vvEPA
United States
Environmental Protection
Agency
Office of Water
Regulations anJ Standards
Criteria and Standards Division
Washington DC 2046C
440 5-80 051
October 1980
Ambient
Water Quality
Criteria for
Halomethanes
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AMBIENT WATER QUALITY CRITERIA FOR
HALOMETHANES
Prepared By
U.S. ENVIRONMENTAL PROTECTION AGENCY
Office of Water Regulations and Standards
Criteria and Standards Division
Washington, D.C.
Office of Research and Development
Environmental Criteria and Assessment Office
Cincinnati, Ohio
Carcinogen Assessment Group
Washington, D.C.
Environmental Research Laboratories
Corvalis, Oregon
Duluth, Minnesota
Gulf Breeze, Florida
Narragansett, Rhode Island
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DISCLAIMER
This report has been reviewed by the Environmental Criteria and
Assessment Office, U.S. Environmental Protection Agency, and approved
for publication. Mention of trade names or commercial products does not
constitute endorsement or recommendation for use.
AVAILABILITY NOTICE
This document is available to the public through the National
Technical Information Service, (NTIS), Springfield, Virginia 22161.
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FOREUORD
Section 304 (a)(l) of the Clean Water Act of 1977 (P.L. 95-217),
requires the Administrator of the Environmental Protection Agency to
publish criteria for water quality accurately reflecting the latest
scientific knowledge on the kind and extent of all identifiable effects
on health and welfare which may be expected from the presence of
pollutants in any body of water, including ground water. Proposed water
quality criteria for the 65 toxic pollutants listed under section 307
(a)(l) of the Clean Water Act were developed and a notice of their
availability was published for public comment on March 15, 1979 (44 FR
15926), July 25, 1979 (44 FR 43660), and October 1, 1979 (44 FR 56628).
This document is a revision of those proposed criteria based upon a
consideration of comments received from other Federal Agencies, State
agencies, special interest groups, and individual scientists. The
criteria contained in this document replace any previously published EPA
criteria for the 65 pollutants. This criterion document is also
published in satisifaction of paragraph 11 of the Settlement Agreement
in Natural Resources Defense Council, et. al. vs. Train, 8 ERC 2120
(D.D.C. 1976J, modified, 12 ERC 1833 (D.D.C. 1979).
The term "water quality criteria" is used in two sections of the
Clean Water Act, section 304 (a}(l) and section 303 (c)(2). The term has
'a different program impact in each section. In section 304, the term
represents a non-regulatory, scientific assessment of ecological ef-
fects. The criteria presented in this publication are such scientific
assessments. Such water quality criteria associated with specific
stream uses when adopted as State water quality standards under section
303 become enforceable maximum acceptable levels of a pollutant in
ambient waters. The water quality criteria adopted in the State water
quality standards could have the same numerical limits as the criteria
developed under section 304. However, in many situations States may want
to adjust water quality criteria developed under section 304 to reflect
local environmental conditions and human exposure patterns before
incorporation into water quality standards. It is not until their
adoption as part of the State water quality standards that the criteria
become regulatory.
Guidelines to assist the States in the modification of criteria
presented in this document, in the development of water quality
standards, and in other water-related programs of this Agency, are being
developed by EPA.
STEVEN SCHATZOW
Deputy Assistant Administrator
Office of Water Regulations and Standards
111
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ACKNOWLEDGEMENTS
Aquatic Life Toxicology:
William A. Brungs, ERL-Narragansett John H. Gentile, ERL-Narragansett
U.S. Environmental Protection Agency U.S. Environmental Protection Agency
Mammalian Toxicology and Human Health Effects:
Joseph Santodonato Julian Andelman
Syracuse Research Corporation University of Pittsburgh
Michael Dourson (doc. mgr.) ECAQ-Cin Jacqueline V. Carr
U.S. Environmental Protection Agency U.S. Environmental Protection Agency
Jerry F. Stara (doc. mgr.) ECAO-Cin Patrick Durkin
U.S. Environmental Protection Agency Syracuse Research Corporation
Terri Laird, ECAO-Cin Si Duk Lee, ECAO-Cin
U.S. Environmental Protection Agency U.S. Environmental Protection Agency
Steven D. Lutkenhoff, ECAO-Cin Yin-Tak Woo
U.S. Environmental Protection Agency
Sorrel! Schwartz Roy E. Albert*
Georgetown University Carcinogen Assessment Group
U.S. Environmental Protection Agency
Technical Support Services Staff: D.J. Reisman, M.A. Garlough, B.L. Zwayer,
P.A. Daunt, K.S. Edwards, T.A. Scandura, A.T. Pressley, C.A."Cooper,
M.M. Denessen.
Clerical Staff: C.A. Haynes, S.J. Faehr, L.A. Wade, D. Jones, B.J. Bordicks,
B.J. Quesnell., T. Highland, B. Gardiner.
*CAG Participating Members:
Elizabeth L. Anderson, Larry Anderson, Dolph Arnicar, Steven Bayard,
David L. Bayliss, Chao W. Chen, John R. Fowls III, Bernard Haberman,
Charalingayya Hiremath, Chang S. Lao, Robert McGaughy, Jeffrey Rosen-
blatt, Dharm V. Singh, and Todd W. Thorslund.
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TABLE OF CONTENTS
Criteria Summary
Introduction A-l
Aquatic Life Toxicology B-l
Introduction 8-1
Effects B-l
Acute Toxicity 8-1
Chronic Toxicity 8-2
Plant Effects B-3
Residues B-3
Summary B-3
Criteria B-4
References B-9
Mammalian Toxicology and Human Health Effects C-l
Introduction C-l
Exposure C-3
Ingestion from Water C-3
Ingestion from Food C-9
Inhalation C-13
Dermal C-20
Pharmacokinetics C-21
Absorption, Distribution, Metabolism and Excretion C-21
Effects C-28
Acute, Subacute, and Chronic Toxicity C-28
Synergism and/or Antagonism C-56
Teratogenicity C-56
Mutagenicity C-57
Carcinogenicity C-59
Criterion Formulation C-66
Existing Guidelines and Standards C-66
Special Groups at Risk C-70
Basis and Derivation of Criteria C-71
References C-79
Appendix C-110
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CRITERIA DOCUMENT
HALOMETHANES
CRITERIA
Aquatic Life
The available data for halomethanes indicate that acute tox-
icity to freshwater aquatic life occurs at concentrations as low as
11,000 ug/1 and would occur at lower concentrations among species
that are more sensitive than those tested. No data are available
concerning the chronic toxicity of halomethanes to sensitive fresh-
water aquatic life.
The available data for halomethanes indicate that acute and
chronic toxicity to saltwater aquatic life occur at concentrations
as low as 12,000 and 6,400 ug/1, respectively, and would occur at
lower concentrations among species that are more sensitive than
those tested. A decrease in algal cell numbers occurs at concen-
trations as low as 11,500 yg/1.
Human Health
For the maximum protection of human health from the potential
carcinogenic effects due to exposure of chloromethane, bromo-
methane, dichloromethane, bromodichloromethane, tribromomethane,
dichlorodifluoromethane, trichlorofluoromethane, or combinations of
these chemicals through ingestion of contaminated water and contam-
inated aquatic organisms, the ambient water concentration should be
zero based on the non-threshold assumption for this chemical. How-
ever, zero level may not be attainable at the present time. There-
fore, the levels which may result in incremental increase of cancer
vi
-------
risk over the lifetime are estimated at 10~ , 10~ and 10" . The
corresponding recommended criteria are 1.9 ,ug/l, 0.19 ,ug/l, and
0.019 ^ig/1, respectively. If the above estimates are made for con-
sumption of aquatic organisms only, excluding consumption of water,
the levels are 157 ug/1, 15.7 jug/1, and 1.57 jug/1, respectively.
VII
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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, bromo-
dichloromethane, trichlorofluoromethane, and dichlorodifluoro-
methane.
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 methylat-
ing agent, a dewaxing agent, and catalytic solvent in synthetic
rubber production (MacDonald, 1964). Methyl bromide has been re-
(B\
ferred to as bromomethane, monobromomethane, and Embaf ume vsy
(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 pro-
duced in the United States with an additional 19,128 metric tons
(42,177,000 Ibs) imported (U.S. EPA, 1977a).
Trichlorofluoromethane is also known as trichloromonofluoro-
(9\ /S}
methane, fluorotr ichloromethane, Frigen 11 ^ Freon 11^, and
A-l
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Arcton 9 . Dichlorodifluoromethane has been referred to as di-
Mfl (Tfl TJ
fluorodichloromethane, Freon 12 , Frigen 12 **, Arcton 6 ,
Genetron 12 , Halon ®, and Isotron 2 . Freon compounds are or-
ganic 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 com-
pounds 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). Bromodichloromethane is
used as a reagent in research (National Academy of Sciences (NAS),
1978).
The physical characteristics of the halomethanes are listed in
Table 1. Monohalomethanes can be hydrolyzed slowly in neutral
waters forming methanol and hydrogen halides. The rate of hydroly-
sis 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 reac-
tion occurs as fast as the exchange of iodomethane into the atmos-
phere (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 a flame
(Stenger and Atchison, 1964). Chloromethane in contact with a
flame will burn, producing C02 and HC1 (Hardie, 1964). Mono-
halomethanes undergo photolysis in the upper atmosphere where
A-2
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TABLE 1
Physical Characteristics of llalomethanes
Molecular
Compound weight
chloromethane 50.49
hromome thane 94.94
J ichloromethane 84.93
tr ichloiof luoro- 137.37
methane
dichlorodif luoro- 120.91
methane
tr ibf omomethane 252.75
btomod ichloro- 163.83
methane
Physical state mp. a bp. a Specific Vapor Solubility
under ambient ,0,,. .oc gravity pressure in water
conditions (mm tig) (ug/1)
colorless gas -97.73 -24.2 0. 973 (-10°C)b 5.38xl06
colorless gas -93.6 3.56 1. 737 (-lO°C)b IxlO6
colorless liquid -95.1 40 1.327(20°C)a 362.4(20°C)C 13.2xl06 °
<25°C)
colorless liquid -11) 23.82 1.467(25°C)a 667.4(20°C)C l.lxlO6 °
(20°C)
colorless gas -158 -29.79 i. 75<-ll5°C)a 4(306(20°C)C 2.8.105 C
(25°C)
colorless liquid 8.3 149.5 2.890(20°C)a slightly
sol.3
colorless liquid -57.1 90 1.980{20°C) insoluble*
Solubility
in organic
solvents
alcohol, ether
acetone, benzene,
chloroform,
acetic acid
alcohol, etber,
acetic acid
alcohol, ether3
alcohol, ether
alcohol, ethera
alcohol, ether,
benzene, chloro-
form, ligroin
alcohol, ether,
acetone, benzene,
chloroform
a) Weast, 1972
b) U.S. EPA, I977b
c) Pearson and McConnell, 1975
(1) VJindholz, 1976
A-3
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ultraviolet radiation is of sufficient energy to initiate a reac-
tion (Basak, 1973).
Prolonged heating of dichloromethane with water at 180°C re-
sults 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
tribroraomethane is accelerated by air and light (Windholz, 1976).
Methylene chloride is a major halogenated pollutant with a
large potential for delivery of chlorine to the stratosphere. 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 photo-
lyzed to yield chlorine atoms in the ozone-rich region of the
stratosphere. It thus appears that there is some potential for
ozone destruction by methylene chloride since the generated chlor-
ine atoms will attack ozone (U.S. EPA, 1975b).
Similarly, fully halogenated substances such as trichloro-
fluoromethane and dichlorodifluoromethane migrate to the strato-
sphere where they are photodissociated, adversely affecting the
ozone balance (U.S. EPA, 1975b).
There are few data in the literature relating to the environ-
mental fate or degradation of bromodichloromethane and tribromo-
methane.
A-4
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REFERENCES
Balmer, M.F., et al. 1976. Effects in the liver of methylene
chloride inhaled alone and with ethyl alcohol. Am. Ind. Hyg.
Assoc. Jour. 37: 345.
Basak, A.K. 1973. The photolytic decomposition of methyl chlo-
ride. Jour. Ind. Chem. Soc. 50: 767.
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.
Hardie, D.W.F. 1964. Methyl chloride. Kirk-Othmer Encyclopedia
of Chemical Technology. 2nd ed. Interscience Publishers, New York.
Kantarjian, A.D. and A.S. Shaheen. 1963. Methyl bromide poison-
ing with nervous system manifestations resembling polyneuropathy.
Neurology. 13: 1054.
MacDonald, J.D.C. 1964. Methyl chloride intoxication. Jour.
Occup. Med. 6: 81.
National Academy of Sciences. 1978. Nonfluorinated halomethanes
in the environment. Washington, D.C.
A-5
-------
Pearson, C.R. and G. McConnell. 1975. Chlorinated Cl and C2
hydrocarbons in the marine environment. Proc. R. Soc. London B.
189: 305.
Stenger, V.A. and G.J. Atchison. 1964. Methyl bromide. Kirk-
Othmer Encyclopedia of Chemical Technology. 2nd ed, Interscience
Publishers, New York.
U.S. EPA. 1975a. Initial scientific and minieconomic review of
folpet. Draft. Rep. Off. Pestic. Prog. Washington, D.C.
U.S. EPA. 1975b. Report on the problem of halogenated air pollu-
tants 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 environmen-
tal contaminants. Monohalomethanes. EPA 560/2-77-007. Washing-
ton, D.C.
Van Auken, et al. 1975. Comparison of the effects of three fluoro-
carbons on certain bacteria. Can. Jour. Microbiol. 21: 221.
Weast, R.C., (ed.) 1972. Handbook of Chemistry and Physics. CRC
Press, Cleveland, Ohio.
A-6
-------
Windholz, M., (ed.) 1976. The Merck Index. Merck and Co., Rahway,
New Jersey.
Zafiriou, O.C. 1975. Reaction of methyl halides with seawater and
marine aerosols. Jour. Mar. Res. 33: 75.
A-7
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Aquatic Life Toxicology*
INTRODUCTION
Although the aouatic toxicity data base for halomethanes is limited, it
allows some generalizations concerning trends within the class. Data on
chloroform and carbon tetrachloride are included for discussion and are also
treated in separate criterion documents. Methylene chloride, methyl chlo-
ride, bromoform, and methyl bromide are the only other halomethanes for
which appropriate data are available.
EFFECTS
Acute Toxicity
The 48-hour EC5Q values for Daphnia magna are 224,000, 28,900, and
35,200 ug/1 for methylene chloride (Table 1), chloroform, and carbon te-
trachloride, 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 dif erence in
sensitivity between Daphnia magna and the bluegill. The LC-. and EC™
values for each species are both 224,000 ug/1 for methylene chloride and
29,300 and 46,500 ug/1, respectively, for bromoform.
Apparently, the brominated compounds are more toxic to fishes than the
chlorinated analogs (Table 1). The 96-hour LCcn values for bluegill are
11,000 and 550,000 ug/1 for methyl bromide and methyl chloride,
respectively, under static test conditions (Dawson, et al. 1977). For bro-
*ThereaderTsreferred to the Guidelines for Deriving Water Quality
Criteria for the Protection of Aauatic Life and Its Uses in order to better
understand the following discussion and recommendation. The following
tables contain the appropriate data that were found in the literature, and
at the bottom of each table are calculations for deriving various measures
of toxicity as described in the Guidelines.
8-1
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moform and chloroform the 96-hour |_C5Q values are 29,300 ug/1 (U.S. EPA,
1978) and 115,000 ug/1 to 100,000 ug/1, respectively. The data from acute
static tests with bluegill show a correlation between increasing chlorina-
tion and toxicity. The 96-hour LC5Q values are 550,000 ug/1 (Dawson, et
a!. 1977) for methyl chloride, 224,000 ug/1 for methylene chloride (U.S.
EPA, 1978), 100,000 to 115,000 ug/1 for chloroform, and 125,000 ug/1
(Oawson, et al. 1977) and 27,300 ug/1 (U.S. EPA, 1978) for carbon tetrachlo-
ride. Alexander, et al. (1978) compared the effect of test procedures 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 wg/l
(Table 1).
The mysid shrimp has been tested with bromoform and methylene chloride
(U.S. EPA, 1978) and the 96-hour LC5Q values are 24,400 and 256,000 ug/l,
respectively (Table 1).
Apparently, the brominated compounds are more toxic to fishes than the
chlorinated analogs, as is true for the freshwater fish (Table 1). The
96-hour LC50 values for the tidewater silverside (Oawson, et al. 1977)
and methyl bromide and methyl chloride are 12,000 and 270,000 ug/1, re-
spectively.
Chronic Toxicity
No life cycle or embryo-larval tests have been conducted with freshwater
organisms and any halomethane other than chloroform and carbon tetrachlo-
ride. 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/'»
and no adverse effects of carbon tetrachloride on the fathead minnow were
observed at the highest test concentration of 3,400 ug/1. Details of these
B-2
-------
tests may be found in the criterion documents for those chemicals.
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
6,400 ug/1 (Table 2). This result and the 96-hour LC5Q (Table 1) provide
an acute-chronic ratio of 2.8 which indicates that the differences between
acute lethality and other chronic effects is small.
Plant Effects
The 96-hour EC™ values for bromoform (Table 3), based on chlorophyll
£ and cell numbers of the freshwater alga, Selenastrum capricornutum, are
112,000 and 116,000 ug/1, respectively. The same tests with methylene chlo-
ride showed the EC™ values were above the highest test concentration,
662,000 ug/1 (U.S. EPA, 1978).
The 96-hour EC^Q values for bromoform (Table 3), based on chlorophyll
a_ and cell numbers of the saltwater alga, Skeletonema costatum, are 12,300
and 11,500 ug/1, respectively. The same tests with methylene chloride
showed the EC™ values were above the highest test concentration, 662,000
ug/1 (U.S. EPA, 1978).
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.
Summary
Among the halomethanes tested with freshwater organisms, toxicity varied
widely with, in general, an increase in toxicity with degree of chlorina-
tion. Where comparable data exist, the brominated compounds were more
B-3
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toxic than the chlorinated analogs. The cladoceran, Daphnia magna, was
about as sensitive as the tested fish species. Overall, the LCcr, and
EC5Q values for these species and the various tested halofonns ranged from
11,000 to 550,000 ug/l. No data are available to estimate chronic tox-
icity. The 96-hour EC™ values for the alga, Selenastrum capricornutum,
for bromoform and methylene chloride ranged from 112,000 to greater than
662,000 ug/l.
