Ambient Water Quality Criteria
            Criteria and Standards Division
            Office of Water Planning and Standards
            U.S. Environmental Protection Agency
            Washington, D.C.

     For methylene chloride the criterion ,to protect  sal twater
aquatic life as derived using procedures o,ther  than the  Guide-
lines is 1,900 ug/1 as a 24-hour average and the  concentration
should never exceed 4,400 ug/1 at any time.
     For bromoform the criterion to protect freshwater aquatic
life as derived using procedures other than the Guidelines  is
840 ug/1 as a 24-hour average and the concentration sho ild
never exceed 1,900 ug/1 at any time.
     For bromoform the criterion to protect saltwater aquatic
life as derived using the Guidelines is 180 ug/1  as a 24-hour
average  and the concentration should never exceed 420 ug/1  at
any time.
                         Human Health
     For the protection of human health from the  toxic proper-
ties of halomethanes ingested through water and through  con-
taminated aquatic organisms, the ambient water  criteria  for
the halomethanes discussed in this document are:
     Compound                          Criterion  Level  (ug/D
     Chloromethane (Methyl Chloride)               2
     Bromomethane (Methyl Bromide)                 2
     Dichloromethane (Methylene Chloride)          2
     Bromodichloromethane                          2
     Tribromomethane (Bromoform)                   2
     Dichlorodifluoromethane                    3,000
     Trichlorofluoromethane                   32,000

                      CRITERION DOCUMENT
                         Aquatic Life
Methyl Chloride
     For methyl chloride the criterion  to~ protect - freshwater ""
aquatic life as derived using procedures  other  than  the Guide-
lines is 7,000 ug/1 as a 24-hour average  and  the concentration
should never exceed 16,000 ug/1 at any  time.
     For methyl chloride the criterion  to protect  saltwater
aquatic life as derived using procedures  other  than  the Guide-
lines is 3,700 ug/1 as a 24-hour average  and  the concentration
should never exceed 8,400 ug/1 at any time.
Methyl Bromide
     For methyl bromide the criterion to  protect freshwater
aquatic life as derived using procedures  other  than  the Guide-
lines is 140 ug/1 as a 24-hour average  and  the  concentration
should never exceed 320 ug/1 at any time.
     For methyl bromide the criterion to  protect saltwater
aquatic life as derived using procedures  other  than  the Guide-
lines is 170 ug/1 as a 24-hour average  and  the  concentration
should never exceed 380 ug/1 at any time.
Methylene Chloride
     For methylene chloride the criterion to  protect fresh-
water aquatic life as derived using procedures  other than the
Guidelines is 4,000 ug/1 as a 24-hour average and  the concen-
tration should never exceed 9,000 ug/1  at any time.


     The halomethanes are a subcategory of halogenated hydro-

carbons.   This  document reviews  the  following halomethanes:

chloromethane,  bromomethane,  methylene  chloride,  bromoform,

bromodichloromethane, tr ichlorof luorometha.ne, _ and dichlorodi--


     Methyl chloride is  also known as chloromethane (Windholz,

1976) .    It is  a  colorless,  flammable,  almost  odorless  gas

at room temperature  and  pressure.  It is used as a refrigerant,

a methylating agent, a  dewaxing agent,  and catalytic solvent

in  synthetic  rubber  production  (MacDonald,  1964).    Methyl

bromide has been referred to as bromomethane, monobromomethane,

and  embafume   (Windholz,  1976) .    It  has  been  widely  used

as a fumigant,  fire  extinguisher,  refrigerant, and insecticide

(Kantarjian  and Shaheen,  1963) .    Today  the major use  of

methyl  bromide  is  as a fumigating agent,  and this  use  has

caused sporadic outbreaks of serious human poisoning.

     Methylene chloride has been referred to as dichloromethane,

methylene  dichloride,   and  methylene  bichloride  (Windholz,

1976).   It is a common industrial solvent found  in insecticides,

metal cleaners,  paints,  and paint and varnish removers  (Balmer,

et  al.  1976).   In  1976,   244,129  metric  tons  (538,304,000

Ibs) were  produced  in  the  United States  with an  additional

19,128  metric  tons  (42,177,000   Ibs)   imported  (U.S.  EPA,


     Trichlorofluoromethane is also known as trichloromono-

fluoromethane, fluorotrichloromethane, Frigen 11, Freon

11, and Arcton 9.  Dichlorodifluoromethane has been referred

to as difluorodichloromethane, Freon 12, Frigen 12, Arcton

6, Genetron 12, Halon, and Isotron 2.  Freon compounds are

organic compounds which contain fluorine.  They have many

desirable characteristics which include a high degree of

chemical stability and relatively low toxicity, and they

are nonflammable.  Freon compounds have found many applications

ranging from use as propellants to refrigerants and solvents

(Van Auken, et al. 1975).

     Bromoform is also known as tribromomethane  (Windholz,

1976).  It is used in pharmaceutical manufacturing, as an

ingredient in fire resistant chemicals and gauge fluid,

and as a solvent for waxes, grease, and oils (U.S. EPA,

1975a).  Bromodichlcromethane is used as a reagent in research

(Natl. Acad. Sci. 1978).

     The physical characteristics of the halomethanes are

listed in Table 1.  Monohalomethanes can be hydrolyzed slowly

in neutral waters forming methanol and hydrogen halide.

The rate of hydrolysis increases with size of the halogen

moiety (Boggs and Mosher, 1960).  Zafiriou (1975) has indicated

that in seawater iodomethane can react with chloride ion

to yield chloromethane and this reaction occurs as fast

as the exchange of iodomethane into the atmosphere (exchange

rate, 4 x 10~'/sec).  The monohalomethanes are not oxidized

readily under ordinary conditions.  Bromomethane at 14.5

percent concentrations in air and intense heat will produce

                                                              TABLE 1

                                             Physical Characteristics of Hale-methanes
Compound Molecular
chloromethane 50.493
bromomethane 94.94a
dichloromethane 84.93a
tnchlorofluoro- 137. 37a
dichlorodifluoro- 120. 913
tribromomethane 252. 753
bromodichloro- 163. 83a
Physical state mo. bp. Specific Vapor Solubility
under ambient ( C) (C) gravity pressure in water
conditions (ram Hg) (ug/1)
colorless gasa -97.73a -24. 2a 0.973 (-10C) b 5.38xl06
colorless gasa -93. 6a 3.56a 1.737 (-10C) b IxlO6
colorless liquid3 -95. I3 40a 1.327(20C)a 362.4(20C)C 13.2xl06 c
colorless liquid3 -1113 23.82a 1.467(25C)a 667.4(20C)C l.lxlO6 c
colorless gasa -158a -29.79a l.75(-115C) a 4,306(20C)C 2.8xl05 c
colorless liquid3 8.3a 149. 5a 2.890(20C)a ' slightly
colorless liquid3 -57. la 90a 1.980(20C) ' insoluble3
in organic
alcohol, ether
acetone, benzene,
acetic acid
, ether,
, ether3
, etherd
, ether3
, ether,
, chloro-
alcohol, ether,
acetone, benzene,
1 >  VI f i t  , I '< 7 ~>
b)  U.S. EPA, 1977b
c)  Pearson and McConnell,  1975
d)  Windholz, 1976

a flame  (Stenger and Atchison, 1964).  Chloromethane in
contact with a flame will burn, producing CO2 and HC1  (Hardie,
1964) .  Monohalomethanes undergo photolysis in the upper
atmostphere where ultraviolet radiation is of sufficient
energy to initiate a reaction (Basak, 1973).
     Prolonged heating of dichloromethane with water at
180C results in the formation of formic acid, methyl chloride,
methanol, hydrochloric acid and some carbon monoxide.
In contact with water at elevated temperatures, methylene
chloride corrodes iron, some stainless steels, copper, and
nickel (Hardie, 1964).
     Trichlorofluoromethane is nonflammable.  Decomposition
of tribromomethane is accelerated by air and light (Windholz,
     Chloromethane has been demonstrated to be toxic to
aquatic organisms at levels of 270,000 to 550,000 ug/1 (96
hr. LC50 values) in controlled laboratory tests (Dawson,
et al. 1977).  Corresponding acute toxicity values for bromo-
methane range from 11,000 to 12,000 ug/1 (Dawson, et al.
1977).  Dichloromethane LC50 values range from 224,000 to
331,000 ug/1 (U.S. EPA, 1978) and tribromomethane LC50 values
range from 17,900 to 46,500 ug/1 (U.S. EPA, 1978).  The
latter compound demonstrates aquatic organism chronic toxicity
effects at 14,000 to 24,000 ug/1 (U.S. EPA, 1978).
     The toxic nature of methyl chloride on humans is thought
to act on the central nervous system.  In a mild to moderate
intoxication, the symptoms consist of blurring of vision,
headache, vertigo, loss of coordination, slurring of speech,

staggering, mental confusion, nausea, and vomiting.  A sever?
exposure involves rapid loss of consciousness leading to
death (MacDonald, 1964).
     Chloromethane is highly mutagenic to the bacteria,
Salmonella typhimurium TA 1535 (Andrews, et al. 1976) and
to the bacteria, Salmonella typhimurium TA 100 (Simmon,
et al. 1977).
     Inhalation of bromomethane is the usual route of systemic
poisoning, but gastrointestinal absorption is a possibility
(Collins, 1965).  Following exposure, irritation of eyes
and mucous membranes may be noticeable.  Within a few hours,
malaise, headache, and nausea develop.  After 2 to 16 hours,
the more serious symptoms develop, including visual disturbance,
speech disturbance, irrational behavior, drunkenness, and
drowsiness.  Under serious exposure, neurologic and psychiatric
abnormalities may persist for months or years (Collins,
1965) .
     As with chloromethane, bromomethane has been reported
to be mutagenic in Salmonella bacterial test systems (Simmon,
et al. 1977).
     In non-human mammals, methylene chloride inhalation
at levels of 1,000 and 5,000 ppm  (3,477 and 17,383 mg/m3)
for not more than 14 hours resulted in severe weight losses,
liver injury,  hepatic failures, and death (Haun,  et al.
1971).  In humans, methylene chloride is a central nervous
system depressant resulting in narcosis at high concentrations
(Berger and Fodor, 1969).  Inhalation levels of 500 to 1,000
ppm  (1,738 to 3,477 mg/m ) resulted in elevated carboxyhemo-

globin saturation levels as well as signs and symptoms of
central nervous system depression  (Stewart, et al. 1972).
     Dichloromethane demonstrated mutagenic properties in
Salmonella typhimurmm TA 100 and in immunosuppressed mice
(Simmon, et al. 1977).  The compound also demonstrated a
carcinogenic response in mice (Theiss; et~al.-1977 rTheiss,
1978) but the significance of results from,this test are
open to question.  The carcinogenicity of dichloromethane
was reported to be under study by the National Cancer Institute
     Trichlorofluoromethane has completely inhibited the
growth of several species of microorganisms at vapor concen-
trations of 5.62 x 104 to 5.62 x 106 mg/m3 (Van Auken, et
al. 1975).  In atmospheric ambient conditions of a 1:1 mixture
of oxygen and dichlorodifluoromethane, a significant increase
in the mutation rate of the yeast, Neurospora crassa, was
noted (Stephens, et al. 1971).  Slater (1965) administered
trichlorofluoromethane to the stomach of rats and noted
no effect on serum-^-glucuronidase activity or liver NADPH
levels.  Taylor (1975) noted that exposure to 7 percent
oxygen-15 percent trichlorofluoromethane caused cardiac
arrhythmias in all rabbits exposed.  Only a slight hyperglycemia
with hyperlactacidema was noted in rats, rabbits, and dogs
exposed to ambient atmospheric conditions of 5 percent trichloro-
fluoromethane  (Paulet, et al. 1975).  In dogs, trichlorofluoro-
methane caused a depression of myocardial function (Aviado
and Belej, 1975) and in the upper respiratory tract lead
to an initial apnea, bradycardia, and a fall in aortic blood

pressure (Aviado, 1971).  Azar,  et al. (1972), noted that

human inhalation of 1,000 ppm (4,949 mg/m )  dichlorodifluoro-

methane did not reveal any adverse effect, while exposure

to 10,000 ppm (49,489 mg/m3)  resulted only in a 7 percent

reduction in a standardized psychomotor test score.

     Tnbromomethane is considered to~be highly" toxic to

both non-human mammalian species and humans.  The compound

has been shown to be mutagenic in the Salmonella typhimur ium

TA 100 and Ta 1535 test systems (Simmon, et al. 1977) and

carcinogenic in mice (Theiss, et al. 1977; Theiss, 1978)

with the same qualifications for result significance as

for dichloromethane noted.  Cantor, et al. (1977), have

reported positive correlations between cancer mortality

rates and levels of brominated trihalomethanes in drinking

water in epidemiological studies.

     Bromodichloromethane is acutely toxic to mice (Bosman,

et al. 1978).  It was mutagenic in the Salmonella typhimurium

TA 100 bacterial test system (Simmon, et al. 1977) and carcino-

genic in mice (Theiss,  et al. 1977; Theiss,  1978) with the

same qualification for result significance as for dichloro-

methane noted.  Cantor, et al. (1977), have reported positive

correlations between cancer mortality rates and levels of

brominated trihalomethanes in drinking water in epidemiological


     The relatively high water solubilities of chloromethane

and bromomethane and their relatively high vapor pressures

indicate that they have a low potential to bioconcentrate

in aquatic species.  By using the equation of Metcalf and

Lu (1973) , the predicted bioconcentration factors are 2

and 6, respectively.

     Methylene chloride is a major halogenated pollutant

with a large potential for delivery of chlor.ine.to the strato-.

sphere.  The photooxidation of the compound in the troposphere

probably proceeds with a half-life of several months, similar

to the case of methyl chloride.  The principal oxidation

product of methylene chloride is phosgene which results

from the two hydrogens being abstracted from the molecule.

It is conceivable that this phosgene may be photolyzed to

yield chlorine atoms in the ozone-rich region of the strato-

sphere.  It thus appears that there is some potential for

ozone destruction by methylene chloride since the generated

chlorine atoms will attack ozone (U.S. EPA, 1975b).

     Similarly, fully halogenated substances such as trichloro-

fluoromethane and dichlorodifluoromethane migrate to the

stratosphere where they are photodissociated, adversely

affecting the ozone balance (U.S. EPA, 1975b).  Trichloro-

fluoromethane does not significantly bioconcentrate in aquatic

organims (Dickson and Riley, 1976).

     There are few data in the literature relating to the

environmental fate or degradation of bromodichloromethane

and tribromomethane.


Andrews, A.W., et al. 1976.  A comparison of the mutagenic

properties of vinyl chloride and methyl chloride.  Mutat.

Res. 40: 273.

Aviado, D.M.  1971.  Cardiopulmonary effects of fluorocarbon

compounds.  Aerospace Med. Res. Lab.  Wright Patterson Air

Force Base, Ohio.

Aviado, D.M., and M.A. Bele}. 1975.  Toxicity of. aerosol


propellants in the respiratory and circulatory systems.

Ventricular function in the dog.  Toxicology 3: 79.

Azar, A., et al. 1972.  Experimental human exposure to fluoro-

carbon 12  (dichlorodifluoromethane).   Am. Ind. Hyg. Assoc.

Jour. 33: 207.

Balmer, M.F., et al.  1976.  Effects in the liver of methyleae

chloride inhaled alone and with ethyl alcohol.  Am. Ind.

Hyg. Assoc. Jour. 37: 345.

Basak, A.K.  1973.  The photolytic decomposition of methyl

chloride.  Jour. Ind. Chem. Soc. 50:  767.

Berger, M., and G.G. Fodor. 1969.   Zentralrervose storunger

inter Einfluso dichloromethanhaltiger Luftgemische-2bl.

Bakt., Abt. 1, Ref. 215, 1963, 503.

Boggs, J.E., and H.P. Mosher. 1960.  Effect of fluorine substi-
tution on the rate of hydrolysis of chloromethane.  Jour.
Am. Chem. Soc. 82: 3517.

Bowman, F.G., et al. 1978.  The toxicity of some halomethanes
in mice.  Toxicol. Appl. Pharmacol. 44: 213.

Cantor, K.P., et al. 1977.  Associations of halomethanes
in drinking water with cancer mortality.  Jour. Natl. Cancer
Inst.  (In press.)

Collins, R.P. 1965.  Methyl bromide poisoning.  Calif. Med.
103: 112.

Dawson, G.W., et al. 1977.  The acute toxicity of 47 industrial
chemicals to fresh and saltwater fishes.  Jour. Hazard.
Mater. 1: 303.

Dickson,.A.G., and J.p. Riley. 1976.  The distribution of
short-chain halogenated aliphatic hydrocarbons in some marine
organisms.  Mar. Pollut. Bull 7: 167.

Bardie, D.W.F. 1964. Methyl chloride.  Kirk-Othmer Encyclopedia
of Chemical Technology. 2nd ed.  Interscience Publishers,
New York.

Haun, C.C., et al. 1971.  Continuous animal exposure to
methylene chloride.  Aerospace Med. Res. Lab. Wright Patterson
Air Force Base, Ohio.

Kantarjian, A.D., and A.S. Shaheen. 1963.  Methyl bromide

poisoning with nervous system manifestations resembling

polyneuropathy.   Neurology 13: 1054.

MacDonald, J.D.C. 1964.  Methyl chloride intoxication.

Jour. Occup. Med. 6: 81.

Metcalf, R.L., and P.Y. Lu. 1973.  Environmental distribution

and metabolic fate of key industrial pollutants and pesticides

in a model ecosystem.  Univ. 111. Water Resour. Center,

UILU-WRC-0069.  PB 225479, Natl. Tech. Inf. Serv., Springfield,


National Academy of Sciences. 1978.  Nonfluorinated halomethanes

in the environment.  Washington, D.C.

National Cancer  Institute. 1977.  Chemicals being tested

for carcinogenicity by the bioassay program.  Rep. Tech.

Inf. Resour. Branch, Natl. Cancer Inst., U.S. Dep. Health

Educ. Welfare, Bethesda, Md.

Paulet, G., et al. 1975.  Fluorocarbons and general metabolism

in the rat, rabbit, and dog.  Toxicol. Appl. Pharmacol.

34: 197.

Pearson, C.R., and G. McConnell. 1975.  Chlorinated Cl and

C2 hydrocarbons  in the marine environment.  Proc. R. Soc.

London B. 189: 305.

Simmon, V.F., et al. 1977.  Mutagenic activity of chemicals
identified in drinking water.  Presented at 2nd Int. Conf.
Environ. Mutagens.  Edinburgh, Scotland.  July, 1977.

Slater, T.F. 1965.  A note on the relative toxic activities
of tetrachloromethane and trichlorfluoromethane" on the rat.
Biochem. Pharmacol. 14: 178.

