidence of accumulation (Carter,
et al. 1970a,b; Van Stee and Back, 1971). There is evidence,
however, that tissues with higher lipid content than blood
concentrate fluorocarbons from the blood, corresponding
to relative order of absorption by blood from air (Howard,
et al. 1974).
Elimination of fluorocarbons (intact) seems to be almost
completely through the respiratory tract, regardless of
the route of entry. In dogs administered a mixture of F-12
and F-14 (30:70 percent, vol./vol.) by several different
routes, elimination was through expired air and none was
detected in urine or feces (Matsumoto, et al. 1968) . Rapid
initial elimination is followed by a slower phase of decline.
Biochemical effects suggesting a slowing down of cellu-
lar oxidation were reported in animals exposed to 2.8 x
105 mg/m3 F-ll in air (but not to F-ll at 1.4 x 105 mg/m3
nor to F-12 at 2.47 x 105 to 9.88 x 105 mg/m3) (Paulet,
et al. 1975).
C-26
-------
In brief exposure experiments with inhaled C-labeled
F-12 only about one percent of F-12 was metabolized and
eliminated in expired air as CG>2 or existed in nonvolatile
urinary or tissue components (Blake and Mergner, 1974).
14
Experiments with oral C-labeled F-12 indicated that about
two percent of the total dose was exhaled as CO-f about
0.5 percent was excreted in urine, and after 30 hours no
F-12 was detectable (Eddy and Griffith, 1961) .
F-ll and F-12 form metabolites which bind to cell constit-
uents, particularly in long-term exposures with extended
equilibrium (Blake and Mergner, 1974). F-ll (or its labeled
metabolites) has been reported to bind in vitro irreversibly
to proteins and to endoplasmic phospholipids and proteins,
but not to ribosomal RNA (Uehleke, et al. 1977; Uehleke
and Warner, 1975). Binding to rat-liver microsomal cyto-
chrome P-450-related phospholipids was reported (Cox, et
al. 1972). More research on fluorocarbon xenobiotic metabo-
lism and pharmacodynamics under prolonged exposure conditions
is needed (U.S. EPA, 1976).
EFFECTS
Acute, Sub-acute, and Chronic Toxicity
For most of the halomethanes considered here, there
is considerable information on clinical toxicity in the
occupational health literature and on experimental toxicity
in the literature on toxicology using laboratory animals.
These data have dealt primarily with inhalation exposure
to grossly poisonous or fairly substantial concentrations
of vapors. Considerably less information is available on
various aspects of toxicity that might result from prolonged
C-27
-------
exposure to low, environmental levels of these contaminants,
by not only the inhalation route but also ingestion or other
routes of exposure. This section summarizes briefly the
important clinical and toxicologic information available
for these compounds.
Chloromethane: Is not generally regarded "as "higTily
toxic, yet reports of poisoning are numerous. Because of
its virtually odorless and colorless properties, low-order
irritancy,and characteristic latency of effect, victims
may receive serious or prolonged exposure before awareness
and effects are apparent (Natl. Acad. Sci., 1978; Davis,
et al. 1977). Toxic dosages for humans are not clearly
defined. Generally, acute inhalation intoxication in humans
has been thought to require exposures on the order of 1,032
mg/m , but lower levels have produced definite toxicity
in animals (MacDonald, 1964; Smith and von Oettingen, 1947b,c)
Chronic inhalation and ingestion toxicity levels are not
established, but the occupational exposure standard for
air in the work environment is currently set for 206 mg/m
(Natl. Acad. Sci. 1978; Occup. Safety Health Admin., 1976).
The monohalomethanes seem to rank in the following order
of decreasing toxicity: iodomethane, bromomethane, chloro-
methane, fluoromethane (Davis, et al. 1977). The similar-
ities in toxicologic responses to the monohalomethanes sug-
gest a similar mode of action. The most probable mechanism
is that the monohalomethane participates in the methylation
of essential enzymes, cofactors, and other cellular macro-
molecules, thereby rendering them inactive (Davis, et al.
C-28
-------
1977). Sulfhydryl-containing molecules seem particularly
susceptible to the action of monohalomethanes (Lewis, 1948;
Redford-Ellis and Gowenlock, 1971a). Various reports on
the effectiveness of cysteine administration in the treatment
of monohalomethane poisoning support the contention that
binding to sulfhydryl compounds is involved in the expres-
sion of toxic effects (Mizyokova and Bakhishev, 1971).
In studies with laboratory animals, several investigators
have shown that monohalomethanes interfere with glutathione
metabolism (Redford-Ellis and Gowenlock, 1971a,b; Boyland,
et al. 1961; Barnsley, 1964; Johnson, 1966; Barnsley and
Young, 1965).
Human experience, largely involving leakage from refrig-
eration equipment using chloromethane as a coolant, shows
it to be a central nervous system (CNS) depressant with
primarily neurological toxic manifestations (Hansen, et
al. 1953). Systemic poisoning cases have also involved
hepatic and renal injury (Spevac, et al. 1976). In the
more mild intoxications there is a characteristic latent
period of one-half to several hours between exposure and
onset of effects (symptoms). Recovery after brief exposures
is typically within a few hours, but repeated or prolonged
exposure may result in more severe toxicity and delayed
recovery (days-weeks). In persons occupationally exposed
at levels of 52 to more than 2 x 10 mg/m the following
toxic manifestations, particularly related to CNS, were
noted: blurred vision, headache, nausea, loss of coordina-
tion, personality changes (depression, moroseness, anxiety),
lasting a few hours to several days; some were more sensi-
C-29
-------
tive to chloromethane upon return to work (MacDonald, 1964;
Hansen, et al. 1953; Browning, 1965; Morgan, 1942). As
mentioned previously, tobacco-smoking may be an additional
significant source of individual human exposure to chloro-
methane.
Severe poisonings are usually characterized by a latent
period and severe and dominant neurological disorder, with
perhaps irreversible and/or persistent sequelae; renal and
hepatic injury are common. In fatal cases coma and death
commonly ensue in hours or days as a result of cerebral
and pulmonary edema and circulatory failure, with pathologic
findings of congestion, edema, and hemorrhage; chloromethane
has been detected in all organs analyzed after death (Natl.
Acad. Sci., 1978, citing Baird, 1954).
There have been no reports of reproductive toxicity
or teratogenicity in humans exposed to chloromethane, but
metabolic, enzymatic, and neuroendocrine disturbances follow-
ing exposure in humans and/or animals suggest the need for
research on this point (Davis, et al. 1977). Epidemiolo-
gical studies of toxicity in human populations exposed to
chloromethane (including mutagenicity and carcinogenic!ty)
have not yet appeared in the published literature.
In animals, a variety of toxic effects have been noted
in experimentally exposed subjects. Many effects are simi-
lar for the monohalomethanes and, consistent with human
data, suggest CNS involvement and altered metabolism involv-
ing binding to sulfhydryl-containing cellular macromolecules
(Davis, et al. 1977; Balander and Polyak, 1962; Gorbachev,
C-30
-------
et al. 1962; Kakizaki, 1967; Redford-Ellis and Gowenlock,
1971a,b). Most toxicity information is from inhalation
studies, with little regarding other routes, apparently
because of the volatility of these compounds and their usual
presence in the gas phase (Davis, et al. I97"7T. Some inhala-
tion toxicity data for chloromethane are summarized in Table
9. In general, chloromethane appears less acutely toxic
by inhalation than bromomethane. In severe acute exposure
conditions chloromethane produces serious neurological dis-
turbances, with functional and behavioral manifestations
and ultimately death. However, these disturbances from
chloromethane occur at higher concentrations than are required
for bromomethane in several species (Davis, et al. 1977).
Under more prolonged exposures to less severe levels,
chloromethane increased mucus flow and reduced mucostatic
effect of other agents (e.g., nitrogen oxides) in cats
(Weissbecker, et al. 1971). Permanent muscular dysfunction
is described in mice surviving several weeks of daily expo-
sures at 1,032 mg/m , and paralysis followed exposure to
531 mg/m for 20 hours in surviving animals (von Oettingen,
et al. 1964). No teratogenic effects have been reported
for chloromethane (Davis, et al. 1977).
Bromomethane: is regarded as a highly toxic substance
by acute exposure and more dangerous than chloromethane.
It has been responsible for many occupational poisoning
incidents, reflecting its widespread use as a fumigant.
Like chloromethane it has a characteristic latent period
and its presence is difficult to detect, so prolonged and
C-31
-------
TABLE 9
Chlotomethane Inhalation Toxicity in Animals
Concentration,
.3
Duration
Response
Reference
O
i
CO
3.1 x 10 to 6.2 x 10
4.1 x 10 to 8.3 x 10
4.1 x 10'
1.4 x 10* ,
6.2 x 10J to 8.3 x 10J
6.5 x 10^
6.2 x 10,
4.1 x 10J
2,065
1,032
620 to 1,032
531
Brief
30-60 nun
2 hr.
Up to 1 hr
6 hrs/day
6 hrs
4 hrs
6 hrs/day
6 hrs/day
6 hrs/day
20 hrs
Quickly lethal to most animals
Dangerous effects. Increased res-
piratory and heart rates and blood
pressure, followed by reversals and
ECG changes; restlessness, saliva-
tion, incoordination, narcosis.
LCLo, guinea pig
No serious effects
Deaths, rats, 3-5 days, spasmodic
dyspnea
LC.n, mouse
LCCo, rat
1 week, cats, weakness, unable to right
1 week, cats, dyspnea, refusal
to eat/drink.
3-4 weeks, cats, death
2-3 days, guinea pigs, deaths
4-7 days, monkeys, convulsions
1-3 days, dogs, deaths
5-6 days, rabbits and rats, death
1-6 days, dogs, deaths
1 expos., dogs and monkeys, signs
of poisoning; 2-4 weeks, dogs, deaths,
permanent neuromuscular damage in survivor;
1 week, mice, convulsions, mortality;
15 weeks, mice, permanent adductor
contraction in survivors
Overt signs of toxicity
detectable in dogs and monkeys.