The brominated compounds were more toxic to the three tested saltwater
species than the chlorinated analogs. The mysid shrimp was similarly sen-
sitive to the sheepshead minnow to bromoform and methylene chloride with the
LC50 and £C50 values in the range of 17,900 to 331,000 ug/l. When the
acute and chronic test results for the sheepshead minnow and bromoform are
compared, the numerical relationship is 2.8. The highest observed no-effect
level was 4,800 ug/l and the 96-hour LC5Q value was 17,900 ug/l. The
96-hour EC-0 values for the alga, Skeletonema costatum for bromoform and
methylene chloride ranged from 11,500 to greater than 662,000 ug/l.
CRITERIA
The available data for halomethanes indicate that acute toxicity to
freshwater aquatic life occurs at concentrations as low as 11,000 ug/l and
would occur at lower concentrations among species that are more sensitive
than those tested. No data are available concerning the chronic toxicity of
halomethanes to sensitive freshwater aquatic life.
The available data for halomethanes indicate that acute and chronic
toxicity to saltwater aquatic life occur at concentrations as low as 12,000
and 6,400 ug/l, respectively, and would occur at lower concentrations among
species that are more sensitive than those tested. A decrease in algal cell
numbers occurs at concentrations as low as 11,500 ug/l.
B-4
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Table 1. Acute values for halowethanes
Species Method*
Chemical
LC50/EC50
Species Acute
Value (ug/l) Reference
FRESHWATER SPECIES
Cladoceran, S, U
Daphnla magno
C ladoceran, S, U
Daphnla maqna
Fathead minnow, FT, M
Plmephales promelas
Fathead minnow, S, U
Plmephales promelas
Blueglll, S, U
Lepomls macrochlrus
Blueglll, S, U
Lepomls macrochlrus
Blueglll, S, U
Lepomis macrochlrus
Bluegl II, S, U
Lepomis macrochlrus
Mysld shrimp, S, U
Mysidopsls bah la
Mysld shrimp, S, U
Mysidopsls bah la
Sheepshead minnow, S, U
Cyprlnodon varlegatus
Sheepshead minnow, S, U
Cyprlnodon varlegatus
bromoform
methyl ene
chloride
methy lene
ch lorlde
methy lene
chloride
bromoform
methy lene
chloride
methy 1
ch lorlde
methy 1
bromide
SALTWATER
bromoform
methy lene
ch lorlde
bromoform
methy lene
chloride
46,500
224,000
193,000
310,000
29,300
224,000
550,000
11,000
SPECIES
24,400
256,000
17,900
331,000
46,500 U.S. EPA, 1978
224,000 U.S. EPA, 1978
Alexander, ef al. 1978
193,000 Alexander, et al. 1978
29,300 U.S. EPA, 1978
224,000 U.S. EPA. 1978
550,000 Dawson, et al. 1977
11,000 Dawson, et al. 1977
24.400 U.S. EPA, 1978
256,000 U.S. EPA, 1978
17,900 U.S. EPA, 1978
331,000 U.S. EPA, 1978
B-5
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Table 1. (Continued)
Species Method*
Tidewater sllverslde, S, U
Menldla beryl 1 Ina
Tidewater sllverslde, S. U
Menldla beryl 1 ina
Che»lcal
methyl
bromide
methyl
ch lor Ide
LC50/EC50 Spec las Acute
<)ig/l) Value (ug/l) Reference
12,000 12,000 Dawson, et al. 1977
270,000 270,000 Oawson, et al. 1977
* S = static, FT = t low-through, U = unmeasured, M = measured
No Final Acute Values are calculable since the minimum data base requirements are not met.
B-6
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Table 2. Chronic values for kaloMthanes (U.S. EPA. 1978)
Species
Sheepshead minnow,
Cyprlnodon varlegatus
Method* Choalcal
SALTWATER SPECIES
E-L bromoform
Ll-lts
Cyg/l)
4.800-
8,500
Chronic
Value
(U9/I)
6,400
* E-L • embryo-larva I
Sheepshead minnow,
Cyprlnodon varlegatus
Acute-Chronic Ratio
Chemical
bromoform
Chronic
Value
(ua/D
6,400
Acute
Value
(ug/1) Ratio
17,900
2.8
B-7
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Table 3. Plant values for ha I (methanes (U.S. EPA, 1978)
Alga,
Sel eras t rum capr 1 cornutum
Alga,
Selenastrum capr I cornutum
Alga,
Selenastrum capr 1 cornutum
Alga,
Selenastrum capr 1 cornutum
Alga,
Skeletonenia cost a turn
Alga,
Skeletonema costatum
Alga,
Skeletonema costatum
Alga,
Skeletonema costatum
Chemical
FRESHWATER SPECIES
bromoform
bromoform
methyl en e
chloride
methy lene
chloride
SALTWATER SPECIES
bromoform
bromotorm
me thy lene
ch lor Ida
met hy lene
chloride
Effect
Ch lorophy 1 1 a
96- hr EC50
Cel 1 number
96-hr EC50
Ch lorophy 1 1 a
96-hr EC50
Cel 1 number
96- hr EC50
Ch lorophy 1 1 a
96-hr £C50
Cel 1 number
96- hr EC50
Chlorophyl 1 a
96-hr EC50
Cel 1 number
96- hr EC50
Result
(ug/1)
112,000
1 16 ,000
>662,000
>662.000
12,300
I) , 500
>662,000
>662,000
B-8
-------
REFERENCES
Alexander, H.C., et al. 1978. Toxicity of perchloroethylene, trichloro-
ethylene, 1,1,1-trichloroethane, and methylene chloride to fathead minnows.
Bull. Environ. Contam. Toxicol. 20: 344.
Dawson, G.W., et al. 1977. The acute toxicity of 47 industrial 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. U.S. Environ. Prot. Agency, Contract No.
68-01-4646.
B-9
-------
Mammalian Toxicology and Human Health Effects
INTRODUCTION
The halomethanes are a subclass of halogenated aliphatic hy-
drocarbon compounds, some of whose members constitute important or
potentially hazardous environmental contaminants. The seven halo-
methane compounds selected for discussion in this document are
listed in Table 1. Many other halogenated methane derivative chem-
icals exist, including various combinations of halogen (bromine,
chlorine, fluorine, iodine) substitutions at 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 sepa-
rate criteria documents. Several recent reviews are available
which present extensive discussions of health effects related to
halomethane exposure (National Academy of Science (NAS), 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 circumstances, 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 information con-
cerning relative exposure for specific compounds via the different
C-l
-------
TABLE 1
i
Halomethanes
,a
Names and CAS Registry Number
Formula
Bromome thane, methyl bromide, monobromo-
methane, Embafume , Iscobrome , Rotox®; 74-83-9
Chloromethane, methyl chloride,
monochloromethane; 74-87-3
Dichloromethane , methylene chlor ide ,
methane dichloride, methylene dichloride,
methylene bichloride; 75-09-2
Tribromome thane, bromoform, methyl
tribromide; 75-25-2
Bromod ichloromethane , dichloromethyl
bromide; 75-25-4
Dichlorodifluoromethane , fluorocarbon 12,
F-12®, Arcton 6®, Freon 12®, Frigen 12®,
Genetron 12R, HalonR, Isotron 12R,
dif luorodichloromethane; 75-71-8
Tr ichlorofluoromethane, fluorocarbon 11,
®
Frigen 11®,
F-ll®, Arcton 9®, Freon 11
Algofrene type 1, tr ichloromonofluoro-
methane, fluorotr ichloromethane; 75-69-4
CH3Br
CH3C1
CHBr.
BrCHCl.
CC12F2
CC13F
*Source: International Agency Research on Cancer (IARC), 1978;
National Cancer Institute (NCI), 1977; Stecher, et al. 1968; Na-
tional Library of Medicine, 1978.
aChemical names, common names (underlined), some trade names (cap-
italized) and synonyms are provided.
C-2
-------
media is incomplete. Inhalation and/or ingestion of fluids are
probably the most important routes of human exposure (NAS, 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 natu-
ral in origin with the oceans as a primary source (Lovelock, 1975);
natural sources have also been proposed for dichloromethane, tri-
bromomethane, and certain other halomethanes (NAS, 1978).
Anthropogenic sources of environmental contamination, such as
manufacturing and use emissions are important for several halo-
methanes. These include: chloromethane (chemical intermediate in
production of silicone, gasoline antiknock, rubber, herbicides,
plastics, and other materials); bromomethane (soil, seed, feed, and
space fumigant agents); dichloromethane (paint remover, solvent,
aerosol sprays, plastics processing); tribromomethane (chemical
intermediate); bromodichloromethane (used as a reagent in re-
search)? dichlorodifluoromethane and trichlorofluoromethane (re-
frigerant and aerosol propellant uses) (NAS, 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, some indus-
trial wastes, and the combustion and thermal degradation o£ prod-
ucts or waste materials (NAS, 1978).
EXPOSURE
Ingestion from Water
The U.S. Environmental Protection Agency has identified at
least ten halogenated methanes in finished drinking waters in the
C-3
-------
U.S. as of 1975: chloromethane, bromomethane, dichloromethane, di-
bromomethane, trichloromethane, tribroraomethane, bromodichloro-
methane, dibromochloromethane, dichloroiodomethane, and tetra-
chloromethane (U.S. EPA, 1975). In the National Organics Recon-
naissance Survey in 80 cities, halogenated 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 wide-
spread in chlorinated drinking waters; concentrations are related
to organic content of raw water. Incidence and levels of halo-
methanes found in the survey are summarized in Table 2.
In its Region V Organics Survey at 83 sites U.S. EPA reported
concentrations of several halomethanes in a large percentage of
finished municipal waters, as summarized in Table 3. Of the halo-
methanes detected in drinking waters, dichloromethane, tetra-
chloromethane, and fully chlorinated higher hydrocarbons probably
are not products of water chlorination (U.S. EPA, 1975; Morris and
McKay, 1975). Because of its solubility, dichloromethane may exist
in water effluents at concentrations of up to 1,500 mg/1, depending
on process and terminal treatment factors (NAS, 1978).
U.S. EPA1s National Organic Monitoring Survey (NOMS), conduct-
ed 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 halomethanes are summar-
ized in Table 4. Some 63 additional organic compounds or classes
were detected, including these halomethanes: bromomethane, dibromo-
methane, bromochloromethane, iodomethane, dichloroiodomethane,
C-4
-------
TABLE 2
Halomethanes in the National Organics
Reconnaissance Survey (80 Cities)*
Compound
Tr ichloromethane
Bromod ichloromethane
Dibromochlorome thane
Tr ibromomethane
Tetr ach lor ome thane
Number of
Cities with
Positive Results
80
78
72
26
10
Minimum
0.0001
0.0003
0.0004
0.0008
0.002
Concentration,
Median
0.021
0.006
0.0012
(a)
--
mg/1
Maximum
0. 311
0.116
0.110
0.092
0.003
*Source: NAS, 1978; Symons, et al. 1975
(a)98.3 percent of 60 cities had
-------
TABLE 3
Halomethanes in the U.S. EPA Region V
Organics Survey (83 Sites)*
Compound
Dromodichlorome thane
Dibromochlorome thane
Tr ichlorome thane
Tr ibromome thane
Tetrach lor orae thane
D ichlorome thane
Percent of
Locations with
Positive Results
78
60
95
14
34**
8
Concentrations (rag/1)
Median
0.006
0.001
0.020
0.001
0.001**
0.001
Max imum
0.031
0.015
0.366
0.007
0.026**
0.007
* Source: U.S. EPA, 1975
**A total of 11 samples may have been contaminated by exposure to laboratory air
containing tetrachloromethane.
C-6
-------
Compound
TABLE 4
Partial Summary of National Organics Monitoring Survey, 1976-1977*
Number of Positive Analyses
per Number of Analyses
Mean Concentration,
mg/1 (Positive
Results only)
Median Concentration,
mg/1 (All Results)
Tr ichloro-
me tliane
Tt ibcomo-
me tliane
Ilromocl i-
chloro-
me thane
Dibronio-
chloro-
melhane
Te l r a -
chloro-
IIIU tlldllC
Dichloro-
ine thane
Phase
Q*
T
Q
T
0
T
Q
T
Q
T
I
102/111**
3/111**
88/lli**
47/111**
3/lH**
15/109
II
18/18
112/113
6/116
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
U/105
I
0.047**
0.021**
0.022**
0.017**
0.0029**
0.0061
II
0.068
0.084
0.026
0.012
0.016
0.018
0.013
0.014
0.0024
III
0.038
0.073
0.013
0.013
0.0092
0.017
0.0075
0.011
0.0064
0.0043
I
0.027
0. 003-0. OOSa
0.0096
0. 0006-0. 0033
0. 001-0. 002a
0. 001-0. 002a
0.
0.
0.
0.
0.
0.
0.
0.
0.
II
068
059
0003a
0003a
018
014
0019
0035
0002a
III
0.022
0.045
0.0002-0
0.0003-0
0.0059
0.011
0.0021
0.0031
0.0002-0
0.0002-0
.0006a
.0006a
.0004a
.0004a
*lioucce: U.S EPA, I978b
**Sdinples shipped Iced, stored 1-2 weeks refrigerated before analyses.
^Quenched (Q) samples preserved with sodium '' losulfate at sampling, shipped at ambient temp., stored 20-25°C 3-6
weeks before analyses. Terminal(T) sampU treated similarly to Q except no Na thiosulfate.
^Minimum quantifiable limits.
1'hases (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: Samples stood at 20-25 C 3-6 weeks before analyses. Trihalomethanes (TIIM) formation proceeded to reaction
endpoints (terminal values).
Ill: Sampled with arid without chlorine-reducing agent (quenched, terminal values) to assess effect of residual chlo-
rine and reaction time.
C-7
-------
and trichlorofluoromethane. Mean and median total trihalomethane
(TTHM) values in 105 to 111 cities over the three phases and sample
modes ranged from 0.052 to 0.120 mg/1 and 0.038 to 0,087 rag/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 fin-
ished water distribution systems showed the following halomethane
concentrations:
Range Median
Chloroform 0 - 121 13 jug/1
Bromod ichloromethane 0-33 1.4 ,ug/l
Chlorodibromomethane 0 - 6.2 0.1 pg/l
Tribromomethane 0 - 0.2 0.01 ug/1
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 halomethane concentrations, and well
sources were associated with much lower halomethane concentrations
than river or lake sources. In addition, an unexplained increase
in the concentration of halomethanes occurred in the distribution
system as compared to halomethane levels in water sampled at the
treatment plant.
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 sur-
face waters, indicating that the oceans are net a significant sink
(long-term pool or repository) for this compound. As noted above,
C-8
-------
trichlorofluoromethane has been detected, but not quantified, in
finished drinking water in the NOMS. Environmental data suggest
that human exposure to the refrigerant-propellant chlorofluoro-
methanes in water is much less significant than to these compounds'
presence in air.
Ingestion from Food
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 pro-
cessing most residual bromomethane will rapidly disappear due to
methylation reactions and volatilization. The more persistent in-
organic bromide residues are products of bromomethane degradation
(NAS, 1978; Davis, et al. 1977). Scudamore and Heuser (1970) re-
ported that residues in fumigated wheat/ flour, raisins, corn, sor-
ghum, cottonseed meal, rice, and peanut meal were reduced to less
than 1 mg/kg within a few days. Initial levels of inorganic bro-
mide were positively related to concentration used, and disappear-
ance 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 fumi-
gated at 370 CH.,Br mg/m after nine days of aeration (Dennis, et al.
1972).
Table 5 summarizes data on organic and inorganic bromide resi-
dues in cheese with time after fumigation, as reported by Roehm, et
al. (1943). Table 6 summarizes specific inorganic bromide residue
maxima analyzed in several food commodities, according to
C-9
-------
TABLE 5
Bromomethane Residues in Cheese pouter % inch) (mg/kg)*
Hours of Longhorn Cheese A Longhorn Cheese B
Ventilation Inorganic Organic Total Inorganic Organic Total
0.5
4
24
48
96
168
15
21
22
25
24
25
62
40
20
0
0
1
77
61
42
25
24
26
23
30
38
39
38
36
78
54
9
4
1
2
101
84
47
43
39
38
*Source: NAS, 1978; Roehm, et al. 1943
C-10
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TABLE 6
Specific Residue Maxima: Inorganic Bromide
in Food Materials*
Max. SRa Materials
0-5 Baking powder, butter, chewing gum, dry
yeast, macaroni, marshmallows, oleomar-
garine, shortening, tapioca, flour, tea,
whole roasted coffee
5-10 Cake mix, candy, cheese, dried milk,
ground ginger, ground red pepper, pan-
cake 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
*Source: NAS, 1978; Getzendaner, et al. 1968
a
Specific Residue (SR) _ increase in bromide from fumigation(mg/kg)
rate of fumigation(Ib/min)
C-ll
-------
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.
A bioconcentration factor (BCF) relates the concentration of a
chemical in aquatic animals to the concentration in the water in
which they live. The steady-state BCFs for a lipid-soluble com-
pound in the tissues of various aquatic animals seem to be propor-
tional to the percent lipid in the tissue. Thus the per capita
ingestion of a lipid-soluble chemical can be estimated from the per
capita consumption of fish and shellfish, and a steady-state BCF
for the chemical.
Data from a recent survey on fish and shellfish consumption in
the United States were analyzed by the Stanford Research Institute
International (U.S. EPA, 1980). These data were used to estimate
that the per capita consumption of freshwater and estuarine fish
and shellfish in the United States is 6.5 g/day (Stephan, 1980).
In addition, these data were used with data on the fat content of
the edible portion of the same species to estimate that the weight-
ed average percent lipids for consumed freshwater and estuarine
fish and shellfish is 3.0 percent.