Stenger, V.A., and G.J. Atchison." 1964.  Methyl bromide.
Kirk-Othmer Encyclopedia of Chemical Technology.  2nd ed.
Interscience Publishers, New York.

Stephens, S., et al. 1971.  Phenotypic and genetic effects
of Neurospora crassa produced by selected gases and gases
mixed with oxygen.  Dev. Ind. Microbiol. 12: 346.

Stewart, R.D., et al. 1972.  Experimental human exposure
to methylene chloride.  Arch. Environ. Health 25:  342.

Taylor, G.J. 1975.  Cardiac arrhythmias in hypoxic rabbits
during aerosol propellant inhalation.  Arch. Environ. Health
30: 349.

Theiss, J.C. 1978.  Personal communication.

Theiss, J.C., et al. 1977.  Test for carcinogenicity of
organic contaminants of United States drinking waters by
pulmonary tumor response in strain A mice.  Cancer Res.
37: 2717.

U.S. EPA. 1975a.  Initial scientific and minieconomic reviev/
of folpet.  Draft. Rep. Off. Pestic. Prog. Washington, D.C.

U.S. EPA. 1975b.  Report on the problem of halogenated air
pollutants and stratospheric ozone.  EPA 600/9-75-008. Washington,
D.C.                                 -    _-_--.--

U.S. EPA. 1977a.  Area 1. Task 2. Determination of sources
of selected chemicals in waters and amounts from these sources.
Draft final rep. Contract No. 68-01-3852. Washington, D.C.

U.S. EPA. 1977b.  Investigation of selected potential environ-
mental contaminants.  Monohalomethanes.  EPA 560/2-77-007.
Washington, D.C.

U.S. EPA. 1978.  In-depth studies on health and environmental
impacts of selected water pollutants.  Contract No. 68-01-
4646. Washington, D.C.

Van Auken, et al. 1975.  Comparison of the effects of three
fluorocarbons on certain bacteria.  Can. Jour. Microbiol.
21: 221.

Weast, R.C., ed. 1972.  Handbook of chemistry and physics.
CRC Press, Cleveland, Ohio.

Windholz, M., ed. 1976.  The Merck Index.  Merck and Co.,
Rahway, N.J.

Zafiriou, O.C. 1975.  Reaction of methyl halides with seawater

and marine aerosols.  Jour. Mar. Res.  33:  75.

                    FRESHWATER ORGANISMS
     Although the aquatic toxicity data base  for halomethanes
is limited, it allows some generalization  concerning  trends
within the class.  Data on chloroform  and"  carbon te^ra-
chloride are included for discussion and are  also treated in
separate criterion documents.  Methylene chloride,  methyl
chloride, bromoform, and methyl bromide are the  only  other
halomethanes for which appropriate data are available.
Acute Toxicity
     Apparently, the brominated compounds  are more  toxic to
fish than the chlorinated analogs (Table 1).  This  pattern is
repeated for the saltwater fish (Table 4).  The  unadjusted
96-hour LC50 values for bluegill are 11,000 u.g/1,  and 550,000
ug/1 for methyl bromide and methyl chloride,  respectively,
under static (renewal) test conditions (Dawson,  et  al.  1977).
For bromoform and chloroform the 96-hour LC50 values  are
*The reader is referred to the Guidelines  for Deriving Water
Quality Criteria for the Protection of Aquatic Life  [43  FR
21506 (May 18, 1978) and 43 FR 29028  (July 5, 1978)]  in  order
to better understand the following discussion and  recommenda-
tion.  The following tables contain the appropriate  data that
were found in the literature, and at  the bottom of each  table
are the calculations for deriving various measures of toxic-
ity as described in the Guidelines.

29,300 ug/1  (U.S. EPA,  1978) and 115,000  ug/1  to  100,000  v.g/1,

respectively.  The data on acute static tests  with  bluegill

show a correlation between increasing  chlorination  and  toxic-

ity.  The 96-hour LC50  values are  550,000  ug/1 (Dawson, et  al.

1977) for methyl chloride, 244,000 U9/1 for  methylene  chloride

(U.S. EPA, 1978), 100,000 to 115, 000-ug/lr for  chloifoform

(Bentley, et al. 1975), and 125,000 ug/1  (Dawson, et al.  1977)

and 27,300 ug/1  (U.S. EPA, 1978) for carbon  tetrachloride.

Alexander, et al. (1978) compared  the  effect of test proce-

dures on the toxicity of methylene chloride  to the  fathead

minnow.  The flow-through test result  was  193,000 ug/1  and  the

static test result was  310,000 U9/1 (Table 1).  After adjust-

ment according to the Guidelines the latter  LC50 value  becomes

169,477 ug/1/ very similar to the  flow-through result,  sup-

porting the appropriateness of the adjustment  factors  for test

conditions and methylene chloride.  The Final  Fish  Acute

Values for bromoform, methylene chloride, methyl bromide,  and

methyl chloride  are 4,100, 38,000, and 1.500,  and 77,000  ug/1r


     The 48-hour EC50 values are 224,000,  28,900, and 35,200

ug/1 for methylene chloride (Table 2), chloroform,  and  carbon

tetrachloride, respectively (U.S.  EPA, 1978).  The  result

with chloroform  (28,900 ug/1) does not support any  conclusion

about the correlation of toxicity  and  amount of chlorination

for the data with Daphnia magna.   For  bromoform and methylene

chloride, there  appears to be little difference is  sensitiv-

ity between Daphnia magna and the  bluegill.  The LC50 and EC50

values are both  224,000 ug/1 for methylene chloride and 29,300

and 46,500 ug/1 respectively, for bromoform.   The  Final  In/erte-
brate Acute Values for bromoform and methylene  chloride  arc  1,900
and 9,000 ug/1/ respectively (Table 2).
     The data indicate that the Final Invertebrate Acute Values
for halomethanes are lower than the comparable  values  for fish.
The Final Fish and Final Invertebrate Acute Value  -comparisons-are:
bromoform - 4,100 and 1,900 ug/1/ respectively, methylene chloride
- 38,000 and 9,000 ug/1, respectively; chloroform  - 11,000 and
1,200 ug/1/ respectively; and carbon tetrachloride - 8,200 and
1,400 ug/lf respectively.  Thus, when a Final  Invertebrate Acute
Value exists, it becomes the Final Acute Value.
Chronic Toxicity
     No life cycle or embryo-larval tests have  been conducted  with
freshwater organisms and any halomethane other  than chloroiorm and
carbon tetrachloride.  In those tests, the concentration at  which
no adverse effects of chloroform were observed  for Daphnia magna
was between 1,800 and 3,600 ug/1, and no adverse effects of  car-
bon tetrachloride were observed on the fathead  minnow  at the high-
est test concentration of 3,400 ug/1.  Details  of  these  tests  may
be found in the criterion documents for those chemicals.
Plant Effects
     The 96-hour EC50 values for bromoform (Table  3),  based  on
chlorophyll a_ and cell numbers of the alga, Selenastrum
capricornutum, are 112,000 and 116,000 ug/lf respectively.   The
same tests with methylene chloride showed the EC50 values were
above the highest test concentration, 662,000 ug/1 (U.S.  EPA,

     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. -"-'--


                     Freshwater-Aquatic Life

Summary of Available Data

     The concentrations below have been rounded  to  two  signi L icart



     Final Fish Acute Value = 4,100 ug/1

     Final Invertebrate Acute Value = 1,900 ug/1

          Final Acute Value = 1,900 y.g/1

     Final Fish Chronic Value = not available

     Final Invertebrate Chronic Value = not. available

     Final Plant Value = 110,000 ug/1

     Residue Limited Toxicant Concentration = not available

          Final Chronic Value = 110,000 ug/1

          0.44 x Final Acute Value = 840 ug/1

Methylene Chloride

     Final Fish Acute Value = 38,000 ug/1

     Final Invertebrate Acute Value = 9,000 ug/1

          Final Acute Value = 9,000 ug/1

     Final Fish Chronic Value = not available

     Final Invertebrate Chronic Value = not available

     Final Plant Value = greater than 660,000 ug/1

     Residue Limited Toxicant Concentration = not available

          Final Chronic Value = greater than 660,000 ug/1

          0.44 x Final Acute Value = 4,000 ug/1

Methyl Bromide

     Final Fish Acute Value = 1,500 ug/1

     Final Invertebrate Acute Value = not available

          Final Acute Value = 1,500 ug/1

     Final Fish Chronic Value = not available

     Final Invertebrate Chronic Value = not  available

     Final Plant Value = not available

     Residue Limited Toxicant Concentration  = not  available

          Final Chronic Value = not a~vaitable ~              "   -

          0.44 x Final Acute Value = 660 ug/1

Methyl Chloride

     Final Fish Acute Value = 77",000 ug/1

     Final Invertebrate Acute Value = not available

          Final Acute Value = 77,000 ug/1

     Final Fish Chronic Value = not available

     Final Invertebrate Chronic Value = not  available

     Final Plant Value = not available

     Residue Limited Toxicant Concentration  = not  available

          Final Chronic Value = not available

          0.44 x Final Acute Value = 34,000  ug/1

     No freshwater criterion can be derived  for any halome~hane

using the Guidelines because no Final Chronic Value for either

fish or invertebrate species or a good substitute  for either

value is available.

     However, results obtained with halomethanes and freshwater

and saltwater fish and invertebrate species  indicate how criteria

may be estimated.

     For bromoform and methylene chloride with freshwater and

saltwater organisms and for chloroform and carbon  tetrachloride

with freshwater organisms, the Final Invertebrate  Acute Value

divided by the Final Fish Acute Value is 0.46, 0.24, 0.16, 0.090,

0.11, and 0.17 respectively,  for  an  average of 0.21.   Multiplying

this value times the Final Acute  Values  for methyl chloride and

methyl bromide with freshwater  fish  results in estimated fresh-

water Final Invertebrate Acute  Values  of 0.21  x 77,000 ug/1 =

16r000 ug/1 and 0.21 x 1,500  ug/1 =  320  ug/1 respectively.   Thus

the Final Acute Values for methyl chloride  -and-methyl bromide

would be based on these estimated values and are 16,000 ug/1 and

320 ug/lf respectively.

     For chloroform and freshwater organisms the Final Chronic

Value is about the same as 0.44 times  the Final Acute Value, and

for bromoform and saltwater organisms  the Final Chronic Value is

greater than 0.44 times the Final Acute  Value,  even though  a

chronic value is available for  fish  or invertebrates  in both

other halomethanes and freshwater organisms using 0.44 times the

Final Acute Value.

     The maximum concentration  of bromoform is the Final Acute

Value of 1,900 ug/1 and the 24-hour  average concentration is 0.44

times the Final Acute Value.  No  important  adverse effects  on

freshwater aquatic organisms  have been reported to be caused by

concentrations lower than the 24-hour  average  concentration.

     CRITERION:  For bromoform  the criterion to protect freshwater

aquatic life as derived using procedures other than the Guidelines

is 840 ug/1 as a 24-hour average  and the concentration should

never exceed 1,900 ug/1 at any  time.

     The maximum concentration  of methylene chloride  is the Final

Acute Value of 9,000 ug/1 and the 24-hour average concentration is

0.44 times the Final Acute Value.  No  important adverse effects on

freshwater aquatic  organisms  have  been  reported to be caused by
concentrations lower  than  the 24-hour average  concentration.
     CRITERION:   For  methylene chloride the  criterion to protect
freshwater' aquatic  life  as derived  using  procedures other than the
Guidelines is 4,000 ug/1 as a 24-hour average  and the concentra-
tion should never exceed 9,000 ug/1  at  any time." -:~
     The estimated  maximum concentration  of  methyl bromide is the
Final Acute Value of  320 ug/1 and  the 24-hour  average concentra-
tion is 0.44 times  the  Final  Acute  Value.  No  important adverse
effects on freshwater aquatic organisms have been reported to be
caused by concentrations lower than  the 24-hour average concentra-
     CRITERION:   For  methyl bromide  the criterion to protect
freshwater aquatic  life  as derived  using  procedures other than the
Guidelines is 140 ug/1  as  a 24-hour  average  and the concentration
should never exceed 320  ug/1  at  any  time.
     The estimated  maximum concentration  of  methyl chloride is the
Final Acute Value of  16,000 ug/1 and the  24-hour average concen-
tration is 0.44 times the  Final  Acute Value.   No important adverse
effects on freshwater aquatic organisms have been reported to be
caused by concentrations lower than  the 24-hour average concentra-
     CRITERION:   For  methyl chloride the  criterion to protect
freshwater aquatic  life  as derived  using  procedures other than the
Guidelines is 7,000 ug/1 as a 24-hour average  and the concentra-
tion should never exceed 16,000  ug/1 at any  time.

              Table  1.  Freshwater  fish acute values  for lialomethanes
                         Bioaaeay  Teat      Time      LC50
                                   Cpnc.**    Jhraj      (uq/lt

Lepomla macrochirua
lepomla macrochirua
Fathead minnow,
Pimephalea promelaa
Fathead minnow,
Pimephalea promelaa
Leporals macrochirua
l.epomts macrochirua
Methyl bromide
U         96
             , TT = riow-Lhrough,  K  -  rcrewal

** U = unmeasured, M  meaaured
                            (uq/ll    Deference
                                                      29,300      16,018   U.S. EPA.  1978
                                                      224,000     122,461   U.S, EPA,  1978
193,000    193,000   Alexander, et al. 1978

310,000    169,477   Alexander, et al. 1978

550,000    300,685   Dawson, et A!. 1977

 11,000      6,014   Dawson, et al. 1977
   Geometric mean of adjusted values  - Bromofortn = 16,018  |ig/l     $-$- " 4.100  |.g/l

                                       Methlyene chloride  - 148,822  ug/1      *4B,B22 =  38.000  ng/l

                                       Methyl chloride - 300.685 ng/l     300'683   77.000  Mg/1

                                       Mechyl bromide = 6,014 pg/1     ^3^9  c :

2, Freshwater  invertebrate  acule  values foe haloroethanes (U S  EPA, 1978)
    iuoassa   Test      fine
Cladoceran. S U 48 46,500 39.386
Daplmia magna
Methylene chloride
Cladoceran. S U 48 224,000 189,728
Dciphnia magna
* S  static
** U  unmeasured
Geometric mean of adjusted values - Bromoforin  39,386 iig/1  $T~ " * *'^ fg/1
 u>k..i 	 _ui 	 jj_ _ ion T>O ..-it 189,728 _ n ftft,
                                                                  - 9.000 ug/1

                       Table 3   Freshwater plane effects for halomethanes (U S  EPA. 1978)

                        Chlorophyll a
                        EC50 96-hr  ~
                        Cell number
                        ECSO 96-hr
                                             Hethylene chloride

                                 Chlorophyll a   .>662.QOO
                                 ECSO 96-hr   ~
                                 Cell number
                                 ECSO 96-hr
         Lowest plant value   Bromoform  112,000 |)g/l

                              Methylene chloride - >662.000 pg/1

                        SALTWATER ORGANISMS


     Although  the aquatic  toxicity  data  base  for halomethanes is

limited,  it allows  some generalizations  concerning  trends  within

the class.  Data on chloroform  and  carbon tetrachloride are  in-

cluded for discussion  and  are also  treated "in separate  criterion -

documents.  Methylene  chloride, methyl chloride, bromoform,  and

methyl bromide are  the  only other halomethanes  for  which appro-

priate data are available.

Acute Toxicity

     Apparently, the brominated compounds are more  toxic to  fish

than the  chlorinated analogs, (Table  4)  as  is true  for  the fresh-

water-fish (Table 1).   The unadjusted 96-hour LC50  values  for the

tidewater silversides  (Dawson,  et al. 1977) and  methyl  bromide  and

methyl chloride are 12,000 and  270,000 ug/1^  respectively.  The

Final Pish Acute Values for bromoform, methylene chloride, methyl

bromide,  and methyl chloride are 2,600,  49,000,  1,800,  and 40,000

ug/1, respectively  (Table  4).

     The  mysid shrimp  has  been  tested with  bromoform and methylene

chloride  (U.S. EPA,  1978)  and the unadjusted  96-hour LC50  values

are 24,400 and 256,000  ug/l respectively (Table 5).  The  Final

Invertebrate Acute  Values, obtained after adjusting the data for

test conditions and species sensitivity  according to the Guidelines

are 420 ug/1 for bromoform and  4,400 ug/1 for methylene chloride.

These concentrations are below  the  comparable values for fish

(Table 4) and, therefore,  become the  Final  Acute Values for

bromoform and methylene chloride.

Chronic Toxicity
     An embryo-larval test has been conducted with  the  sheepshead
minnow and bromoform (U.S. EPA, 1978) and  the chronic value
derived from this test is 9,165 ug/1  (Table 6).   There  are  ro
other chronic data for any halomethane.  The Final  Fish  Chronic
Value, and Final Chronic Value, for bromoform is"  1,400  ug/1
Plant Effects
     The 96-hour EC50 values for bromoform (Table 7), based  on
chlorophyll a. and cell numbers of the alga, Skeletonema  costatum,
are 12,300 and 11,500, respectively.  The  same  tests with
methylene chloride showed the EC50 values  were  above the highest
test concentration, 662,000 ug/1 (U.S. EPA, 1978).
     No residue data for saltwater aquatic organisms are available
for any halomethane.