Paralysis in survivors.(but in another
exposure at 620 mg/m , no cumulative
overt toxicity or neurotoxic changes
over several months in several species).
Patty, 1958
von Oettingen, 1964
NIOSH. 1976b
Patty, 1958
von Oettingen, 1964
Davis, et al. 1977
DHEW, 1975
von Oettingen, 1964
von Oet^ingen, 1964
von Oettingen, 1964
Smith & von Oettingen, 1947a
von Oettingen, 1964; Smith
& von Oettingen, 1947a
-------
more severe exposure may be incurred (Natl. Acad. Sci.f
1978; Davis, et al. 1977). Toxicologic and metabolic similari-
ties among the monohalomethanes (C1-, Br-, l-substituted)
suggest a common mechanism of toxic action, probably methyla-
tion and disturbance or inactivation of essential proteins
(rather than presence of the parent co~mpouhd or free halide
per se) (Davis, et al. 1977).
Human experience indicates that acute fatal intoxica-
tion can result from exposures to vapor levels as low as
1,164 to 1,552 mg/m , and harmful effects can occur at 388
mg/m or more. Systemic poisoning has been reported to
occur from two weeks' exposure (eight hrs/day) at about
136 mg/m3 (Natl. Acad. Sci., 1978, citing: Kubota, 1955,
Johnstone, 1945, Bruhin, 1943, Wyers, 1945, Watrous, 1942,
Rathus and Landy, 1961, Miller, 1943, Tourangeau and Plamondon,
1945, Viner, 1945, Collins, 1965, Clarke, et al. 1945).
Symptoms generally increase in severity with increasing
levels of exposure and may vary somewhat according to exposure
circumstances and individual susceptibility. In sublethal
poisoning cases a latency period of 2 to 48 hours (usually
about four to six) between exposure and onset of symptoms
is characteristic (Araki, et al. 1971).
Like the other monohalomethanes, bromomethane is a
CNS depressant and may invoke psychic, motor, and GI disturb-
ances. (Mellerio, et al. 1973, 1974; Greenberg, 1971; Longley
and Jones, 1965; Hine, 1969). In light poisoning cases
effects may be limited to mild neurological and GI disturb-
ances, with recovery in a few days. Moderate cases involve
C-33
-------
the CNS further, with more extensive neurological symptoms
and visual disturbances. Recovery may be prolonged for
weeks or months, with persisting symptoms and/or disturb-
ed function. Severe cases also involve a latent period
and similar initial symptoms, with development of disturbed
speech and gait, incoordination, tremors that "may develop
to convulsions, and psychic disturbances. Recovery can
be quite protracted with persisting neurological disorders
(Araki, et al. 1971). In fatal cases the convulsions may
become more intense and frequent, with unconscious periods.
Death may occur in a few hours from pulmonary edema or in
one to three days from circulatory failure. Pathology often
includes hyperemia, edema, and inflammation in lungs and
brain. Degenerative changes in kidney, liver, and/or stomach,
and perhaps the brain, occur although brain changes are
usually more functional in character (Natl. Acad. Sci.,
1978; Davis, et al. 1977). Apparently blood bromide levels
of 100 mg/1 or less result in recovery, 135 in moderate
disability, 195 in residual ataxia, and 250 in convulsions
(Hine, 1969).
Direct skin contact with bromomethane may produce prick-
ling, itching, cold sensation, erythema, vesication, blisters
(similar to second degree burn), and damage to peripheral
nerve tissue or delayed dermatitis (Davis, et al. 1977).
A case of brief skin exposure (spray) to liquid bromomethane,
quickly decontaminated, did not produce a burn, but resulted
in severe, delayed, neuromuscular disturbances (twitching,
fits, convulsions) and permanent brain damage (cerebellum
and pyramidal tract) (Longley and Jones, 1965). The OSHA
C-34
-------
(1976) standard for bromomethane in workroom air is 78 mg/m
(celling) and carries a warning notation of possible signifi-
cant skin absorption (Natl. Inst. Occup. Safety Health,
1976b; Occup. Safety Health Admin., 1976).
In animals bromomethane is highly toxic. It is more
toxic by inhalation to several species than chloromethane
(Davis, et al. 1977). Correspondence between effective
doses by inhalation vs, ingestion is difficult to assess
until more is known of GI absorption and first-pass detoxifi-
cation (Davis, et al. 1977). In several species acute fatal
poisoning has involved marked CNS disturbances with a varie-
ty of manifestations: ataxia, twitching, convulsions, coma,
as well as changes in lung, liver, heart, and kidney tissues
(Sayer, et al. 1930; Irish, et al. 1940; Gorbachev, et al.
1962; von Oettingen, 1964). In subacute and protracted
exposure studies similar neurological disturbances developed
(Irish, et al. 1940; Sokolova, 1972) as in animal and human
(Drawneek, et al. 1964) acute toxicoses. Inhalation toxicity
in animal species is briefly reviewed in Table 10. In general
the monohalomethanes rank in decreasing order of acute toxi-
city as follows: iodomethane, bromomethane, chloromethane,
fluoromethane (Davis, et al. 1977).
Dogs receiving bromomethane chronically by ingestion
(fumigated diet yielding residual bromide at a dose level
of 150 mg/kg/day) were adversely affected, whereas if they
received sodium bromide at 78 mg/kg/day (residual bromide)
no effects were noted (Rosenblum, et al. 1960) . In another
experiment using fumigated food with residual bromide Vitte,
C-35
-------
TABLE 10
Bromomethane Inhalation Toxicity in Animals
Concentration
mg/m
69,452
24,929
20,952
7,760-11,640
7,760-11,640
3,391
o 1,940-2,328
L 2,293
°> 1,536-1,940
1,536
1,164
1,164
997
846
846
582
504
419
252
128
97
70
Duration
15 mm
1 hr
20 min
30 mm
70 mm
30-40 mm
4.5 hrs
12 hrs
6 hr/daily
Not specified
5 hrs
13.5 hrs
22 hrs
3 hr
26 hr
9 hrs
18 hrs (2 exp.
at 3 mo
interval)
7-8 hrs daily
8 hr/day, 5
da/wk.
8 hr/day, 5
da/wk .
4-5 mos
40 mm
Response
Lethal, cats
LCLo, rabbit
Delayed deaths (6 days) , guinea pigs
Delayed deaths (9 hr) , 1 of 6 guinea pigs
^IDO' 9umea pigs
Lethal, dogs
Lethal within 2 days, salivation, guinea pigs
Lethal, rabbits
Cumulative overt toxic ity, dogs & monkeys
LC5Q, mice
Delayed death, 1 of 6 guinea pigs
Lethal, all died within 3 days, guinea pigs
100% lethal in rats
Lethal, rabbits
Lethal, rats
Lethal to most in 1-3 days; guinea pigs
Altered conditioned reflexes, mice
Weight loss, prostration, convulsions; rats
At 22 days: typical poisoning, rabbits
Eventually lung irrit., paralysis, rabbits
(but not rats, guinea pigs, or monkeys)
Altered neuroendocrme controlled metabo-
lism, rabbits
Changes in motor responses
Reference
von Oettingen, 1964
NIOSH, 1976b
von Oettingen, 1964
von Oettingen, 1964
von Oettingen, 1964
von Oettingen, 1964
von Oettingen, 1964
Gorbachev, et al. 1962
Smith & von Oettingen, 1947a
Balander & Polyak, 1962
von Oettingen, 1964
von Oettingen, 1964
Irish, et al. 1940
von Oettingen, 1964
Irish, et al. 1940
von Oettingen, 1964
Sokolova, 1972
1
iri'sh, et al. 1940
Irish, et al. 1941
Irish, et al. 1941
Balander & Polyak, 1962
Balander & Polyak, 1962
-------
et al. (1970) detected changes in blood iodine and calcium
and pathologic changes in thyroid and parathyroid glands.
Toxic responses in rabbits administered bromomethane sub-
cutaneously (in oil) at 20-120 mg/kg included limb paraly-
sis/ cessation of drinking, reduced urine excretion._ Levels
greater than 50 mg/kg sharply increased the blood bromide
level and reduced platelets, serotonin, and water content
(Kakizaki, 1967).
Groups of cattle were fed oat hay from a bromomethane-
fumigated field or pelleted ration containing sodium bromide
added at various concentrations. The hay contained bromide
ion at 6,800 to 8,400 mg/1. Groups fed the hay and highest
dose-rate of bromide in pelleted ration developed signs
of CNS toxicity (motor incoordination) at 10 to 12 days
of exposure. Incoordination correlated with serum bromide
concentrations of 2,400 mg/1 (30 meq/1) or more. Serum
bromide levels and neurologic signs were markedly reduced
two weeks after termination of exposure (Knight and Reina-
Guerra, 1977).
No reports of bromomethane teratogenicity studies were
available, but high levels in eye and testes after ingestion
of fumigated food, and enzymatic and neuroendocrine distur-
bances, could have teratogenic implications. Further stud-
ies in this area would appear to be warranted (Williford,
et al. 1974).
Dichloromethane: As with chloromethane, dichlorome-
thane has not generally been regarded as highly toxic, but
poisonings, primarily from inhalation exposures, have been
C-37
-------
reported. Human minimal toxic concentrations or doses have
not been determined. At this time the OSHA occupational
exposure standard (air concentrations as a TWA for eight
hours) is 1,737 mg/m with ceiling and peak values of 3,474
and 6,948 mg/m , respectively (Occup. Safety Health Admin.,
1976). However, NIOSH has recommended an "eigfit-hour TWA
concentration of 260 mg/m with a peak limit of 1,737 mg/m
(Natl. Inst. Occup. Safety Health, 1976b). A TCLo* (eight
hours) of 1,737 mg/m for humans is reported (Natl. Inst.