No measured steady-state bioconcentration factor (BCF) is
available for any of the following compounds, but the equation
"Log BCF = (0.85 Log P) - 0.70" can be used (Veith et al., 1979) to
estimate the steady-state BCF for aquatic organism that contain
C-12
-------
about 7.6 percent lipids (Veith, 1980) from the octanol/water par-
tition coefficient (P). The measured log P value was obtained from
Hansch and Leo (1979). When no measured value could be found, a
calculated log P value was obtained using the method described in
Hansch and Leo (1979). The adjustment factor of 3.0/7.6 = 0.39 is
used to adjust the estimated BCF from the 7.6 percent lipids on
which the equation is based to the 3.0 percent lipids that is the
weighted average for consumed fish and shellfish in order to obtain
the weighted average bioconcentration factor for the edible portion
of all aquatic organisms consumed by Americans.
Log P Estimated steady Weighted
Chemical Meas. Calc. state BCF Average BCF
Bromoform 2.38 21 8.3
Methylene
chloride 1.25 2.3 0.91
Chloromethane and bromomethane are considered to have rela-
tively 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, bio-
magnification factors for these compounds are relatively low (two
and six, respectively). No directly determined bioaccumulation
factors are available.
Inhalation
Reported concentrations of several halomethanes in general
air masses are summarized in Table 7. For comparison, some
C-13
-------
TABLE 7
Ranges of Mean Concentrations (mg/m ) of
llalomethanes Measured in General Air Masses
Compound
Chlororoethane
Dichlorome thane
ruomome thane
Continental
Background
0. 0011-0. 0021ac
0.00042d
lodomethane
Tr ichloromethane
Te t r achlo r ome t ha ne
(0.000002-0.000004)
0.000052d
0. 000044-0.000122a'C'd
0.000041 .
« 0.000006-0.000064)1
0.000132, 0.000234C
0.000126-0.000838
a.c.d,j
0.000699-0.000806b
-------
halomethanes other than those addressed by this document (Table 1)
are included.
Saltwater atmospheric background concentrations of chloro-
methane 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 continental 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 (NAS, 1978).
Localized sources, such as burning of tobacco or other combustion
processes, may produce high indoor-air concentrations of chloro-
methane (up to 0.04 mg/m ) (NAS, 1978, citing Palmer, 1976, and
Harsch, 1977). Chloromethane is the predominant halomethane in in-
door air, and is generally in concentrations two to ten times am-
bient background levels (NAS, 1978). Although direct anthropogenic
sources of chloromethane greatly influence indoor atmosphere con-
centrations, they are not significant contributors to urban and
background tropospheric levels (NAS, 1978).
Data on atmospheric bromomethane are few (Singh, et al. 1977;
Grimsrud and Rasmussen, 1975). Its continental background concen-
trations of 7.8 x 10 mg/m or less are much lower than saltwater
background and urban air concentrations (NAS, 1978). Relatively
high concentrations of bromomethane 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 concen-
trations 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
C-15
-------
bromomethane, and this is corroborated by urban air concentrations
at least as high as those in saltwater air masses (NAS, 1978, cit-
ing Harsch and Rasmussen, 1977; Singh, et al. 1977). Table 7 sum-
marizes reported levels of bromomethane in tropospheric air masses.
-4 3
Outdoor bromomethane concentrations of up to 8.5 x 10 mg/m may
occur locally near light traffic as a result of use of EDB in leaded
gasoline. Similarly, indoor air contaminated by exhaust from cars
burning EDB-containing leaded gasoline can have elevated concentra-
tions of bromomethane (NAS, 1978, citing Harsch and Rasmussen,
L977).
Data on concentrations of dichloromethane in tropospheric air
masses are scarce. As shown in Table 7, reported background con-
centrations in both continental and saltwater atmospheres were
about 1.2 x 10~ mg/m , and urban air concentrations ranged from
below 7 x 10~5 to 5 x 10"4 mg/m3 (NAS, 1978, citing Pierotti and
Rasmussen, 1976, and Cox, et al. 1976). Concentrations of di-
chloromethane in indoor air typically exceed tropospheric back-
ground levels because of local sources of contamination such as the
use of aerosol hair spray or solvents (NAS, 1978, citing Harsch,
1977). Air sampled from various indoor locations contained di-
- 4
chloromethane at concentrations ranging from a low of 2 x 10
mg/m (in a laundromat) to higher 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)
(NAS, 1978, citing Harsch, 1977). Indoor air has 10 to 1,000 tiwes
more dichloromethane than is present in unpolluted tropospheric
C-16
-------
air, and sometimes dichloromethane is the predominant halomethane
contaminant (NAS, 1978).
Data through 1974 indicate that dichlorodifluoromethane is
produced and used considerably more than trichlorofluoromethane 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 oceans. This probably
reflects that the primary modes of entry to the environment,the use
of refrigerants and aerosols, are greater in industrialized 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. Converse-
ly, concentrations in offshore 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) re-
-4 - 3
ported for urban atmospheres have ranged from 9 x 10 to 3 x 10
mg/m , and for ocean sites, from 2.2 x 10~ to 5 x 10~ mg/m . Mean
urban concentrations for dichlorodifluoromethane (F-12) ranged
- 3 -2 3
from 3.5 x 10 to 2.9 x 10 mg/m , and an ocean atmosphere mean of
— 4 3
5.7 x 10 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). Concentra-
tions in air near fluorocarbon release sites may be many times the
average city levels. F-ll concentrations of 1.3 x 10 to 2.4 x 10
mg/m , about 100 times the city average, were measured near a
C-17
-------
polyurethane plant 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 F-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 atmospheric half-life of 15 to 30 years
for F-ll has been calculated (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 cata-
lytically destroy stratospheric ozone, with possible global health
and meteorologic effects.
Trichlorofluoromethane and dichlorodifluoromethane have been
measured at highly varying levels indoors in homes. F-ll concen-
trations 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.
Data on environmental concentrations of halomethanes indicate
that human uptake of the trihalomethanes, bromodichloromethane and
C-18
-------
TABLE 8
Dichlorodifluoromethane Concentrations in Room Air as
a Result of Release of Aerosol Can Products*
Level at Periods after 60- Level at Periods after 30-
second Release of Hair Spray second Release,of Insect ..
in 29.3m Room (mg/m ) Spray in 21.4m Room (mg/m }
During:
30 min:
60 min:
306.8
12.4
0.5
1 min:
60 min:
150 min:
2,304.0
130.4
56.8
*Source: U.S. EPA, 1976; Bridbord, et al. 1974
C-19
-------
tribromomethane from fluids is less than that of trichloromethane.
Uptake of chloromethane, dichloromethane, bromomethane, and the
chlorofluoromethanes from fluids is apparently minor; for these,
uptake from sources other than fluid consumption is more important
(MAS, 1978).
Human uptake of chloromethane from fluids should be consider-
ably less than that for bromodichloromethane and tribromomethane.
However, human exposure to chloromethane from cigarette smoke, lo-
cal in nature and affecting discrete target populations, can be
quite significant (NAS, 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, since the range of
reported chloromethane is 0.5 to 2 mg per cigarette.
Dermal
Uptake of halomethanes from dermal exposure can occur under
certain circumstances. Occupational exposure standards warn of
possible significant skin absorption for bromomethane and tribromo-
methane under industrial exposure conditions (Occupational Safety
and Health Administration (OSHA), 1976; NAS, 1978). But there was
no evidence in the available literature that dermal exposure con-
tributes significantly to total dose of halomethanes for the gen-
eral public.
C-20
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PHARMACOKINETICS
Absorption, Distribution, Metabolism, and Excretion
Most of the literature regarding biological aspects of the
halomethanes has focused on the usual case with respect to expo-
sure, 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 gastro-
intestinal (GI) tract, although this is generally more significant
for the nonfluorinated halomethanes than for the fluorocarbons
(NAS, 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, par-
ticularly in skin exposures to the compound in liquid form (Davis,
et al. 1977; von Oettingen, 1964). Occupational Safety and Health
Administration (1976) exposure standards warn of possible signifi-
cant dermal absorption. Significant absorption can also occur via
the gastrointestinal tract when bromomethane is ingested. Upon ab-
sorption, 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 se-
vere, and 83 to 2,116 mg/1 in fatal, bromomethane poisonings; nor-
mal background blood bromide levels ranged up to 15 mg/1 (NAS,
C-21
-------
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 tissue levels were in fat, skele-
tal muscle, bone, and liver. In similar bovine experiments, bro-
mide 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 (methyla-
tion of sulfhydryl groups in critical cellular proteins and en-
zymes), rather than by the bromide ion residue resulting from
breakdown of the parent compound (Davis, et al. 1977). Bromo-
methane readily penetrates cell membranes while the bromide ion
does not. Intracellular bromomethane reactions and decomposition
result in inactivation of intracellular metabolic processes, dis-
turbed function, and irritative, irreversible, or paralytic con-
sequences (NAS, 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 {NAS,
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 elimination may take
longer, accounting in part for prolonged toxicity (NAS, 1978 citing
Miller and Haggard, 1943, and Clarke, et al. 1945).
C-22
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Chloromethane: As with bromomethane, chloromethane is usually
encountered as a gas and is absorbed readily via the lungs. Skin
absorption is less significant (NAS, 1978; Davis, et al. 1977). No
poisonings involving gastrointestinal absorption have been report-
ed. Uptake of chloromethane by the blood is rapid but results in
only moderate blood levels with continued exposure. Signs and
pathology of intoxication suggest wide tissue (blood, nervous tis-
sue, liver, and kidney) distribution of absorbed chloromethane.
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 (NAS, 1978; Davis, et al.
1977; Lewis, 1948; Morgan, et al. 1967; von Oettingen, 1964).
Dichloromethane: Absorption occurs mainly through the lung
but also through the gastrointestinal tract and to some extent
through intact skin. Lung absorption efficiencies of 31 to 75 per-
cent have been reported, influenced by length of exposure, concen-
tration, and activity level (NAS, 1978; National Institute for
Occupational Safety and Health (NIOSH), 1976a, citing: Lehmann and
Schmidt-Kehl, 1936, Riley, et al. 1966, DiVincenzo, et al. 1972,
and Astrand, et al. 1975). Upon inhalation and absorption, di-
chloromethane levels increase rapidly in the blood to equilibrium
levels that depend primarily upon atmospheric concentrations; fair-
ly uniform distribution to heart, liver, and brain is reported
(NAS, 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
C-23
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descending order by level's in brain and liver tissue, Dichloro-
methane is excreted intact primarily via the lungs, with some in
the urine. DiVincenzo, et al. (1972) have reported that about 40
percent of absorbed dichloromethane undergoes some reaction and
decomposition process in the body (NAS, 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 carboxyhemoglobin (COHb).
The formation of COHb leads to interference with normal oxygen
transport capabilities of blood, so relative oxygen deprivation and
secondary effects ensue (NIOSH, 1976a, citing Stewart, et al.
1972ar Fassett, 1972; and DiVincenzo and Hamilton, 1975; NAS, 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 dichloro-
methane exposure than from exposure to CO alone (Stewart and Hake,
1976). Other metabolites of dichloromethane include carbon di-
oxide, formaldehyde, and formic acid (NAS, 1978).
Tribromomethane: Absorption occurs through the lungs upon in-
halation of vapors, from the GI tract upon ingestion, and to some
extent through the skin. The OSHA (1976) standard warns of pos-
sible significant skin absorption. Some of the body burden is bio-
transformed in the liver to inorganic bromide. After inhalation or
rectal administration of tribromomethane, bromides were found in
tissues and urine (NAS/ 1977). Bioconversion of tribromomethane and
other trihalomethanes, apparently by a cytochrome P-450 dependent
mixed function oxidase system, to carbon monoxide has been reported
C-24
-------
(Ahmed, et al. 1977). Excretion occurs partly through the lungs as
tribromomethane, and complete excretion requires considerable time
(NAS, 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 (NAS, 1978). Current in-
creased environmental interest in bromodichloromethane focuses on
its presence in drinking water (Kleopfer, 1976) along with other
trihalomethanes, as a consequence of chlorination. Absorption,
distribution, metabolism, and excretion may resemble that of bromo-
chloromethane (see the following), dichloromethane, or dibromo-
methane, in view of close chemical similarities among these com-
pounds and bromodichloromethane. Further possible evidence for
similarity exists in that the mutagenic, carcinogenic, and general
toxic effects of the latter are similar to those of other di-and
trihalogenated (Cl and Br) methanes (NAS, 1978; Sax, 1968).
Patty (1963) placed bromochloromethane "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 inorgan-
ic bromide. Tissue concentrations of both organic and inorganic
bromine increased in dogs and rats exposed daily to bromochloro-
methane. After exposure, blood levels decreased to undetectable or
insignificant levels in 17 to 65 hours. Significant absorption by
the GI tract after exposure by ingestion was indicated by hepatic
C-25
-------
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 characteristics (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 inhala-
tion and ingestion routes; (2) be distributed widely, preferential-
ly 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 (F-ll) and dichlorodifluocome thane (F-
12): Inhalation and absorption through the lungs are the exposure
and uptake modes of most concern; however, when ingested, absorp-
tion of F-12 does occur via the GI tract. Some absorption through
the skin could occur also, judging from tests with F-113 (CC^F-
CC1F2) (U.S. EPA, 1976; Howard, et al. 1974; Clark and Tinston,
1972a,b; Allen and Hanburys, 1971; Azar, et al. 1973; Sherman,
1974; DuPont, 1968). Absorption and elimination are dynamic pro-
cesses 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 pat-
tern 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,
C-26
-------
1972; Morgan, et al. 1972). These authors agree in general with
partition coefficients for the fluorocarbons in blood, serum, and
lipid (oil) (Allen and Hanburys, 1971; Chiou and Niazi, 1973;
Morgan, et al. 1972). More easily absorbed compounds are retained
longer. Under conditions of prolonged, lower-level exposure, per-
iods of elimination (washout) are longer. Although varying among
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, et al. 1974).
F-ll and F-12 are distributed by blood and stored temporarily
by various tissues. Allen and Hanburys (1971) reported maximum
concentrations in adrenals followed by fat and then heart. Chem-
ically 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 com-
pletely through the respiratory tract, regardless of the route of
entry. In dogs administered a mixture of F-12 and F-14 (30:70 per-
cent, 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.
C-27
-------
Biochemical effects suggesting a slowing down of cellular oxi-
dation were reported in animals exposed to 2.8 x 10 mg/m 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 Id5 mg/m3) (Paulet, et al. 1975).
14
In brief exposure experiments with inhaled C-labeled F-12,
only about 1 percent of F-12 in nonvolatile urinary or tissue com-
ponents or metabolized and eliminated in expired air as CO- (Blake
14
and Mergner, 1974). Experiments with oral C-labeled F-12 indi-
cated that about two percent of the total dose was exhaled as CO.,
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-L2 form metabolites which bind to cell constit-
uents, particularly in long-term exposures with extended equilib-
rium (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 cytochrome P-450-related phospholipids was re-
ported (Cox, et al. 1972). More research on fluorocarbon xeno-
biotic metabolism and pharmacodynamics under prolonged exposure
conditions is needed (U.S. EPA, 1976).
EFFECTS
Acute, Subacute, and Chronic Toxicity
For most of the halomethanes considered here, there is con-
siderable 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
C-28
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with inhalation exposure to grossly poisonous or fairly substantial
concentrations of vapors of various halomethanes. Considerably
less information is available on various aspects of toxicity that
might result from prolonged exposure to low, environmental levels
of these compounds, by not only the inhalation route but also
ingestion or other routes of exposure. This section summarizes
briefly the important clinical and toxicologic information avail-
able for these compounds.
Chloromethane: Is not generally regarded as highly toxic, yet
reports of poisoning are numerous. Because of its virtually odor-
less and colorless properties, low-order irritancy,and character-
istic latency of effect, victims may receive serious or prolonged
exposure before awareness and effects are apparent {NAS, 1978;
Davis, et al. 1977). Toxic dosages for humans are not clearly de-
fined. 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, 1947a,b). Chronic inhalation and inges-
tion toxicity levels are not established, but the occupational ex-
posure standard for air in the work environment is currently set
for 206 mg/m (NAS, 1978; OSHA, 1976). The monohalomethanes seem
to rank in the following order of decreasing toxicity: iodo-
methane, bromomethane, chloromethane, fluoromethane (Davis, et al.
1977). The similarities in toxicologic responses to the monohalo-
methanes suggest a similar mode of action. The most probable
mechanism is that the monohalomethane participates in the meth-
ylation of essential enzymes, cofactors, and other cellular
C-29
-------
macromolecules, thereby rendering them inactive (Davis, et al.
1977). Sulfhydryl-containing molecules seem particularly suscept-
ible to the action of monohalomethanes (Lewis, 1948; Redford-Ellis
and Gowenlock, L971a). Various reports on the effectiveness of
cysteine administration in the treatment of monohalomethane poi-
soning support the contention that binding to sulfhydryl compounds
is involved in the expression 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 refrigera-
tion 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 on-
set of effects (symptoms). Recovery after brief exposures is typ-
ically 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 co-
ordination, personality changes (depression, moroseness, anxiety),
lasting a few hours to several days; some were more sensitive to
chloromethane upon return to work (MacDonald, 1964; Hansen, et al.
C-30
-------
1953; Browning, 1965; Morgan, 1942). As mentioned previously,
tobacco-smoking may be an additional significant source of individ-
ual human exposure to chloromethane.
Severe poisonings are usually characterized by a latent period
and severe and dominant neurological disorder, with perhaps ir-
reversible 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 hemor-
rhage; chloromethane has been detected in all organs analyzed after
death (NAS, 1978, citing Baird, 1954).
There have been no reports of reproductive toxicity or tera-
togenicity in humans exposed to chloromethane, but metabolic, en-
zymatic, and neuroendocrine disturbances following exposure in hu-
mans and/or animals suggest the need for research on this point
(Davis, et al. 1977). Epidemiological studies of toxicity in human
populations exposed to chloromethane (including mutagenicity and
carcinogenicity) have not yet appeared in the published literature.