                      Saltwater-Aquatic Life

Summary of Available Data

     The concentrations below have been rounded  to  two significant



     Final Fish Acute Value = 2,600 ug/1

     Final Invertebrate Acute Value = 420 ug/1

          Final Acute Value = 420 ug/1

     Final Fish Chronic Value = 1,400 ug/1

     Final Invertebrate Chronic Value = not available

     Final Plant Value = 12,000 ug/1

     Residue Limited Toxicant Concentration = not available

          Final Chronic Value = 1,400 ug/1

          0.44 x Final Acute Value = 180 ug/1

Methylene Chloride

     Final Fish Acute Value = 49,000 ug/1

     Final Invertebrate Acute Value = 4,400 ug/1

          Final Acute Value = 4,400 ug/1

     Final Fish Chronic Value = not available

     Final Invertebrate Chronic Value = not available

     Final Plant Value = greater than 660,000 ug/1

     Residue Limited Toxicant Concentration = not available

          Final Chronic Value = greater than 660,000 ug/1

          0.44 x Final Acute Value = 1,900 ug/1

Methyl Bromide

     Final Fish Acute Value = 1,800 ug/1

     Final Invertebrate Acute Value = not available

          Final Acute Value = 1,800 ug/1
     Final Fish Chronic Value = not available
     Final Invertebrate Chronic Value = not  available
     Final Plant Value = not available
     Residue Limited Toxicant Concentration  =  not  available
          Final Chronic Value - not available
          0.44 x Final Acute Value = 790 ug/1
Methyl Chloride
     Final Fish Acute Value = 40,000 ug/1
     Final Invertebrate Acute Value = not available
          Final Acute Value = 40,000 ug/1
     Final Fish Chronic Value = not available
     Final Invertebrate Chronic Value = not  available
     Final Plant Value = not available
     Residue Limited Toxicant Concentration  =  not  available
          Final Chronic Value = not available
          0.44 x Final Acute Value = 18,000  ug/1
     The maximum concentration of bromoform  is  the Final  Acute
Value of 420 ug/1 end. the 24-hour average concentration  is 0.44
times the Final Acute Value.  No important adverse effects on
saltwater aquatic organisms have been reported  to  be caused  by
concentrations lower then the 24-hour average  concentration.
     CRITERION:  For bromoform the criterion to protect  saltwater
aquatic life as derived using the Guidelines is 180 ug/1  as  a
24-hour average and the concentration should never exceed 420 ug/1
at any time.
     No saltwater criterion can be derived for methylene  chloride,
methyl bromide, or methyl chloride using the Guidelines  because no

Final Chronic Value  for  either  fish  or  invertebrate species or a
good substitute  for  either  value  is  available.
     However, results  obtained  with  halomethanes  and freshwater
and saltwater fish and  invertebrate  species  indicate how criteria
may be derived.
     For bromoform and methylene  chloride- with'freshwater and"
saltwater organisms  and  for chloroform  and carbon te trachlonde
with freshwater  organisms,  the  Final Invertebrate Acute  Value
divided by the Final Fish Acute Value is  0.46,  0.24, 0.16,  0.090,
0.11, and 0.17 respectively,  for  an  average  of  0.21.  Multiplying
this value times the Final  Acute  Values for  methyl chloride and
methyl bromide with  saltwater fish results in estimated  saltwater
Final Invertebrate Acute Values of 0.21 x 40,000  y.g/1 =  8,400 ug/1
and 0.21 x 1,800 ug/1  =  380 ug/l respectively.   Thus the Final
Acute Values for methyl  chloride  and methyl  bromide would be based
on these estimated values and are 8,400 ug/1 and  380 ug/lr  respec-
     For chloroform  and  freshwater organisms the  Final Chronic
Value is about the same  as  0.44 times the Final Acute Value, and
for bromoform and saltwater organisms the Final Chronic  Value is
greater than 0.44 times  the Final Acute Value, even though  a
chronic value is available  for  fish  or  invertebrate species in
both cases.  Therefore,  it  seems  reasonable  to estimate  criteria
for other halomethanes and  saltwater organisms  using 0.44 times
the Final Acute Value.
     The maximum concentration  for methylene chloride is the Final
Acute Value of 4,400 ug/1 and the 24-hour average concentration is
0.44 times the Final Acute  Value.  No important adverse  effects on

saltwater aquatic organisms have  been  reported to be caused by
concentrations lower than the 24-hour  average  concentration.
     CRITERION:  For methylene  chloride  the  criterion to protect
saltwater aquatic life as derived  using  procedures other than the
Guidelines is 1,900 ug/1 as a 24-hour  average  and the concen-
tration should never exceed 4,400  ug/1 at  any  time.
     The estimated maximum concentration of  methyl bromide is the
Final Acute Value of 380 ug/1 and  the  24-hour  average concen-
tration is 0.44 times the Final Acute  Value.   No important adverse
effects on saltwater aquatic organisms have  been reported to  be
caused by concentrations lower  than  the  24-hour average
     CRITERION:  For methyl bromide  the  criterion to protect
saltwater aquatic life as derived  using  procedures other than the
Guidelines is 170 ug/1 as a 24-hour  average  and the concentration
should never exceed 380 ug/1 at any  time.
     The estimated maximum concentration of  methyl chloride is the
Final Acute Value of 8,400 ug/1 and  the  24-hour average concentra-
tion is 0.44 times the Final Acute Value.  No  important adverse
effects on saltwater aquatic organisms have  been reported to  be
caused by concentrations lower  than  the  24-hour average concentra-
     CRITERION:  For methyl chloride the criterion to protect
saltwater aquatic life as derived  using  procedures other than the
Guidelines is 3,700 ug/1 as a 24-hour  average  and the concentra-
tion should never exceed 8,400 ug/1  at any time.

                         Tabl  4. Marine fish acute values for haloroethanea

                        Bloaaaay  Teat      Tima       LC60      LC60
                        flethod.*   Cone.**    (hra)      (uq/^l    jug/lt    {teferunce
Sheepshead minnow,         S
Cyprlnodon variegatus
Sheepehead minnow,         S
Cyprtnodon variegotua
Tidewater ailveraidea,     R
Hcntdia beryllina
Tidewater silveraidea,     R
Mcnidla beryllina
                                               U         96      17,900     9,786    U.S. EPA, 1978

                                                Methylene chloride
                                               U         96     331,000   180.958    U.S. EPA. 1978

                                                  Methyl bromide
                                               U         96      12,000     6,560    Dawaon, et al, 1977

                                                  Methyl chloride
                                               U         96     270,000   147,610    Dawson, et al. 1977
           *  S = static, R  renewal

           ** U = unmeasured
              Geometric mean of adjusted values:    Br onto form - 9,786 pg/1    ~JT~7~  " 2-600
                                                   Methylene chloride - 180,958 Mg/1     37   " 49.000 gg/1

                                                   Methyl bromide = 6.560 ng/l   ~^j~ = 1,800 yg/1
                                                   Methyl chloride - 147.610 |ig/l  lj7^-0 - 40.000

          *  S = static

03         ** u = unmeasured
                               S.   Marine invertebrate acute values for halomechanea (U S  EPA,  1978)

                                  biddssay  Teat      Time      1X50      LCbO
                                  ttslUSili-  2iii**   IfiiS)     fM'i/M    ton/U	


          Hysld shrimp.               S       U        96       24.400    20,667
          Hysidopaia bahla

                                                Methylene chloride

          Mysld shrimp.               S       U        96      256,000   216,832
          Hyaldopais Lahia
             Geometric mean of adjusted valuesi    Bromoform - 20,667 wg/1       tg   = 420 tig/1

                                                   Methylene chloride - 216.8J2  ug/1    21^i83- = 4,400 ng/1


                         Table  6.  Marine  fieh  chronic values for haloroethane (U.S. EPA, 1978)

                                                   Units    Value
           Organism                     feec*      (u<[/i)    (J1/U


           Sheepshead minnow,             E-L      14,000-    9,165
           Cyprinodon varlegatus                   24,000
             E-L *> embryo-larval

             Geometric mean chror

             Lowest chronic value for  bromoforro  9,165 iig/1
                                                            Q 1  C
Geometric mean chronic value  for bromoform  9,165  Mg/1    "A'7" " 1.^00 |ig/l

                          &tolo  I',  Marine plane eCfecta  for  haioaethanee  (U S   EPA.  1978)
                                   Kf feet
           Uge,                   Ch1 crept*)-' j.  a    12.300
           SkelaConeina ccsEaEum    EG5G
Alga.                   Cpll number
Skeletonema coacacum    ECiO
           Skeletonepia costatua

           SkeleConema coscaCurn
                          Mathylene chloride

                        Chlorophyll a   >662.000

                        Cell number     >662,000
           Lowest plant value.  Broraofono =  11,500  yg/1

                                Methylene chloride  = >662,000


Alexander, H.C. , et al.  1978.  Toxicity of perchloroethylene,
trichloroethylene, 1,1,1-trichloroethane, and methylene
chloride to fathead minnows.  Bull- Environ." ontam.~~ Tox-icol.
20: 344.

Bentley, R.E.,  et al. 1975.  Acute toxicity of chloroform
to bluegill (Lepomis macrochiras), rainbow trout,  (Salmo
gairdneri), and pink shrimp  (Penaeus duorarum).  Contract
No. WA-6-99-1414-B. U.S. Environ. Prot. Agency.

Dawson, G.W., et al.  1977.  The acute toxicity of 47 indus-
trial chemicals to fresh and saltwater fishes.  Jour. Hazard
Mater.  1: 303.

U.S. EPA.  1978.  In-depth studies on health and environmental
impacts of selected water pollutants.   Contract No. 68-
01-4646.  Washington, D.C.

Mammalian Toxicology and Human Health Effects
     The halomethanes are a subclass of halogenated aliphatic
hydrocarbon compounds, some of whose members constitute
important or potentially hazardous environmental contaminants.
The seven halomethane compounds selected for discussion
in this document are listed in Table 1.  Many other halo-
genated methane derivative chemicals exist, including various
combinations of halogen (bromine, chlorine, fluorine, iodine)
substitutions on one, two, three, or all four of the hydrogen
positions of methane.  Of these, two other particularly
important halomethanes, trichloromethane (chloroform) and
tetrachloromethane (carbon tetrachloride) are subjects of
separate criteria documents.  Several recent reviews are
available which present extensive discussions of health
effects related to halomethane exposure (Natl. Acad. Sci.,
1978; Davis, et al. 1977;  Howard, et al. 1974).
     Humans are exposed to halomethanes by any of three
primary routes:  (a)  intake in water or other fluids, (b)
ingestion in food;  and (c) inhalation.  In certain circum-
stances (e.g., occupational),  exposure by skin absorption
may be significant.  Halomethanes have been identified in
air (Grimsrud and Rasmussen, 1975; Lovelock, et al. 1973;
Lovelock, 1975; Singh, et al.  1977;  Lillian and Singh, 1974),
water (Shackelford and Keith,  1976;  Lovelock, 1975; Symons,
et al. 1975; Morris and McKay, 1975; Kleopfer, 1976) and
food  (McConnell, et al. 1975;  Monro, et al. 1955), but infor-

                           TABLE 1

      Names and CAS Registry Number   -   -  ~ ~

Bromomethane, methyl bromide, monobromo-
  methane, Embafume, Iscobrome, Rotox; 74-83-9

Chloromethane, methyl chloride,
  monochloromathane; 74-87-3

Dichloromethane, methylene chloride/
  methane dichloride, methylene dichloride,
  methylene bichloride; 75-09-2

Tribromomethane, bromoform, methyl
  tribromide; 75-25-2

Bromodichloromethane, dichloromethyl
  bromide; 75-25-4

Dichlorodifluoromethane, fluorocarbon 12,
  P-12, Arcton 6, Freon 12, Frigen 12,
  Genetron 12, Halon, Isotron 12,
  difluorodichloromethane; 75-71-8

Trichlorofluoromethane, fluorocarbon 11,
  F-ll, Arcton 9, Freon 11, Frigen 11,
  Algofrene type 1, trichloromonofluoro-
  methane, fluorotrichloromethane; 75-69-4

  *Chemical names, common names (underlined),  some trade names
   (capitalized) and synonyms are provided.  References:
   Int. Agency Res. Cancer (1978), Natl. Cancer Inst. (1977),
   Stecher, et al. (1968), Natl. Library Med.  (1978b).

mation concerning relative exposure for specific compounds

via the different media is incomplete. Inhalation and/or

ingestion of fluids are probably the most important routes

of human exposure (Natl. Acad. Sci., 1978).

     Presence of the halomethanes in the environment is

generally the result of natural, anthropogenic, or secondary

sources.  The monohalomethanes (bromo-, chloro-, iodomethane)

are believed natural in origin with the oceans as a priirary

source  (Lovelock, 1975); natural sources have also been

proposed for dichloromethane, tribromomethane, and certain

other halomethanes (Natl.  Acad. Sci., 1978).

     Anthropogenic sources of environmental contamination,

such as manufacturing and use emissions are important for

several halomethanes.  These include: chloromethane (chemical

intermediate in production of silicone, gasoline antiknock,

rubber, herbicides, plastics, and other materials); bromo-

methane (soil, seed,  feed, and space fumigant agents); dichlo-

romethane (paint remover,  solvent, aerosol sprays, plastics

processing); tribromomethane (chemical intermediate);  bromodi-

chloromethane (used as a reagent in research); dichlorodi-

fluoro methane and trichlorofluoromethane (refrigerant and

aerosol propellant uses) (Natl. Acad. Sci., 1978; Davis,

et al. 1977; Stecher, et al. 1968).

     Secondary sources of halomethanes include such processes

as the use of chlorine to treat municipal drinking water

and some industrial wastes, and the combustion and thermal

degradation of products or waste materials, wherein secondary

formation reactions or incidental contamination occur  (Natl.

Acad. Sci., 1978).

Ingestion from Water
     The U.S. Environmental Protection Agency has identified
at least ten halogenated methanes in finished drinking waters
in the U.S. as of 1975:  chloromethane, bromometnane, dichloro-
methane, dibromomethane, trichloromethane, tribromomethane,
bromodichloromethane, dibromochloromethane, dichloroiodo-
methane, and tetrachloromethane  (U.S. EPA, 1975).  In the
National Organics Reconnaissance Survey in 80 cities, halo-
genated hydrocarbons were found  in finished waters at greater
concentrations than in raw waters (Symons, et al. 1975).
It was concluded by Symons, et al. (1975) that trihalomethanes
(THM) result from chlorination and are widespread in chlori-
nated drinking waters; concentrations are related to organic
content of raw water.  Incidence and levels of halomethanes
found in the survey are summarized in Table 2.

                            TABLE 2
             Kalomethanes in the National Organics
               Reconnaissance Survey (80 Cities)

                     Number of
                    Cities with       Concentration, mg/1
Compound Positive
Tr ichloromethane
Bromodichlorome thane
Dibromochlor ome thane
Tr ibroraome thane

"" ^
   (a) 98.3 percent of 80 cities had 	 0.005 mg/1 tribromo-
   Source:  Natl. Acad. Sci., 1978 (data from Symons, et
   al. 1975)

     In its Region V Organics Survey at 83 sites U.S. SPA

reported concentrations of several halomethanes in a large

percentage of finished municipal waters, as summarized in

Table 3.  Of the halomethanes detected in drinking waters,

dichloromethane, tetrachloromethane, and fully chlorinated

higher hydrocarbons probably are not products of water chlori-

nation  (U.S. EPA, 1975; Morris and McKay, 1975).  Because

of its solubility, dichloromethane may exist in water efflu-

ents at concentrations of up to 1,500 mg/1, depending on

process and terminal treatment factors (Natl. Acad. Sci.,


                            TABLE 3

             Halomethanes in the U.S. EPA Region V
                   Organics  Survey  (83  Sites)

                          Percent of
                       Locations with   Concentrations (mg/1)
Compound Positive Results Median
Bromodichlorome thane
Dibromochlorome thane
Tr ichloromethane
Tr ibromomethane
    *A total of 11 samples may have been contaminated by
     exposure to laboratory air containing tetrachloromethane.

    Source: (U.S. EPA, 1975)

     U.S. EPA's National Organic Monitoring Survey (NOMS),

conducted in 1976 and 1977 (Phases L-III), sampled 113 water

supplies representing various sources and treatments (U.S.

EPA, 1978a, b).  Incidence and concentration data for six


halomethanes are summarized in Table 4.  Some 63 additional
organic compounds or classes were detected, including these
halomethanes:  bromomethane, dibromomethane, bromochloro-
methane, iodomethane, dichloroiodomethane, and trichloro-
fluoromethane.  Mean and median total trihalomethane (TTHM)
values in 105 to 111 cities over the Ifhree" phases arid sample
modes ranged from 0.052 to 0.120 mg/1 and 0.038 to 0.087
mg/1, respectively.
     Data from a Canadian national survey for halomethanes
in drinking water are in general agreement with those from
the United States  (Health and Welfare Can. 1977).  Samples
taken from 70 finished water distribution systems showed
the following halomethane concentrations:
                                   range        median
Chloroform                         0 -  121      13 ug/1
Bromodichloromethane                0-33     1.4  ug/1
Chlorodibromomethane               0-6.2     0.1  ug/1
Tribromomethane                    0-0.2     0.01 ug/L

     As would be expected, based upon previous observations,
(Symons, et al. 1975), chlorination as part of the water
treatment process led to considerable enhancement of Salome-
thane concentrations, and well sources were associated with
much lower halomethane concentrations than river  or lake
sources.  In addition, an unexplained increase in the concen-
tration of halomethanes occurred in the distribution system
as compared to halomethane levels in  water sampled at the
treatment plant.

                                                           TABLE 4
                     Partial summary of National Organics Monitoring Survey,  1976-1977  (U.S. EPA,  I978b)
                     Number of Positive Analyses
                        per Number of Analyses
Mean Concentration,
 mg/1 (Positive
 Results only)
Median Concentration,
  mg/1 (All Results)

me thane
rae thane
me thane
me thane
me thane





<0. 003-0. 005a
<0. 0006-0. 003a
0. 001-0. 002a
<0. 001-0. 002a
<0. 0002-0.
<0. 0003-0.
<0. 0002-0.
<0. 0002-0



'Samples shipped iced, stored 1-2 weeks refrigerated before analyses.

^Quenched (Q) samples preserved with sodium thiosulfate at sampling,  shipped  at  ambient  temp.,  stored  2.0-25C
 3-6 weeks before analyses.  Terminal(T) samples  treated similarly  to Q except no  Na  thiosulfate.

aM minium Ljudnll Ciable limits.

Phases (I, II, III) refer  to sampling projects and corresponding  sample treatment  and storage  conditions.
    I  Collected and analyzed as in National Organics Reconnaissance  Survey  (earlier)  (Symons,  et  al.  1975).
       Shipped and stored  refrigerated  (1-8C) 1-2 weeks before analyses.
   II: S
       Evidence of the presence of trichlorofluoromethane in ocean

  surface waters has been reported (Howard, et al. 1974; Lovelock,

  et al. 1973; Wilkness, et al. 1975).  None was detectable

  below surface waters, indicating that the oceans are not

  a significant sink (long-term pool or repository) for this

  compound.  As noted above, trichlorofluoromethane has been

  detected, but not quantified, in finished drinking water

  in the NOMS.  Environmental data suggest that human exposure

  to the refrigerant-propellant chlorofluoromethanes in water

  is much less significant than to these compounds' presence

  in air.

  Ingestion from Foods

       Bromomethane residues from fumigation decrease rapidly

  through loss to the atmosphere and reaction with protein

  to form inorganic bromide residues.  With proper aeration

  and product processing most residual bromomethane will rapidly

  disappear due to methylatibn reactions and volatilization.

  The more persistent inorganic bromide residues are products

  of bromomethane degradation (Natl.  Acad. Sci., 1978;  Davis,

'  et al. 1977).  Scudamore and Heuser (1970)  reported that

  residues in fumigated wheat, flour, raisins,  corn, sorghum,

  cottonseed meal, rice, and peanut meal were reduced to less

  than 1 rag/kg within a few days.  Initial levels of inorganic

  bromide were positively related to concentration used, and

  disappearance rate was lower at low temperatures.  No residual

  bromomethane was found in asparagus, avocados, peppers,

  or tomatoes after two-hour fumigation at 320  mg CH-,Br/m

  air (Seo, et al.  1970) .  Only trace amounts  were present

  in wheat flour and other products fumigated at 370 CHjBR


mg/m after nine days of aeration  (Dennis, et al.  1972).