Occup. Safety Health, 1976b), and exposures of 740 or 1,786
mg/m for one hour were reported as being without adverse
effect by Stewart, et al. (1972a,b). However, Winneke (1974)
reported exposure to 1,101 mg/m or more for three to four
hours decreased psychomotor performance (Natl. Acad. Sci.,
1978). Dichloromethane affects central nervous system function.
It is also irritating to mucous membranes (eyes, respiratory
tract) and skin. In addition, it results in production
of carbon monoxide (CO) as a metabolite, which increases
carboxyhemoglobin (COHb) in the blood and interferes with
oxygen transfer and transport (Natl. Acad. Sci., 1978).
Mild poisonings by dichloromethane produce somnolence,
lassitude, anorexia, and mild lightheadedness, followed
by rapid and complete recovery. Severe cases are character-
ized by greater degrees of disturbed CNS function and depres-
sion. Permanent disability has not been reported. In fatal
poisonings cause of death has been reported as cardiac injury
and heart failure (Natl. Acad. Sci., 1978, citing: Hughes,
*Abbreviation used to denote lowest reported toxic concentration.
038
-------
1954, Stewart and Hake, 1976, Collier, 1936, Moskowitz and
Shapiro, 1952).
The formation of CO and COHb from dichloromethane forms
a basis for concern about combined exposures to dichloro-
methane and carbon monoxide. Fodor and Roscovanu (1976)
and NIOSH (1976a) recommend re-examination of dichlorome-
thane exposure standards with a view to reducing them.
These authors report that exposure at the current threshold
limit value (TLV) of dichloromethane produces COHb levels
equivalent to those produced by the TLV for CO. Mixed expo-
sures could be a problem, especially in workers, smokers,
and cardiorespiratory patients or other susceptibles. Con-
cern about mixed exposure to dichloromethane and other lipo-
philic solvents, with enhanced danger of marked CNS and
metabolic effects resulting from modest exposure to indivi-
dual materials, has been expressed (Savolainen, et al. 1977).
Gynecologic problems in female workers exposed for
long periods to gasoline and dichloromethane vapors were
reported by Vozovaya (1974) . In pregnant women, chronic
exposure resulted in dichloromethane passing through the
placenta into the fetus. Dichloromethane also was found
in milk of lactating women a few hours into a work shift.
Functional circulatory disorders in workers exposed for
more than three years to organochlorine compounds (including
dichloromethane) at "permissible" levels have been reported
by Dunavskii (1972). Symptoms included chest pain, electro-
cardiograph irregularities, bradycardia, decreased myocar-
dial contractility, and altered adaption to physical stress.
C-39
-------
More recently it has been reported (Stewart and Hake, 1976;
Scott, 1976) that fatal heart attacks have been caused by
exposure to dichloromethane in paint and varnish removers
(Natl. Acad. Sci., 1978).
Animal toxicology of dichloromethane is briefly review-
ed in Table 11, with some human data included. Both di-
and tri-halogenated methane derivatives have been found
to produce increased blood levels of COHb; the greatest
increase caused by iodo-, followed by bromo- and chloro-
compounds. CNS functional disturbances are reported, includ-
ing depression of REM-sleep, as seen in carbon monoxide
exposures (Fodor and Roscovanu, 1976). Liver pathology
has been reported in experimental exposure to dichloromethane
vapors (Balmer, et al. 1976). NAS (1978) cites Haun, et
al. (1972) reporting liver changes in mice continuously
exposed to dichloromethane at 87 and 347 mg/m for up to
two weeks. As a liquid or vapor dichloromethane was ophthal-
motoxic in rabbit tests, producing persistent (up to two
weeks) conjunctivitis and blepharitis, corneal thickening,
keratitis and iritis, and increased intraocular tension
(Ballantyne, et al. 1976). Inhalation exposures of rats
and mice to vapor levels of 4,342 mg/m for seven hours
daily on gestation days 6 to 15 produced increased blood
levels of COHb and evidence of feto - or embryo-toxicity,
but not teratogenicity (Schwetz, et al. 1975; Natl. Inst.
Occup. Safety Health, 1976a, citing Heppel and Neal, 1944).
At 1.737 mg/m voluntary running activity was depresse
in rats. Sleep alterations were noted in rats exposed to
C-40
-------
TABLE Jl
Toxicity of Dichloromethane
o
i
Exposure Con-
centration
or Dose
6,460 mg/kg..
17,370 mg/m
3,000 mg/kg
2,700 mg/kg
2,136 mg/kg
1,900 mg/kg
1,500 mg/kg
4,342 mg/m
•j
3,425 mg/ni
950 mg/kg .,
1,737 mg/nr
T
1,737 mg/ni
2
1,737 mg/nu
1,737 ing/in
200 mg/kg -.
87-347 mg/ni
Duration
Subcut.
2 hrs
Oral
Subcut.
Oral
Oral
I. P.
7 hr/day,
9 da
1 hr
I. P.
6 hr/day,
few days
year, in-
termittent
8 hrs
3 hrs
I.V.
Contin.
up to
2 wks.
Response
LD50 , mouse
LCLo, guinea pig. Depressed
running activity, rats
LDLo , dog
LDLo, rabbit and dog
LD5Q, rat
LDLo, rabbit
LD5Q, mouse
Fetotox., teratogenicity, mice.
rats
Transient lightheadedness, human
LDLo , dog
Altered brain metabolism,
behavior, rats
TCLo, CSN, human
TCLo, blood, human (12% COHb)
13% COHb, rats
LDLo , dog
Liver changes, mice
Reference
NIOSH, 1976b
NIOSH, 1976b
Heppel & Neal, 1944*
NIOSH, 197bb
NIOSH, 1976b
NIOSH, 1976b
NIOSH, 1976b
NIOSH, 1976b
Schwetz, et al. 1975
Stewart, et al. 1972a,b*
NIOSH, 1976b
Savolainen, et al. 1977
.
NIOSH, 1976b
NIOSH; 1976b
Fodor & Roscovanu, 1976
NIOSH f 1976b
Haun, et al. 1972
Cited by NIOSH, 1976a
hCited by NAS, 1978
-------
dichloromethane at 3,474 mg/m or more (Wolburg, 1973).
Depressed CNS excitability, along with increased blood levels
and expiratory/ hepatic/ and renal excretion of dichloro-
methane in subecute studies, was reported (Avilova, et al.
1973).
Tribromomethane: Little information is available concern-
ing the toxicology of tribromomethane. It is regarded as
a highly toxic material, more toxic than dibromomethane
but less than tetrabromomethane and triiodomethane (Natl.
Acad. Sci., 1978/ citing Dep. Health Edu. Welfare/ 1975).
Minimum toxic concentrations have not been established,
but its general toxic potential is reflected in a quite
low occupational exposure standard (Occup. Safety Health
Admin., 1976): eight-hour time-weighted-average air concentra-
tion, 5.2 mg/m (the most stringent standard of the halome-
thanes considered herein). It is absorbed by all major
routes (lungs, GI tract, skin) after appropriate exposure
(Natl. Acad. Sci., 1978).
In humans, exposure to toxic levels of vapor produces
irritation of respiratory tract, pharynx, and larynx, with
lacrimation and salivation. Most reported cases of poison-
ings have resulted from accidental overdoses administered
in the treatment of whooping cough. Toxic symptoms appear
after a shorter latent period than that typical of other
halomethanes. Obvious toxic effects in light cases may
be limited to headache, listlessness, and vertigo. Uncon-
sciousness, loss of reflexes, and convulsions occur in severe
cases, and in fatal cases the primary cause of death is
C-42
-------
respiratory failure, Clinical recovery in moderate poison-
ings may be relatively rapid and without permanent damage
or disabiltiy. Presence of tribromomethane in all organs
is indicated by pathologic findings, which also indicate
fatty degenerative and centralobular necrotic changes in
the liver (as in trichloro - and triiodomethane poisonings)
(Natl. Acad. Sci., 1978, citing von Oettingen, 1955).
Animal data are generally consistent with those from
human case histories. Impaired liver function (prolonged
pentobarbital sleeping time and/or BSP retention) in mice
resulted from single subcutaneous doses of tribromomethane
ranging between 278 and 1,112 mg/kg. These functional effects
correlated with pathological liver changes at the higher
dose levels (Kutob and Plaa, 1962). Pathological changes
in liver and kidney have been reported (Dykan, 1962) in
guinea pigs after systemic administration of a level of
100 to 200 mg/kg per day for ten days (Natl. Acad. Sci.,
1978) . Experimental data for animals are briefly summarized
in Table 12. Reticuloendothelial system function (liver
125
and spleen phagocytic uptake of I-Listeria monocytogenes)
was suppressed in mice exposed 90 days to tribromomethane
at daily dose levels of 125 mg/kg or less (Munson, et al.
1977, 1978).
Bromodichloromethane: No information on human intoxica-
tion by this compound was available and there have been
no occupational exposures reported by Sax (1968). However,
he reported the compound as "dangerous" and "probably narco-
tic in high concentrations."
C-43
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TABLE 12
Bromoform Toxicity in Animals
Concentration
or Dose
Duration
or Route
Response
Reference.
1,820 mg/kg
1,400 mg/kg
581 mg/kg
410 mg/kg
250 mg/m3
Subcut., single
Intragastric,
single
Subacut., oil,
single
LD^g t mouse
LPcn/ mouse, ICR, 0;
fatty liver; kidney
palor; hemorrhage in
adrenals, lungs, brain
Median effective dose
for prolongation of
phenobarb. sleeping
time. Approx. thresh.
278 mg/kg. Mouse.
Subacut., single LDLo, rabbit
Inhal., 4 hrs
daily, 2 mos.