In animals, a variety of toxic effects have been noted in ex-
perimentally exposed subjects. Many effects are similar for the
monohalomethanes and, consistent with human data, suggest CNS in-
volvement and altered metabolism involving binding to sulfhydryl-
containing cellular macromolecules (Davis, et al. 1977; Balander
and Polyak, 1962; Gorbachev, 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. 1977). Some inhalation
toxicity data for chloromethane are summarized in Table 9. In
general, chloromethane is less acutely toxic by inhalation than
broraomethane. In severe acute exposure conditions chloromethane
produces serious neurological disturbances, with functional and be-
havioral manifestations and ultimately death. However, these dis-
turbances 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, chloro-
methane 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 sev-
eral weeks of daily exposures at 1,032 mg/m , and paralysis fol-
lowed 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 re-
sponsible for many occupational poisoning incidents, reflecting its
widespread use as a fumigant. Like chloromethane it has a char-
acteristic latent period and its presence is difficult to detect,
so prolonged and more severe exposure may be incurred (NAS, 1978;
Davis, et al. 1977). Toxicologic and metabolic similarities among
the monohalomethanes (C1-, Br-, I-substituted) suggest a common
mechanism of toxic action, probably methylation and disturbance or
C-32
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TABLE 9
Chloromethane Inhalation Toxicity in Animals
Concent rat ion,
mg/m
3.1 x 10 to 6.2 x 10
4.1 x 10 to 8.3 x ]0
4.1 x 10]j
1.4 x lo:*
6.2 x 10J to 8.3 x 10J
6.5 x
6.2 x
10:
10:
4.1 x 1(T
2,065
1,032
620 to 1,032
531
Duration
Dcief
30-60 min
2 hr.
Up to 1 hr
6 hcs/day
6 hrs
4 hrs
6 hrs/day
Response
6 hrs/day
6 hrs/day
20 hrs
Quickly lethal to most animals
Dangerous effects. Increased respira-
tory and heart rates and blood pres-
sure, followed by reversals and ECG
changes; restlessness, salivation,
incoordInation, narcosis.
LC , guinea pig
No Serious effects
Deaths, rats, 3-5 days, spasmodic
dyspnea
t,C,-n, mouse
LCLO' rflt
1 week, cats, weakness, unable to right
I 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 o£
poisoning; 2-4 weeks, dogs, deaths,
permanent neuromuscular damage in survi-
vor; 1 week, mice, convulsions, mortality;
15 weeks, mice, permanent adductor contrac-
tion in survivors
Overt signs of toxicity detectable in
dogs and monkeys.
Paralysis in survivors (but in another ex-
posure at 620 mg/m , no cumulative overt
toxicity or neurotoxic changes over
several months In several species).
Re £e re nee
Patty, 1958
von Oettingen, 1964
NIOSI1, 1976b
Patty, 1958
von Oettingen, 1964
Davis, et al. 1977
DI1EVJ, 1975
von Oettingen, 1964
von Oettingen, 1964
von Oettingen, 1964
Smith & von Oettingen, I947a
von Oeltingen, 1964;
Smith & von Oettingen, 1947a
C-33
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inactivation of essential proteins (rather than presence of the
parent compound or free halide per se) (Davis, et al. 1977).
Human experience indicates that acute fatal intoxication 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. System-
ic poisoning has been reported to occur from two weeks' exposure
(eight hrs/day) at about 136 mg/m (WAS, 1978, citing: Kubota,
1955; Johnstone, 1945; Bruhin, 1943; Wyers, 1945; Watrous, 1942;
Rathus and Landy, 1961; Miller and Haggard, 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 hours)
between exposure and onset of symptoms is characteristic (Araki, et
al. 1971).
Like the other monohalomethanes, bromomethane is a CNS depres-
sant and may invoke psychic, motor, and GI disturbances.
(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 disturbances, with recovery in a few
days. Moderate cases involve the CNS further, with more extensive
neurological symptoms and visual disturbances. Recovery may be
prolonged for weeks or months, with persisting symptoms and/or dis-
turbed 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
:-34
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psychic disturbances. Recovery can be quite protracted with per-
sisting 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 occur in the kidneys, liver, and/or
stomach, and perhaps the brain; although brain changes are usually
more functional in character (NAS, 1978; Davis, et al. 1977).
Apparently blood bromide levels of LOO mg/1 or less result in re-
covery, 135 in moderate disability, 195 in residual ataxia, and 250
in convulsions (Hine, 1969).
Direct skin contact with bromomethane may produce prickling,
itching, cold sensation, erythema, vesication, blisters (similar to
second degree burn), and damage to peripheral nerve tissue or de-
layed dermatitis (Davis, et al. 1977). A case of brief skin expo-
sure (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 (1976) standard for bromomethane in workroom air is 78
mg/m (ceiling) and carries a warning notation of possible signifi-
cant skin absorption (NIOSH, 1976b; OSHA, 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
C-35
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absorption and first-pass detoxification (Davis, et al. 1977). In
several species acute fatal poisoning has involved marked CNS
disturbances with a variety of manifestations: ataxia, twitching,
convulsions, coma, as well as changes in lung, liver, heart, and
kidney tissues (Sayers, 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) in animal and human (Drawneek,
et al. 1964) as acute toxicoses. Inhalation toxicity in animal
species is briefly reviewed in Table 10. In general the monohalo-
methanes rank in decreasing order of acute toxicity as follows:
iodomethane, bromomethane, chloromethane, fluoromethane (Davis, et
al. 1977).
Dogs receiving bromomethane chronically by ingestion (fumi-
gated diet yielding residual bromide at a dose level of 150
nig/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, et al. (1970) detected changes
in blood iodine and calcium and pathologic changes in thyroid and
parathyroid glands. Toxic responses in rabbits administered bromo-
methane subcutaneously (in oil) at 20-120 mg/kg included limb
paralysis, 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 (Xakizaki, 1967).
Groups of cattle were fed oat hay from a bromomethane-fumi-
gated field or pelleted ration containing sodium bromide added at
various concentrations. The hay contained bromide ion at 6,300 to
C-36
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TABLE 10
BroBOBethane Inhalation Toxicity in AniBals
Concentrat ion
•9/«3
69,452
24.929
20.952
7,760-11.640
7,760-11,640
3.391
1,940-2,128
2,293
1,536-1,940
1,536
1,164
1,164
997
846
846
582
504
419
252
120
97
70
Duration
15 Bin
1 hr
20 Bin
30 uln
70 Bin
30-40 Bin
4.5 hcs
12 hrs
6 he/dally
Not specified
5 hrs
13.5 hrs
22 hrs
3 hr
26 hr
9 hrs
18 hra (2 exp. at
3 BO interval)
7-8 hrs daily
8 he/day, 5
da/uk.
8 hr/day, 5
da/wk.
4-5 BOS
40 Bin
Response
Lethal, cats
""Lo' rabblt
Delayed deaths (6 days), guinea pigs
Delayed deaths (9 hr), 1 of 6 guinea pigs
LClofl, guinea pigs
Lethal, dogs
Lethal within 2 days, salivation, guinea pigs
Lethal, rabbits
CuBulative overt toxicity, dogs t Bonkeys
LC5Q, Bice
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 Bost in 1-3 daysj guinea pigs
Altered conditioned reflexes, Bice
Height loss, prostration, convulsions} rats
At 22 days: typical poisoning, rabbits
Eventually lung irrit., paralysis, rabbits
(but not rats, guinea pigs, or Bonkeys)
Altered neuroendocr ine controlled Betabo-
llsB, rabbits
Changes in «otor 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
SBith fc von Oettingen. I947a
Balander £ Polyak, 1962
von Oettingen, 1964
von Oettingett, 1964
Irish, et al. 1940
von Oettingen, 1964
Irish, et al. 1940
von Oettingen, 1964
Sokolova, 1972
Irish, et al. 1940
Irish, et al. 1941
Irish, et al. 1941
Balander t Polyak, 1962
Balander t Polyak, 1962
C-37
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8,400 mg/1 concentrations. 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. Incoordina-
tion 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 on bromomethane teratogenicity studies were avail-
able, but high levels in testes after ingestion of fumigated food,
and enzymatic and neuroendocrine disturbances, could have terato-
genic implications. Further studies in this area would appear to
be warranted (Williford, et al. 1974).
Dichloromethane: As with chloromethane, dichloromethane has
not generally been regarded as highly toxic, but poisonings, pri-
marily from inhalation exposures, have been reported. Human mini-
mal toxic concentrations or doses have not been determined. At
this time the OSHA occupational exposure standard (air concentra-
tions 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 (OSHA, 1976). How-
ever, NIOSH has recommended an eight-hour TWA concentration of 260
mg/m3 with a peak limit of 1,737 mg/m3 (NIOSH, 1976b). A TCTn (low-
LO
est reported toxic concentration) over eight hours of 1,737 mg/m
for humans is reported (NIOSH, 1976b), and exposures of 740 or
1,786 mg/m for one hour were reported as being without adverse ef-
fect by Stewart, et al. (1972a,b). However, Winneke (1974) report-
ed exposure to 1,101 mg/m or more for three to four hours de-
creased psychomotor performance (NAS, 1978). Dichloromethane
C-38
-------
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 inter-
feres with oxygen transfer and transport (NAS, 1978).
Mild poisonings by dichloromethane produce somnolence, lassi-
tude, anorexia, and mild lightheadedness, followed by rapid and
complete recovery. Severe cases are characterized by greater de-
grees of disturbed CMS function and depression. Permanent disabil-
ity has not been reported. In fatal poisonings cause of death has
been reported as cardiac injury and heart failure (NAS, 1978,
citing: Hughes, 1954, Stewart and Hake, 1976, Collier, 1936,
Moskowitz and Shapiro, 1952).
The formation of CO and COHb from dichlororaethane forms a ba-
sis for concern about combined exposures to dichloromethane and
carbon monoxide. Fodor and Roscovanu (1976) and NIOSH (1976a) re-
commend re-examination of dichloromethane exposure standards with
intent 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
exposures could be a problem, especially in workers, smokers, and
cardiorespiratory patients or other susceptibles. Concern about
mixed exposure to dichloromethane and other lipophilic solvents,
with enhanced danger of marked CNS and metabolic effects resulting
from modest exposure to individual materials, has been expressed
(Savolainen, et al. 1977).
C-39
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Gynecologic problems in female workers exposed for long per-
iods 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. Di-
chloromethane also was found in the milk of lactating women a few
hours into a work shift. Functional circulatory disorders in work-
ers exposed for more than three years to organochlorine compounds
(including dichloromethane) at "permissible" levels have been
reported by Dunavskii (1972). Symptoms included chest pain, elec-
trocardiograph irregularities, bradycardia, decreased myocardial
contractility, and altered adaption to physical stress. More
recently it has been reported (Stewart and Hake, 1976) that fatal
heart attacks have been caused by exposure to dichloromethane in
workers removing paint and varnish (NAS, 1978).
Animal toxicology of dichloromethane is briefly reviewed in
Table 11, with some human data included. Both di-and tri-halo-
genated methane derivatives have been found to produce increased
blood levels of COHb; the greatest increase caused by iodo-, fol-
lowed by bromo- and chloro-compounds. CNS functional disturbances
are reported, including 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 dichloro-
methane at 87 and 347 mg/m for up to two weeks. As a liquid or
vapor dichloromethane was ophthalmotoxic in rabbit tests, producing
persistent (up to two weeks) conjunctivitis and blepharitis,
C-40
-------
TABLE 11
Toxicity of Dichloromethane
Exposure Con-
centration
or Dose
6,460 mg/kg
17,370 mg/m3
3,000 mg/kg
2,700 mg/kg
2,136 mg/kg
1,900 mg/kg
1,500 mg/kg
*j
4,342 mg/m
•3
3,425 mg/m
950 mg/kg -
1,737 mg/m
-5
1,737 mg/ni
1,737 mg/m:?
1,737 mg/m
200 mg/kg
87-347 mg/m3
Duration
Subcut.
2 hrs
Oral
Subcut.
Oral
Oral
I. P.
7 hr/day,
9 day
1 he
I. P.
6 hr/day,
few days
year, in-
termi ttent
6 hrs
3 hrs
I.V.
Contin.
up to
2 wks
Response
LD5Q, mouse
LC , guinea pig. Depressed
running activity, rats
LDLo, dog
LDT , rabbit and dog
L>O
LD 0, rat
LD^, rabbit
LD5Q, mouse
Fetotox., teratogenicity , mice,
rats
Transient lightheadedness, human
LDLo' dog
Altered brain metabolism,
behav ior , rats
TCLo, CSN, human
TC , blood, human (12% COHb)
13* COHb, rats
LD , dog
Liver changes, mice
Reference
NIOSH, 1976b
NIOSH, 1976b
Heppel & Neal,
NIOSH, 1976b
NIOSH, 1976b
NIOSH, 1976b
NIOSH, 1976b
NIOSH, 1976b
Schwetz, et al.
Stewart, et al.
NIOSH, 1976b
Savolainen, et
NIOSH, 1976b
NIOSH, 1976b
1944*
1975 +
j.
1972a,b
al. 1977
Fodor & Roscovanu, 1976
NIOSH, 1976b
Haun, et al. 1972T
*Cited by NIOSH, 1976a
+Cited by NAS, 1978
C-41
-------
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 ges-
tation days from 6 to 15 produced increased blood levels of COHb
and evidence of feto- or embryo-toxicity, but not teratogenicity
(Schwetz, et al. 1975; NIOSH, 1976a, citing Heppel and Neal, 1944).
At 1.737 mg/m voluntary running activity was depressed in
rats. Sleep alterations were noted in rats exposed to dichloro-
methane at 3,474 mg/m or more (Wolburg, 1973). Depressed CNS ex-
citability, along with increased blood levels and expiratory, he-
patic, and renal excretion of dichloromethane in subacute studies,
was reported (Avilova, et al. 1973).
Tribromomethane: Little information is available concerning
the toxicology of tribromomethane. It is regarded as a highly tox-
ic material, more toxic than dibromomethane but less than tetra-
bromomethane and triiodomethane (NAS, 1978, citing Dep. Health Edu.
Welfare, 1975). Minimum toxic concentrations have not been estab-
lished, but its general toxic potential is reflected in a quite low
occupational exposure standard {OSHA, 1976): eight-hour time-
weighted-average air concentration, 5.2 mg/m (the most stringent
standard of the halomethanes considered herein). It is absorbed by
all major routes (lungs, GI tract, skin) after appropriate exposure
(NAS, 1978).
In humans, exposure to toxic levels of vapor produces irrita-
tion of respiratory tract, pharynx, and larynx, with lacrimation
and salivation. Most reported cases of poisonings have resulted
from accidental overdoses administered in the treatment of whooping
C-42
-------
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. Un-
consciousness, loss of reflexes, and convulsions occur in severe
cases, and in fatal cases the primary cause of death is respiratory
failure. Clinical recovery in moderate poisonings may be relative-
ly rapid and without permanent damage or disability. Presence of
tribromomethane in all organs is indicated by pathologic findings,
which also indicate fatty degenerative and centrilobular necrotic
changes in the liver (as in trichloro- and triiodomethane poison-
ings) (NAS, 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 tr ibromomethane 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). Patho-
logical 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 (NAS, 1978). Experimental
data for animals are briefly summarized in Table 12. Reticuloendo-
thelial system function (liver and spleen phagocytic uptake of
125
I-Lister ia monocytogenes) was suppressed in mice exposed 90 days
to tr ibromomethane at daily dose levels of 125 mg/kg or less
(Munson, et al. 1977, 1978).
Bromodichloromethane: No information on human intoxication by
this compound was available, and there have been no occupational
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
100-200 mg/kg/da
0.3-125 mg/kg/da
Subcutaneous, single
Intragastric, single
Subacutaneous, oil,
single
Subacutaneous, single
Inhalation, 4 hrs
daily, 2 mos.
Injection, daily,
10 days
Intragastric,
90 days
LD,.-, mouse
LD5Q, mouse, ICR, O; fatty
liver; kidney palor; hemor-
rhage in adrenals, lungs,
brain
Median effective dose for
prolongation of phenobarb.
sleeping time. Approx.
threshold. 278 mg/kg.
Mouse.
LD. , rabbit
LiO
Disorders in liver glyco-
genesis and prothrorobin
synthesis; reduced renal
filtration capacity.
Threshold: 50 mg/m .
Rat.
Liver and kidney pathol.,
guinea pig
Suppressed liver phago-
cytosis, mice
Kutob & Plaa, 1962
Bowman, et al. 1978
Kutob & Plaa, 1962
NIOSH, 1976b
MAS, 1977, citing
Dykan, 1962
NAS, 1978, citing
Dykan, 1962
Munson, et al. 1978
C-44
-------
exposures reported by Sax (1968). However, he reported the compound
as "dangerous" and "probably narcotic in high concentrations."
Bowman, et al. (1978) have recently reported on acute toxicity
tests in mice. Median lethal doses LD5Q for ICR Swiss mice admin-
istered bromodichloromethane (solubilized in emulphor: alcohol and
saline mix) by gavage were 450 and 900 mg/kg for males and females,
respectively. Based on comparative LD,.- data among four trihalo-
methanes, bromodichloromethane 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 infiltration in livers,
pale kidneys, and hemorrhage in kidneys, adrenals, lungs, and
brain.
In mice that were offered bromodichloromethane in drinking
water at 300 mg/1 (with and without use of emulphor), water con-
sumption and body-weight decreased dramatically (Campbell, 1978).
Body weight regained parity with controls in several weeks, but wa-
ter consumption did not. There was no obvious effect on suscep-
tibility to pathogenic Salmonella typhimur ium 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 bromo-
dichloromethane at 125 mg/kg daily. Sanders, et al. (1977) ob-
served hepatomegaly and a depression in a reticuloendothelial system
functional index (phagocytic) in mice exposed to bromodichloromethane
C-45
-------
Munson, et al. (1977) reported a dose-dependent suppression of
hepatic phagocytosis in mice exposed for 90 days to daily doses of
bromodichloromethane by gavage ranging up to L25 mg/kg.
Teratogenic properties of bromodichloromethane have not been
clearly demonstrated, but some fetal anomalies were reported in ex-
periments 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 dichlorodifluoromethane
(F-12): These propellant fluorocarbons are discussed together be-
cause of their physicochemical and general toxicologic similar-
ities. They may be regarded as the least toxic of the halomethanes
considered in this document. Standards for maximum average concen-
trations in air of work spaces are established at 5,600 and 4,950
mg/m for F-ll and F-12, respectively (OSHA, 1976). For reference,
these may be compared to the following standards for other halo-
methanes :
tribromomethane 5 mg/m
bromomethane 80 mg/m
chloromethane 206 mg/m
dichloromethane 1,737 mg/m
It has been recommended that these standards for maximum average
concentration be reduced to 260 mg/m .