     Table 5 summarizes data on organic and inorganic bromide

residues in cheese with time after fumigation, as reported

by Roehm, et al. (1943).  Table 6 summarizes specific inor-

ganic bromide residue maxima analyzed in several food commodi-

ties, according to Getzendaner, et al.  (1968).  Lynn, et

al.  (1963) reported that cows fed grain fumigated with

bromomethane gave milk containing bromide levels proportional

to those in feed intake.  Milk bromide levels of up to 20

mg/1 were noted at exposure levels up to 43 mg inorganic

bromide/kg diet, at which level milk production was not

affected.  Blood total bromides correlated with milk bromides.

                             TABLE 5

     Bromomethane  Residues  in  Cheese  (outer %  inch)  (mg/kg)
      (Natl. Acad.  Sci.,  1978,  data  from Roehm,  et  al.  1943)

  Hours of       Longhorn Cheese A         Longhorn Cheese B
Ventilation  Inorganic  Organic Total  Inorganic  Organic Total

      0.5       15        62      77       23       78     101
      4         21        40      61       30       54      84
     24         22        20      42       38        9      47
     48         25         0      25       39        4      43
     96         24         0      24       38        1      39
    168         25         1      26       36        2      38

                           TABLE 6

         Specific Residue Maxima:  Inorganic Bromide
           in Food Materials  (NAS, 1978, data from
                  Getzendaner, et al. 1968)
Max. SRa                              ~    ---------

mg-kg  Ib  min           Materials

0-5                      Baking powder, butter, chewing gum,
                         dry yeast, macaroni, marshmallows,
                         oleomargarine, shortening, tapioca,
                         flour, tea, whole roasted coffee
5-10                     Cake mix, candy, cheese, dried milk,
                         ground ginger, ground red pepper,
                         pancake mix, precooked breakfast
                         cereals, veal loaf
10-15                    Cocoa, ground roasted coffee, powdered
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

 Specific Residue  (SR) _ increase in bromide from fumigation(mg/kg)
                                  rate of fumigation(Ib/min)

     Chloromethane and bromomethane are considered to have

relatively low potentials for bioconcentration, judging

from their relatively high vapor pressure and water solubility.

Estimating from solubility and use of the Metcalf and Lu

(1973) equation, biomagnification factors for these compounds

are relatively low (two and six, respectively). No directly

determined bioaccumulation factors were available.

     A bioconcentration factor (ECF) relates the concert-ration
of a chemical in water to the concentration in aquatic organisms,
but BCF's are not available for the edible portions of all
four major groups of aquatic organisms consumed in the United
States.  Since data indicate that the _BCF >_or lipid-tsoluble  ...
compounds is proportional to percent lipids, BCF's can be
adjusted to edible portions using data on percent lipids
and the amounts of various species consumed by Americans.
A recent survey on fish and shellfish consumption in the
United States (Cordle, et al. 1978)  found that the per capita
consumption is 18.7 g/day.  From the data en the nineteen
major species identified in the survey and data on the fat
content of the edible portion of these species (Sidwell,
et al. 1974), the relative consumption of the four major
groups and the weighted average percent lipids for each
group can be calculated:                  '
                         Consumption       Weighted Average
     Group                (Percent)          Percent Lipids
Freshwater fishes            12                   4.8
Saltwater fishes             61                   2.3
Saltwater molluscs            9                   1.2
Saltwater decapods           18                   1.2
Using the percentages for consumption and lipids for each
of these groups, the weighted average percent lipids is
2.3 for consumed fish and shellfish.
     No measured steady-state bioconcentration factor (BCF)
is available for methylene chloride or  bromoform but the
equation "Log BCF =0.76 Log P - 0.23"  can be used (Vei-h,

et al. Manuscript) to estimate the BCF  for  aquatic  organisms
that contain about eight percent lipids  from  the octanol-
water partition coefficient  (P).  Based  on  an octanol-water
partition coefficient of 18  for methylene chloride  the  steady-
state bioconcentration factor for methylene chloride  is
estimated to be 5.2.  The steady-state  bioconcentration
factor for bromoform is estimated to be  48, based on  an
octanol-water coefficient of 330.  An adjustment factor
of 2.3/8.0 = 0.2875 can be used .to adjust the estimated BCF
from the 8.0 percent lipids  on which the equation is  based
to the 2.3 percent lipids that is the weighted average  for
consumed fish and shellfish.  Thus, the weighted average
bioconcentration factor for  methylene chloride and  the  edible
portion of all aquatic organisms consumed by  Americans  is
calculated to be 5.2 x 0.2875 = 1.5.  Similarly, for  bromoform
it is calculated to be 48 x  0.2875 = 14.
     Reported concentrations of several halomethanes  in
general air masses are summarized in Table  7.  For  comparison,
some halomethanes other than those addressed  by this  docu-
ment (Table 1)  are included.
     Saltwater atmospheric background concentrations  of
chloromethane averaging about 0.0025 mg/m   have been  reported
(Grimsrud and Rasmussen, 1975; Singh, et al.  1977;  Lovelock,
et al.  1973).   These are higher than reported average contin-
ental background and urban levels (ranging from 0.001 to
0.002 mg/m )  and suggest that the oceans are a major source
of global chloromethane (Natl. Acad. Sci., 1978).  Localized

                                                 TABLE 7

                                Ranges of Mean Concentrations  (mg/m ) of
                               Halomethanes  Measured in General Air  Masses




Tr ichloromethane





                                                         0.0023;  0.0026'


(  0.000006-0.000064)

  0.000132,  0.000234
(  0.00007-0.0005)

(  0.00004-0.00085)e

(  0.000006-0.02204)g


  .    (0.00882)n
      Brackets  identify individual reported values;  other numerals represent reported means or range
      of  reported  means.
        Adapted  from Natl.  Acad.  Sci.,  1978,  data from:   (aj  Cronn,  et al.  1976;  (b)  Pierotti,  et
        al.  1976;  (c)  Pierotti  and Rasmussen, 1976;  (d)  Singh,  et al.  1977;  (e)  Harisch and Rasmussen,
        1977;  (f)  Cox,  et al.  1976;  (g)  Lillian,  et  al.  1975; (h)  Ohta,  et  al.  1976;  (i)  Su and
        Goldberg,  J.976;  (j)  Lovelock,  et al.  1973;  (k)  Grimsrud and  Rasmussen,  1975;  (1)  Lovelock,

sources, such as burning of tobacco or other combustion
processes, may produce high indoor-air concentrations of
chloromethane (up to 0.04 mg/m )  (Natl. Acad. Sci., 1J78,
citing Palmer, 1976, and Harsch, 1977).  Chlor MICthan* is
the predominant halomethane in indoor air, and is generally
in concentrations two to ten times ambient background levels
(Natl. Acad. Sci., 1978).  Although direct anthropogenic
sources of chloromethane greatly influence indoor atmosphere
concentrations, they are not significant contributors to
urban and background tropospheric levels (Natl. Acad. Sci.,
1978) .
     Data on atmospheric bromomethane are few (Singh, et
al. 1977; Grimsrud and Rasmussen, 1975).  Its continental
background concentrations of 7.8 x 10~  mg/m  or less are
much lower than saltwater background and urban air concentra-
tions (Natl. Acad. Sci., 1978).  Relatively high concentra-
tions of bromo-methane reported in surface seawater suggest
that oceans are a major source of the compound (Lovelock,
et al: 1973; Lovelock, 1975), and this is supported by high
concentrations in saltwater atmosphere (Singh, et al. 1977).
There is evidence that combustion of gasoline containing
ethylene dibromide (EDB, an additive)  is also a significant
source of environmental bromomethane,  and this is corroborated
by urban air concentrations at least as high as those in
saltwater air masses (Natl. Acad. Sci., 1978, citing Harsch
and Rasmussen, 1977, and Singh, et al. 1977).  Table 7
summarizes reported levels of bromomethane in tropospharic
air masses.  Concentrations of up to 8.5 to 10~  mg/m  may
occur outdoors locally with light traffic as a result of

exhaust containing bromomethane as a combus :ion oreakdown

product of EDB in leaded gasoline.  Similarly, indoor air

contaminated by exhaust from cars burning EJB-containing

leaded gasoline can have elevated concentra :ions of bromo-

methane (Natl. Acad. Sci., 1978, citing Barsch and Rasmussen,

1977).                               ~    ~

     Data on concentrations of dichloromethane in tropospheric

air masses are scarce.  As shown in Table 7, reported back-

ground concentrations in both continental and saltwater

atmospheres were about 1.2 x 10   mg/m , and urban air concen-

trations ranged from less than 7 x 10   to  5 x 10   mg/m

(Natl. Acad. Sci., 1978, citing Pierotti and Rasmussen,

1976, and Cox, et al.  1976).  Concentrations of dichloromethane

in indoor air typically exceed tropospheric background levels

because of local sources of contamination such as the use

of aerosol hair spray or solvents (Natl. Acad. Sci., 1978,

citing Harsch, 1977) .  Air sampled from various indoor loca-

tions contained dichloromethane at concentrations ranging

from a low of 2 x 10   mg/m  (in a laundromat washer)  to

high values of 2.5 mg/m  (automobile dealer display floor),

4.9 mg/m  (records and automotive section of discount store),

and even 8.1 mg/m  (beauty parlor waiting area)  (Natl. Acad.

Sci., 1978,  citing Harsch, 1977).  Indoor air has 10 to

1,000 times more dichloromethane than is present in unpolluted

tropospheric air, and sometimes dichloromethane is the pre-

dominant halomethane contaminant (Natl. Acad. Sci., 1978).

     Data through 1974 indicate that dichlorodifluoromethane

is produced and used considerably more than trichlorofluoro-

methane and the other major fluorocarbon refrigerants  (Howard,

et al. 1974).  This production and use appears to be reflected

in atmospheric analyses showing higher concentrations  for

dichlorodifluoromethane than for trichlorofluoromethane.

Concentrations over urban areas are several times those

over rural areas and over oceans.  This probably reflects

that the primary modes of entry to the environment, use

of refrigerants and aerosols, are greater in industrializ-

ed and populated areas  (Howard, et al. 1974).  Atmospheric

concentrations of trichlorofluoromethane are higher during

stagnant air conditions and decrease upon displacement or

dilution by clean air.  Conversely, concentrations in off-

shore air masses increase when displaced by polluted air

masses from industrialized urban areas (Howard, et al.

1974; U.S. EPA, 1976; Wilkness, et al. 1975; Lovelock, 1971,

1972) .  Average concentrations of trichlorofluoromethane

(F-ll) reported for urban atmospheres have ranged from 9

x 10   to 3 x 10   mg/m , and for ocean sites, from 2.2

    4          4     3
x 10   to 5 x 10   mg/m .  Mean urban concentrations for

dichlorodifluoromethane (F-12) ranged from 3.5 x 10   to

        2     3
2.9 x 10   mg/m , and an ocean atmosphere mean of 5.7 x

10~4 mg/m  was reported (Howard, et al. 1974; Hester,

et al.  1974; Simmonds, et al. 1974; Su and Goldberg, 1976;

Wilkness, et al. 1973, 1975; Lovelock, et al. 1973; Lovelock,

1974) .  Concentrations in air near fluorocarbon release

sites may be many times the average city levels.  F-ll concen-

trations of 1.3 x 10~4 to 2.4 x 10~4 mg/m3, about 100 times

the city average, were measured near a polyurethane plant


using the material as a blowing agent; near a cosmetics
plant where aerosol cans are filled, levels were three to
four times typical city readings (Howard, et al.  1974;
Hester, et al. 1974).
     The F-ll and 7-12 fluorocarbons are regarded as very
stable and persistent in the environment and are without
tropospheric or oceanic sinks.  Tropospheric lifetimes of
ten to more than 40 years have been asserted, and an atmos-
pheric half-life of 15 to 30 years for F-ll has been calcu-
lated (Howard, et al. 1974; U.S. EPA, 1976; Howard and Hanchett,
1975; Lovelock, et al. 1973; Wilkness, et al. 1973; Krey,
et al. 1976).  Concern has developed that fluorocarbons
in the troposphere will diffuse into the stratosphere and
catalytically destroy stratospheric ozone, with possible
health and meteorologic effects, globally.
     Trichlorofluoromethane and dichlorodifluoromethane
have been measured at highly varying levels indoors in homes.
F-ll concentrations of 1.7 x 10   to 2.9 mg/m  have been
reported (Hester, et al. 1974).  Similar levels have been
measured in public buildings.  Indoor concentrations were
generally higher than in outside air.  In a beauty shop,
where fluorocarbon-pressured cosmetic sprays were apt to
be used, concentrations of 0.28 and 1.8 mg/m  were reported
for F-ll and F-12, respectively.  Evidence of quite high
levels of propellants F-ll and F-12 after spray-product
releases indoors was presented by Bridbord, et al. (1974
cited in U.S.  EPA, 1976).  These data are summarized in
Table 8.

                           TABLE 8

    Dichlorodifluoromethane Concentrations in Room Air as
    a Result of Release of Aerosol Can Products  (U.S. EPA,
            1976,  data from Bridbord,  et  al.  1974)
Level at Periods after 60-      Level -at Periods'af-ter 30-
second Release of Hair Spray    second Release,of Insect  ,
in 29.3m  Room (mg/m )          Spray in 21.4m  Room {mg/m

During:  306.8                       1 min:       2,304.0
30 min:   12.4                      60 min':         130.4
60 min:    0.5                     150 min:          56.8
     Data on environmental concentrations of halomethanes

indicate that human uptake of the trihalomethanes bromodi-

chloromethane and tribromomethane from fluids is less than

that of trichloromethane.  Uptake of chloromethane, dichloro-

methane, bromomethane and the chlorofluoromethanes from

fluids is apparently minor; for these, uptake from

sources other than fluid consumption is more important (Natl.

Acad. Sci., 1978).

     Human uptake of chloromethane from fluids should be

considerably less than that for bromodichloromethane and

triboromomethane.  However, human exposure to chloromethane

from cigarette smoke, local in nature and affecting discrete

target populations, can be quite significant (Natl. Acad.

Sci., 1978, citing Philippe and Hobbs, 1956, Owens and Rossano,

1969, and Chopra and Sherman, 1972).  Reports or estimates

of air concentrations in rooms with people smoking range

roughly from 0.03 to 0.12 mg/m .  The smoker's exposure

from direct inhalation could be considerably greater still,

since the range of reported chloromethane is 0.5 to 2 rag
per cigarette.
     Uptake of halomethanes from dermal exposure can occur
under certain circumstances.  Occupational exposure stand-
ards warn of possible significant skin absorption for bromo-
methane and tribromomethane under industrial exposure condi-
tions (Occup. Safety Health Admin., 1976; Natl. Acad. Sci.,
1978).  But there was no evidence in the available literature
that dermal exposure contributes significantly to total
dose of halomethanes for the general public.
Absorption, Distribution, Metabolism, and Excretion
     Most of the literature regarding biological aspects
of the halomethanes has focused on the usual case with res-
pect to exposure, absorption, and intoxication.  Absorption
via the lungs upon inhalation is of primary importance and
is fairly efficient for the halomethanes; absorption can
also occur via the skin and gastrointestinal (GI) tract,
although this is generally more significant for the nonfluori-
nated halomethanes than for the fluorocarbons  (Natl. Acad.
Sci., 1978; Davis, et al. 1977; U.S. EPA, 1976; Howard,
et al. 1974).
     Bromomethane:  The usual route for systemic poisoning
by bromomethane is by inhalation, and absorption commonly
occurs via the lungs; some absorption can also occur through
the skin, particularly in skin exposures to the compound
in liquid form (Davis, et al. 1977; von Oettingen, 1964).

Occupational Safety and Health Administration  (1976) exposure
standards warn of possible significant dermal absorption.
Significant absorption can also occur via the gastrointestinal
tract when bromomethane is ingested.  Upon absorption, blood
levels of residual nonvolatile bromide increase, indicating
rapid uptake of bromomethane or its metabolites  (Miller
and Haggard, 1943).  Bromomethane is rapidly distributed
to various tissues and is broken down to inorganic bromide.
Storage, only as bromides, occurs mainly in lipid-rich tissues.
     Blood bromide levels of 24 to 250 mg/1 were reported
in severe, and 83 to 2,116 mg/1 in fatal, bromomethane poison-
ings; normal background blood bromide levels ranged up to
15 mg/1  (Natl. Acad. Sci., 1978, citing: Clarke, et al.
1945, Benatt and Courtney, 1948).  In rats fed bromomethane-
fumigated diets with residual bromide levels, higher tissue
bromide levels were in their eyes, lungs, blood, spleen,
and testes, while lowest tissu^levels were in fat, skeletal
muscle, bone, and liver.  In similar bovine experiments,
bromide was secreted in milk (Williford, et al. 1974; Lynn,
et al.  1963).
     Evidently the toxicity of bromomethane is mediated
by the bromomethane molecule itself and its reaction with
tissue  (methylation of sulfhydryl groups in -critical cellular
proteins and enzymes), rather than by the bromide ion residue
resulting from breakdown of the parent compound  (Davis,
et al. 1977).  Bromomethane readily penetrates cell membranes
while the bromide ion does not.  Intracellular bromomethane
reactions and decomposition result in inactivation of intra-

cellular metabolic processes, disturbed function, and irrita-

tive, irreversible, or paralytic consequences (Natl. Acad.

Sci., 1978; Davis, et al. 1977; Miller and Haggard, 1943;

Lewis, 1948; Rathus and Landy, 1961; Dixon and Needham,

1946).  Poisoning with bromomethane is generally associated

with lower blood bromide levels than is poisoning with inorganic

bromide (Natl. Acad. Sci., 1978, citing Collins, 1965).

     Elimination of bromomethane is rapid initially, largely

through the lungs as bromomethane.  The kidneys eliminate

much of the remainders as bromide in urine,.  Final elimina-

tion may take longer, accounting in part for prolonged toxi-

city (Natl. Acad. Sci., 1978 citing  Miller and Haggard,

1943, and Clarke, et al. 1945).

     Chloromethane:  As with bromomethane, chloromethane

is usually encountered as a gas and is absorbed readily

via the lungs.  Skin absorption is less significant (Natl.

Acad. Sci., 1978; Davis, et al. 1977).  No poisonings involving

gastrointestinal absorption have been reported.   Uptake

of chloromethane by the blood is rapid but results in only

moderate blood levels with continued exposure.  Signs and

pathology of intoxications suggest wide tissue (blood, nervous

tissue, liver, and kidney) distribution of absorbed chloro-

methane.  Initial disappearance from the blood occurs rapidly.