100-200 mg/kg/da Inject., daily,
10 days
0.3-125 mg/kg/da Intragastric,
90 days
Disorders in liver
glycogenesis and pro-
thrombin synthesis;
reduced renal filtration
capacity. Threshold:
50 mg/m . Rat.
Liver and kidney
pathol., guinea pig
Suppressed liver
phagocytosis, mice
Kutob & Plaa, 1962
Bowman, et al. 1978 .
Kutob & Plaa, 1962
NIOSH, 1976b
NAS, 1977, citing
Dykan, 1962
NAS, 1978, citing
Dykan, 1962
Munson, et al. 1978
C-44
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Bowman, et al. (1978) have recently reported on acute
toxicity tests in mice. Median lethal doses 1^50 for ICR
Swiss mice administered bromodichloromethane (solubilized
in emulphor: alcohol and saline mix) by gavage were 450
and 900 mg/kg for males and females, respectively. J3ased
on comparative LDgg data among four trihalomethanes bromo-
dichloromethane was the most acutely toxic in both males
and females, and males were more susceptible than females
for all compounds. Sedation and anesthesia occurred within
30 minutes at the 500 mg/kg dose level for bromodichloromethane,
and lasted for about four hours. Animals that died in groups
dosed over a range of 500 to 4,000 mg/kg showed fatty infiltra-
tion in livers, pale kidneys, and hemorrhage in kidneys,
adrenals, lungs, and brain.
In mice that were offered bromodichloromethane in drink-
ing water at 300 mg/1 (with and without use of emulphor),
water consumption and body-weight decreased dramatically
(Campbell, 1978). Body weight regained parity with controls
in several weeks, but water consumption did not. There
was no obvious effect on susceptibility to pathogenic Salmon-
ella typhimurium delivered by gavage after several weeks'
exposure. However, Schuller, et al. (1978) have observed
a suppression of cellular and humoral immune response indices
in female ICR mice exposed by gavage for 90 days to bromodi-
chloromethane at 125 mg/kg daily. Sanders, et al. (1977)
observed hepatomegaly and a depression in a reticuloendothe-
lial system functional index (phagocytic) in mice exposed
to bromodichloromethane. Munson, et al. (1977) reported
C-45
-------
a dose-dependent suppression of hepatic phagocytosis in
mice exposed for 90 days to daily doses of bromodichloro-
methane by gavage ranging up to 125 mg/kg.
Teratogenic properties of bromodichloromethane have
not been clearly demonstrated, but some fetal anomalies
were reported in experiments in which ~mice~ were" exposed
to vapors at 8,375 mg/m seven hrs/day during gestation
days 6 to 15 (Schwetz, et al. 1975).
Trichlorofluoromethane (F-ll) and dichlorodifluoro-
methane (F-12): These propellant fluorocarbons are discussed
together because of their physicochemical and general toxi-
cologic similarity. They may be regarded as the least toxic
of the halomethanes considered in this document. Standards
for maximum average concentrations in air of work spaces
are established at 5,600 and 4,950 mg/m3 for F-ll and F-
12, respectively (Occup. Safety Health Admin., 1976).
For reference, these may be compared to the following standards
for other halomethanes:
tribromomethane 5 mg/m
bromomethane 80 mg/m
chloromethane 206 mg/m
dichloromethane 1,737 mg/m
It has been recommended that these standards be reduced
to 260 mg/m .
Because of their physical properties and use patterns
the primary route of exposure in toxicity studies has been
by inhalation of vapors at high concentrations, resulting
in rapid pulmonary absorption. The two toxicologic features
C-46
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of the fluorocarbons that have received the greatest atten-
tion are their cardiovascular and bronchopulmonary actions.
The toxicities of F-ll and F-12 are thought to be mediated
at least in part by metabolic products which bind to lipid
and protein cell constituents and affect vital processes
(e.g., retard cellular oxidation). There ^remains a: "heed-
for more metabolic and toxicologic information on the con-
sequences of prolonged exposure to environmental levels
(U.S. EPA, 1976; Howard, et al. 1974).
Human experience in fluorocarbon toxicity has largely
involved the intentional or unintentional misuse of fluoro-
carbon products, resulting in acute inhalation of high vapor
concentrations. Numerous severe and fatal cases of abuse
are on record, such as from inhaling deeply from spray-filled
bags to achieve a "jag." These probably involve cardiac
arrhythmia complicated by elevated circulating catecholamines
and C02 (Bass, 1970; Killen and Harris, 1972). Similar
toxic consequences could occur in asthmatics using fluoro-
carbon-propellant bronchodilator products (Taylor and Harris,
1970; Archer, 1973). Occupational-exposure data are limited.
Speizer, et al. (1975) have reported a relationship between
cardiac palpitation episodes and level of use of F-12 and
F-22* propellants in hospital pathology department workers
(frozen-section preparation).
*F-22 is CHCIF2
C-47
-------
In brief experimental exposures of humans to F-12 at
3 3
198 x 10 mg/m vapor concentration in air, tingling sensation,
humming in the ears, apprehension, EEC and speech changes,
and deficits in psychological performance were reported.
In other tests exposures to F-12 at 49 x 103 to 543 x 103
mg/m caused cardiac arrhythmia, decreased- consciousness,
and amnesia or deficits in performance on psychomotor tests
scores (Kehoe, 1943; Azar, et al. 1972). However, in women
using fluorocarbon-propellant (F-ll, F-12, F-114*) aerosol
products and receiving nine or more times the exposure from
normal use, Marier, et al. (1973) found no measurable blood
levels of the fluorocarbons or abnormalities in overall
health, respiratory, or hematologic parameters.
Good, et al. (1975) reported an excess of atypical
metaplastic cells in sputum of frequent aerosol-product
users. The authors suggested the possibility of some products
altering the resident bacterial flora of the respiratory
tract or containing tumorigenic constituents (not necessarily
the propellants). Data from a survey of aerosol product
use and respiratory symptoms by Lebowitz (1976) led him
to suggest a "tendency for more symptoms to follow increased
aerosol usage, most consistently among non-smokers" (U.S.
EPA, 1976). Human data on halothane** suggest potential
toxic hazards (liver, kidney, and CNS changes; risk of abor-
tion and developmental anomalies, increased susceptibiltiy
to cancer in females) from prolonged exposure at relatively
*F-114 is CC1F2-CC1F2
*Halothane is a gaseous anesthetic and chemical cousin,
CF3-CHBrCl.
C-48
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low levels, with implications particularly for operating
room personnel. Animal data on halothane are generally
supportive (U.S. EPA, 1976). The primary human hazard from
F-ll inhalation (by whatever circumstance: intentional misuse
of aerosol products to achieve intoxication .or overuse of
propellant bronchodilators) is the "induction of cardiac
arrhythmias (Howard, et al. 1974).
The inhalation toxicology of F-ll and F-12 in animals
is selectively summarized in Tables 13, 14, and 15. Several
propellant substances have been classified according to
their cardiopulmonary toxicities in animal studies, as summar-
ized in Table 16. Of all the aerosol propellants studied
and classified on the basis of cardiopulmonary effects,
Aviado (1975a) concluded that F-ll is the most toxic and
that the most serious effects are induction of cardiac arrhythmia
and sensitization to epinephrine-induced arrhythmias. The
Underwriters Laboratories (1971) classification system for
refrigerants is shown in Table 17. In this system F-ll
and F-12 are in Toxicity Classes 5 and 6, respectively (the
lowest two of six classes).
C-49
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TABLE 13
Inhalation Toxicology of P-ll (U.S. EPA, 1976)
Concentration
of Vapor, ,
(rag x 10J/m )
1,851
1,402
1,122
842
561
561
561
140; 280; 561
140-561
337
? 280
Ul
i~i
° 280
280
140
140
140
140
112
70
67
28-67
58
28
22
5.6
*9-P- denotes
LCcQ denotes
A Jf
Exposure, Duration
or Regimen
Brief (N.S.)
30 mm
5 nun
30 nun
20 mm
6 nun
5 mm
5 mm
N.S.
4 hrs
20 mm or repeated daily
5 nun
5 mm
5 mm
5 mm
5 ram
3.4 hr/day 20 days
4 hrs
3.5 hr/day 20 days
4 hr/day x 10 days
5 mm
8 hr/day x 30 days
Brief
6 hr/day x 28 days
90 days
guinea pig
median lethal concentration
Subject
Rat
Rabbit, g.p.
Rat
Rat
Rat
Mouse (anesthetized)
Rat (anesthetized)
Rat (unanesthetized)
Rat (anesthetized)
Rat
Rat, rabbit, dog
Monkey (anesthetized)
Mouse, dog
Cardiomyopathic hamster
Monkey (anesthetized)
Monkey
Cat, g.p., rat
Cardiomyopathic hamster
Dog
Rat
Dog
Rat, g p
Monkey and dog
Rat, mouse, g.p.,
rabbit
Rat, g.p.
.
Effect(s)
Tremors
T C *
Rfl
Letnal to some
LCj-n
Loss of reflex, anesthesia
A-V block
Cardiac arrythmias in all
Tachycardia, atrial fibrill., ventric.
extrasystoles in some (incid. related to' dose)
Bradycardia; also ectopic beats at 561 mg/m
Lethal to some
Biochemical changes indicative of slowed
cellular respiration.
Tachycardia, ventric. premature beats, A-V clock
SEIA** 3
Cardiac arrythmias (compared to 5bl x 10
mg/m in normal hamsters)
Tachycardia
SEIA
No signs of overt tox.', no mortality
High mortality and reduced lethal times
compared to normal hamsters
No signs of overt tox.', no mortality
Respiratory and neuromusc. signs of tox.,
(recovery after expos)'. Pathology in brain
liver, lungs; spleen changes
SEIA
No significant signs of tox.
Influence on circulatory system
No significant signs of tox.
Lung, liver changes
t
SEIA denotes sensitization to epmephrme-mduced arrhythmia
-------
TABLE 14
Inhalation Toxicology of F-12 (U.S. EPA, 1976)
Concentration
of Vapor. .