Because of their physical properties and use patterns the pri-
mary route of exposure in toxicity studies has been by inhalation
of vapors at high concentrations, resulting in rapid pulmonary ab-
sorption. The two toxicologic features of the fluorocarbons that
have received the greatest attention are their cardiovascular and
C-46
-------
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 pro-
cesses (e.g., retard cellular oxidation). There remains a need for
more metabolic and toxicologic information on the consequences 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 fluorocarbon products,
resulting in acute inhalation of high vapor concentrations. Numer-
ous severe and fatal cases of abuse are on record, such as from in-
haling deeply from spray-filled bags to achieve a "jag." These
probably involve cardiac arrhythmia complicated by elevated circu-
lating catecholamines and CO- (Bass, 1970; Killen and Harris,
1972). Similar toxic consequences could occur in asthmatics using
fluorocarbon-propellant bronchodilator products (Taylor and
Harris, 1970; Archer, 1973). Occupational-exposure data are lim-
ited. Speizer, et al. (1975) have reported a relationship between
cardiac palpitation episodes and level of use of F-12 and F-22
(CHC1F2) propellants in hospital pathology department workers
(frozen-section preparation).
In brief experimental exposures of humans to F-12 at 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 10 to 543 x 10" mg/m caused cardiac arrhythmia,
decreased consciousness, and amnesia or deficits in performance on
C-47
-------
psychomotor tests scores (Kehoe, 1943; Azar, et al. 1972). How-
ever, in women using fluorocarbon-propellant (F-ll; F-12; F-114
(CC1F_-CC1F2)) aerosol products and receiving nine or more times
the exposure from normal use, Marier, et al. (1973) found no mea-
surable blood levels of the fluorocarbons or abnormalities in over-
all 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 in-
creased aerosol usage, most consistently among nonsmokers" (U.S.
EPA, 1976). Human data on halothane (a chemically similar
CF,CHBrCl gaseous anesthetic) suggest potential toxic hazards
(liver, kidney, and CNS changes; risk of abortion and developmental
anomalies, increased susceptibiltiy to cancer in females) from pro-
longed exposure at relatively low levels, with implications part-
icularly for operating room personnel. Animal data on halothane
are generally supportive (U.S. EPA, 1976). The primary human haz-
ard 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 se-
lectively summarized in Tables 13, 14, and 15. Several propellant
C-48
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TABLE 13
Inhalation Toxicology of F-ll*
Concentration
of Vapor. .
(mg x 10J/«J)
1,851
1,402
1,122
842
561
561
561
140; 280; 561
140-561
337
280
280
280
140
140
140
140
112
70
67
28-67
58
28
22
5.6
Exposure, Duration
or Regimen
Brief (H.S.)
30 *ln
S min
30 min
20 min
6 min
5 min
5 min
H.S.
4 hrs
20 min or repeated daily
5 min
5 min
5 min
5 min
5 min
3.4 hr/day 20 days
4 hrs
3. 5 hr/day 20 days
4 hr/day x 10 days
5 min
8 hr/day x 30 days
Br ief
6 hr/day x 28 days
90 days
Animals
Rat
Rabbit, g.p.
Rat
Rat
Rat
Mouse (anesthetized)
Rat (anesthetized)
Rat (unanesthetized)
Rat (anesthetized)
Rat
Rat, rabbit, dog
Monkey (anesthetized)
Mouse , dog
Caid Iomyopathlc hamster
Monkey (anesthetized)
Monkey
Cat, g. p. , rat
Card Iomyopathlc hamster
Dog
Rat
Dog
Rat, g.p.
Monkey and dog
Rat, mouse, g. p. ,
rabbit
Rat, g.p.
Effect(s)
Tremors
LC **
Lethal to some
LC
LoSS of reflex, anesthesia
A-V block
Cardiac arrythmias in all
Tachycardia, atrlal f ibrill. , ventric.
extrasystoles in some (incid. related to dose)
Dradycardia; also ectoplc beats at 561 mg/m
Lethal to some
Biochemical changes indicative of slowed
cellular respiration.
Tachycardia, ventric. premature beats, A-v block
SEIA*** ,
Cardiac arrythmias (compared to 561 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 neuroausc. 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
Source: U.S. EPA, 1976
* g.p. denotes guinea pig
** ^tn denotes ntedian lethal concentration
***SEIA denotes sens!tlzation to eplnephctne-Induced arrhythmia
C-49
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TABLE 14
Inhalation Toxicology of F-12*
Concentration
of Vapor. ,
(rag x 103/m )
Exposure, Duration
or Regimen
Animal
Effect(s)
0,952
3,754
2,470
2,638(F11/F12, 1:1)
1,976
1,482-1,976
1,482
1,582(FU/F12, 1:1)
1,160(FU/F12, 1:1)
988
988
988
494, 988> 1,976
494; 988
494
494
494
247
247
41
4
30 rain
30 min
1 hr
30
U.S.
Brief (N.S.)
30 min
30 min
30 min
5 min
7-8 hr/day x 35-53 days
6 min
N.S.
N.S.
N.S.
5 min
3.5 hr/day x 20 days
5 min
5 min
8 hr/day x 5 day/wk x 30 days
Continuous, 90 days
Guinea pig,rabbit,rat
House
Rat
Guinea pig
Rat (anesthetized)
Rat
Rat
Rat
Mouse
Rat
Dog,monkey
Mice (anesthetized)
Rat (unanesthetized)
Rat (anesthetized)
Rat (anesthetized)
Monkey (anesthetized)
Rat,guinea pig,cat,dog
Monkey (anesthetized)
Dog
Guinea pig
Guinea pig
Anesthesia
Arrhythmia in •»; no ch. In heart rate
Tremors
Letnal to some
Tremors disappear after 2 wks- tolerance
and depressed wt. gain
No arrhythmias
Tachycardia, no arrhythmias
No change in heart rate, or arrhythmias
Arrhythmias in 10%
Ar rhy thmlas
No mortal, and no overt signs of tox.
No arrhythmias
SEIA***
Liver changes
Liver changes
* Source: U.S. EPA, 1976
** LCcQ denotes median lethal concentration
***SEIA denotes sens!tization to epinephrine-Induced arrhythmia
:-so
-------
TABLE 15
Bronchopulmonary and Cardiovascular Effects
(other than arrhythmia) of F-ll and F-12*
Effect
Tachycard ia
Myocardial
depression
Hypotension
Early respiratory
depression
Dronchoconstr iction
Decreased
compliance
Animal
Dog
Monkey
Dog
Monkey
Dog
Monkey
Dog
Monkey
Mouse
Rat
Dog
Monkey
Mouse
Rat
Dog
Monkey
Mouse
Rat
F-ll
Cone.** De^ree °S
response
56 ++ +
140 4-4-
140 ++
140 4-4-
140 ++
140 4-4-
561 +
280 +
140 4-4-
140 4-4-
0
0
56 4-4-
140 4-4-
0
0
56 4-4-
140 4-4-
F-12
Cone.** Degree °I
response
494 4-
494 +
494 4-
0
494 4-
988 4-
0 4-
247 4-
494 4-
494 4-
494 4-
99 4-
0
988 4-
494 4-
99 4-
494 4-
* Source: U.S. EPA, 1976: Aviado, 1975b,c
**Approx. minimal concentration (10 mg/m ) producing response; 0 indicates absent or oppo-
site responses
4-, ++ or 4-4-4- indicate degree of response
C-51
-------
substances have been classified according to their cardiopulmonary
toxicities in animal studies, as summarized in Table 16. Of all
the aerosol propellants studied and classified on the basis of car-
diopulmonary effects, Aviado (1975a) concluded that P-ll is the
most toxic and that the most serious effects are induction of car-
diac arrhythmia and sensitization to epinephrine-induced arrhyth-
mias. 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).
Several animal studies provide evidence that pre-existing car-
diac 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 Aviado, 1975). Also, Wills (1972)
demonstrated a dose related (in range of 0.005 to 0.015 mg/kg) re-
sponse to epinephrine (arrhythmic 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
bronchodilators 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).
Pathologic liver changes were reported in guinea pigs chronic-
ally 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
C-52
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TABLE 16
Classification of Fluorocarbon and Other Propellant Compounds
on the Basis of Cardiovascular and Bronchopulmonary Toxicity*
Class and Compounds
Characteristics
I .
II
III.
IV.
Low Pressure Propellants of
High Toxicity
CCl^F (F-ll), CHC1?F(F-21)
CC12F-CC1F2(F-113)7 CH2C12,
and trichloroethane.
Low Pressure Propellants of
Intermediate Toxicity
CC1F2-CC1F2(F-114),
CClF2-CH3(F-142b), isobutane
and octafluorocyclobutane
High Pressure Propellants
of Intermediate Toxicity
CC12F2(F-12),CHClF2(F-22),
propane, and vinyl chloride
High Pressure Propellants
of Low Toxicity
F-115 and F-125b
Toxic at 0.5-5% (v/v) in monkey and dog, and 1-10%
in rat and mouse. Induce cardiac arrhythmias; sen-
sitize heart to epinephrine-induced arrhythmias;
cause tachycardia, myocardial depression, hypoten-
sion. Primarily cardiovascular 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 bronchoconstric-
tion 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 car-
diosensitization and circulatory effects, but
respiratory depression and broncho-effects predomi-
nate 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.
*Source: U.S. EPA, 1976; Aviado, 1975b
C-53
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TABLE 17
Comparative Acute Toxicity Classification
Refrigerants*
Toxicity Concentration, Exposure duration to
class percent (v/v) produce death or serious
injury in animals (hours)
1 0.5-1 0.83 (5 min.)
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
*Source: Underwriters Labs, 1971
C-54
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(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/m for 90 days or at 57.5 x 10
mg/m for eight hrs/day for five days/week for six weeks; pneumon-
itic changes were noted in all test groups (except in dogs exposed
intermittently), 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); de-
creased oxygen consumption and increase in the stimulus strength
required to induce response (rats); several hematologic and blood
chemistry changes (rabbits) and degenerative patnoanatomic changes
in heart, liver, kidney, nervous system, and lungs (Clayton, 1966).
Applications of F-ll, F-12 and some mixed fluorocarbons re-
peated twice daily over several weeks to skin and oral mucosa of
rats have produced irritation, edema, and inf lairmat ion. These ef-
fects were most marked in the F-ll/F-22 mixture in older subjects.
The healing rate of burn lesions was retarded by appliations of
F-ll, F-12 and F-22 (Quevauviller, et al. 1964; Quevauviller,
1965). The rapid evaporation of fluorocarbons applied directly to
integumentary surfaces may result in chilling or freezing and may
be the principal hazard in acute dermal exposure to the more vola-
tile compounds. Dermal absorption and resulting systemic coxicity
are more important in the less volatile fluorocarbons.
C-55
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Information on oral route toxicity is limited (Howard, et al.
1974). Acute intragastric doses of F-ll at 7,380 mg/kg were re-
ported 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, he-
matology, or histopathology were noted. There were no signs of
toxicity in dogs given 8 and 80 mg/kg daily in their diet (Sherman,
1974).
Synergism and/or Antagonism
Probably the most obvious concern in regard to this aspect is
the cardiac sensitization by fluorocarbons to arrhythmogenic ef-
fects of circulating or administered catecholamines (e.g., epineph-
rine) or asphyxia. Stress situations or certain drugs taken in
conjunction with or as a component of fluorocarbon propellant prod-
ucts may present an opportunity for synergistic consequences
(Howard, et al. 1974).
Teratogenicity
There are no available data on the teratogenicity of halo-
methanes.
C-56
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Mutagen icity
Information on the mutagenicity of halomethanes is very lim-
ited. Recently, however, three groups of investigators have re-
ported positive results with certain alkyl halides in the Ames Sal-
monella 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 dichloromethane
were all mutagenic to Salmonella typhimur ium strain TA100 when as-
sayed in a dessicator whose atmosphere contained the test compound.
Metabolic activation was not required for the expression of muta-
genic 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 indi-
cated, and the criteria used for determination of a significant
C-57
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mutagenic response were not specified. If the most stringent eval-
uation criteria were applied (in which the ratio of: experimental -
control/control must exceed 2.5), bromoform and bromodichloro-
methane 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 Salmonella typhimur ium strain TA1535 in the pres-
ence and absence of added liver homogenate preparations. Simmon,
et al. (1977) indicated that although dichloromethane was muta-
genic in the Ames assay, it did not increase mitotic recombination
in S_. cerevis iae strain D3. In addition, it was reported that
dichloromethane was negative on testing for mutagenicity in Droso-
phila (Filippova, et al. 1967).
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 frameshift mutations, dose-
related increases in mutation rate were obtained using vapor phase
exposures (5,700 - 57,000 ppm). The addition of a microsomal prep-
aration was not necessary for the production of mutations, although
a slight enhancement in mutation rate could be obtained with rat
liver homogenate. An explanation why certain halomethanes 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 incu-
bation of labeled F-ll (also CC1., CHC1, and halothane) with liver
4 J
:-58
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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 test system.
Further testing is obviously required to establish the muta-
gneic potential of any or all of the halomethanes. Many investiga-
tors agree that a compound should demonstrate positive results in
at least two different short-term assay systems before it is ac-
cepted as a mutagen/carcinogen. Nevertheless, based on the pres-
ently available mutagenicity 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-
chloride, and iodomethane are generally regarded to be carcinogenic
in animals (NAS, 1978). Limited new data, however, implicate sev-
eral additional compounds as potential tumorigens. These data were
developed using the strain A mouse lung tumor assay system, a bio-
assay 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
C-59
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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 dichloromethane in strain A
mice. Male animals, six to eight weeks old, were injected intra-
peritoneally up to three times weekly over a period of eight weeks.
Three dose levels were employed with each test chemical, represent-
ing the maximum 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 in 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 summarized
in Table 18. These data indicate that in no case were all three
criteria met, as indicated above, for the establishment of a posi-
tive response. Nevertheless, it is clear that bromoform produced a
significant increase in tumor response at the intermediate dose.
In addition, d ichloromethane at the low dose only, and bromodi-
chloromethane at the high dose only, produced results which were
marginally significant. Overall, the results of this study are
C-60
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TABLE 18
Pulmonary Timor Response to Organic Water Contaminants*
Compound
Tr icaprylin
Dromoforn
Dromodichloromethane
D 1 c h lo rorae t hane
Urethane
0.9% NaCl solution
Dose/
Vehicle Injection
(mg/Kg)
Ta
T 4
48
100
T 20
40
100
T 160
400
800
S 1,000
S
No. of l.p.
Injections
24
18
23
24
18
24
24
17
17
16
1
24
Total dose No. of animals
(mg/kg) survivors/initial
72
1,100
2,400
360
960
2,400
2,720
6,800
12,800
1,000
15/20
17/20
15/20
15/20
15/20
16/20
13/20
18/20
5/20
12/20
20/20
47/50
No. of lung
tumors/mouse
0
0
1
0
0
0
.27 1
.53 +
.13 +
.67 +
.20 +
.25 +
0.85 +
0
0
0
0
.94 i
.80 +
.50 +
19.6
.19 +
0.
0.
0.
0.
0.
0.
0.
0.
0.
0.
t 2
0.
15b
21
36
21
11
11
27
03
5B
15
.4
06
0.
0.
0.
0.
0.
0.
0.
0.
0.
P
335
04 1C
136
724
930
067
053
417
295
•Source: The 1ss, et al. 1977
aTrIcaprylln, S, 0.9% NaCl solution
Average 4; S.E.
cp<0.05
C-61
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suggestive of carcinogenic activity but do not in themselves pro-
vide an adequate basis for the development of a carcinogenic based
risk assessment for humans. Moreover, it has been stated with
regard to the strain A mouse lung tumor system that, "positive com-
pounds require extension to other systems, such as lifetime expo-
sure of rats" (Shirnkin and Stoner, 1975).
Unfortunately, there are little additional data to either con-
firm or deny the potential carcinogenicity of most halomethanes.
Poirier and cowor
-------
however, only dichloromethane has been investigated for cell trans-
formation activity.
Price, et al. (1978) reported that Fischer rat embryo cells
(F1706) were transformed by dichloromethane at high concentrations
-3 -4
(1.6 x 10 M and 1.6 x 10 M) in the growth medium. In addition,
transformed cells produced fibrosarcomas when injected subcuta-
neous ly into newborn rats.
Further research by Sivak (1978) has indicated, however, that
the observed cell transforming capability of dichloromethane may
have been due to impurities in the test material. Sivak (1978) re-
ported that when the experiments of Price, et al. (1978) were re-
peated using highly purified food grade dichloromethane no trans-
formation occurred. Additional studies were conducted by Sivak
(1978) in which food grade dichloromethane was tested in the
BALD/C-3T3 mouse cell transformation assay system at three concen-
trations in the growth medium. Although transformed foci were ob-
served at all dose levels, a dose-response relationship was not re-
vealed, nor were the number of foci increased relative to results
with untreated controls. Difficulty in the interpretation of these
results, however, arises from the fact that dichloromethane (boil-
ing 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 dichloromethane in in
vitro test systems is not known. This problem may be particularly
C-63
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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
carcinogenic 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 di-
chloromethane included: cyclohexane (305 ppm), transdichloro-
ethylene (86 ppm), vinyldene chloride (33 ppm), methyl bromide (11
ppm), chloroform ( 10 ppm), carbon tetrachloride ( 5 ppm) and ethyl
chloride (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 ob-
served biological effects.
Careinogenicity data on the fluorocarbons are scant. No human
or animal data on carci nogenici ty 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 de-
veloped in recent years. The possibility that increasing use and
release of fluorocarbons to the atmosphere may contaminate the
stratosphere and cause depletion of protective, ultraviolet-
absorptive 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 deple-
tion); (b) altered animal cancer and disease patterns; (c) reduced
C-64
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growth and productivity of plants; and (d) climatic changes and
ecologic shifts (U.S. EPA, 1976).
A number of studies have sought to establish an association
between trihalomethane levels in municipal drinking water supplies
and the incidence of cancers in the U.S. population (NAS, 1978).
Several epidemiologic studies have shown positive correlations
between certain cancer death rates (various sites) and water qual-
ity 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 reported positive
associations between cancer mortality rates (several sites) and
brominated trihalomethanes (BTHM). BTHM is comprised mostly of
bromodichloromethane and chlorodibromomethane, but measurable le-
vels 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 on the epidemiologic evi-
dence 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 attributable to the presence of trihalomethanes
(U.S. EPA, 1978a).