Decomposition and sequestration result primarily by reaction

with sulfhydryl groups in intracellular enzymes and proteins.

Excretion via bile and urine occurs only to a minor degree

(Natl. Acad. Sci., 1978; Davis, et al. 1977; Lewis, 1948;

Morgan, et al. 1967; von Oettingen, 1964).

     Dichloromethane:  Absorption occurs mainly through

the lung but also through the gastrointestinal tract and

to some extent through intact skin.  Lung absorption effi-

ciencies of 31 to 75 percent have been reported, influenced

by length of exposure, concentration, and activity level

(Natl. Acad. Sci., 1978; Natl. Inst. Occup. Safety "Health,

1976a, citing:  Lehmann and Schmidt-Kehl, 1936, Riley, et

al. 1966, DiVincenzo, et al. 1972, and Astrand, et al. 1975).

Upon inhalation and absorption, dichloromethane levels increase

rapidly in the blood to equilibrium levels that depend primarily

upon atmosphere concentration; fairly uniform distribution

to heart, liver, and brain is reported (Natl. Acad. Sci.,

1978, citing von Oettingen, et al. 1949, 1950).  Carlsson

and Hultengren (1975) reported that dichloromethane and

its metabolites were in highest concentrations in white

adipose tissue, followed in descending order by levels in

brain and liver.  Dichloromethane is excreted intact primarily

via the lungs, with some in the urine.  DiVincenzo, et al.

(1972.) have reported that about 40 percent of absorbed dichlo-

romethane undergoes some reaction and decomposition process

in the body (Natl. Acad. Sci., 1978).

     Some of the retained dichloromethane is metabolized

to carbon monoxide (CO).  Some of this CO is exhaled, but

a significant amount is involved in the formation of carboxy-

hemoglobin (COHb).  The formation of COHb leads to inter-

ference with normal oxygen transport capabilities of blood,

so relative oxygen deprivation and secondary effects ensue

(Natl. Inst. Occup. Safety Health, 1976a, citing Stewart,

et al. 1972a, Fassett, 1978, and DiVincenzo and Hamilton,


1975; Natl. Acad. Sci., 1978, citing Stewart, et al. 1972a,b)
Bioconversion of CO and formation of COHb,continues after
exposure.  Therefore, cardiorespiratory stress from elevated
COHb may be greater as a result of dichloromethane exposure
than from exposure to CO alone (Stewart and Hake, 1976).
Other metabolites of dichloromethane rnclude" carBori "dioxide,
formaldehyde, and formic acid (Natl. Acad. Sci., 1978).
     Tribromomethane:  Absorption occurs through the lungs
upon inhalation of vapors, from the GI tract upon ingestion,
and to some extent through the skin.  The OSHA (1976) stand-
ard warns of possible significant skin absorption.  Some
of the body burden is biotransformed in the liver to inorgan-
ic bromide.  After inhalation or rectal administration of
tribromomethane bromides were found in tissues and urine
(Natl. Acad. Sci., 1977). Bioconversion of tribromomethane
and other trihalomethanes, apparently by a cytochrome P-450
dependent mixed function oxidase system, to carbon monoxide
has been reported (Ahmed, et al. 1977).  Excretion occurs
partly through the lungs as tribromomethane, and complete
excretion requires considerable time (Natl. Acad. Sci.,
1978) .
     Bromodichloromethane:  Little information is available
on the pharmacokinetics or other biological aspects of this
compound.  This reflects its very limited use, primarily
in research, and limited discharge to the environment (Natl.
Acad. Sci., 1978).  Current increased environmental interest
in bromodichloromethane focuses on its presence in drinking
water (Kleopfer, 1976)  along with other trihalomethanes,
as a consequence of chlorination.   Absorption, distribution,


metabolism, and excretion may resemble that of bromochloro-
methane  (see the following) dichloromethane, or dibromomethane,
in view of close chemical similarities among these compounds
and bromodichloromethane.  Further possible evidence for
similarity exists in that the mutagenic, carcinogenic, and
general toxic effects of the latter are srmirlar' to-"those
of other di-and trihalogenated  (Cl and Br), methanes  (Natl.
Acad. Sci., 1978; Sax, 1968).
     Patty (1963) placed bromochlbromethane "roughly in
a class with methylene chloride," but "somewhat more toxic,"
among "the less toxic halomethanes."  Animal experiments
have indicated that inhaled bromochloromethane is readily
absorbed intact by the blood and hydrolyzed in significant
amounts by the body to yield inorganic bromide.  Tissue
concentrations of both organic and inorganic bromine increased
in dogs and rats exposed daily to bromochloromethane.  After
exposure, blood levels decreased to undetectable or insignifi-
cant levels in 17 to 65 hours.  Significant absorption by
the GI tract after exposure by ingestion was indicated by
hepatic and renal pathology in mice dosed by stomach tube.
Similar injury in these organs was not observed in animals
exposed to vapors.  Absorption through the skin would also
seem likely in view of its irritation and solubility charac-
teristics  (Patty, 1963).
     If the pharmacokinetics of bromodichloromethane does
resemble that of chemically similar halomethanes, it would
be expected that bromodichloromethane would:   (1) Be absorbed
readily by the inhalation and ingestion routes; (2) be distri-

buted widely, preferentially to tissues with high lipid
content; (3) be eliminated in part via expired breath; and
(4) combine with cellular protein and be metabolized to
CO and inorganic halide.                  >
     Trichlorofluoromethane (P-ll) and dichlorodifluorometh-
ane (F-12):  Inhalation and absorption thrpugh the lungs
are the exposure and uptake modes of most concern; however,
when ingested, absorption of F-12 does occur via the GI
tract.  Some absorption through the skin could occur also,
judging from tests with F-113 (CC12F-CC1F2) (U.S. EPA, 1976;
Howard, et al. 1974; Clark and Tinston, 1972a,b; Allen and
Hanbury, 1971; Azar, et al. 1973; Sherman, 1974; DuPont,
1968).  Absorption and elimination are dynamic processes
involving equilibria among air,  blood, and various tissues.
Upon absorption a biphasic blood-level pattern occurs, with
an initial rapid then slower rise in blood levels (arterial,
venous) during which the material is absorbed from blood
into tissues.  After termination of exposure a similar but
inverse biphasic pattern of elimination occurs.  The relative
decreasing order of several fluorocarbons with respect to
absorption into blood has been reported as F-ll,  F-113,  F-
12, F-114 (Shargel and Koss, 1972; Morgan, et al. 1972).
These authors agree in general with partition coefficients
for the fluorocarbons in blood,  serum, and lipid (oil)  (Allen
and Hanbury, 1971; Chiou and Niazi, 1973; Morgan, et al.
1972).  More easily absorbed compounds are retained longer.
Under conditions of prolonged, lower-level exposure, periods
of elimination (washout) are longer.  Although varying among

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 tempo-
rarily by various tissues.  Measured tissue levels in rats
after pulse inhalation exposure in one report were:  adrenals
greater than fat greater than heart (Allen and Hanbury,
1971).  Chemically related fluorocarbons have been found
primarily in tissues of high lipid content (fat, brain,
liver, heart), but elimination following pulse exposure
was rapid, and there was no evidence of accumulation  (Carter,
et al. 1970a,b; Van Stee and Back, 1971).  There is evidence,
however, that tissues with higher lipid content than blood
concentrate fluorocarbons from the blood, corresponding
to relative order of absorption by blood from air  (Howard,
et al. 1974).
     Elimination of fluorocarbons (intact) seems to be almost
completely through the respiratory tract, regardless of
the route of entry.  In dogs administered a mixture of F-12
and F-14 (30:70 percent, vol./vol.)  by several different
routes, elimination was through expired air and none was
detected in urine or feces (Matsumoto, et al. 1968) .  Rapid
initial elimination is followed by a slower phase of decline.
     Biochemical effects suggesting a slowing down of cellu-
lar oxidation were reported in animals exposed to 2.8 x
105 mg/m3 F-ll in air (but not to F-ll at 1.4 x 105 mg/m3
nor to F-12 at 2.47 x 105 to 9.88 x 105 mg/m3)  (Paulet,
et al.  1975).

     In brief exposure experiments with inhaled   C-labeled
F-12 only about one percent of F-12 was metabolized and
eliminated in expired air as CG>2 or existed in nonvolatile
urinary or tissue components (Blake and Mergner, 1974).
Experiments with oral   C-labeled F-12 indicated that about
two percent of the total dose was exhaled as CO-f about
0.5 percent was excreted in urine, and after 30 hours no
F-12 was detectable (Eddy and Griffith, 1961) .
     F-ll and F-12 form metabolites which bind to cell constit-
uents, particularly in long-term exposures with extended
equilibrium (Blake and Mergner, 1974).  F-ll (or its labeled
metabolites)  has been reported to bind in vitro irreversibly
to proteins and to endoplasmic phospholipids and proteins,
but not to ribosomal RNA (Uehleke, et al. 1977; Uehleke
and Warner, 1975).  Binding to rat-liver microsomal cyto-
chrome P-450-related phospholipids was reported (Cox, et
al.  1972).  More research on fluorocarbon xenobiotic metabo-
lism and pharmacodynamics under prolonged exposure conditions
is needed (U.S. EPA, 1976).
Acute, Sub-acute, and Chronic Toxicity
     For most of the halomethanes considered here, there
is considerable information on clinical toxicity in the
occupational health literature and on experimental toxicity
in the literature on toxicology using laboratory animals.
These data have dealt primarily with inhalation exposure
to grossly poisonous or fairly substantial concentrations
of vapors.  Considerably less information is available on
various aspects of toxicity that might result  from prolonged

exposure to low, environmental levels of these contaminants,
by not only the inhalation route but also ingestion or other
routes of exposure.  This section summarizes briefly the
important clinical and toxicologic information available
for these compounds.
     Chloromethane: Is not generally regarded "as "higTily
toxic, yet reports of poisoning are numerous.  Because of
its virtually odorless and colorless properties, low-order
irritancy,and characteristic latency of effect, victims
may receive serious or prolonged exposure before awareness
and effects are apparent (Natl. Acad. Sci., 1978; Davis,
et al. 1977).  Toxic dosages for humans are not clearly
defined.  Generally, acute inhalation intoxication in humans
has been thought to require exposures on the order of 1,032
mg/m , but lower levels have produced definite toxicity
in animals  (MacDonald, 1964; Smith and von Oettingen, 1947b,c)
Chronic inhalation and ingestion toxicity levels are not
established, but the occupational exposure standard for
air in the work environment is currently set for 206 mg/m
(Natl. Acad. Sci. 1978; Occup. Safety Health Admin., 1976).
The monohalomethanes seem to rank in the following order
of decreasing toxicity:  iodomethane, bromomethane, chloro-
methane, fluoromethane (Davis, et al. 1977).  The similar-
ities in toxicologic responses to the monohalomethanes sug-
gest a similar mode of action.  The most probable mechanism
is that the monohalomethane participates in the methylation
of essential enzymes, cofactors, and other cellular macro-
molecules, thereby rendering them inactive (Davis, et al.

1977).  Sulfhydryl-containing molecules seem particularly
susceptible to the action of monohalomethanes  (Lewis, 1948;
Redford-Ellis and Gowenlock, 1971a).  Various  reports on
the effectiveness of cysteine administration in the treatment
of monohalomethane poisoning support the contention that
binding to sulfhydryl compounds is involved in the expres-
sion of toxic effects (Mizyokova and Bakhishev, 1971).
In studies with laboratory animals, several investigators
have shown that monohalomethanes interfere with glutathione
metabolism (Redford-Ellis and Gowenlock, 1971a,b; Boyland,
et al. 1961; Barnsley, 1964; Johnson, 1966; Barnsley and
Young, 1965).
     Human experience, largely involving leakage from refrig-
eration equipment using chloromethane as a coolant, shows
it to be a central nervous system  (CNS)  depressant with
primarily neurological toxic manifestations (Hansen, et
al. 1953).  Systemic poisoning cases have also involved
hepatic and renal injury (Spevac, et al. 1976).  In the
more mild intoxications there is a characteristic latent
period of one-half to several hours between exposure and
onset of effects (symptoms).  Recovery after brief exposures
is typically within a few hours, but repeated or prolonged
exposure may result in more severe toxicity and delayed
recovery (days-weeks).  In persons occupationally exposed
at levels of 52 to more than 2 x 10  mg/m  the following
toxic manifestations,  particularly related to CNS, were
noted:  blurred vision,  headache, nausea,  loss of coordina-
tion, personality changes (depression,  moroseness, anxiety),
lasting a few hours to several days;  some were more sensi-

tive to chloromethane upon return to work  (MacDonald, 1964;

Hansen, et al. 1953; Browning, 1965; Morgan, 1942).  As

mentioned previously, tobacco-smoking may be an additional

significant source of individual human exposure to chloro-


     Severe poisonings are usually characterized by a latent

period and severe and dominant neurological disorder, with

perhaps irreversible and/or persistent sequelae; renal and

hepatic injury are common.  In fatal cases coma and death

commonly ensue in hours or days as a result of cerebral

and pulmonary edema and circulatory failure, with pathologic

findings of congestion, edema, and hemorrhage; chloromethane

has been detected in all organs analyzed after death (Natl.

Acad. Sci., 1978, citing Baird, 1954).

     There have been no reports of reproductive toxicity

or teratogenicity in humans exposed to chloromethane, but

metabolic, enzymatic, and neuroendocrine disturbances follow-

ing exposure in humans and/or animals suggest the need for

research on this point  (Davis, et al. 1977).  Epidemiolo-

gical studies of toxicity in human populations exposed to

chloromethane (including mutagenicity and carcinogenic!ty)

have not yet appeared in the published literature.

     In animals, a variety of toxic effects have been noted

in experimentally exposed subjects.  Many effects are simi-

lar for the monohalomethanes and, consistent with human

data, suggest CNS involvement and altered metabolism involv-

ing binding to sulfhydryl-containing cellular macromolecules

(Davis, et al. 1977; Balander and Polyak, 1962; Gorbachev,

et al. 1962; Kakizaki, 1967; Redford-Ellis and Gowenlock,
1971a,b).  Most toxicity information is from inhalation
studies,  with little regarding other routes, apparently
because of the volatility of these compounds and their usual
presence in the gas phase (Davis, et al. I97"7T.  Some inhala-
tion toxicity data for chloromethane are summarized in Table
9.  In general, chloromethane appears less acutely toxic
by inhalation than bromomethane.  In severe acute exposure
conditions chloromethane produces serious neurological dis-
turbances, with functional and behavioral manifestations
and ultimately death.  However, these disturbances from
chloromethane occur at higher concentrations than are required
for bromomethane in several species (Davis, et al. 1977).
     Under more prolonged exposures to less severe levels,
chloromethane increased mucus flow and reduced mucostatic
effect of other agents (e.g., nitrogen oxides)  in cats
(Weissbecker, et al. 1971).   Permanent muscular dysfunction
is described in mice surviving several weeks of daily expo-
sures at 1,032 mg/m , and paralysis followed exposure to
531 mg/m  for 20 hours in surviving animals (von Oettingen,
et al.  1964).  No teratogenic effects have been reported
for chloromethane (Davis, et al. 1977).
     Bromomethane: is regarded as a highly toxic substance
by acute exposure and more dangerous than chloromethane.
It has been responsible for  many occupational poisoning
incidents, reflecting its widespread use as a fumigant.
Like chloromethane it has a  characteristic latent period
and its presence is difficult to detect, so prolonged and

                                                       TABLE 9

                                    Chlotomethane Inhalation Toxicity in Animals
      3.1  x 10   to 6.2 x 10
      4.1  x 10   to 8.3 x 10
4.1 x 10'
1.4 x 10*            ,
6.2 x 10J to 8.3 x 10J

6.5 x 10^
6.2 x 10,
4.1 x 10J
      620  to 1,032

                         30-60 nun
2 hr.
Up to 1 hr
6 hrs/day

6 hrs
4 hrs
6 hrs/day
                         6 hrs/day
                         6 hrs/day
                               20  hrs
Quickly lethal to most animals
Dangerous effects.  Increased res-
  piratory and heart rates and blood
  pressure, followed by reversals and
  ECG changes; restlessness, saliva-
  tion, incoordination, narcosis.
LCLo, guinea pig
No serious effects
Deaths, rats, 3-5 days, spasmodic
LC.n, mouse
LCCo, rat
1 week, cats, weakness, unable to right
    1 week, cats, dyspnea, refusal
  to eat/drink.
3-4 weeks, cats, death
2-3 days, guinea pigs, deaths
4-7 days, monkeys, convulsions
1-3 days, dogs, deaths
5-6 days, rabbits and rats, death
1-6 days, dogs, deaths
1 expos., dogs and monkeys, signs
of poisoning; 2-4 weeks, dogs, deaths,
permanent neuromuscular damage in survivor;
1 week, mice, convulsions, mortality;
15 weeks, mice, permanent adductor
  contraction in survivors
Overt signs of toxicity
  detectable in dogs and monkeys.
Paralysis in survivors.(but in another
  exposure at 620 mg/m  , no cumulative
  overt toxicity or neurotoxic changes
  over several months in several species).
                                                            Patty, 1958
                                                            von Oettingen, 1964
NIOSH. 1976b
Patty, 1958
von Oettingen, 1964

Davis, et al. 1977
DHEW, 1975
von Oettingen, 1964
                                                            von Oet^ingen, 1964
                                                            von Oettingen, 1964
                                                                                     Smith & von Oettingen, 1947a

                                                                                     von Oettingen, 1964; Smith
                                                                                      & von Oettingen, 1947a

more severe exposure may be incurred  (Natl. Acad. Sci.f

1978; Davis, et al. 1977).  Toxicologic and metabolic similari-

ties among the monohalomethanes  (C1-, Br-, l-substituted)

suggest a common mechanism of toxic action, probably methyla-

tion and disturbance or inactivation of essential proteins

(rather than presence of the parent co~mpouhd or free halide

per se) (Davis, et al. 1977).

     Human experience indicates that acute fatal intoxica-

tion can result from exposures to vapor levels as low as

1,164 to 1,552 mg/m , and harmful effects can occur at 388

mg/m  or more.  Systemic poisoning has been reported to

occur from two weeks' exposure (eight hrs/day) at about

136 mg/m3 (Natl. Acad. Sci., 1978, citing:  Kubota, 1955,

Johnstone, 1945, Bruhin, 1943, Wyers, 1945, Watrous, 1942,

Rathus and Landy, 1961, Miller, 1943, Tourangeau and Plamondon,

1945, Viner, 1945, Collins, 1965, Clarke, et al. 1945).

Symptoms generally increase in severity with increasing

levels of exposure and may vary somewhat according to exposure

circumstances and individual susceptibility.  In sublethal

poisoning cases a latency period of 2 to 48 hours (usually

about four to six) between exposure and onset of symptoms

is characteristic (Araki,  et al.  1971).