(mg x 10J/» »
3,»52
3,754
2,470
2,638(F11/F12, 1:1)
1,976
1,482-1,976
1,482
1,582(F11/F12, 1:1)
o 1,160(F11/F12, 1:1)
J, 988
£ 988
988
494, 988; 1,976
494; 988
494
494
494
247
247
41
4
Exposure, Duration
or Reg imen
30 nun
30 mm
1 hr
30
N.S.
Brief (N.S.)
30 mm
30 mm
30 mm
5 nun
7-8 hr/day x 35-53 days
6 mm
N.S.
N.S.
N.S.
5 nun
3.5 hr/day x 20 days
5 mm
5 mm
8 hr/day x 5 day/wk x 30 days
Continuous, 90 days
Subject
G.p. , rabbit, rat
Mouse
Rat
G.p.
Rat (anesthetized)
Rat
Rat
Rat
Mouse
Rat
Dog , monkey
Mice (anesthetized)
Rat (unanesthetized)
Rat (anesthetized)
Rat (anesthetized)
Monkey (anesthetized)
Rat, g.p., cat, dog
Monkey (anesthetized)
Dog
G.p.
G.p.
Effect(s)
^50*
LC50
Anesthesia
^50
Arrhythmia in h; no ch.
Tremors
^50
LC5Q
LCcjv
Letnal to some
Tremors disappear after
and depressed wt. gain
No arrhythmias
in heart rate
2 wks-tolerance
Tachycardia, no arrhythmias
No change in heart rate
Arrhythmias in, 10%
Arrhythmias
No mortal, and' no overt
No arrhythmias'
SEIA**
Liver changes
Liver changes
, or arrhythmias
signs of tox.
LCj-Q denotes median lethal concentration
+G.p. denotes guinea pig
* *
SEIA denotes sensitization to epmephrme-induced arrhythmia
-------
TABLE 15
>
Bronchopulmonary and Cardiovascular Effects
(other than arrhythmia) of F-ll and F-12
(U.S. EPA, 1976, data from Aviado, 1975b,c)
Effect
Subject
Tachycardia
Myocardial
depression
Hypotension
\ — i
Early respiratory
depression
Bronchoconstr iction
Decreased
compliance
Dog
Monkey
Dog
Monkey
Dog
Monkey
Dog
Monkey
Mouse
Rat
Dog
Monkey
Mouse
Rat
Dog
Monkey
Mouse
Rat
Cone.
56
140
140
140
140
140
561
280
140
140
0
0
56
140
0
0
56
140
Intens.
"4-4-4.
++
4-4-
++
4-4-
4-4-
4-
4-
4-4-
4-4-
4-4-
4-4-
4-4-
4-4-
Conc.
494
494
494
0
494
988
0
247
494
494
494
99
0
988
494
99
494
Intens.
4-
4-
+
4-
4-
4-
4-
4-
+
4-
4-
4-
4-
4-
4-
Approx. minimal concentration (10 mg/m ) producing response;
0 indicates absent or opposite responses
1, 2 or 3 pluses indicate intensity of response
-------
TABLE 16
Classification of Fluorocarbon and Other Propellant Compounds
on the Basis of Cardiovascular and Bronchopulmonary Toxicity
(U.S. EPA, data from Aviado, 1975b)
I.
II
Class and Compounds
Low Pressure Propellants of
High Toxicity
CC17F (F-ll), CHC19F(F-21)
CC12F-CC1F2(F-113)7 CH2C12,
and trichloroethane.
Low Pressure Propellants of
Intermediate Toxicity
CC1F.,-CC1F:,(F-114) ,
CClF2-CH3(F-142b), isobutane
and octafluorocyclobutane
Characteristics
III.
IV.
High Pressure Propellants
of Intermediate Toxicity
CCl2F2(F-12),CHClF2(F-22),
propane, and vinyl chloride
High Pressure Propellants
of Low Toxicity
F-115 and F-152b
Toxic" at"(J. 5-"5% (v/v) i'ri monkey
and dog, and 1-10% in rat and
mouse. Induce cardiac arrhythmias;
sensitize heart to epinephrine-
induced arrhythmias; cause tachy-
cardia, myocardial depression,
hypotension. Primarily cardio-
vascular effects.
Sensitize to epinephrine-arrhythmia
in the dog at 5-25% (Cf. 0.5% or
less for Class I). Do not induce
arrhythmias in mouse (Class I do at
10-40%). Affect circulation in
anesthetized dog and monkey at
10-20% (Cf at 0.5-2.5% for Class I).
Cause bronchoconstriction in dog
(Class I compounds do not), and,
except in this respect, are less
toxic than those in Class I.
Cardiovascular effects predominate.
Effective concentrations similar to
Class II for cardiosensitization and
circulatory effects, but respiratory
depression and broncho-effects pre-
dominate over cardiovascular effects
(in contrast to Classes I and II).
Extent of circulatory effects less
than those of Class III. Do not
cause bronchoconstriction or early
respiratory depression.
C-53
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TABLE 17
Comparative Acute Toxicity Classification
of Refrigerants
(Underwriters Labs., 1971)
Toxicity Concentration, Exposure duration to
class percent (v/v) produce death or serious
injury in animals (hours)
1 0.5 - 1 0.83 (5min.)
2 0.5-1 0.5
3 2-2.5 1
4 2-2.5 2
5 Intermed. Intermed.
6 20 No injury after 2 hrs
Several animal studies provide evidence that pre-existing
cardiac or pulmonary lesions (diseased state) may enhance
the toxicity (enhance toxic effect or reduce the level of
exposure required to produce effect) of fluorocarbons (Taylor
and Drew, 1975; Doherty and Aviado, 1975; Watanabe and Aviaco,
1975). Also, Wills (1972) demonstrated a dose related (in
range of 0.005 to 0.015 mg/kg) response to epinephrine (arrhy-
thmic heart beats) in subjects briefly exposed to F-ll at
49 x 10 mg/m (0.87 percent by volume). Thus, exposure
to the fluorocarbons (such as from use of propellant broncho-
dilators or misuse of other products), in combination with
use of cardioactive drugs or a stressful situation increasing
endogenous epinephrine levels, could be hazardous and present
a toxic risk greater than that from either factor alone
(U.S. EPA, 1976; Howard, et al. 1974).
C-54
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Pathologic liver changes were reported in guinea pigs
chronically exposed (continuously for 90 days or eight hours
daily, five days weekly, for six weeks) to F-12 at levels
of about 4,000 mg/m (0.08 percent by volume) (Prendergast,
et al. 1967). In other chronic exposure experiments with
rats, guinea pigs, monkeys, and dogs exposed to F-ll at
5,610 mg/m3 for 90 days or at 57.5 x 103 mg/m3 for eight
hrs/day x five days/week x six weeks, pneumonitic changes
were noted in all test groups (except in dogs exposed intermit-
tently) , liver changes were noted in rats and guinea pigs,
and serum urea nitrogen was elevated in exposed dogs (Jenkins,
et al. 1970). Several adverse changes were reported by
Karpov (1963) in various species exposed to F-22 (in same
class as and chemically similar to F-12) six hours daily
for ten months at 50.1 x 10 mg/m (1.42 percent, v/v) ,
including: reduced endurance in swimming test and increased
trials to establish conditioned reflex (mice); decreased
oxygen consumption and increase in the stimulus strength
required to induce response (rats); several hematologic
and blood chemistry changes (rabbits) and degenerative patho-
anatomic changes in heart, liver, kidney, nervous system,
and lungs (Clayton, 1966).
Applications of F-ll, F-12 and some mixed fluorocarbons
repeated twice daily over several weeks to skin and oral
mucosa of rats have produced irritation, edema, and inflam-
mation. These effects were most marked in the F-ll/F-22
mixture and in older subjects. The healing rate of burn
lesions was retarded by appliations of F-ll, F-12 and F-
C-55
-------
22 (Quevauviller, et al. 1964; Quevauviller, 1965). The
rapid evaporation of fluorocarbons applied directly to integu-
mentary surfaces may result in chilling or freezing and
may be the principal hazard in acute dermal exposure to
the more volatile compounds. Dermal absorption and jresult-
ing systemic toxicity are more important in the less volatile
fluorocarbons.
Information on oral route toxicity is limited (Howard,
et al. 1974) . Acute intragastric doses of F-ll at 7,380
mg/kg were reported as not lethal or grossly hepatoxic in
rats (Slater, 1965), but Clayton (1966) noted that F-ll
doses of 1,000 mg/kg (in peanut oil) were lethal in rats.
In one chronic (90 day) feeding study of F-12 in rats
at 35 and 350 mg/kg/day Waritz (1971) reported somewhat
elevated urinary fluoride and plasma alkaline phosphatase
levels. No changes in dogs at 10 and 100 mg/kg/day were
observed. In a two-year study using rats intubated with
F-12 in corn oil at 15 and 150 mg/kg/day there was some
suppression of weight gain at the high dose level, but no
effects with respect to clinical signs, liver function,
hematology, or histopathology were noted. In dogs given
eight and 80 mg/kg daily in treated dog food there were
no signs of toxicity, but some retention of F-12 (up to
1 mg/kg) in fat and bone marrow was observed (Sherman, 1974).
Synergism and/or Antagonism
Probably the most obvious concern in regard to this
aspect is the cardiac sensitization by fluorocarbons to
arrhythmogenic effects of circulating or administered catechol-
C-56
-------
amines (e.g., epinephrine) or asphyxia. Stress situations
or certain drugs taken in conjunction with or as a component
of fluorocarbon propellant products may present an opportunity
for synergistic consequences (Howard, et al. 1974).
Teratogenicity ~ _ - . - —
There are no available data on the teratogenicity of
halomethanes.