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CRITERION FORMULATION
Existing Guidelines and Standards
Chloromethane
1. A warning label is required by Federal Insecticide, Fungi-
cide and Rodenticide Act (FIFRA). Interpretation is with respect
to warning, caution, and antidote statements required to appear on
labels of economic poisons (27 FR 2267).
2. Food tolerance requirement of Federal Food, Drug and Cos-
metic Act: chloromethane is permitted as the propellant in pesti-
cide formulations, up to 30 percent of finished formulation, when
used in food storage/processing areas not contacting fatty foods.
27 FR 4623.
3. Human exposure: (1) A maximum permissible concentration
(MFC) of 5 mg/m in industrial plant atmospheres was established in
Russia based on rat studies of chronic poisoning (Evtushenko,
1966); (2) OSHA (L976) has established the maximum acceptable time-
weighted average air concentration for daily eight-hour occupation-
al 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. Multimedia Environmental Goals, (MEG) Estimated Permissi-
ble 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/1
EPC, land, health: 5.8 mg/kg
C-66
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Bromome thane
1. A warning and antidote labeling is required by FIFRA.
Interpretation with respect to warning, caution, and antidote
statements is 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 re-
sulting from fumigation with methyl bromide. 22 FR 5682 and sub-
sequent 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/m ,
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
interlocking period ceilings of 97 mg/m , and 194 mg/m (five min-
utes) (Am. Natl. Stand. Inst., 1970); (4) The industrial TLV
(threshold limit value) of 78 mg/m to prevent neurotoxic and pul-
monary effects was established by the American Conference of
Governmental Industrial Hygienists (Stokinger, et al. 1963; ACGIH,
1971).
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Dichloromethane
1. As an oil and fat solvent, dichloromethane is allowed in
spice oleoresins at up to 30 mg/kg and in decaffeinated coffee at
up to 10 mg/kg (21 CFR 121.1039).
2. Human exposure: (1) OSHA (1976) has established occupa-
tional exposure standards as follows: eight-hour time weighted av-
erage (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 meta-
bolic 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 le-
vels, lower levels of dichloromethane are required. (3) Permissi-
ble 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 NIOSH, 1976a). (4) The maximum permissable concen-
tration 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).
3. MEG values for Estimated Permissible Concentrations (U.S.
EPA, 1977):
EPC, air, health: 0.619 mg/m
EPC, water, health (1) 9.18 mg/1
EPC, water, health (2) 3.59 mg/1
EPC, land, health: 7.2 mg/kg
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Tr ibromomethane
Human exposure: (1) The OSHA Occupational Exposure Standard
for workroom air (eight-hour TWA) is 5 mg/m , with a dermal absorp-
tion warning notation (OSHA, 1976). (2) Tribromomethane is one of
four trihalomethanes 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).
Bromod ichloromethane
Human exposure: (1) There is no currently established occupa-
tional exposure standard for bromodichloromethane in the U.S. (2)
Bromodichloromethane, along with chlorodibromomethane, trichloro-
methane (chloroform) and tribromomethane form the group of halo-
methanes termed total trihalomethanes (TTHM), which are to be regu-
lated in finished drinking water in the U.S. The maximum permissi-
ble concentration set for TTHM in the proposed regulations is 0.100
mg/1.
Trichlorofluoromethane 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 (32 FR 6739).
Human exposure: (1) The current OSHA eight-hour TWA occupa-
tional standards for F-ll and F-12 are 5,600 and 4,950 mg/m ,
respectively (OSHA, 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
C-69
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(Howard, et al. 1974). (2) The U.S. EPA has requested that pesti-
cide formulators seek suitable alternative propellants for products
dispensed as aerosols, in view of the ozone depletion concern. (3)
Pressurized containers must meet Interstate Commerce Commission
(ICC) regulations 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 trihalo-
methanes as a group, determined that they represent a potential yet
reducible hazard to public health, and proposed regulations estab-
lishing 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 (rationale,
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 considerations
among the halomethanes is that for dichloromethane. 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 dis-
turbed oxygen transport. NIOSH, recognizing this combined stress
hazard, has recommended lowering the existing TLV for dichloro-
methane and tying it with existing CO exposure levels.
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A second possible special risk concerns exposures to fluoro-
carbon vapors. In this case there is evidence that a characteris-
tic toxicity involves sensitization to cardioarrhythmogenic ef-
fects of endogenous or administered epinephrine and related cate-
cholamines. An individual with cardiac disease taking certain med-
ication or in an acutely stressed state may be especially suscepti-
ble to fluorocarbon cardiotoxicity.
Basis and Derivation of Criteria
Data on current levels of the halomethanes in water, food, and
ambient air are not sufficient to permit adequate estimates of to-
tal human exposures from these media. Available data discussed in
an earlier section of this report (Occurrence) indicate that the
greatest human exposure to the trihalomethanes occurs through the
consumption of liquids (including drinking water and beverages con-
taining it), and that exposure to chlorofluorocarbons, chloro-
methane, dichloromethane,and bromomethane occurs primarily by in-
halation.
Observed correlations among concentrations of trihalomethanes
in finished water are attributed to the presence of common organic
precursor materials in raw water (NAS, 1978). Among the halo-
methanes considered in this report, bromodichloromethane seems to
predominate in drinking waters. Concentrations of bromodichloro-
methane in raw and finished water samples are generally in the area
of 6 pg/1 or less, and thus represent a reasonable upper limit for
anticipated levels of any halomethane in water (excluding chloro-
form and carbon tetrachloride).
C-71
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Recent reports showing that chloromethane, bromomethane, tri-
bromomethane, 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 carcinogenicity data base for these compounds
is judged qualitatively informative but quantitatively inadequate
for risk extrapolation, an alternative approach is necessary for
criteria development.
The halomethanes included in this document have not been
adequately tested for carcinogenicity. However, bromomethane,
chloromethane, dichloromethane, tribromomethane and bromodichloro-
methane have been found to be mutagenic in the Ames test without
metabolic activation (Simmon et al. 1977). Based on the demon-
strated if variable relationship between positive responses in the
Ames assay and positive results in cancer bioassays (Purchase, et
al. 1978), the mutagenicity data suggest that these compounds may
pose a carcinogenic risk. In the absence of carcinogenic data in
mammalian species, the U.S. EPA's Carcinogen Assessment Group has
considered the structural similarity of chloroform with these halo-
methanes as well as their mutagenic activity, and has recommended
that the criterion for the class be identical to that of chloro-
form. The major drawback of this approach is that relatively minor
structural changes in a molecule can have a profound effect on car-
cinogenic potency. Consequently, it cannot be determined whether
this criteria is protective of carcinogenic risk. The criterion
for chloroform is 1.9 ug/1 (see Appendix 1).
C-'
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An alternative approach is to derive criteria for the individ-
ual halomethanes based on the available toxicity data.
Chlo route thane:
There are no reports in the published literature concerning
the toxicity of Chloromethane resulting from chronic oral exposure
in either laboratory animals or man. However, human experience
with Chloromethane in the workplace has provided a fairly extensive
data base concerning its inhalation toxicity in man. Consequently,
the currently recommended ACGIH TLV of 100 ppm is based upon the
known CNS effects of inhaled Chloromethane in humans. This TLV
represents an acceptable 8-hour time-weighted average exposure in
the workplace. Exposure to the general population, however, should
be considerably less since worker groups are assumed to be healthy
and are not continuously exposed.
A water quality criterion for Chloromethane based upon the
ACGIH TLV of 100 ppm (210 mg/m ) can be derived using the approach
of Stokinger and Woodward (1958). It must be recognized, however,
that assumptions must be made in the estimation of equivalent oral
doses from inhalation data. This involves primarily an approxima-
tion of the efficiency of inhalation absorption and the average
breathing rate. Thus a safety factor of 100 is included in the
derivation in order to provide a wider margin of safety in light of
the uncertainty in these assumptions. This calculation for Chloro-
methane is illustrated as follows:
210 mg/m x 50 m /week x 0.50*
7 days/week x 100** = 7'5 mg/day
*Estimated coefficient of absorption via inhalation and in-
gestion
**Safety factor
C-73
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Assuming a daily water consumption of 2 liters, the acceptable con-
centration of chloromethane would be 3.8 mg/liter on the basis of
noncarcinogenic risks. Note that bioconcentration is considered
not to occur with chloromethane,
Bromomethane:
Similar to the case with chloromethane, a large data base ex-
ists regarding the human toxicity of inhaled bromomethane whereas
little is known concerning the effects of chronic ingestion by lab-
oratory animals or man. The current ACGIH TLV of 20 ppm (77.6
mg/m } for bromomethane can be used for derivation of a water qual-
ity crtierion based upon the approach of Stokinger and Woodward
(1958). However, the same precautions apply to this derivation for
bromomethane by this approach as for chloromethane. The TLV ap-
proach is considered worthwhile, nevertheless, since the TLV is
based upon the systemic toxicity produced in humans which has been
well documented. This calculation for bromomethane is illustrated
as follows:
77.6 mg/m3 x 50 m3***/week x 0.50* - __ „„,,,,,,
7 days/Week x 100** = 2'77 mg/day
*Estimated coefficient of absorption via inhalation vs. in-
gestion
**Safety factor
***Estimated weekly respiratory volume during a 40 hr work week
Assuming a daily water consumption of 2 liters, the acceptable con-
centration of bromomethane would be 1.39 mg/liter on the basis of
noncarcinogenic risks. Since no bioconcentration factor is availa-
ble for bromomethane, it is not known how the consumption of fish
and shellfish may alter the acceptable level for water.
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Dichloromethane:
The toxicity of dichloromethane has not been studied by chron-
ic ingestion in laboratory animals. However, a chronic study has
been undertaken by the National Cancer Institute which may provide
the necessary dose-response data for criterion formulation once it
is published. Considerable human experience with dichloromethane
in the workplace has led to the development of an ACGIH TLV for in-
halation exposure. A limit of 200 ppm (694 mg/m ) has been recom-
mended for protection against excessive carboxyhemoglobin forma-
tion. Previously, a limit of 500 ppm had been proposed for preven-
tion of narcotic effects or liver injury. Using the Stokinger and
Woodward (1958) approach as discussed above, a water quality cri-
terion may be derived from the TLV as illustrated below:
694 mg/m3 x 50m3/week x 0.50* = 24>8 mg day
7 days/week x 100**
*Estimated coefficient of absorption via inhalation vs. in
gestion
**Safety factor
Assuming a daily water intake of 2 liters, and the consumption of
6.5 g of fish and shellfish per day (bioconcentration factor 0.91),
the derived water quality criterion would be 12.4 mg/liter based on
noncarcinogenic risks.
Tr ibromomethane:
Quantitative dose-response information regarding tribromo-
methane toxicity is very limited. In particular chronic exposure
studies have not been published in sufficient detail to be used as
the basis for criterion formulation. Suggestive evidence of car-
cinogenic activity for tribromomethane (i.e., in the Strain A mouse
C-75
-------
pulmonary tumor assay) is not adequate for quantitative risk as-
sessment. Furthermore, since the ACGIH TLV for tribromomethane is
based primarily upon irritation as the toxic end-point, it is also
inappropriate for use as the basis for criterion formulation.
Therefore, pending the results of chronic bioassay studies, it is
not presently possible to derive a valid water quality criterion
for tribromomethane.
Bromodichloromethane:
The human toxicity of bromodichloromethane has not been sys-
tematically studied, nor has its chronic toxicity in other animals
been reported in great detail. In two studies where mice were ex-
posed by gavage for 90 days at a dose of 125 mg/kg/day, effects on
cellular defense mechanisms were noted (Schuller et al. 1978;
Munson et al. 1977). However, since dose-response relationships
were not reported, this free standing adverse effects level cannot
be used for criteria derivation. Furthermore, there are no TLVs
for human exposure to bromodichloromethane in the workplace.
Therefore, it is not presently possible to derive a valid water
criterion for bromodichloromethane based on noncarcinogenic risks.
Dichlorod ifluoromethane:
Evidence for mutagenicity of dichlorodifluoromethane is equi-
vocal and there is no evidence as yet for carcinogenic!ty as a re-
sult of direct exposure. Chronic toxicity data for dichlorodi-
fluoromethane 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 (NAS,
C-76
-------
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.
Trichlorofluoromethane:
There is no evidence for mutagenicity of trichlorofluoro-
methane, and no evidence as yet for carcinogenicity as a result of
direct exposure. The only data on toxicity testing using prolonged
exposure at relatively low test concentrations is from a report
{Jenkins, et al. 1970) in which no adverse effects were observed
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,
his estimated exposure dose would be 5,610 x 23 (24 hour respira-
tory volume in m ) x 0.5 = 64,515 mg/day or 922 mg/kg/day. Applying
an uncertainty factor of 1,000 (NAS, 1977) to this data yields a
presumptive "acceptable daily intake" of 0.922 mg/kg/day for tri-
chlorofluoromethane. 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.
C-77
-------
In summary, criterion levels intended to protect the public
against noncarcinogenic effects resulting from exposure to selected
halomethanes are as follows:
Compound mg/1
Chloromethane 3.8
Bromomethane 1.4
Dichloromethane 12.4
Tribromomethane *
Bromodichloromethane *
Dichlorofluoromethane 2.8
Trichlorofluoromethane 32,3
*No criterion derived
C-78
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REFERENCES
Ahmed, A.E., et al. 1977. Metabolism of haloforms to carbon mon-
oxide. I. In vitro studies. Drug Metab. Dispos. 5: 198. (Abst.)
Allen and Hanburys. 1971. An investigation of possible cardio-
toxic effects of the aerosol propellants, Arctons 11 and 12. Vol.
1. (Unpubl. rep.}
American Conference of Governmental and Industrial Hygienists.
1971. Documentation of the threshold limit values for substances
in workroom air. Cincinnati, Ohio.
American National Standards Institute. 1970. American national
standard for acceptable concentrations of methyl bromide (mono-
bromomethane). ANSI Z37.24.
Andrews, A.W., et al. 1976. A comparison of the mutagenic prop-
erties of vinyl chloride and methyl chloride. Mutat. Res.
40: 273.
Araki, S., et al. 1971. Methyl bromide poisoning. A report based
on fourteen cases. Jap. Jour. Ind. Health. 13: 507.
Archer, V.E. 1973. Letter to editor. Br. Med. Jour. 3: 5882.
C-79
-------
Astrand, I., et al. 1975. Exposure to methylene chloride. I. Its
concentration in alveolar air and blood during rest and exercise
and its metabolism. Scand. Jour. Workplace Environ. Health.
1: 78.
Aviado, D.M, 1975a. Toxicity of aerosol propellents on the res-
piratory and circulatory systems. IX. Summary of the most toxic:
Trichlorofluoromethane (FC-11). Toxicology. 3: 311.
Aviado, D.M. 1975b. Toxicity of aerosol propellants on the res-
piratory and circulatory systems. X. Proposed classification.
Toxicology. 3: 321.
Aviado, D.M. 1975c. Toxicity of aerosols. Jour. Clin.
Pharmacol. 15: 86.
Avilova, G.G., et al. 1973. Itogi Navki Tekh., Farmakol.,
Khimioter. Svedstva, Toksikol. Probl. Toksikol. 5: 92. (Rus.)
(Abst.)
Azar, A., et al. 1972. Experimental human exposures to fluoro-
carbon 12 (dichlorofluoromethane). Am. Ind. Hyg. Assoc. Jour.
33: 207.
Azar, A., et al. 1973. Blood levels of fluorocarbon related to
cardiac sensitization. Am. Ind. Hyg. Assoc. Jour. 34: 102.B
C-80
-------
Baird, T.T. 1954. Methyl chloride poisoning. Br. Med. Jour.
2: 1353.
Balander, P.A. and M.G. Polyak. 1962. Toxicological characteriza-
tion of methyl bromide. Gig. i Toksikol. Novykh. Pestitsidov i
Klinika Otravlenii, Dokl. 2-oi (Vtoroi) Vses. Konf. 412.
Ballantyne, B. , et al. 1976. The ophthalmic toxicology of di-
chloromethane. Toxicology. 6: 173.
Balmer, M.F., et al. 1976. Effects in the liver of methylene
chloride inhaled alone and with ethyl alcohol. Am. Ind. Hyg.
Assoc. Jour. 37: 345.
Barnsley, E.A. 1964. The metabolism of S-methyl-L-cysteine in the
rat. Biochem. Biophys. Acta. 90: 24.
Barnsley, E.A. and L. Young. 1965. Biochemical studies of toxic
agents. The metabolism of iodomethane. Biochem. Jour. 95: 77.
Bass, M. 1970. Sudden sniffing death. Jour. Am. Med. Assoc.
212: 2075.
Benatt, A.J. and T.R.B. Courtney. 1948. Uraemia in methyl bromide
poisoning: Case report. Br. Jour. Ind. Med. 5: 21.
C-81
-------
Blake, D.A. and G.W. Mergner. L974. Inhalation studies on the
14
biotransformation and elimination of ( C)-trichlorofluoromethane
14
and ( C)-dichlorodifluoromethane in beagles. Toxicol. Appl.
Pharmacol. 30: 396.
Bowman, F.G., et al. 1978. The toxicity of some halomethanes in
mice. Toxicol. Appl. Pharmacol. 44: 213.
Boyland, E., et al. 1961. Metabolism of polycyclic compounds. 18.
The secretion of naphthalene 1:2-dihydronaphthlene and l:2-epoxy-
1,2,3,4-tetrahydronapthalene in rat bile. Biochem. Jour. 78: 376.
Bridbord, K. , et al. 1974. Exposure to halogenated hydrocarbons
in the indoor environment. Presented at Conf. Publ. Health Impli-
cations of Plastic Manufacturing, Pinehurst, North Carolina.
Browning, E. 1965. Toxicity and Metabolism of Industrial Sol-
vents. Elsevier Publishing Co., Amsterdam.
Bruhin, J. 1943. Deutsches Gesund Gerichtles Medicine 37, A253.
Thesis. Zurich, Switzerland. (See von Oettingen, 1964).
Campbell, K. 1978. Unpubl. data.