     Like the other monohalomethanes, bromomethane is a

CNS depressant and may invoke psychic, motor, and GI disturb-

ances.   (Mellerio, et al.  1973, 1974; Greenberg, 1971;  Longley

and Jones, 1965; Hine, 1969).   In light poisoning cases

effects may be limited to mild neurological and GI disturb-

ances,  with recovery in a few days.   Moderate cases involve

the CNS further, with more extensive neurological symptoms
and visual disturbances.  Recovery may be prolonged for
weeks or months, with persisting symptoms and/or disturb-
ed function.  Severe cases also involve a latent period
and similar initial symptoms, with development of disturbed
speech and gait, incoordination, tremors that "may develop
to convulsions, and psychic disturbances.  Recovery can
be quite protracted with persisting neurological disorders
(Araki, et al. 1971).  In fatal cases the convulsions may
become more intense and frequent, with unconscious periods.
Death may occur in a few hours from pulmonary edema or in
one to three days from circulatory failure.  Pathology often
includes hyperemia, edema, and inflammation in lungs and
brain.  Degenerative changes in kidney, liver, and/or stomach,
and perhaps the brain, occur although brain changes are
usually more functional in character (Natl. Acad. Sci.,
1978; Davis, et al. 1977).  Apparently blood bromide levels
of 100 mg/1 or less result in recovery, 135 in moderate
disability, 195 in residual ataxia, and 250 in convulsions
(Hine, 1969).
     Direct skin contact with bromomethane may produce prick-
ling, itching, cold sensation, erythema, vesication, blisters
(similar to second degree burn), and damage to peripheral
nerve tissue or delayed dermatitis (Davis, et al. 1977).
A case of brief skin exposure (spray) to liquid bromomethane,
quickly decontaminated, did not produce a burn, but resulted
in severe, delayed, neuromuscular disturbances (twitching,
fits, convulsions)  and permanent brain damage (cerebellum
and pyramidal tract) (Longley and Jones, 1965).  The OSHA

(1976) standard for bromomethane in workroom air is 78 mg/m
(celling) and carries a warning notation of possible signifi-
cant skin absorption (Natl. Inst. Occup. Safety Health,
1976b; Occup. Safety Health Admin., 1976).
     In animals bromomethane is highly toxic.  It is more
toxic by inhalation to several species than chloromethane
(Davis, et al. 1977).  Correspondence between effective
doses by inhalation vs, ingestion is difficult to assess
until more is known of GI absorption and first-pass detoxifi-
cation (Davis, et al. 1977).  In several species acute fatal
poisoning has involved marked CNS disturbances with a varie-
ty of manifestations:  ataxia, twitching, convulsions, coma,
as well as changes in lung, liver, heart, and kidney tissues
(Sayer, et al. 1930; Irish, et al. 1940; Gorbachev, et al.
1962; von Oettingen, 1964).  In subacute and protracted
exposure studies similar neurological disturbances developed
(Irish, et al. 1940; Sokolova, 1972) as in animal and human
(Drawneek, et al. 1964) acute toxicoses.  Inhalation toxicity
in animal species is briefly reviewed in Table 10.  In general
the monohalomethanes rank in decreasing order of acute toxi-
city as follows:  iodomethane, bromomethane, chloromethane,
fluoromethane (Davis, et al. 1977).
     Dogs receiving bromomethane chronically by ingestion
(fumigated diet yielding residual bromide at a dose level
of 150 mg/kg/day) were adversely affected, whereas if they
received sodium bromide at 78 mg/kg/day (residual bromide)
no effects were noted (Rosenblum, et al. 1960) .   In another
experiment using fumigated food with residual bromide Vitte,

                 TABLE 10

Bromomethane Inhalation Toxicity in Animals
o 1,940-2,328
L 2,293
> 1,536-1,940




15 mm
1 hr
20 min
30 mm
70 mm
30-40 mm
4.5 hrs
12 hrs
6 hr/daily
Not specified
5 hrs
13.5 hrs
22 hrs
3 hr
26 hr
9 hrs
18 hrs (2 exp.
at 3 mo
7-8 hrs daily
8 hr/day, 5
8 hr/day, 5
da/wk .
4-5 mos

40 mm
Lethal, cats
LCLo, rabbit
Delayed deaths (6 days) , guinea pigs
Delayed deaths (9 hr) , 1 of 6 guinea pigs
^IDO' 9umea pigs
Lethal, dogs
Lethal within 2 days, salivation, guinea pigs
Lethal, rabbits
Cumulative overt toxic ity, dogs & monkeys
LC5Q, mice
Delayed death, 1 of 6 guinea pigs
Lethal, all died within 3 days, guinea pigs
100% lethal in rats
Lethal, rabbits
Lethal, rats
Lethal to most in 1-3 days; guinea pigs
Altered conditioned reflexes, mice

Weight loss, prostration, convulsions; rats
At 22 days: typical poisoning, rabbits

Eventually lung irrit., paralysis, rabbits
(but not rats, guinea pigs, or monkeys)
Altered neuroendocrme controlled metabo-
lism, rabbits
Changes in motor responses
von Oettingen, 1964
NIOSH, 1976b
von Oettingen, 1964
von Oettingen, 1964
von Oettingen, 1964
von Oettingen, 1964
von Oettingen, 1964
Gorbachev, et al. 1962
Smith & von Oettingen, 1947a
Balander & Polyak, 1962
von Oettingen, 1964
von Oettingen, 1964
Irish, et al. 1940
von Oettingen, 1964
Irish, et al. 1940
von Oettingen, 1964
Sokolova, 1972

iri'sh, et al. 1940
Irish, et al. 1941

Irish, et al. 1941

Balander & Polyak, 1962

Balander & Polyak, 1962

et al.  (1970) detected changes in blood iodine and calcium
and pathologic changes in thyroid and parathyroid glands.
Toxic responses in rabbits administered bromomethane sub-
cutaneously  (in oil) at 20-120 mg/kg included limb paraly-
sis/ cessation of drinking, reduced urine excretion._ Levels
greater than 50 mg/kg sharply increased the blood bromide
level and reduced platelets, serotonin, and water content
(Kakizaki, 1967).
     Groups of cattle were fed oat hay from a bromomethane-
fumigated field or pelleted ration containing sodium bromide
added at various concentrations.  The hay contained bromide
ion at 6,800 to 8,400 mg/1.  Groups fed the hay and highest
dose-rate of bromide in pelleted ration developed signs
of CNS toxicity (motor incoordination)  at 10 to 12 days
of exposure.  Incoordination correlated with serum bromide
concentrations of 2,400 mg/1 (30 meq/1) or more.  Serum
bromide levels and neurologic signs were markedly reduced
two weeks after termination of exposure (Knight and Reina-
Guerra, 1977).
     No reports of bromomethane teratogenicity studies were
available, but high levels in eye and testes after ingestion
of fumigated food, and enzymatic and neuroendocrine distur-
bances, could have teratogenic implications.  Further stud-
ies in this area would appear to be warranted (Williford,
et al.  1974).
     Dichloromethane:  As with chloromethane, dichlorome-
thane has not generally been regarded as highly toxic,  but
poisonings, primarily from inhalation exposures, have been

reported.  Human minimal toxic concentrations or doses have
not been determined.  At this time the OSHA occupational
exposure standard  (air concentrations as a TWA for eight
hours) is 1,737 mg/m  with ceiling and peak values of 3,474
and 6,948 mg/m  , respectively (Occup. Safety Health Admin.,
1976).  However, NIOSH has recommended an "eigfit-hour TWA
concentration of 260 mg/m  with a peak limit of 1,737 mg/m
(Natl. Inst. Occup. Safety Health, 1976b).  A TCLo* (eight
hours) of 1,737 mg/m  for humans is reported (Natl. Inst.
Occup. Safety Health, 1976b), and exposures of 740 or 1,786
mg/m  for one hour were reported as being without adverse
effect by Stewart, et al. (1972a,b).  However,  Winneke (1974)
reported exposure  to 1,101 mg/m  or more for three to four
hours decreased psychomotor performance  (Natl.   Acad.  Sci.,
1978).  Dichloromethane affects central nervous system function.
It is also irritating to mucous membranes (eyes, respiratory
tract) and skin.   In addition, it results in production
of carbon monoxide  (CO) as a metabolite, which increases
carboxyhemoglobin  (COHb) in the blood and interferes with
oxygen transfer and transport (Natl. Acad. Sci., 1978).
     Mild poisonings by dichloromethane produce somnolence,
lassitude, anorexia, and mild lightheadedness,  followed
by rapid and complete recovery.   Severe cases are character-
ized by greater degrees of disturbed CNS function and depres-
sion.  Permanent disability has not been reported.  In fatal
poisonings cause of death has been reported as  cardiac injury
and heart failure  (Natl. Acad. Sci., 1978,  citing:  Hughes,

*Abbreviation used to denote lowest reported toxic concentration.


1954, Stewart and Hake, 1976, Collier, 1936, Moskowitz and
Shapiro, 1952).
     The formation of CO and COHb from dichloromethane forms
a basis for concern about combined exposures to dichloro-
methane and carbon monoxide.  Fodor and Roscovanu  (1976)
and NIOSH (1976a) recommend re-examination of dichlorome-
thane exposure standards with a view to reducing them.
These authors report that exposure at the current threshold
limit value (TLV) of dichloromethane produces COHb levels
equivalent to those produced by the TLV for CO.  Mixed expo-
sures could be a problem, especially in workers, smokers,
and cardiorespiratory patients or other susceptibles.  Con-
cern about mixed exposure to dichloromethane and other lipo-
philic solvents, with enhanced danger of marked CNS and
metabolic effects resulting from modest exposure to indivi-
dual materials,  has been expressed (Savolainen, et al. 1977).
     Gynecologic problems in female workers exposed for
long periods to gasoline and dichloromethane vapors were
reported by Vozovaya (1974) .  In pregnant women, chronic
exposure resulted in dichloromethane passing through the
placenta into the fetus.  Dichloromethane also was found
in milk of lactating women a few hours into a work shift.
Functional circulatory disorders in workers exposed for
more than three years to organochlorine compounds  (including
dichloromethane) at "permissible" levels have been reported
by Dunavskii (1972).  Symptoms included chest pain, electro-
cardiograph irregularities,  bradycardia, decreased myocar-
dial contractility,  and altered adaption to physical stress.

More recently it has been reported  (Stewart and Hake, 1976;

Scott, 1976) that fatal heart attacks have been caused by

exposure to dichloromethane in paint and varnish removers

(Natl. Acad. Sci., 1978).

     Animal toxicology of dichloromethane is briefly review-

ed in Table 11, with some human data included.  Both di-

and tri-halogenated methane derivatives have been found

to produce increased blood levels of COHb; the greatest

increase caused by iodo-, followed by bromo- and chloro-

compounds.  CNS functional disturbances are reported, includ-

ing depression of REM-sleep, as seen in carbon monoxide

exposures  (Fodor and Roscovanu, 1976).  Liver pathology

has been reported in experimental exposure to dichloromethane

vapors (Balmer, et al. 1976).  NAS  (1978) cites Haun, et

al. (1972) reporting liver changes in mice continuously

exposed to dichloromethane at 87 and 347 mg/m  for up to

two weeks.  As a liquid or vapor dichloromethane was ophthal-

motoxic in rabbit tests, producing persistent (up to two

weeks) conjunctivitis and blepharitis, corneal thickening,

keratitis and iritis, and increased intraocular tension

(Ballantyne, et al. 1976).  Inhalation exposures of rats

and mice to vapor levels of 4,342 mg/m  for seven hours

daily on gestation days 6 to 15 produced increased blood

levels of COHb and evidence of feto - or embryo-toxicity,

but not teratogenicity (Schwetz, et al. 1975; Natl. Inst.
Occup. Safety Health, 1976a, citing Heppel and Neal, 1944).

     At 1.737 mg/m  voluntary running activity was depresse

in rats.  Sleep alterations were noted in rats exposed to

                                                   TABLE Jl

                                          Toxicity  of  Dichloromethane
Exposure Con-
or Dose
6,460 mg/kg..
17,370 mg/m

3,000 mg/kg
2,700 mg/kg
2,136 mg/kg
1,900 mg/kg
1,500 mg/kg
4,342 mg/m
3,425 mg/ni
950 mg/kg .,
1,737 mg/nr
1,737 mg/ni
1,737 mg/nu
1,737 ing/in
200 mg/kg -.
87-347 mg/ni

2 hrs

I. P.
7 hr/day,
9 da
1 hr
I. P.
6 hr/day,
few days
year, in-
8 hrs
3 hrs
up to
2 wks.
LD50 , mouse
LCLo, guinea pig. Depressed
running activity, rats
LDLo , dog
LDLo, rabbit and dog
LD5Q, rat
LDLo, rabbit
LD5Q, mouse
Fetotox., teratogenicity, mice.
Transient lightheadedness, human
LDLo , dog
Altered brain metabolism,
behavior, rats
TCLo, CSN, human

TCLo, blood, human (12% COHb)
13% COHb, rats
LDLo , dog
Liver changes, mice

NIOSH, 1976b
NIOSH, 1976b
Heppel & Neal, 1944*
NIOSH, 197bb
NIOSH, 1976b
NIOSH, 1976b
NIOSH, 1976b
NIOSH, 1976b
Schwetz, et al. 1975

Stewart, et al. 1972a,b*
NIOSH, 1976b
Savolainen, et al. 1977
NIOSH, 1976b

NIOSH; 1976b
Fodor & Roscovanu, 1976
NIOSH f 1976b
Haun, et al. 1972

     Cited by NIOSH,  1976a

     hCited by NAS,  1978

dichloromethane at 3,474 mg/m  or more (Wolburg, 1973).

Depressed CNS excitability, along with increased blood levels

and expiratory/ hepatic/ and renal excretion of dichloro-

methane in subecute studies, was reported  (Avilova, et al.


     Tribromomethane:  Little information  is available concern-

ing the toxicology of tribromomethane.  It is regarded as

a highly toxic material, more toxic than dibromomethane

but less than tetrabromomethane and triiodomethane  (Natl.

Acad. Sci., 1978/ citing Dep. Health Edu. Welfare/  1975).

Minimum toxic concentrations have not been established,

but its general toxic potential is reflected in a quite

low occupational exposure standard (Occup. Safety Health

Admin., 1976):  eight-hour time-weighted-average air concentra-

tion, 5.2 mg/m  (the most stringent standard of the halome-

thanes considered herein).  It is absorbed by all major

routes (lungs, GI tract, skin) after appropriate exposure

(Natl. Acad. Sci., 1978).

     In humans, exposure to toxic levels of vapor produces

irritation of respiratory tract, pharynx, and larynx, with

lacrimation and salivation.  Most reported cases of poison-

ings have resulted from accidental overdoses administered

in the treatment of whooping cough.  Toxic symptoms appear

after a shorter latent period than that typical of other

halomethanes.  Obvious toxic effects in light cases may

be limited to headache, listlessness, and vertigo.  Uncon-

sciousness, loss of reflexes, and convulsions occur in severe

cases, and in fatal cases the primary cause of death is

respiratory failure,  Clinical recovery in moderate poison-

ings may be relatively rapid and without permanent damage

or disabiltiy.  Presence of tribromomethane in all organs

is indicated by pathologic findings, which also indicate

fatty degenerative and centralobular necrotic changes in

the liver (as in trichloro - and triiodomethane poisonings)

(Natl. Acad. Sci., 1978, citing von Oettingen, 1955).

     Animal data are generally consistent with those from

human case histories.  Impaired liver function (prolonged

pentobarbital sleeping time and/or BSP retention)  in mice

resulted from single subcutaneous doses of tribromomethane

ranging between 278 and 1,112 mg/kg.  These functional effects

correlated with pathological liver changes at the higher

dose levels (Kutob and Plaa, 1962).  Pathological changes

in liver and kidney have been reported (Dykan, 1962) in

guinea pigs after systemic administration of a level of

100 to 200 mg/kg per day for ten days (Natl. Acad. Sci.,

1978) .  Experimental data for animals are briefly summarized

in Table 12.  Reticuloendothelial system function (liver

and spleen phagocytic uptake of    I-Listeria monocytogenes)

was suppressed in mice exposed 90 days to tribromomethane

at daily dose levels of 125 mg/kg or less (Munson, et al.

1977, 1978).

     Bromodichloromethane:  No information on human intoxica-

tion by this compound was available and there have been

no occupational exposures reported by Sax (1968).  However,

he reported the compound as "dangerous" and "probably narco-

tic in high concentrations."


                                      TABLE 12

                            Bromoform  Toxicity  in Animals
or Dose
or Route
1,820 mg/kg

1,400 mg/kg

581 mg/kg
410 mg/kg

250 mg/m3
Subcut., single

Subacut., oil,
LD^g t mouse

LPcn/ mouse, ICR, 0;
fatty liver; kidney
palor; hemorrhage in
adrenals, lungs, brain

Median effective dose
for prolongation of
phenobarb. sleeping
time.  Approx.  thresh.
278 mg/kg.  Mouse.
Subacut., single  LDLo, rabbit
Inhal., 4 hrs
 daily, 2 mos.
100-200 mg/kg/da  Inject., daily,
                   10 days

0.3-125 mg/kg/da  Intragastric,
                   90 days
Disorders in liver
glycogenesis and pro-
thrombin synthesis;
reduced renal filtration
capacity.  Threshold:
50 mg/m .  Rat.