Mutagenicity
Information on the mutagenicity of halomethanes is
very limited. Recently, however, three groups of investiga-
tors have reported positive results with certain alkyl nalides
in the Ames Salmonella typhimurium test system (Andrews,
et al. 1976; Jongen, et al. 1978; Simmon, et al. 1977) .
Because of the formal relationship between molecular events
involved in mutagenesis and carcinogenesis (Miller, 1978;
Weinstein, 1978), the demonstration of mutagenic activity
for a substance is often taken as presumptive evidence for
the existence of carcinogenic activity as well. Therefore,
it is believed that an investigation of the mutagenicity
of xenobiotics may be predictive of carcinogenic potential
(but not necessarily potency), and may serve as an early
warning of a possible threat to human health where positive
results are obtained.
Simmon and coworkers (1977) reported that chloromethane,
bromomethane, bromodichloromethane, bromoform, and dichloro-
methane were all mutagenic to Salmonella typhimurium strain
TA100 when assayed in a dessicator whose atmosphere contained
the test compound. Metabolic activation was not required
C-57
-------
for the expression of mutagenic effect, since the addition
of microsomes was not necessary. In all cases, the number
of revertants per plate was directly dose-related.
Interpretation of these data with regard to carcinogenic
risk, however, is complicated by several factors. Data
were generally reported for only one Salmonella tester strain,
and the vapor-phase exposure is one which is not extensively
employed for mutagenesis testing. The number of plates
assayed at each dose was not indicated, and the criteria
used for determination of a significant mutagenic response
were not specified. If the most stringent evaluation criteria
were applied (in which the ratio of: experimental - control/control
must exceed 2.5), bromoform and bromodichloromethane would
not be considered positive in this study.
Confirmation of mutagenicity for all the chemicals
examined by Simmon, et al. (1977) has not been reported
by other investigators, either in the Ames assay or with
other test systems. However, Andrews and coworkers (1976)
have demonstrated that chloromethane was mutagenic to Salmon-
ella typhimunum strain TA1535 in the presence and absence
of added liver homogenate preparations. Simmon, et al.
(1977) indicated that although dichloromethane was mutagenic
in the Ames assay, it did not increase mitotic recombination
in S_. cerevisiae D3. In addition, it was reported that
dichloromethane was negative on testing for mutagenicity
in Drosophila (Filippova, et al. 1967).
C-58
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The positive results for dichloromethane in the Ames
assay were recently confirmed by Jongen, et al. (1978).
Using Salmonella strains TA98 and TA100, which detect frame-
shift mutations, dose-related increases in mutation rate
were obtained using vapor phase exposures (5,700 - 57,000
ppm). The addition of a microsomal preparation was not
necessary for the production of mutations, although a slight
enhancement in mutation rate could be obtained with rat
liver homogenate. An explanation for why certain halometh-
anes are mutagenic in the Ames assay without the addition
of a metabolic activating system has not been proposed.
Mutagenicity data on the fluorocarbons are scant.
Upon incubation of labeled F-ll (also CC14/ CHC13 and halothane)
with liver microsomes and NADPH the label was found to be
bound irreversibly to endoplasmic protein and lipid but
was not detected in ribosomal RNA. None of the compounds
was mutagenic in Salmonella tester strains TA1535 or 1538
with added liver microsomes (Uehleke, et al. 1977). Sherman
(1974) found no increase in mutation rates over controls
in a rat feeding study of F-12. Stephens, et al. (1970)
reported significant mutagenic activity of F-12 at 2.47
x 10 mg/m (50 percent) in air in a Neurospora crassa (a
mold) test system.
Further testing is obviously required to establish
the mutagneic potential of any or all of the halomethanes.
Many investigators agree that a compound should demonstrate
positive results in at least two different short-term assay
systems before it is accepted as a mutagen/carcinogen.
Nevertheless, based on the presently available mutagenicity
C-59
-------
data, it seems prudent to regard chloromethane, bromomethane,
bromoform, dichloromethane, and bromodichloromethane as
suspected mutagens/carcinogens pending the results of further
research.
Carcinogenicity _
Among the halomethanes, only chloroform, carbon tetra-
chlonde, and lodomethane are generally regarded to be car-
cinogenic in animals (Natl. Acad. Sci., 1978). Limited
new data, however, implicate several additional compounds
as potential tumorigens. These data were developed using
the strain A mouse lung tumor assay system, a bioassay which
is known for its extremely high sensitivity to both strong
and weak carcinogens (Shimkin and Stoner, 1975). The inter-
pretation of lung tumor data in the strain A mouse is somewhat
unique in that certain specific criteria should be met before
a compound is considered positive:
(a) A significant increase in the mean number of lung
tumors in test animals, preferably to one or more
per mouse, should be obtained.
(b) A dose-response relationship should be evident.
(c) The mean number of lung tumors in control mice
should be consistent with the anticipated incidence
of spontaneous tumors for untreated strain A mice.
Theiss and coworkers (1977) examined the biological
activity of bromoform, bromodichloromethane, and dichloro-
methane in strain A mice. Male animals, six to eight weeks
old, were injected intraperitoneally up to three times weekly
over a period of eight weeks. Three dose levels were em-
ployed with each test chemical, representing the maximum
C-60
-------
tolerated dose and a 1:2 and 1:5 dilution of the maximum
tolerated dose. Twenty animals were used at each dose level,
including negative (tricaprylin, saline) and positive (urethan)
controls. Mice were sacrificed 24 weeks after the first
injection and the frequency of lung tumors, i-n.each -.test
group was statistically compared with that in the vehicle-
treated controls using the Student t test.
The results obtained by Theiss, et al. (1977) are summar-
ized in Table 18. These data indicate that in no case were
all three criteria met, as indicated above, for the establish-
ment of a positive response. Nevertheless, it is clear
that bromoform produced a significant increase in tumor
response at the intermediate dose. In addition, dichloro-
methane at the low dose only, and bromodichloromethane at
the high dose only, produced results which were marginally
significant. Overall, the results of this study are sugges-
tive of carcinogenic activity but do not in themselves provide
an adequate basis for the development of a quantitative
health risk assessment for humans. Moreover, it has been
stated with regard to the strain A mouse lung tumor system
that, "positive compounds require extension to other systems,
such as lifetime exposure of rats" (Shimkin and Stoner,
1975).
Unfortunately, there are little additional data to
either confirm or deny the potential carcinogenicity of
most halomethanes. Poirier and coworkers (1975) used the
strain A mouse lung tumor system to show that lodomethane
was tumorigenic. They concluded that, "a high proportion
C-61
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TABLE 18
Pulmonary Tumor Response to Organic Water Contaminants
(Theiss, et al. 1977)
Compound Vehicle
Tricaprylin Ta
Bromoform T
Bromodichloromethane T
Dichloromethane T
Urethan S
0.9% NaCl solution S
Dose/
injection
(mg/kg)
4
48
100
20
40
100
160
400
800
1,000
No. of i.p.
injections
24
18
23
24
18
24
24
17
17
16
1
24
Total dose
(mg/kg)
72
1,100
2,400
360
960
2,400
2,720
6,800
12,800
1,000
No. of ani-
mals survi-
vors/initial
15/20
17/20
15/20
15/20
15/20
16/20 ,
13/20
i
18/20
5/20
12/20
20/20 *
47/50
No. of lung
tumors/mouse
0,27 + 0.15b
0.53 + 0.21
1.13 + 0.36
0.67 + 0.21
0.20 + 0.11
0.25 + 0.11
0.85 + 0.27
0.94 + 0.03
0.80 + 0.58
0.50 + 0.15
19.6 + 2.4
0.19 + 0.06
P
0.335
0.041C
0.136
0.724
0.930
0.067
0.053
0.417
0.295
Tricaprylin, S, 0.9% NaCl solution
""Average + S.E.
'p 0.05
-------
of low molecular weight alkyl halides may be carcinogenic."
Thus, pending bioassay results on chloromethane and bromo-
methane, it may be prudent to regard these two compounds
as suspected carcinogens, especially in light of their muta-
genic effects in the Ames assay. - ----- --—
The potential carcinogenicity of dichloromethane is
reportedly under study at the U.S. National Cancer Institute
(NCI) using rats and mice treated by gavage (Natl. Cancer
Inst., 1977). Dichloromethane has also been chosen by NCI
for further testing by inhalation in mice and rats, and
a study of bioactivation and covalent binding to macromolecules
in mice, rats, and hamsters is planned (Natl. Cancer Inst.,
1977, 1978).
Since the early 1960's a vast amount of work has been
conducted on the ability of various chemicals to induce
malignant transformation in cultured mammalian cells. Several
of these ir\ vitro techniques have been adopted as convenient
screening methods for the detection of potential carcinogens.
Among the halomethanes, however, only dichloromethane has
been investigated for cell transformation activity.
Price, et al. (1978) reported that Fischer rat embryo
cells (F1706) were transformed by dichloromethane at high
_•* —4
concentrations (1.6 x 10 JM and 1.6 x 10 M) in the growth
medium. In addition, transformed cells produced fibrosar-
comas when injected subcutaneously into newborn rats.
Further research by Sivak (1978) has indicated, however,
that the observed cell transforming capability of dichloro-
methane may have been due to impurities in the test material.
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Sivak (1978) reported that when the experiments of Price,
et al. (1978) were repeated using highly purified food grade
dichloromethane no transformation occurred. Additional
studies were conducted by Sivak (1978) in which food grade
dichloromethane was tested in the BALD/C-3.T3- mouse.cell
transformation assay system at three concentrations in the
growth medium. Although transformed foci were observed
at all dose levels, a dose-response relationship was not
revealed, nor were the number of foci increased relative
to historical results with untreated controls. Difficulty
in the interpretation of these results, however, arises
from the fact that dichloromethane (boiling point, 40°C)
was added to the growth medium and incubated at 37°C for
72 hours. Thus, the possibility exists that significant
losses of the test material due to volatilization from the
growth medium may have occurred.