C-82
-------
Cantor, K.P. and L.J. McCabe. 1977. The epidemiologic approach to
the evaluation of organics in drinking water. In; Proc. Conf. Wa-
ter Chlorination: Environ. Impact and Health Effects. Gatlinburg,
Tennessee, Oct. 31 - Nov. 4.
Cantor, K.P., et al. 1978. Associations of halomethanes in drink-
ing water with cancer mortality. Jour. Natl. Cancer Inst. 61:
979.
Carlsson, A. and M. Hultengren. 1975. Exposure to methylene
14
chloride. III. Metabolism of C-labeled methylene dichloride in
rat. Scand. Jour. Work Environ. Health. 1: 104.
Carter, V.L., et al. 1970a. Effects of inhalation of freon 113 on
laboratory animals. Rep. AD 727524. Natl. Tech. Inf. Serv.
Springfield, Virginia.
on
Carter, V.L., et al. 1970b. Effect of bromotrifluoromethane
operant behavior in monkeys. Toxicol. Appl. Pharmacol. 17: 307.
Chiou, W.L. and 5. Niazi. 1973. A simple and ultra-sensitive
headspace gas chromatographic method for the assay of fluorocarbon
propellants in blood. Res. Commun. Chem. Pathol. Pharmacol.
6: 481.
Chopra, N.M. and L.R. Sherman. 1972. Systemic studies on the
breakdown of p,p'-DDT in tobacco smokes. Anal. Chem. 44: 1036.
C-83
-------
Clark, D.G. and D.J. Tinston. 1972a. The influence of fluorocarbon
propellants on the arrythmogenic activities of adrenaline and iso-
prenaline. Proc. Eur. Soc. Study Drug Toxic. 13: 212.
Clark, D.G. and D.J. Tinston. 1972b. Cardiac effects of isopro-
terenol, hypoxia, hypercapnia, and fluorocarbon propellants and
their use in asthma inhalers. Ann. Allergy. 30: 536.
Clarke, C.A., et al. 1945. Methyl bromide poisoning: Account of
four recent cases met with in one of H.M. ships. Br. Jour. Ind.
Med. 2: 17.
Clayton, J.W. 1966. The mammalian toxicology of organic compounds
containing fluorine. Handbuch Exp. Pharmakol. 20: 459.
Collier, H. 1936. Methylene dichloride intoxication industry - a
report of two cases. Lancet. 1: 594.
Collins, R.P. 1965. Methyl bromide poisoning: A bizarre neuro-
logical disorder. Calif. Med. 103: 112.
Cox, P.J., et al. 1972. A comparison of the interactions of tri-
chlorofluoromethane and carbon tetrachloride with hepatic cyto-
chrome P-450. Biochem. Jour. 130: 87.
Cox, R.A., et al. 1976. Photochemical oxidation of halocarbons in
the troposphere. Atmos. Environ. 10: 305.
:-34
-------
Cronn, D.R., et al. 1976. Measurement of tropospheric halocarbon
by gas chromatography - mass spectrometry. Rep. Phase I of EPA
Grant No. R0804033-01. U.S. EPA, Research Triangle Park, North
Carolina.
Davis, L.N., et al. 1977. Investigation of selected potential en-
vironmental contaminants: Monohalomethanes. EPA 560/2-77-007; TR
77-535. Final rep. June, 1977, on Contract No. 68-01-4315. Off.
Toxic Subst. U.S. EPA, Washington, D.C.
Dennis, N.M., et al. 1972. Formation of methyl chloride during
methyl bromide fumigations. Jour. Econ. Entomol. 65: 1753.
DiVincenzo, G.D. and M.L. Hamilton. 1975. Fate and disposition of
14
( C) methylene chloride in the rat. Toxicol. Appl. Pharmacol.
32: 385.
DiVincenzo, G.D., et al. 1972. Human and canine exposures to
methylene chloride vapor. Am. Ind. Hyg. Assoc. Jour. 33: 125.
Dixon, M. and D.M. Needham. 1946. Biochemical research on chem-
ical warfare agents. Nature. 158: 432.
Doherty, R.E. and D.M. Aviado. 1975. Toxicity of aerosol propel-
lants on the respiratory and circulatory systems. VI. Influence
of cardiac and pulmonary vascular lesions in the rat. Toxicology.
3: 213.
C-85
-------
Donahue, E.V., et al. 1978. Detection of mutagenic impurities in
carcinogens and noncarcinogens by high-pressure liquid chromato-
graphy and the Salmonella/Microsome test. Cancer Res. 38: 431.
Drawneek, W. , et al. 1964. Industrial methylbromide poisoning in
fumigators. Lancet. 2: 855.
Dunavskii, G.A. 1972. Functional condition of circulatory organs
in workers employed in the production of organochlorine compounds.
Gig. Tr. Prof. Zabol. 16: 48. (Rus.) (Abst.)
Du Pont de Nemours and Co. 1968. Human skin absorption studies
with tr ichlorotr if luoroethane, F-113. Med. Res. Proj. Rep. No.
84-68.
Du Pont de Nemours and Co. 1973. Interstate Commerce Commission
regulations and containers for freon fluorocarbons. Bull. D-75.
Dykan, V.A. 1962. Changes in liver and kidney functions due to
raethylene bromide and bromoform. Nauchn. Trudy Ukr. Nauchn.-
Issled. Inst. Gig. Truda Profzabol. 29: 82.
Eddy, C.W. and F.D. Griffith. 1961. Metabolism of 14C-dichloro-
difluoromethane by rats. Presented at Am. Ind. Hyg. Assoc. Conf.
Toronto, Can. May, 1971.
C-86
-------
Evtushenko, G.Y. 1966. Methyl chloride toxicology. Gig. Tr.
Prof. Zabol. 10: 20.
Fassett, D. W. 1972. Toxicity of halogenated solvents, aerosol
propellants, and fire-extinguishants. In: Proc. Third Annu. Conf.
Environ. Toxicol. AMRL-TR-72-130. Aerospace Med. Res. Lab.,
Wright-Patterson Air Force Base, Ohio.
Filippova, L.M., et al. 1967. Chemical mutagens. IV. Mutagenic
activity of geminal system. Genetika. 8: 134.
Fodor, G.G. and A. Roscovanu. 1976. Increased blood-CO-content in
humans and animals by incorporated halogenated hydrocarbons.
Zentralbl Bakteriol. (Orig B) 162: 34. (Ger. ) (Abst.}
Getzendaner, M.E., et al. 1968. Bromide residues from methyl bro-
mide fumigation of food commodities. Jour. Agric. Food Chem.
16: 265.
Good, W.O., et al. 1975. Sputum cytology among frequent users of
pressurized spray cans. Cancer Res. 35: 316.
Gorbachev, E.M., et al. 1962. Disturbances in neuroendocrine reg-
ulation and oxidation-reduction by certain commercial poisons.
Plenuma Patofiziol Sibiri Dal'n. Vost. Sb. 88.
C-87
-------
Greenberg, J.O. 1971. The neurological effects of methyl bromide
poisoning. Ind. Med. Surg. 40: 27.
Grimsrud, E.P. and R.A. Rasmussen. 1975. Survey and analysis of
halocarbons in the atmosphere by gas chromatography-mass spectrome-
try. Atmos. Environ. 9: 1014.
Hansch, C. and A. J. Leo. 1979. Substituent Constants for Cor-
relation Analysis in Chemistry and Biology. Wiley Interscience,
New York.
Hansen, H., et al. 1953. Methyl chloride intoxification: Report
of 15 cases. AMA Arch. Ind. Hyg. Occup. Med. 8: 328.
Harsch, D. 1977. Study of halocarbon concentrations in indoor en-
vironments. Final rep. EPA Contract No. WA 6-99-2922-J. U.S.
EPA, Washington, D.C.
Harsch, D. and R.A. Rasmussen. 1977. Identification of methyl
bromide in urban air. EPA Contract No. WA 6-99-2922-Jour. Off.
Res. Dev., U.S. EPA, Washington, D.C. (Unpubl. rep.)
Haun, C. , et al. 1972. Continuous Animal Exposure to Low Levels of
Dichloromethane. In; Proc. Third Annu. Conf. Environ. Toxicol.
AMRL-TR-130: 12. Aerospace Med. Res. Lab., Wright Patterson Air
Force Base, Ohio.
C-88
-------
Health and Welfare Canada. 1977. Environmental Health Directorate
national survey of halomethane in drinking water.
Heppel, L.A. and P.A. Neal. 1944. Toxicology of dichloromethane
(methylene chloride). II. Its effect upon running activity in the
male rat. Jour. Ind. Hyg. Toxicol. 26: 17.
Hester, N.E., et al. 1974. Fluorocarbons in the Los Angeles ba-
sin. Air Pollut. Control Assoc. Jour. 24: 591.
Hine, C.H. 1969. Methyl bromide poisoning. Jour. Occup. Med.
11: 1.
Howard, P. and A. Hanchett. 1975. Chlorofluorocarbon sources of
environ-contamination. Science. 189: 217.
Howard, P.H., et al. 1974. Environmental hazard assessment of one
and two carbon fluorocarbons. EPA 560/2-75-003. TR-74-572.1.
Off. Toxic Subst. U.S. EPA, Washington, D.C.
Hughes, J.P. 1954. Hazardous exposure to some so-called safe sol-
vents. Jour. Am. Med. Assoc. 156: 234.
International Agency for Research on Cancer. 1978. Information
bulletin on the survey of chemicals being tested for carcinogen-
icity, No. 7. World Health Organ., Lyon, France.
C-89
-------
Irish, D.D., et al. 1940. The response attending exposure of lab-
oratory animals to vapors of methyl bromide. Jour. Ind. Hyg.
Toxicol. 22: 218.
Irish, D.D., et al. 1941. Chemical changes of methyl bromide in
the animal body in relation to its physiological effects. Jour.
Ind. Hyg. Toxicol. 23: 408.
Jenkins, L.J., et al. 1970. Repeated and continuous exposure of
laboratory animals to trichlorofluoromethane. Toxicol. Appl.
Pharmacol. 16: 133.
Johnson, M.K. 1966. Metabolism of iodomethane in the rat.
Biochem. Jour. 98: 38.
Johnstone, R. 1945. Methyl bromide intoxication of large group of
workers. Ind. Med. 14: 495.
Jongen, W.M.F., et al. 1978. Mutagenic effect of dichloromethane on
Salmonella typhimurium. Mutat. Res. 56: 245.
Kakizaki, T. 1967. Studies on methyl bromide poisoning. Ind.
Health. 5: 135.
Karpov, B.C. 1963. Tr. Leningr. Sanit.-Gigien. Med. Inst.
75: 231. (Summarized in Clayton, 1966).
C-90
-------
Kehoe, R.A. 1943. Unpublished report. In; Azar, et al. 1972.
Killen, S.M. and W.3. Harris. 1972. Direct depression of myocar-
dial contractility by the aerosol propellant gas, dichlorodifluoro-
methane. Jour. Pharm. Exp. Ther. 183: 245.
Kleopfer, R.D. 1976. Analysis of drinking water for organic com-
pounds. Identification and analysis of organic pollutants in
water. Ann Arbor Science, Ann Arbor, Michigan.
Knight, H.D. and M. Reina-Guerra. 1977. Intoxication of cattle
with sodium bromide-contaminated feed. Am. Jour. Vet. Res.
38: 407.
Krey, P.W., et al. 1976. Stratospheric concentrations of CC1,F in
1974. Jour. Geophys. Res. 81: 1557.
Kubota, S. 1955. Industrial poisoning in chemical plants. I.
Methyl bromide poisoning. Jour. Soc. Org. Synth. Chem. 13: 605.
Kutob, S.D. and G.L. Plaa. 1962. A procedure for estimating the
hepatotoxic potential of certain industrial solvents. Toxicol.
Appl. Pharmacol. 4: 354.
Lebowitz, M.D. 1976. Aerosol usage and respiratory symptoms.
Arch. Environ. Health. 31: 83.
C-91
-------
Lehmann, K.B. and I. Schmidt-Kehl. 1936. The thirteen most impor-
tant chlorinated aliphatic hydrocarbons from the standpoint of in-
dustrial hygiene. Arch. Hyg. 116: 131.
Lewis, S.E. 1948. Inhibition of SH enzymes by methyl bromide. Na-
ture. 161: 692.
Lillian, D. and H.B. Singh. 1974. Absolute determination of
atmospheric halocarbons by gas phase conlometry. Anal. Chem.
46: 1060.
Lillian, D., et al. 1975. Atmospheric fates of halogenated com-
pounds. Environ. Sci. Technol. 9: 1042.
Longley, E.O. and A.T. Jones. 1965. Methyl bromide poisoning in
man. Ind. Med. Surg. 34: 499.
Lovelock, J.E. 1971. Atmospheric fluorine compounds as indicators
of air movements. Nature. 230: 379.
Lovelock, J.E. 1972. Atmospheric turbidity and CCl^F concentra-
tions in rural southern England and southern Ireland. Atmos.
Environ. 6: 917.
Lovelock, J.E. 1974. Atmospheric halocarbons and stratospheric
ozone. Nature. 252: 292.
C-92
-------
Lovelock, J.E. 1975. Natural halocarbons in the air and in the
sea. Nature. 256: 193.
Lovelock, J.E., et al. 1973. Halogenated hydrocarbons in and over
the Atlantic. Nature. 241: 194.
Lucas, G.H.W. 1928. A study of the fate and toxicology of bromine
and chlorine anesthetics. Jour. Pharm. Exp. Ther. 34:237.
Lynn, G.E., et al. 1963. Occurrence of bromide in the milk of cows
fed sodium bromide and grain fumigated with methyl bromide. Jour.
Agric. Food Chem. 11: 87.
MacDonald, J.D.C. 1964. Methyl chloride intoxication. Jour.
Occup. Med. 6: 81.
Marier, G., et al. 1973. Blood fluorocarbon levels following ex-
posures to a variety of household aerosols. Household Pers. Prod.
Ind. 10: 68.
Matsumoto, T., et al. 1968. Aerosol tissue adhesive spray: Fate
of freons and their acute topical and systemic toxicity. Arch.
Surg. 97: 727.
McConnell, G., et al. 1975. Chlorinated hydrocarbons and the en-
vironment. Endeavour. 34: 13.
C-93
-------
Mellerio, F., et al. 1973. Electroencephalography and acute methyl
bromide poisoning. Electroenceph. Clin. Neurophysiol. 34: 732.
Mellerio, F. , et al. 1974. Electroencephalographie au cours des
intoxicantions aiques par brocure de methyle. Jour. Eur. Toxicol.
7: 119.
Metcalf, R.L. and P.Y. Lu. 1973. Environmental distribution and
metabolic fate of key industrial pollutants and pesticides in a
model ecosystem. Univ. Illinois Water Resour. Center, UILU-WRC-
0069. PB 225479, Natl. Tech. Inf. Serv., Springfield, Virginia.
Miller, D.P. and H.W. Haggard. 1943. Intracellular penetration of
bromide as feature in toxicity of alkyl bromides. Jour. Ind. Hyg.
Toxicol. 25: 423.
Miller, E.G. 1978. Some current perspectives on chemical carcino-
genesis in humans and experimental animals: Presidential address.
Cancer Res. 38: 1479.
Mizyokova, I.G. and G.N. Bakhishev. 1971. Specific treatment of a-
cute methylbromide poisoning. Vrach. Delo. 7: 128.
Monro, H.A.U., et al. 1955. Methyl bromide concentrations in ship
and railway car fumigation of peanuts. Sntomoi. Soc. Ontario,
Annu. Rep. 86: 65.
C-94
-------
Morgan, A., et al. 1967. Studies on the retention and metabolism
of inhaled methyl iodine. II. Metabolism of methyl iodide.
Health Physics. 13: 1067.
Morgan, A. , et al. 1972. Absorption and retention of inhaled
fluorinated hydrocarbon vapors. Int. Jour. Appl. Radiat. Isotop.
23: 285.
Morgan, A.J. 1942. Methyl chloride intoxication. Q. Jour. Med.
41: 29.
Morris, J.C. and G. McKay. 1975. Formation of halogenated organ-
ics by chlorination of water supplies. EPA 600/1-75-002. PB 241-
511. Natl. Tech. Inf. Serv., Springfield, Virginia.
Moskowitz, S. and H. Shapiro. 1952. Fatal exposure to methylene
chloride vapor. Arch. Ind. Hyg. Occup. Med. 6: 116.
Munson, A.E., et al. 1977. Functional activity of the reticulo-
endothelial system in mice exposed to haloalkanes for ninety days.
14th Natl. Reticuloendothelial Soc. Meet. Tucson, Arizona. Dec.
6-9. (Ab t.)
Munson, A.E., et al. 1978. Reticuloendothelial system function in
mice exposed to four haloalkanes: Drinking water contaminants.
Submitted: Soc. Toxicol. (Abst.)
C-95
-------
National Academy of Sciences. 1977. Drinking Water and Health.
Washington, D.C.
National Academy of Sciences. 1978. Nonfluorinated halomethanes
in the environment. Washington, D.C.
National Cancer Institute. 1977. Chemicals being tested for car-
cinogenicity by the bioassay program. Rep. Tech. Inf. Resour.
Branch, Natl. Cancer Inst., U.S. Dep. Health Edu. Welfare,
Bethesda, Maryland.
National Institute for Occupational Safety and Health. 1976a.
Criteria for a recommended standard: occupational exposure to
methylene chloride. HEW Pub. No. 76-138. U.S. Dep. Health Edu.
Welfare, Cincinnati, Ohio.
National Institute for Occupational Safety and Health. 1976b.
Registry of toxic effects of chemical substances. HEW Pub. No. 76-
191. U.S. Dep. Health Edu. Welfare, Rockville, Maryland.
National Library of Medicine. 1978. Toxicity of halomethanes.
Off-line bibliographic citation list generated by Medlars II,
Toxline before 1975 and 1975-1978.
Occupational Safety and Health Administration. 1976. General in-
dustry standards. OSHA 2206, revised January, 1976. U.S. Dep.
Labor, Washington, D.C.
:-96
-------
Ohta, T., et al. 1976. Local distribution of chlorinated hydro-
carbons in the ambient air in Tokyo. Atmos. Environ. 10: 557.
Owens, D.F. and A.T. Rossano. 1969. Design procedures to control
cigarette smoke and other air pollutants. ASHPAE Trans. 75: 93.