Liver and kidney
pathol., guinea pig

Suppressed liver
phagocytosis, mice
Kutob & Plaa, 1962

Bowman, et al.  1978 .
Kutob & Plaa, 1962
NIOSH, 1976b

NAS, 1977, citing
Dykan, 1962
                                            NAS, 1978, citing
                                            Dykan, 1962

                                            Munson, et al. 1978

     Bowman, et al. (1978)  have recently reported on acute
toxicity tests in mice.  Median lethal doses 1^50 for ICR
Swiss mice administered bromodichloromethane (solubilized
in emulphor: alcohol and saline mix) by gavage were 450
and 900 mg/kg for males and females, respectively.  J3ased
on comparative LDgg data among four trihalomethanes bromo-
dichloromethane was the most acutely toxic in both males
and females, and males were more susceptible than females
for all compounds.  Sedation and anesthesia occurred within
30 minutes at the 500 mg/kg dose level for bromodichloromethane,
and lasted for about four hours.  Animals that died in groups
dosed over a range of 500 to 4,000 mg/kg showed fatty infiltra-
tion in livers, pale kidneys, and hemorrhage in kidneys,
adrenals, lungs, and brain.
     In mice that were offered bromodichloromethane in drink-
ing water at 300 mg/1 (with and without use of emulphor),
water consumption and body-weight decreased dramatically
(Campbell, 1978).  Body weight regained parity with controls
in several weeks, but water consumption did not.  There
was no obvious effect on susceptibility to pathogenic Salmon-
ella typhimurium delivered by gavage after several weeks'
exposure.  However, Schuller, et al. (1978) have observed
a suppression of cellular and humoral immune response indices
in female ICR mice exposed by gavage for 90 days to bromodi-
chloromethane at 125 mg/kg daily.  Sanders, et al.  (1977)
observed hepatomegaly and a depression in a reticuloendothe-
lial system functional index (phagocytic) in mice exposed
to bromodichloromethane.  Munson, et al. (1977) reported

a dose-dependent suppression of hepatic phagocytosis in
mice exposed for 90 days  to daily doses of bromodichloro-
methane by gavage ranging  up to 125 mg/kg.
     Teratogenic properties of bromodichloromethane have
not been clearly demonstrated, but some fetal anomalies
were reported in experiments in which ~mice~ were" exposed
to vapors at 8,375 mg/m   seven hrs/day during gestation
days 6 to 15 (Schwetz, et  al. 1975).
     Trichlorofluoromethane  (F-ll) and dichlorodifluoro-
methane (F-12):  These propellant fluorocarbons are discussed
together because of their  physicochemical and general toxi-
cologic similarity.  They  may be regarded as the least toxic
of the halomethanes considered in this document.  Standards
for maximum average concentrations in air of work spaces
are established at 5,600 and 4,950 mg/m3 for F-ll and F-
12, respectively (Occup. Safety Health Admin., 1976).
For reference,  these may be compared to the following standards
for other halomethanes:

               tribromomethane               5 mg/m
               bromomethane                  80 mg/m
               chloromethane                 206 mg/m
               dichloromethane               1,737 mg/m

It has been recommended that these standards be reduced
to 260 mg/m .
     Because of their physical properties and use patterns
the primary route of exposure in toxicity studies has been
by inhalation of vapors at high concentrations, resulting
in rapid pulmonary absorption.  The two toxicologic features

of the fluorocarbons that have received the greatest atten-

tion are their cardiovascular and bronchopulmonary actions.

The toxicities of F-ll and F-12 are thought to be mediated

at least in part by metabolic products which bind to lipid

and protein cell constituents and affect vital processes

(e.g., retard cellular oxidation).  There ^remains a: "heed-

for more metabolic and toxicologic information on the con-

sequences of prolonged exposure to environmental levels

(U.S. EPA, 1976; Howard, et al. 1974).

     Human experience in fluorocarbon toxicity has largely

involved the intentional or unintentional misuse of fluoro-

carbon products, resulting in acute inhalation of high vapor

concentrations.  Numerous severe and fatal cases of abuse

are on record, such as from inhaling deeply from spray-filled

bags to achieve a "jag."  These probably involve cardiac

arrhythmia complicated by elevated circulating catecholamines

and C02 (Bass, 1970; Killen and Harris, 1972).  Similar

toxic consequences could occur in asthmatics using fluoro-

carbon-propellant bronchodilator products (Taylor and Harris,

1970; Archer, 1973).  Occupational-exposure data are limited.

Speizer, et al. (1975)  have reported a relationship between

cardiac palpitation episodes and level of use of F-12 and

F-22* propellants in hospital pathology department workers

(frozen-section preparation).

*F-22 is CHCIF2

     In brief experimental exposures of humans to F-12 at

        3     3
198 x 10  mg/m  vapor concentration in air, tingling sensation,

humming in the ears, apprehension, EEC and speech changes,

and deficits in psychological performance were reported.

In other tests exposures to F-12 at 49 x 103 to 543 x 103

mg/m  caused cardiac arrhythmia, decreased- consciousness,

and amnesia or deficits in performance on psychomotor tests

scores (Kehoe, 1943; Azar, et al. 1972).  However, in women

using fluorocarbon-propellant (F-ll, F-12, F-114*) aerosol

products and receiving nine or more times the exposure from

normal use, Marier, et al.  (1973) found no measurable blood

levels of the fluorocarbons or abnormalities in overall

health, respiratory, or hematologic parameters.

     Good, et al.  (1975) reported an excess of atypical

metaplastic cells  in sputum of frequent aerosol-product

users.  The authors suggested the possibility of some products

altering the resident bacterial flora of the respiratory

tract or containing tumorigenic constituents (not necessarily

the propellants).  Data from a survey of aerosol product

use and respiratory symptoms by Lebowitz (1976) led him

to suggest a "tendency for more symptoms to follow increased

aerosol usage, most consistently among non-smokers" (U.S.

EPA, 1976).  Human data on halothane** suggest potential

toxic hazards (liver, kidney,  and CNS changes;  risk of abor-

tion and developmental anomalies, increased susceptibiltiy

to cancer in females) from prolonged exposure at relatively

*F-114 is CC1F2-CC1F2

*Halothane is a gaseous anesthetic and chemical cousin,


low levels, with implications particularly for operating

room personnel.  Animal data on halothane are generally

supportive (U.S. EPA, 1976).  The primary human hazard from

F-ll inhalation (by whatever circumstance: intentional misuse

of aerosol products to achieve intoxication .or overuse of

propellant bronchodilators) is the "induction of cardiac

arrhythmias (Howard, et al. 1974).

     The inhalation toxicology of F-ll and F-12 in animals

is selectively summarized in Tables 13, 14, and 15.  Several

propellant substances have been classified according to

their cardiopulmonary toxicities in animal studies, as summar-

ized in Table 16.   Of all the aerosol propellants studied

and classified on the basis of cardiopulmonary effects,

Aviado (1975a) concluded that F-ll is the most toxic and

that the most serious effects are induction of cardiac arrhythmia

and sensitization to epinephrine-induced arrhythmias.  The

Underwriters Laboratories (1971)  classification system for

refrigerants is shown in Table 17.  In this system F-ll

and F-12 are in Toxicity Classes 5 and 6, respectively (the

lowest two of six classes).

                                                         TABLE 13

                                      Inhalation  Toxicology  of P-ll  (U.S.  EPA,  1976)
of Vapor, ,
(rag x 10J/m )
140; 280; 561

? 280




*9-P- denotes
LCcQ denotes
A Jf
Exposure, Duration
or Regimen

Brief (N.S.)
30 mm
5 nun
30 nun
20 mm
6 nun
5 mm
5 mm

4 hrs
20 mm or repeated daily

5 nun
5 mm
5 mm

5 mm
5 ram
3.4 hr/day 20 days
4 hrs

3.5 hr/day 20 days
4 hr/day x 10 days

5 mm
8 hr/day x 30 days
6 hr/day x 28 days

90 days
guinea pig
median lethal concentration

Rabbit, g.p.
Mouse (anesthetized)
Rat (anesthetized)
Rat (unanesthetized)

Rat (anesthetized)
Rat, rabbit, dog

Monkey (anesthetized)
Mouse, dog
Cardiomyopathic hamster

Monkey (anesthetized)
Cat, g.p., rat
Cardiomyopathic hamster


Rat, g p
Monkey and dog
Rat, mouse, g.p.,
Rat, g.p.


T C *
Letnal to some
Loss of reflex, anesthesia
A-V block
Cardiac arrythmias in all
Tachycardia, atrial fibrill., ventric.
extrasystoles in some (incid. related to' dose)
Bradycardia; also ectopic beats at 561 mg/m
Lethal to some
Biochemical changes indicative of slowed
cellular respiration.
Tachycardia, ventric. premature beats, A-V clock
SEIA** 3
Cardiac arrythmias (compared to 5bl x 10
mg/m in normal hamsters)
No signs of overt tox.', no mortality
High mortality and reduced lethal times
compared to normal hamsters
No signs of overt tox.', no mortality
Respiratory and neuromusc. signs of tox.,
(recovery after expos)'. Pathology in brain
liver, lungs; spleen changes
No significant signs of tox.
Influence on circulatory system
No significant signs of tox.

Lung, liver changes

SEIA denotes sensitization to epmephrme-mduced arrhythmia

                                                          TABLE 14

                                       Inhalation  Toxicology of F-12 (U.S.  EPA,  1976)
of Vapor. .
(mg x 10J/ 
2,638(F11/F12, 1:1)
1,582(F11/F12, 1:1)
o 1,160(F11/F12, 1:1)
J, 988

494, 988; 1,976
494; 988
Exposure, Duration
or Reg imen
30 nun
30 mm
1 hr
Brief (N.S.)
30 mm
30 mm
30 mm
5 nun
7-8 hr/day x 35-53 days

6 mm
5 nun
3.5 hr/day x 20 days
5 mm
5 mm
8 hr/day x 5 day/wk x 30 days
Continuous, 90 days
G.p. , rabbit, rat
Rat (anesthetized)
Dog , monkey

Mice (anesthetized)
Rat (unanesthetized)
Rat (anesthetized)
Rat (anesthetized)
Monkey (anesthetized)
Rat, g.p., cat, dog
Monkey (anesthetized)
Arrhythmia in h; no ch.
Letnal to some
Tremors disappear after
and depressed wt. gain
No arrhythmias

in heart rate

2 wks-tolerance

Tachycardia, no arrhythmias
No change in heart rate
Arrhythmias in, 10%
No mortal, and' no overt
No arrhythmias'
Liver changes
Liver changes
, or arrhythmias

signs of tox.

 LCj-Q denotes median lethal concentration

+G.p. denotes guinea pig
* *
  SEIA denotes sensitization to epmephrme-induced arrhythmia

                                   TABLE 15
                 Bronchopulmonary and Cardiovascular Effects
                   (other than arrhythmia)  of F-ll and  F-12
                 (U.S. EPA,  1976, data  from Aviado, 1975b,c)


\  i
Early respiratory

Bronchoconstr iction








 Approx. minimal concentration (10 mg/m ) producing response;
   0 indicates absent or opposite responses
 1, 2 or 3 pluses indicate  intensity of response

                                TABLE  16

     Classification of Fluorocarbon and Other Propellant Compounds
      on  the Basis  of  Cardiovascular and  Bronchopulmonary Toxicity
                  (U.S. EPA, data from Aviado, 1975b)
Class and Compounds

Low Pressure Propellants of
High Toxicity

CC17F (F-ll), CHC19F(F-21)
CC12F-CC1F2(F-113)7 CH2C12,
and trichloroethane.
Low Pressure Propellants of
Intermediate Toxicity

CC1F.,-CC1F:,(F-114) ,
CClF2-CH3(F-142b), isobutane
and octafluorocyclobutane
High Pressure Propellants
of Intermediate Toxicity

propane, and vinyl chloride
High Pressure Propellants
of Low Toxicity

F-115 and F-152b
Toxic" at"(J. 5-"5%  (v/v)  i'ri monkey
and dog, and 1-10%  in  rat and
mouse.  Induce cardiac arrhythmias;
sensitize heart  to  epinephrine-
induced arrhythmias; cause  tachy-
cardia, myocardial  depression,
hypotension.  Primarily cardio-
vascular effects.

Sensitize to epinephrine-arrhythmia
in the dog at 5-25%  (Cf. 0.5% or
less for Class I).  Do not  induce
arrhythmias in mouse (Class I do at
10-40%).  Affect circulation in
anesthetized dog and monkey at
10-20%  (Cf at 0.5-2.5% for Class I).
Cause bronchoconstriction in dog
(Class I compounds  do not), and,
except in this respect, are less
toxic than those in Class I.
Cardiovascular effects predominate.

Effective concentrations similar to
Class II for cardiosensitization and
circulatory effects, but respiratory
depression and broncho-effects pre-
dominate over cardiovascular effects
(in contrast to Classes I and II).

Extent of circulatory effects less
than those of Class III.  Do not
cause bronchoconstriction or early
respiratory depression.

                           TABLE 17

          Comparative Acute Toxicity Classification
                       of Refrigerants
                  (Underwriters Labs.,  1971)
   Toxicity  Concentration,     Exposure duration to
   class     percent  (v/v)      produce death or serious
                                injury in animals (hours)
      1        0.5 - 1          0.83  (5min.)
      2        0.5-1          0.5
      3        2-2.5          1
      4        2-2.5          2
      5        Intermed.        Intermed.
      6           20            No injury after 2 hrs
     Several animal studies provide evidence that pre-existing

cardiac or pulmonary lesions  (diseased state) may enhance

the toxicity (enhance toxic effect or reduce the level of

exposure required to produce effect) of fluorocarbons  (Taylor

and Drew, 1975; Doherty and Aviado, 1975; Watanabe and Aviaco,

1975).  Also, Wills (1972) demonstrated a dose related (in

range of 0.005 to 0.015 mg/kg) response to epinephrine (arrhy-

thmic heart beats) in subjects briefly exposed to F-ll at

49 x 10  mg/m  (0.87 percent by volume).  Thus, exposure

to the fluorocarbons (such as from use of propellant broncho-

dilators or misuse of other products), in combination with

use of cardioactive drugs or a stressful situation increasing

endogenous epinephrine levels, could be hazardous and present

a toxic risk greater than that from either factor alone

(U.S. EPA, 1976; Howard, et al.  1974).

     Pathologic liver changes were reported in guinea pigs
chronically exposed  (continuously for 90 days or eight hours
daily, five days weekly, for six weeks) to F-12 at levels
of about 4,000 mg/m  (0.08 percent by volume) (Prendergast,
et al. 1967).  In other chronic exposure experiments with
rats, guinea pigs, monkeys, and dogs exposed to F-ll at
5,610 mg/m3 for 90 days or at 57.5 x 103 mg/m3 for eight
hrs/day x five days/week x six weeks, pneumonitic changes
were noted in all test groups (except in dogs exposed intermit-
tently) , liver changes were noted in rats and guinea pigs,
and serum urea nitrogen was elevated in exposed dogs (Jenkins,
et al. 1970).  Several adverse changes were reported by
Karpov (1963) in various species exposed to F-22 (in same
class as and chemically similar to F-12) six hours daily
for ten months at 50.1 x 10  mg/m  (1.42 percent, v/v) ,
including:  reduced endurance in swimming test and increased
trials to establish conditioned reflex  (mice); decreased
oxygen consumption and increase in the stimulus strength
required to induce response (rats); several hematologic
and blood chemistry changes (rabbits) and degenerative patho-
anatomic changes in heart, liver, kidney, nervous system,
and lungs (Clayton, 1966).
     Applications of F-ll, F-12 and some mixed fluorocarbons
repeated twice daily over  several weeks to skin and oral
mucosa of rats have produced irritation, edema,  and inflam-
mation.  These effects were most marked in the F-ll/F-22
mixture and in older subjects.   The healing rate of burn
lesions was retarded by appliations of F-ll, F-12 and F-

22  (Quevauviller, et al.  1964; Quevauviller, 1965).  The
rapid evaporation of fluorocarbons applied directly to  integu-
mentary surfaces may result in chilling or freezing and
may be the principal hazard in acute dermal exposure to
the more volatile compounds.  Dermal absorption and jresult-
ing systemic toxicity are more important in the less volatile
     Information on oral  route toxicity is limited  (Howard,
et al. 1974) .  Acute intragastric doses of F-ll at 7,380
mg/kg were reported as not lethal or grossly hepatoxic in
rats  (Slater, 1965), but Clayton (1966) noted that F-ll
doses of 1,000 mg/kg (in peanut oil) were lethal in rats.
     In one chronic (90 day) feeding study of F-12 in rats
at 35 and 350 mg/kg/day Waritz (1971) reported somewhat
elevated urinary fluoride and plasma alkaline phosphatase
levels.  No changes in dogs at 10 and 100 mg/kg/day were
observed.  In a two-year study using rats intubated with
F-12 in corn oil at 15 and 150 mg/kg/day there was some
suppression of weight gain at the high dose level, but no
effects with respect to clinical signs, liver function,
hematology, or histopathology were noted.  In dogs given
eight and 80 mg/kg daily in treated dog food there were
no signs of toxicity, but some retention of F-12 (up to
1 mg/kg)  in fat and bone marrow was observed (Sherman, 1974).
Synergism and/or Antagonism
     Probably the most obvious concern in regard to this
aspect is the cardiac sensitization by fluorocarbons to
arrhythmogenic effects of circulating or administered catechol-

amines (e.g., epinephrine)  or asphyxia.  Stress situations
or certain drugs taken in conjunction with or as a component
of fluorocarbon propellant products may present an opportunity
for synergistic consequences (Howard, et al. 1974).
Teratogenicity                        ~   _  - .  -   
     There are no available data on the teratogenicity of
     Information on the mutagenicity of halomethanes is
very limited.  Recently,  however, three groups of investiga-
tors have reported positive results with certain alkyl nalides
in the Ames Salmonella typhimurium test system (Andrews,
et al. 1976; Jongen, et al. 1978; Simmon, et al.  1977) .
Because of the formal relationship between molecular events
involved in mutagenesis and carcinogenesis (Miller, 1978;
Weinstein, 1978), the demonstration of mutagenic activity
for a substance is often taken as presumptive evidence for
the existence of carcinogenic activity as well.  Therefore,
it is believed that an investigation of the mutagenicity
of xenobiotics may be predictive of carcinogenic potential
(but not necessarily potency),  and may serve as an early
warning of a possible threat to human health where positive
results are obtained.
     Simmon and coworkers (1977)  reported that chloromethane,
bromomethane, bromodichloromethane, bromoform,  and dichloro-
methane were all mutagenic  to Salmonella typhimurium strain
TA100 when assayed in a dessicator whose atmosphere contained
the test compound.  Metabolic activation was not required


for the expression of mutagenic effect, since the addition
of microsomes was not necessary.  In all cases, the number
of revertants per plate was directly dose-related.
     Interpretation of these data with regard to carcinogenic
risk, however, is complicated by several factors.  Data
were generally reported for only one Salmonella tester strain,
and the vapor-phase exposure is one which is not extensively
employed for mutagenesis testing.  The number of plates
assayed at each dose was not indicated, and the criteria
used for determination of a significant mutagenic response
were not specified. If the most stringent evaluation criteria
were applied  (in which the ratio of: experimental - control/control
must exceed 2.5), bromoform and bromodichloromethane would
not be considered positive in this study.
     Confirmation of mutagenicity for all the chemicals
examined by Simmon, et al. (1977) has not been reported
by other investigators, either in the Ames assay or with
other test systems.  However, Andrews and coworkers (1976)
have demonstrated that chloromethane was mutagenic to Salmon-
ella typhimunum strain TA1535 in the presence and absence
of added liver homogenate preparations.  Simmon, et al.
(1977) indicated that although dichloromethane was mutagenic
in the Ames assay, it did not increase mitotic recombination
in S_. cerevisiae D3.  In addition, it was reported that
dichloromethane was negative on testing for mutagenicity
in Drosophila (Filippova, et al. 1967).