The degree to which carcinogenic impurities may have
accounted for the biological activity attributed to dichloro-
methane in in vitro test systems is not known. This problem
may be particularly relevant to the halomethanes, since
high concentrations of test chemical must be employed for
expression of mutagenic/carcinogenic effects. It has been
established that misleading results can be obtained with
the Ames assay due to trace level contamination by carcino-
genic impurities (Donahue, et al. 1978), and a similar situ-
ation probably exists with mammalian cell transformation
assays. Sivak (1978) reported that impurities present in
food grade dichloromethane included: cyclohexane (305 ppm),
C-64
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transdichloroethylene (86 ppm), vinyldene chloride (33 ppm),
methyl bromide (11 ppm), chloroform «10 ppm), carbon tetra-
chloride (<5 ppm) and ethyl cnloride (3 ppm) . Therefore,
the results of sensitive assays in which technical grade
material is employed must be interpreted with the knowledge
that low level contamination may contribute to observed
biological effects.
Carcinogenicity data on the fluorocarbons are scant.
No human or animal data on carcinogenicity from exposure
to F-ll or F-12 were available. However, concern about
possible increased risk of cancer resulting indirectly from
the use of fluorocarbons has developed in recent years.
The possibility that increasing use and release of fluoro-
carbons to the atmosphere may contaminate the stratosphere
and cause depletion of protective, ultraviolet-absorptive
I
ozone has been recognized. The following adverse effects
from increased penetration of UV radiation to the biosphere
are suspected: (a) Increased incidence of skin cancer in
humans (estimated at 20 to 35 percent increase for 10 percent
ozone depletion); (b) altered animal cancer and disease
patterns; (c) reduced growth and productivity of plants;
(d) climatic changes and ecologic shifts (U.S. EPA, 1976).
A number of studies have sought to establish an associa-
tion between trihalomethane levels in municipal drinking
water supplies and the incidence of cancers in the U.S.
population (Natl. Acad. Sci., 1978). Several of these epi-
demiologic studies have shown positive correlations between
certain cancer death rates (various sites) and water quality
C-65
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indices, including water source, chlorination, and trihalo-
methanes (Cantor and McCabe, 1977, citing Cantor, et al.
1978 and Salg, 1977). Cantor, et al. (1978) have also repor-ed
positive associations between cancer mortality rates (several
sites) and brominated trihalomethanes (BTHM). BTHM is compri-
sed mostly of bromodichloromethane and chforodibromomethane,
but measurable levels of tribromomethane have been found
in some water supplies. The authors caution that these
studies have not been controlled for all confounding variables,
and the limited monitoring data that were available may
not have accurately reflected past exposures. Thus the
need was recognized for further studies which will utilize
exposure and disease information from individuals, rather
than from population aggregates. However, based upon the
epidemiologic evidence which is presently available, it
is felt that sufficient justification exists for maintaining
a hypothesis that observed positive correlations between
drinking water quality and cancer mortality may be attri-
butable to the presence of trihalomethanes (U.S. EPA, 1978a).
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CRITERION FORMULATION
Existing Guidelines and Standards
Chloromethane
1. Warning label required by Federal_ Insecticide,
Fungicide and Rodenticide Act (FIFRA). Interpretation with
respect to warning, caution, and antidote statements requirec
to appear on labels of economic poisons. 27 FR 2267.
2. Food tolerance requirement of Federal Food, Drug
and Cosmetic Act: chloromethane is permitted as propellant
in pesticide fomulations up to 30 percent of finished formu-
lation when used in food storage/processing areas not con-
tacting fatty foods. 27 FR 4623.
3. Human exposure: (1) A maximum permissible concen-
tration (MFC) of 5 mg/m in industrial plant atmospheres
was established in Russia based on rat studies of chronic
poisoning (Evtushenko, 1966); (2) OSHA (1976) has established
the maximum acceptable time-weighted average air concent-
ration for daily eight-hour occupational exposure at 210
mg/m with ceiling and peak (five minutes during (or in)
any three hours) concentration values of 413 and 620 mg/m ,
respectively.
4. Other: (1) Chlorinated hydrocarbons are under
consideration for addition to the list of compounds for
Toxic Effluent Standards (U.S. EPA Water Program Proposed
Toxic Pollutant Effluent Standards. 40 CFR Part 129.(2)
Listed on EPA Consent Decree Priority II list.
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5. Multimedia Environmental Goals, (MEG) Estimated
Permissible Concentrations (EPC) (U.S. EPA, 1977):
EPC, air, health: 0.5 mg/m
EPC, water, health (1): 7.5 mg/1
EPC, water, health (2): - - -2.9-mg/i
EPC, land, health: 5.8 mg/kg
Bromomethane
1. A warning and antidote labeling required by PIFRA.
Interpretation with respect to warning, caution, and antidote
statements required to appear on labels of economic poisons.
27 FR 2267.
2. Food tolerance limits required under Federal Food,
Drug and Cosmetic Act Tolerances for residues of inorganic
bromides resulting from fumigation with methyl bromide.
22 FR 5682 and subsequent regulations set inorganic bromide
residue concentration limits for many food commodities at
levels ranging from 20 to 400 mg/kg.
3. Human Exposure: (1) Occupational exposure during
eight-hour work day limited to 78 mg/m by the Texas State
Department of Health; also regulated are use periods for
respirators (Tex. State Dep. Health, 1957); (2) OSHA (1976)
has established the eight-hour air concentration ceiling
for occupational exposure at 80 mg/m3, with an added warning
of skin exposure hazard; (3) The (American National Standards
Institute) has set a standard of 58 mg/m time-weighted
average air concentration for an eight-hour day, with inter-
locking period ceilings of 97 mg/m , and 194 mg/m (five
minutes) (Am. Natl. Stand. Inst., 1970); (4) The industrial
C-68
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TLV (threshold limit value) of 78 mg/m to prevent neurotoxic
and pulmonary effects was established by the American Con-
ference of Governmental Industrial Hygienist (Stokinger,
et al. 1963; Am. Conf. Gov. Ind. Hy., 1971).
Dichloromethane
1. As an oil and fat solvent, dichloromethane is allow-
ed in spice oleoresins at up to 30 mg/kg and in decaffeinated
coffee at up to 10 mg/kg (21 CFR 121.1039, cited by Natl.
Inst. Occup. Safety Health, 1976a).
2. Human exposure: (1) OSHA (1976) has established
occupational exposure standards as follows: eight-hour
time weighted average (TWA), 1,737 mg/m ; acceptable ceiling
concentration, 3,474 mg/m ; and acceptable maximum peak
above ceiling, 6,948 mg/m (five minutes in any three hours).
(2) However, in recognition of metabolic formation of COHb
and additive toxicity with CO, NIOSH (1976a) has recommended
a ten-hour workday TWA exposure limit of 75 ppm (261 mg/m )
in the presence of no more CO than 9.9 mg/m TWA and a 1,737
mg/m peak (15 min. sampling); in the case of higher CO
levels, lower levels of dichloromethane are required; (3)
Permissible exposure levels in several other countries range
from 49 up to 1,737 mg/m (maximum allowable concentration)
or 2,456 mg/m (peak) (discussed in Natl. Inst. Occup. Safety
Health, 1976a); (4) The maximum permissable concentration
for dichloromethane in water in the U.S.S.R. is 7.5 mg/1;
this is intended to be proportionately reduced in the presence
of other limited compounds (Stofen, 1973).
C-69
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3. MEG values for Estimated Permissible Concentrations
(U.S. EPA, 1977):
EPC, air, health: 0.619 mg/m3
EPC, water, health (1) 9.18 mg/1
EPC, water, health (2) 3.59 mg/1
EPC, land, health: 7.2 mg/kg
Tr ibromomethane
Human exposure: (1) The OSHA Occupational Exposure
Standard for workroom air (eight-hour TWA) is 5 mg/m , with
a dermal absorption warning notation (Occup. Safety Health
Admin., 1976); (2) Tribromomethane is one of four trihalo-
methanes comprising the group "total trihalomethanes" (TTHM)
for which the U.S. EPA has proposed to regulate a maximum
contaminant level in drinking water (0.100 mg/1).
Bromodichloromethane
Human exposure: (1) There is no currently established
occupational exposure standard for bromodichloromethane
in the U.S. (2) Bromodichloromethane, along with chlorodibro-
momethane, trichloromethane (chloroform) and tribromomethane
form the group of halomethanes termed total trihalomethanes
(TTHM), which are to be regulated in finished drinking water
in the U.S. The maximum permissible concentration set for
TTHM in the proposed regulations is 0.100 mg/1.
Tnchlorofluoromethane and Dichlorodifluoromethane
Food use: FDA regulations permit use of dichlorodifluoro-
methane (F-12) as a direct contact freezing agent for food,
and specify labeling and instructions for use. Food and
Drug Administration. Dichlorodifluoromethane. 32 FR 6739.
C-70
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Human exposure: (1) The current OSHA eight-hour TWA
occupational standards for F-ll and F-12 are 5,600 and 4,950
mg/m , respectively (Occup. Safety Health Admin., 1976).
(2) Underwriters Laboratories classify F-ll and F-12 in
groups 5 and 6, respectively (see Effects section).
Other: (1) F-ll, F-12, and several other fluorocarbons
have been exempted from regulation under the Texas Clean
Air Act (Howard, et al. 1974); (2) The U.S. EPA can control
fluorocarbon uses in pesticide applications and has requested
formulators to seek suitable alternative propellants for
products dispensed as aerosols, in view of the ozone deple-
tion concern; (3) Pressurized containers must meet ICC regula-
tions for compressed gases to be shipped (Howard, et al.
1974, citing DuPont, 1973).
Standard for regulation of trihalomethanes: The U.S.