Palmer, T.Y. 1976. Combustion sources of atmospheric chlorine.
Nature. 263: 44.
Pattyf F.A. 1958. Industrial hygiene and toxicology. 2nd ed.
Vol. I. Toxicology. Interscience Publishers, John Wiley and
Sons, Inc., New York.
Patty, F.A. .1.363. Industrial hygiene and toxicology. 2nd ed.
Vol. II. Toxicology. Interscience Publishers, John Wiley and
Sons, Inc., New York.
Paulet, G., et al. 1975. Fluorocarbons and general metabolism in
the rat, rabbit, and dog. Toxicol. Appl. Pharmacol. 34: 197.
Philippe, R.J. and M.E. Hobbs. 1956. Some components of the gas-
phase of cigarette smoke. Anal. Chem. 28: 2002.
Pierotti, D. and R.A. Rasmussen. 1976. Interim report on the
atmospheric measurement of nitrous oxide and the halocarbons. NASA
Grant NSG 7214. Natl. Aeronautics Space Admin., Washington, D.C.
C-97
-------
Pierotti, D., et al. 1976. Trip report on the cruise of the R/V
Alpha Helix from San Diego, Calif., to San Martin, Peru. NSF Grant
No. OCE 75-04688A03. Natl. Sci. Foundation, Washington, D.C.
Poirier, L.A., et al. 1975. Bioassay of alkylhalides and nucle-
oxide base analogs by pulmonary tumor response in Strain A mice.
Cancer Res. 35: 1411.
Prendergast, J.A., et al. 1967. Effects on experimental animals
of long-term inhalation of trichloroethylene, carbon tetra-
chloride, 1,1,1-trichloroethane, dichlorodifluoromethane, and 1,1-
dichloroethylene. Toxicol. Appl. Pharmacol. 10: 270.
Price, P.J., et al. 1978. Transforming activities of trichloro-
ethylene and proposed Ind. alternatives. In Vitro. 14: 290.
Purchase, I.F.H., et al. 1978. An evaluation of six short-term
tests for detecting organix chemical carcinogens. Br. Jour.
Cancer. 37: 873.
Quevauviller, A. 1965. Hygiene et securite des pulseurs pour aer-
osols medicamenteaux. Prod. Probl. Pharm. 20: 14.
Quevauviller, A., et al. 1964. Local tolerance in animals to
chlorofluorinated hydrocarbons. Therapie. 19: 247.
C-98
-------
Rathus, E.M. and P.J. Landy. 1961. Methyl bromide poisoning. Br.
Jour. Ind. Med. 18: 53.
Redford-Ellis, M. and A.H. Gowenlock. 1971a. Reaction of chloro-
methane with human blood. Acta Pharmacol. Toxicol. 30: 36.
Redford-Ellis, M. and A.H. Gowenlock. 1971b. Reaction of chloro-
methane with preparations of liver, brain, and kidney. Acta
Pharmacol. Toxicol. 30: 49.
Riley, E.G., et al. 1966. Methylene chloride vapor in expired air
of human subjects. Am. Ind. Hyg. Assoc. Jour. 27: 341.
Roehm, R.S., et al. 1943. The fumigation of dairy products with
methyl bromide. Jour. Dairy Sci. 26: 205.
Rosenblum, I., et al. 1960. Chronic ingestion by dogs of methyl
bromide-fumigated foods. Arch. Environ. Health. 1: 316.
Salg, J. 1977. Cancer mortality rates and drinking water in 346
counties of the Ohio River Valley Basin. EPA Contract No. PO-5-03-
4528-J. Ph.D. thesis. Univ. of North Carolina.
Sanders, V.M., et al. 1977. Functional activity of the reticulo-
endothelial system (RES) in mice exposed to the halomethanes,
drinking water contaminants. Submitted: Va. Jour. Sci. (Abst.)
>99
-------
Savolainen, H. , et al. 1977. Biochemical and behavioral effects
of inhalation exposure to tetrachloroethylene and dichlormethane.
Jour. Neuropathol. Exp. Neurol. 36: 941.
Sax, N.I. 1968. Dangerous Properties of Industrial Materials.
3rd ed. Reinhold Book Corp., New York.
Sayers, R.R., et al. 1930. Toxicity of dichlorodiflouromethane.
U.S. Bur. Mines Rep. R.I. 3013.
Schuller, G.B., et al. 1978. Effect of four haloalkanes on humor-
al and cell mediated immunity in mice. Presented Soc. Toxicol.
Meet.
Schwetz, B.A., et al. 1975. The effect of maternally inhaled tri-
chloroethylene, perchloroethylene, methyl chloroform, and meth-
ylene chloride on embryonal and fetal development in mice and rats.
Toxicol. Appl. Pharmacol. 32: 84.
Scudamore, K.A. and S.G. Heuser. 1970. Residual free methyl bro-
mide in fumigated commodities. Pestic. Sci. 1: 14.
Seo, S.T., et al. 1970. Residues of ethylene dibromide, methyl
bromide, and ethylene chlorobromide resulting from fumigation of
fruits and vegetables infested with fruit flies. Jour. Econ.
Entomol. 63: 1093.
C-100
-------
Shackelford, W.M. and L.H. Keith. 1976. Frequency of organic com-
pounds identified in water. EPA-600/4-76-062. Environ. Res. Lab.
U.S. EPA, Athens, Georgia.
Shargel, L. and R. Koss. 1972. Determination of fluorinated
hydrocarbon propellants in blood of dogs after aerosol administra-
tion. Jour. Pharmacol. Sci. 61: 1445.
Sherman, H. 1974. Long-term feeding studies in rats and dogs with
dichlorodifluoromethane (Freon 12 Food Freezant). Haskell Lab.
(Unpubl. rep.)
Shimkin, M.B. and G.D. Stoner. 1975. Lung tumors in mice: Ap-
plication to carcinogenesis bioassay. Adv. Cancer Res. 21: 1.
Simmon, V.F., et al. 1977. Mutagenic Activity of Chemicals Identi-
fied in Drinking Water. In; S. Scott, et al. (eds.), Progress in
Genetic Toxicology.
Simmonds, P.G., et al. 1974. Distribution of atmospheric halo-
carbons in the air over the Los Angeles basin. Atmos. Environ.
8: 209.
Singh, H.B., et al. 1977. Urban nonurban relationships of halo-
carbons, SFg, N-0 and other atmospheric constituents. Atmos.
Environ. 11: 819.
C-101
-------
Sivak, A. 1978. BALE flash C-3T3 neoplastic transformation assay
with methylene chloride (food grade test specification). Rep.
Natl. Coffee Assoc. Inc.
Slater, T.F. 1965. Relative toxic activities of tetrachloro-
methane and trichlorofluoromethane. Biochem. Pharmacol. 14: 178.
Smith, W.W. and W.F. von Oettingen. 1947a. The acute and chronic
toxicity of methyl chloride: I. Mortality resulting from exposure
to methyl chloride in concentrations of 4,000 to 300 ppm. Jour.
Ind. Hyg. Toxicol. 29: 47.
Smith, W.W. and W.F. von Oettingen. 1947b. The acute and chronic
toxicity of methyl chloride. II. Symptomatology of animals poi-
soned by methyl chloride, Jour. Ind. Hyg. Toxicol. 29: 123.
Sokolova, I.P. 1972. Hygienic standardization of some fumigants
in the air of ship chambers after gas treatment. Tr. Nauch. Konf.,
Nauch.-lssled. Inst. Gig. Vod. Transp. 2: 160.
Speizer, F.E., et al. 1975. Palpitation rates associated with
fluorocarbon exposure in a hospital setting. New England Jour.
Med. 292: 624.
Spevac, L., et al. 1976. Methyl chloride poisoning in four mem-
bers of a family. Br. Jour. Ind. Med. 33: 272.
C-102
-------
Stecher, P.G., et al. 1968. The Merck Index. 8th ed. Merck and
Co., Inc., Rahway, New Jersey.
Stephan, C.E. 1980. Memorandum to J. Stara. U.S. SPA. July 3.
Stephens, S., et al. 1970. Phenotypic and genetic effects in
Neurospora crassa produced by selected bases and gases mixed with
oxygen. Dev. Ind. Microbiol. 12: 346.
Stewart, R.D. and C.L. Hake. 1976. Paint remover hazard. Jour.
Am. Med. Assoc. 235: 398.
Stewart, R.D., et al. 1972a. Experimental human exposure to meth-
ylene chloride. Arch. Environ. Health. 25: 342.
Stewart, R.D., et al. 1972b. Carboxyhemoglobin elevation after
exposure to dichloromethane. Science. 176: 295.
Stofen, D. 1973. Tolerance levels for toxic substances in drink-
ing water. Stadtehyg. 24: 109. (Transl. by R. Mansfield, Oak
Ridge Natl. Lab. ORNL-Tr-2975).
Stokinger, H.E. and R.L. Woodward. 1958. Toxicologic methods for
establishing drinking water standards. Jour. Am. Water Works
Assoc. 50: 515.
C-103
-------
Stokinger, H.E., et al. 1963. Threshold limit values for 1963.
Jour. Occup. Med. 5: 491.
Su, C. and E. Goldberg. 1973. Chlorofluorocarbons in the atmos-
phere. Nature. 245: 27.
Su, C. and E. Goldberg. 1976. Environmental Concentrations and
Fluxes of Some Halocarbons. In; H.L. Windom and R.A. Duce (eds.),
Marine Pollutant Transfer. Lexington Books, B.C. Heath and Co.,
Lexington, Massachusetts.
Symons, J.M., et al. 1975. National organics reconnaissance sur-
vey for halogenated organics. Jour. Am. Water Works Assoc.
67: 634.
Taylor, G.J. and R.T. Drew. 1975. Cardiomyopathy predisposes ham-
sters to trichlorofluoromethane. Submitted Toxicol. Appl.
Pharmacol.
Taylor, G.J. and w.S. Harris. 1970. Glue sniffing causes heart
block in mice. Science. 170: 866.
Texas State Department of Health. 1957. Methyl bromide poisoning.
Rep. No. OH-14, Div. Occup. Health.
C-L04
-------
Theiss, J.C., et al. 1977. Test for careinogenicity of organic
contaminants of United States drinking waters by pulmonary tumor
response in strain A mice. Cancer Res. 37: 2717.
Tourangeau, F.J. and S.R. Plamondon. 1945. Cases of exposure to
methyl bromide vapours. Can. Jour. Pub. Health. 36: 362.
Uehleke, H. and T. Warner. 1975. A comparative study of the ir-
reversible binding of labeled halothane, trichlorofluoromethane,
chloroform, and carbon tetrachloride to hepatic protein and lipids
in vitro and in vivo. Arch. Toxicol. 34: 289.
Uehleke, H., et al. 1977. Metabolic activation of haloalkanes and
tests ir> vitro for mutagenicity. Xenobiotica. 7: 393.
Underwriters Laboratories. 1971. Comparative hazards of modern
refrigerants. Data card No. UL5 and UL5-A.
U.S. Department of Health, Education, and Welfare. 1975. Registry
of toxic effects of chemical substances. Washington, D.C.
U.S. EPA. 1975. Preliminary assessment of suspected carcinogens
in drinking water, and appendices. Report to Congress, Washington,
D.C.
C-105
-------
U.S. EPA. 1976. Environmental hazard assessment report, major
one-and two-carbon saturated fluorocarbons, review of data. EPA
560/8-76-003. Off. Toxic Subst. Washington, D.C.
U.S. EPA. 1977. Multimedia environmental goals for environmental
assessment. Interagency energy-environment research and develop-
ment program report. EPA 600/7-77-136a,b. Environ. Res. Lab., Re-
search Triangle Park, North Carolina.
U.S. EPA. 1978a. Statement of basis and purpose for an amendment
to the national interim primary drinking water regulations on tri-
halomethanes, January, 1978. Off. Water Supply, Washington, D.C.
U.S. EPA. 1978b. The National Organic Monitoring Survey. Tech.
Support Div., Off. Water Supply, Washington, D.C. (Unpubl. rep.)
U.S. EPA. 1980. Seafood consumption data analysis. Stanford Re-
search Institute International. Menlo Park, California. Final
Report, Task 11, Contract No. 68-01-3887.
Van Stee, E.W. and K.C. Back. 1971. Brain and heart accumulation
of bromotrifluoromethane. Rep. AD 721211. Natl. Tech. Inf. Serv.,
Springfield, Virginia.
Veith, G.D. 1980. Memorandum to C.E. Stephan. U.S. EPA. April 14.
C-106
-------
Veith, G.D., et al. 1979. Measuring and estimating the bioconcen-
tration factor of chemicals in fish. Jour. Fish Res. Board Can.
36: 1040.
Viner, N. 1945. Methyl bromide poisoning: New industrial hazard.
Can. Med. Assoc. Jour. 53: 43.
Vitte, V.I., et al. 1970. Residual amounts of bromides in plant
food products fumigated with methyl bromide and characteristics of
their biological action. Gig. Primen., Toksikol. Pestifcs, Klin.
Otravlenii. 8: 386.
von Oettingen, W.F. 1955. The halogenated hydrocarbons: Toxicity
and potential dangers. No. 414. U.S. Pub. Health Serv.,
Washington, D.C.
von Oettingen, W.F. 1964. The Halogenated Hydrocarbons of Indus-
trial and Toxicological Importance. Elsevier Publ. Co., Amsterdam.
von Oettingen, W.F., et al. 1949. Relation between the toxic ac-
tion of chlorinated methanes and their chemical and physiochemical
properties. Natl. Inst. Health Bull. No. 191.
von Oettingen, W.F., et al. 1950. Comparative studies of the tox-
icity and pharmacodynamic action of chlorinated methanes with spe-
cial reference to their physical and chemical characteristics.
Arch. Int. Pharmacodyn. Ther. 81: 17.
C-107
-------
Vozovaya, M.A. 1974. Gynecological illnesses in workers of major
industrial rubber products plants occupations. Gig. Tr. Sostoyanie
Spetsificheskikh Funkts. Rab. Neftekhim. Khim. Prom-sti. 56.
(Rus.) (Abst.)
Waritz, R.S. L971. Toxicology of some commercial fluorocarbons.
Rep. AD 751429. Natl. Tech. Inf. Serv. Springfield, Virginia.
Watanabe, T. and D.M. Aviado. 1975. Toxicity of aerosol propel-
lants in the respiratory and circulatory systems. VII. Influence
of pulmonary emphysema and anesthesia in the rat. Toxicology.
3: 225.
Watrous, R.M. 1942. Methyl bromide: Local and mild systemic toxic
effects. Ind. Med. 11: 575.
Weinstein, I.B. 1978. Current concepts on mechanisms of chemical
carcinogenesis. Bull. N.Y. Acad. Med. 54: 366.
Weissbecker, L., et al. 1971. Cigarette smoke and tracheal mucus
transport rate: Isolation of effect of components of smoke. Am.
Rev. Resp. Dis. 104: 182.
Wilkness, P.E., et al. 1973. Atmospheric trace gases in the
southern hemisphere. Nature. 245: 45.
C-108
-------
Wilkness, P.E., et al. 1975. Trichlorofluoromethane in the tropo-
sphere, distribution and increase, 1971 to 1974. Science.
187: 832.
Williford, J.H., et al. 1974. Residual bromide in tissues of rats
fed methyl bromide fumigated diets. Jour. Anim. Sci. 38: 572.
Wills, J.H. 1972. Sensitization of the heart to catecholamine-
induced arrhythmia. Proc. 3rd Ann. Conf. Environ. Toxicol. AD Rep.
No. 773766. Natl. Tech. Inf. Serv. Springfield, Virginia.
Winneke, G. 1974. Behavioral Effects of Methylene Chloride and
Carbon Monoxide as Assessed by Sensory and Psychomotor Performance.
In; Behavioral Toxicology - Early Detection of Occupational Haz-
ards. Publ. No. (NIOSH) 74-126. U.S. Dep. Health Edu. Welfare.
Wolburg, I. 1973. The use of electroencephalography in industrial
toxicology. Activ. Nerv. Super. 15: 226. (Ger.) (Abst.)
Wyers, H. 1945. Methyl bromide intoxication. Br. Jour. Ind. Med.
2: 24.
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APPENDIX I
Summary and Conclusions Regarding
the Careinogenicity of Halomethanes*
The halomethanes addressed in this report are bromomethane,
chloromethane, d ichloromethane, tr ibromomethane , broitiod ichloro-
methane, dichlorodifluoromethane, and trichlorofluoromethane.
Chloroform, which is also a trihalomethane, is discussed in another
document.
Positive associations between cancer mortality rates in humans
and trihalomethanes in drinking water have been reported. In addi-
tion to chloroform, these trihalomethanes consisted primarily of
bromodichloromethane, chlorodibromomethane, and also barely mea-
surable levels of tribromomethane. There have been positive re-
sults for tribromomethane using strain A/St. male mice in the pul-
monary adenoma bioassay. Bromomethane, chloromethane, dichloro-
methane, bromodichloromethane, and tribromomethane have been re-
ported as mutagenic in the Ames1 test without metabolic activation.
Dichlorodifluoromethane caused a significant increase in mutant
frequency in Neurospora crassa, but was negative in the Ames1 test.
No data implicating trichlorofluoromethane as a possible carcinogen
have been published.
Because positive results for the mutagenic endpoint correlate
with positive results in i n vivo bioassay for oncogenicity, muta-
genic data for the halomethanes suggests that several of the com-
pounds might be carcinogenic. Carcinogenic!ty data currently
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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 (1.9 )ag/D in order to keep the
individual lifetime cancer risk below 10
In cases such as halomethanes where one criterion is derived
for an entire class of compounds, the Agency does not state that
each chemical in the class is a carcinogen. The intended inter-
pretation of the criterion is that the risk is less than 10 when-
ever the total concentration of all halomethanes in water is less
than the criterion. In a hypothetical case where all of the halo-
methanes in a sample are non-carcinogenic, the criterion would be
too strict; however, this situation seldom occurs. In most cases
where halomethanes are detected, a mixture of compounds occurs and
in calculation of the criterion the assumption is made that all
components have the same carcinogenic potency as chloroform.
*This summary has been prepared and approved by the Carcinogens
Assessment Group, EPA, June, 1979.
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