EPA has considered the available health and exposure data
for trihalomethanes as a group, determined that they repre-
sent a potential yet reducible hazard to public health,
and proposed regulations establishing a maximum contaminant
level (MCL) of 0.100 mg/1 for total trihalomethanes (TTHM)
in finished drinking water of cities greater than 75,000
(served population) employing added disinfectants (U.S.
EPA, 1978a).A detailed discussion of the background (ration-
ale, extrapolation models, and interpretations used) for
this standard is beyond the scope of this document.
Special Groups at Risk
Perhaps the greatest concern for special risk consider-
ations among the halomethanes is that for dichloromethane.
C-71
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In this case, the added threat is for those such as smokers
or workers in whom significant COHb levels exist, or those
with pre-existing heart disease, for whom COHb formation
by dichloromethane metabolism would present an added stress
or precipitate an episode from disturbed oxygen-tran-sport.
NIOSH, recognizing this combined stress hazard, has recom-
mended lowering the existing TLV for dichloromethane and
tying it with existing CO exposure levels.
A second possible special risk concerns exposures to
fluorocarbon vapors. In this case there is evidence that
a characteristic toxicity involves sensitization to cardio-
arrhythmogenic effects of endogenous or administered epineph-
rine and related catecholamines. An individual with cardiac
disease taking certain medication or in an acutely stressed
state may be especially susceptible to fluorocarbon cardio-
toxicity.
Basis and Derivation of Criterion
Data on current levels of the halomethanes in water,
food, and ambient air are not sufficient to permit adequate
estimates of total human exposures from these media. Available
data discussed in an earlier section of this report (Occurrence)
indicate that the greatest human exposure to the trihalo-
methanes occurs through the consumption of liquids (including
drinking water and beverages containing it), and that exposure
to chlorofluorocarbons, chloromethane, dichloromethane,and
bromomethane occurs primarily by inhalation.
Observed correlations among concentrations of trihalo-
methanes in finished water are attributed to the presence
C-72
-------
of common organic precursor materials in raw water (Natl.
Acad. Sci., 1978). Among the halomethanes considered in
this report, bromodichloromethane seems to predominate in
drinking waters. Concentrations of bromodichloromethane
in raw and finished water samples are generally in the area
of 6 iig/1 or less, and thus represent a reasonable upper
limit for anticipated levels of any halomethane in water
(excluding chloroform and carbon tetrachloride).
Recent reports showing that chloromethane, bromomethane,
tribromomethane, dichloromethane, and bromodichloromethane
exhibit carcinogenic and/or mutagenic effects in certain
bioassay systems suggests the need for conservatism in the
development of water quality criteria for the protection
of human health. Since the presently available carcinogen-
icity data base for these compounds is judged qualitatively
informative but quantitatively inadequate for risk extrapol-
ation, an alternative approach is necessary for criteria
development.
At present levels in relatively unpolluted raw and
finished waters ( 10 jig/1) / the halomethanes pose little
threat for the production of non-carcinogenic toxic effects
in humans. However, the possibility of carcinogenic effects
must be evaluated in light of current and past exposures
to halomethanes via water supplies. Limited epidemiologic
studies have failed to show a clear association between
cancer mortality and bromine-containing trihalomethanes
at levels in water of about 5-10 ug/1. Since the possible
association between human cancers and halomethanes cannot
C-73
-------
presently be disproven, it would be wise to limit their presence in water
to no more than the median levels which are currently encountered (pendinq
better human risk data). Thus, a maximum level of 6 uq/J in raw and finished
waters could be considered as acceptable for bromethane, chloromethane,
dichloromethane, tribromomethane, and bromodichloromethane. From the limited
animal bioassay data which are available in the strain A mouse lung tumor
system, a daily human intake of halomethanes at 12 ug/day (6 ug/1 x 2 I/day)
represents a dose which is about 100,000-fold less than the minimun daily
dose of tribromomethane which caused a significant increase in tumor formation
in mice if dose comparisons for the two species are made on a per kilogram
body weight basis. Since there exists considerable uncertainty over the
human carcinogenic risks of halomethanes, a safety factor of 100,000 seems
prudent for the development of an interim standard for all halomethanes
pending the results of further research.
The 6 ug/1 maximum acceptable concentration for brontomethane, chloro-
methane, tribromomethane, dichloromethane, and bromodichloromethane does not
take into consideration the contribution to total exposure from air and food.
Exposure via these media cannot be accurately predicted, although it is likely
that it is sufficient large for chloromethane, dichloromethane, and broroome-
thane to warrant the recommendation of a water quality criterion below 6 ug/1.
Present levels of these three compounds are generally much less than 6 ua/1
and it is not likely that current anthropogenic sources would significantly
increase their level in water.
C-74
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For criteria-setting purposes it is recommended that
a criterion of 2 ug/1 be adopted for branomethane, chloro-
metbane, dichloromethane, tribromomethane, and bromodichloro-
methane, based upon analogy to the structure and biological
activity of chloroform. Despite the presently inadequate
data base for most of these compounds, it can nevertheless
be predicted that similar biological effects, including
neoplastic transformation, may be encountered. Since the
recommended criterion for chloroform was derived from reli -
able experimental data, it represents the most applicable
value for all of the halomethanes which are suspected carcino-
gens.
Evidence for mutagenicity of dichlorodifluoromethane
is equivocal and there is no evidence as yet for carcino-
genicity as a result of direct exposure. Chronic toxicity
data for dichlorodifluoromethane is quite limited. In the
only long-term (two years) feeding study reported (U.S.
EPA, 1976, citing Sherman, 1974) the maximum dose level
producing no observed adverse effect (in dogs) was 80 mg/kg/day,
Applying an uncertainty factor of 1000 (Natl. Acad. Sci.,
1977) to this data yields a presumptive "acceptable daily
intake" of 0.08 mg/kg/day. For a man weighing 70 kg, consuming
two liters of water per day and absorbing at 100 percent
efficiency, and assuming that the water is the sole source
of exposure, this acceptable intake level translates into
a criterion level as follows: (0.08) (70)/2 = 2.8 mg/1.
C-75
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There is no evidence for mutagenicity of trichlorofluoro-
methane, and no evidence as yet for carcinogenic!ty as a
result of direct exposure. The only data on toxicity testing
using prolonged exposure at relatively low test concentra-
tions is from a report (Jenkins, et al. 1970) which showed
no observed adverse effects in rats and guinea pigs exposed
continuously by inhalation for 90 days at 5,610 mg/m .
If the reference man weighing 70 kg breathed this atmosphere
and absorbed the compound at 50 percent efficiency, h:s
estimated exposure dose would be 5,610 x 23 x 0.5 = 64,515
ing/day or 922 mg/kg/day. Applying an uncertainty factor
of 1,000 (Natl. Acad. Sci., 1977) to this data yields a
presumptive "acceptable daily intake" of 0.922 mg/kg/day
for trichlorofluoromethane. Assuming man's weight to be
70 kg and his absorption of ingested compound to be 100
percent efficient, and that his sole source of exposure
is water consumed at two liters/day, the acceptable intake
is translated into a criterion level as follows: (0.922)
(70)/2 = 32.3 mg/1.
Criterion levels intended to protect the public against
unacceptable risk of toxicity, mutagenicity, or carcinogeni-
city from exposure to selected halomethanes in water for
consumption, derived as described in the foregoing text,
are summarized as follows (rounded off):
C-76
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Compound (mg/1)
Bromodichloromethane 2 x 10
Tribromomethane 2 x 10
Dichloromethane _ 2 x _10~_
Bromomethane 2 x 10
Chloromethane 2 x 10~
Dichlorodifluoromethane 3
Trichlorofluoromethane 32
Adoption of the presently recommended criterion ror
chloroform (2 fig/1) as the recommended level for other pos
sibly carcinogenic halomethanes should provide an adequate
margin of safety in the absence of sufficient data foi quanti-
tative risk assessment. This criterion is intended to reduce
carcinogenic risks to the public, and takes into account
the fact that exposure to halomethanes also occurs through
foods and via inhalation. Although the potential carcinogen-
•
icity of bromodichloromethane, tribromomethane, dichloro-
methane, bromomethane, and chloromethane cannot be adequately
assessed at present, the adoption of an interim water quality
standard in excess of 2 /jg/1 may be interpreted as approval
to discharge larger quantities of these substances than
of chloroform. Such a practice is clearly unwarranted until
such time that concerns over possible carcinogenic activity
have been resolved.
C-77
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APPENDIX I
Summary and Conclusions Regarding
the Carcinogenicity of Halomethanes*
The halomethanes addressed in this report afe-b~romomethane,
chloromethane, dichloromethane, tribromomethane, bromodich]oro-
methane, dichlorodifluoromethane, and trichlorofluoromethare.
Chloroform, which is also a trihalomethane, is discussed
in another document.
Positive associations between cancer mortality rctes
in humans and trihalomethanes in drinking water have teen
reported. In addition to chloroform, these trihalomethanes
consisted primarily of bromodichloromethane, chlorodibromo-
methane, and also barely measurable levels of tribromomethane.
There have been positive results for tribromomethane using
strain A/St. male mice in the pulmonary adenoma bioassay.
Bromomethane, chloromethane, dichloromethane, bromodichloro-
methane, and tribromomethane have been reported as mutagenic
in the Ames1 test without metabolic activation. Dichloroci-
fluoromethane caused a significant increase in mutant frequency
in Neurospora crassa (mold), but was negative in the Ames'
test. No data implicating trichlorofluoromethane as a possible
carcinogen have been published.
Because positive results for the mutagenic endpoint
correlate with positive results in ir\ vivo bioassay for
oncogenicity, mutagenic data for the halomethanes suggests
that several of the compounds might be carcinogenic. Carcino-
C-78
-------
genicity data currently available for the halomethanes are
not adequate for the development of water criteria levels.
We suggest that the criteria level be the same as that: for
chloroform (2 ug/1).
*This summary has been prepared and approved by the Carcinogens
Assessment Group, EPA, June, 1979.
C-79
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14
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