     The positive results for dichloromethane in the Ames
assay were recently confirmed by Jongen, et al.  (1978).
Using Salmonella strains TA98 and TA100, which detect  frame-
shift mutations, dose-related increases in mutation rate
were obtained using vapor phase exposures (5,700 - 57,000
ppm).  The addition of a microsomal preparation was not
necessary for the production of mutations, although a  slight
enhancement in mutation rate could be obtained with rat
liver homogenate.  An explanation for why certain halometh-
anes are mutagenic in the Ames assay without the addition
of a metabolic activating system has not been proposed.
     Mutagenicity data on the fluorocarbons are scant.
Upon incubation of labeled F-ll (also CC14/  CHC13 and  halothane)
with liver microsomes and NADPH the label was found to be
bound irreversibly to endoplasmic protein and lipid but
was not detected in ribosomal RNA.  None of the compounds
was mutagenic in Salmonella tester strains TA1535 or 1538
with added liver microsomes (Uehleke, et al. 1977).  Sherman
(1974)  found  no increase in mutation rates over controls
in a rat feeding study of F-12.  Stephens, et al.  (1970)
reported significant mutagenic activity of F-12 at 2.47
x 10  mg/m  (50 percent) in air in a Neurospora crassa (a
mold)  test system.
     Further testing is obviously required to establish
the mutagneic potential of any or all of the halomethanes.
Many investigators agree that a compound should demonstrate
positive results in at least two different short-term assay
systems before it is accepted as a mutagen/carcinogen.
Nevertheless,  based on the presently available mutagenicity

data, it seems prudent  to  regard chloromethane, bromomethane,

bromoform, dichloromethane, and bromodichloromethane as

suspected mutagens/carcinogens pending the results of further


Carcinogenicity                                     _

     Among the halomethanes, only chloroform, carbon tetra-

chlonde, and lodomethane  are generally regarded to be car-

cinogenic in animals  (Natl. Acad. Sci., 1978).  Limited

new data, however, implicate several additional compounds

as potential tumorigens.   These data were developed using

the strain A mouse lung tumor assay system, a bioassay which

is known for its extremely high sensitivity to both strong

and weak carcinogens  (Shimkin and Stoner, 1975).  The inter-

pretation of lung tumor data in the strain A mouse is somewhat

unique in that certain  specific criteria should be met before

a compound is considered positive:

     (a)   A significant increase in the mean number of lung
          tumors in test animals, preferably to one or more
          per mouse,  should be obtained.

     (b)   A dose-response  relationship should be evident.

     (c)   The mean number  of lung tumors in control mice
          should be consistent with the anticipated incidence
          of spontaneous tumors for untreated strain A mice.

     Theiss and coworkers  (1977)  examined the biological

activity of bromoform, bromodichloromethane, and dichloro-

methane in strain A mice.  Male animals, six to eight weeks

old, were injected intraperitoneally up to three times weekly

over a period of eight weeks.  Three dose levels were em-

ployed with each test chemical, representing the maximum

tolerated dose and a 1:2 and 1:5 dilution of the maximum
tolerated dose.  Twenty animals were used at each dose level,
including negative (tricaprylin, saline) and positive  (urethan)
controls.  Mice were sacrificed 24 weeks after the first
injection and the frequency of lung tumors, i-n.each -.test
group was statistically compared with that in the vehicle-
treated controls using the Student t test.
     The results obtained by Theiss, et al. (1977) are summar-
ized in Table 18.  These data indicate that in no case were
all three criteria met, as indicated above, for the establish-
ment of a positive response.  Nevertheless, it is clear
that bromoform produced a significant increase in tumor
response at the intermediate dose.  In addition, dichloro-
methane at the low dose only, and bromodichloromethane at
the high dose only, produced results which were marginally
significant.  Overall, the results of this study are sugges-
tive of carcinogenic activity but do not in themselves provide
an adequate basis for the development of a quantitative
health risk assessment for humans.  Moreover,  it has been
stated with regard to the strain A mouse lung tumor system
that, "positive compounds require extension to other systems,
such as lifetime exposure of rats" (Shimkin and Stoner,
     Unfortunately, there are little additional data to
either confirm or deny the potential carcinogenicity of
most halomethanes.  Poirier and coworkers (1975) used the
strain A mouse lung tumor system to show that lodomethane
was tumorigenic.  They concluded that,  "a high proportion


                                                 TABLE  18

                          Pulmonary Tumor Response  to Organic Water Contaminants
                                           (Theiss,  et al.  1977)
Compound Vehicle
Tricaprylin Ta
Bromoform T

Bromodichloromethane T

Dichloromethane T

Urethan S
0.9% NaCl solution S



No. of i.p.

Total dose



No. of ani-
mals survi-
16/20 ,
20/20 *
No. of lung
0,27 + 0.15b
0.53 + 0.21
1.13 + 0.36
0.67 + 0.21
0.20 + 0.11
0.25 + 0.11
0.85 + 0.27

0.94 + 0.03
0.80 + 0.58
0.50 + 0.15
19.6 + 2.4
0.19 + 0.06



 Tricaprylin,  S,  0.9% NaCl solution
""Average  +  S.E.
'p   0.05

of low molecular weight alkyl halides may be carcinogenic."

Thus, pending bioassay results on chloromethane and bromo-

methane, it may be prudent to regard these two compounds

as suspected carcinogens, especially in light of their muta-

genic effects in the Ames assay.      -    -----  --

     The potential carcinogenicity of dichloromethane is

reportedly under study at the U.S. National Cancer Institute

(NCI) using rats and mice treated by gavage (Natl. Cancer

Inst., 1977).  Dichloromethane has also been chosen by NCI

for further testing by inhalation in mice and rats, and

a study of bioactivation and covalent binding to macromolecules

in mice, rats, and hamsters is planned (Natl. Cancer Inst.,

1977, 1978).

     Since the early 1960's a vast amount of work has been

conducted on the ability of various chemicals to induce

malignant transformation in cultured mammalian cells.  Several

of these ir\ vitro techniques have been adopted as convenient

screening methods for the detection of potential carcinogens.

Among the halomethanes, however, only dichloromethane has

been investigated for cell transformation activity.

     Price, et al. (1978) reported that Fischer rat embryo

cells (F1706) were transformed by dichloromethane at high

                        _*              4
concentrations (1.6 x 10 JM and 1.6 x 10  M)  in the growth

medium.   In addition, transformed cells produced fibrosar-

comas when injected subcutaneously into newborn rats.

     Further research by Sivak (1978) has indicated, however,

that the observed cell transforming capability of dichloro-

methane may have been due to impurities in the test material.


Sivak  (1978) reported  that  when  the experiments of Price,
et al.  (1978) were repeated using highly purified food grade
dichloromethane no transformation occurred.  Additional
studies were conducted by Sivak  (1978) in which food grade
dichloromethane was  tested  in the BALD/C-3.T3- mouse.cell
transformation assay system at three concentrations in the
growth medium.  Although transformed foci were observed
at all dose levels, a dose-response relationship was not
revealed, nor were the number of foci increased relative
to historical results with  untreated controls.  Difficulty
in the interpretation of these results, however, arises
from the fact that dichloromethane (boiling point, 40C)
was added to the growth medium and incubated at 37C for
72 hours.  Thus, the possibility exists that significant
losses of the test material due to volatilization from the
growth medium may have occurred.
     The degree to which carcinogenic impurities may have
accounted for the biological activity attributed to dichloro-
methane in in vitro test systems is not known.  This problem
may be particularly relevant to the halomethanes, since
high concentrations of test chemical must be employed for
expression of mutagenic/carcinogenic effects.  It has been
established that misleading results can be obtained with
the Ames assay due to trace level contamination by carcino-
genic impurities (Donahue,  et al. 1978), and a similar situ-
ation probably exists with  mammalian cell transformation
assays.  Sivak (1978) reported that impurities present in
food grade dichloromethane  included:  cyclohexane (305 ppm),

transdichloroethylene  (86 ppm), vinyldene chloride  (33 ppm),

methyl bromide  (11 ppm), chloroform  10 ppm), carbon tetra-

chloride  (<5 ppm) and ethyl cnloride  (3 ppm) .  Therefore,

the results of sensitive assays in which technical grade

material  is employed must be interpreted with the knowledge

that low  level contamination may contribute  to observed

biological effects.

     Carcinogenicity data on the fluorocarbons are scant.

No human or animal data on carcinogenicity from exposure

to F-ll or F-12 were available.  However, concern about

possible  increased risk of cancer resulting  indirectly from

the use of fluorocarbons has developed in recent years.

The possibility that increasing use and release of fluoro-

carbons to the atmosphere may contaminate the stratosphere

and cause depletion of protective, ultraviolet-absorptive
ozone has been recognized.  The following adverse effects

from increased penetration of UV radiation to the biosphere

are suspected:  (a) Increased incidence of skin cancer in

humans (estimated at 20 to 35 percent increase for 10 percent

ozone depletion);  (b)  altered animal cancer and disease

patterns; (c)  reduced growth and productivity of plants;

(d) climatic changes and ecologic shifts (U.S. EPA, 1976).

     A number of studies have sought to establish an associa-

tion between trihalomethane levels in municipal drinking

water supplies and the incidence of cancers in the U.S.

population (Natl. Acad. Sci., 1978).  Several of these epi-

demiologic studies have shown positive correlations between

certain cancer death rates (various sites)  and water quality

indices, including water source, chlorination, and trihalo-
methanes (Cantor and McCabe, 1977, citing Cantor, et al.
1978 and Salg, 1977).  Cantor, et al.  (1978) have also repor-ed
positive associations between cancer mortality rates (several
sites) and brominated trihalomethanes  (BTHM).  BTHM is compri-
sed mostly of bromodichloromethane and chforodibromomethane,
but measurable levels of tribromomethane have been found
in some water supplies.  The authors caution that these
studies have not been controlled for all confounding variables,
and the limited monitoring data that were available may
not have accurately reflected past exposures.  Thus the
need was recognized for further studies which will utilize
exposure and disease information from individuals, rather
than from population aggregates.  However, based upon the
epidemiologic evidence which is presently available, it
is felt that sufficient justification exists for maintaining
a hypothesis that observed positive correlations between
drinking water quality and cancer mortality may be attri-
butable to the presence of trihalomethanes  (U.S. EPA, 1978a).

                    CRITERION FORMULATION

Existing Guidelines and Standards


     1.  Warning label required by Federal_ Insecticide,

Fungicide and Rodenticide Act (FIFRA).  Interpretation with

respect to warning, caution, and antidote statements requirec

to appear on labels of economic poisons. 27 FR 2267.

     2.  Food tolerance requirement of Federal Food, Drug

and Cosmetic Act:  chloromethane is permitted as propellant

in pesticide fomulations up to 30 percent of finished formu-

lation when used in food storage/processing areas not con-

tacting fatty foods. 27 FR 4623.

     3.  Human exposure:  (1) A maximum permissible concen-

tration (MFC) of 5 mg/m  in industrial plant atmospheres

was established in Russia based on rat studies of chronic

poisoning (Evtushenko, 1966); (2) OSHA (1976) has established

the maximum acceptable time-weighted average air concent-

ration for daily eight-hour occupational exposure at 210

mg/m  with ceiling and peak (five minutes during (or in)

any three hours) concentration values of 413 and 620 mg/m ,


     4.  Other:  (1) Chlorinated hydrocarbons are under

consideration for addition to the list of compounds for

Toxic Effluent Standards (U.S. EPA Water Program Proposed

Toxic Pollutant Effluent Standards. 40 CFR Part 129.(2)

Listed on EPA Consent Decree Priority II list.

     5.  Multimedia Environmental Goals,  (MEG) Estimated
Permissible Concentrations  (EPC)  (U.S. EPA, 1977):

          EPC, air, health:                  0.5 mg/m
          EPC, water, health  (1):            7.5 mg/1
          EPC, water, health  (2):     -    -  -2.9-mg/i
          EPC, land, health:                 5.8 mg/kg
     1.  A warning and antidote labeling required by PIFRA.
Interpretation with respect to warning, caution, and antidote
statements required to appear on labels of economic poisons.
27 FR 2267.
     2.  Food tolerance limits required under Federal Food,
Drug and Cosmetic Act Tolerances for residues of inorganic
bromides resulting from fumigation with methyl bromide.
22 FR 5682 and subsequent regulations set inorganic bromide
residue concentration limits for many food commodities at
levels ranging from 20 to 400 mg/kg.
     3.  Human Exposure:   (1) Occupational exposure during
eight-hour work day limited to 78 mg/m  by the Texas State
Department of Health; also regulated are use periods for
respirators (Tex. State Dep. Health, 1957); (2)  OSHA (1976)
has established the eight-hour air concentration ceiling
for occupational exposure at 80 mg/m3, with an added warning
of skin exposure hazard; (3) The (American National Standards
Institute) has set a standard of 58 mg/m  time-weighted
average air concentration for an eight-hour day, with inter-
locking period ceilings of 97 mg/m , and 194 mg/m  (five
minutes)  (Am.  Natl. Stand. Inst., 1970); (4) The industrial

TLV (threshold limit value) of 78 mg/m  to prevent neurotoxic
and pulmonary effects was established by the American Con-
ference of Governmental Industrial Hygienist (Stokinger,
et al. 1963; Am. Conf. Gov. Ind. Hy., 1971).
     1.  As an oil and fat solvent, dichloromethane  is allow-
ed in spice oleoresins at up to 30 mg/kg and in decaffeinated
coffee at up to 10 mg/kg (21 CFR 121.1039, cited by  Natl.
Inst.  Occup. Safety Health, 1976a).
     2.  Human exposure:   (1)  OSHA (1976)  has established
occupational exposure standards as follows:  eight-hour
time weighted average (TWA), 1,737 mg/m ;  acceptable ceiling
concentration, 3,474 mg/m  ; and acceptable maximum peak
above ceiling, 6,948 mg/m  (five minutes in any three hours).
(2) However, in recognition of metabolic formation of COHb
and additive toxicity with CO, NIOSH (1976a) has recommended
a ten-hour workday TWA exposure limit of 75 ppm (261 mg/m )
in the presence of no more CO than 9.9 mg/m  TWA and a 1,737
mg/m  peak (15 min. sampling); in the case of higher CO
levels, lower levels of dichloromethane are required;  (3)
Permissible exposure levels in several other countries range
from 49 up to 1,737 mg/m   (maximum allowable concentration)
or 2,456 mg/m  (peak)  (discussed in Natl.  Inst. Occup. Safety
Health, 1976a);  (4)  The maximum permissable concentration
for dichloromethane in water in the U.S.S.R. is 7.5  mg/1;
this is intended to be proportionately reduced in the presence
of other limited compounds (Stofen, 1973).

     3.  MEG values  for Estimated Permissible Concentrations

 (U.S. EPA, 1977):

     EPC, air, health:                       0.619 mg/m3

     EPC, water, health  (1)                  9.18 mg/1

     EPC, water, health  (2)                  3.59 mg/1

     EPC, land,  health:                      7.2 mg/kg

Tr ibromomethane

     Human exposure:   (1) The OSHA Occupational Exposure

Standard for workroom air  (eight-hour TWA) is 5 mg/m  , with

a dermal absorption  warning notation  (Occup. Safety Health

Admin., 1976);  (2) Tribromomethane is one of four trihalo-

methanes comprising  the group "total trihalomethanes"  (TTHM)

for which the U.S.   EPA has proposed to regulate a maximum

contaminant level in drinking water  (0.100 mg/1).


     Human exposure:   (1) There is no currently established

occupational exposure standard for bromodichloromethane

in the U.S.  (2) Bromodichloromethane, along with chlorodibro-

momethane, trichloromethane (chloroform) and tribromomethane

form the group of halomethanes termed total trihalomethanes

 (TTHM), which are to be regulated in finished drinking water

in the U.S.  The maximum permissible concentration set for

TTHM in the proposed regulations is 0.100 mg/1.

Tnchlorofluoromethane and Dichlorodifluoromethane

     Food use:  FDA  regulations permit use of dichlorodifluoro-

methane (F-12) as a  direct contact freezing agent for food,

and specify labeling and instructions for use.  Food and

Drug Administration.  Dichlorodifluoromethane.  32 FR 6739.

     Human exposure:  (1) The current OSHA eight-hour TWA
occupational standards for F-ll and F-12 are 5,600 and 4,950
mg/m , respectively (Occup. Safety Health Admin., 1976).
(2) Underwriters Laboratories classify F-ll and F-12 in
groups 5 and 6, respectively (see Effects section).
     Other:  (1) F-ll, F-12, and several other fluorocarbons
have been exempted from regulation under the Texas Clean
Air Act (Howard, et al.  1974);  (2) The U.S. EPA can control
fluorocarbon uses in pesticide  applications and has requested
formulators to seek suitable alternative propellants for
products dispensed as aerosols, in view of the ozone deple-
tion concern; (3) Pressurized containers must meet ICC regula-
tions for compressed gases to be shipped (Howard, et al.
1974, citing DuPont, 1973).
     Standard for regulation of trihalomethanes:  The U.S.
EPA has considered the available health and exposure data
for trihalomethanes as a group, determined that they repre-
sent a potential yet reducible  hazard to public health,
and proposed regulations establishing a maximum contaminant
level (MCL) of 0.100 mg/1 for total trihalomethanes (TTHM)
in finished drinking water of cities greater than 75,000
(served population)  employing added disinfectants (U.S.
EPA, 1978a).A detailed discussion of the background (ration-
ale, extrapolation models, and  interpretations used)  for
this standard is beyond   the scope of this document.
Special Groups at Risk
     Perhaps the greatest concern for special risk consider-
ations among the halomethanes is that for dichloromethane.

In this case, the added  threat  is for those such as smokers

or workers in whom significant  COHb levels exist, or those

with pre-existing heart  disease, for whom COHb formation

by dichloromethane metabolism would present an added stress

or precipitate an episode  from  disturbed oxygen-tran-sport.

NIOSH, recognizing this  combined stress hazard, has recom-

mended lowering the existing TLV for dichloromethane and

tying it with existing CO  exposure levels.

     A second possible special  risk concerns exposures to

fluorocarbon vapors.  In this case there is evidence that

a characteristic toxicity  involves sensitization to cardio-

arrhythmogenic effects of  endogenous or administered epineph-

rine and related catecholamines.  An individual with cardiac

disease taking certain medication or in an acutely stressed

state may be especially  susceptible to fluorocarbon cardio-


Basis and Derivation of  Criterion

     Data on current levels of  the halomethanes in water,

food, and ambient air are  not sufficient to permit adequate

estimates of total human exposures from these media.  Available

data discussed in an earlier section of this report (Occurrence)

indicate that the greatest human exposure to the trihalo-

methanes occurs through  the consumption of liquids (including

drinking water and beverages containing it), and that exposure

to chlorofluorocarbons,  chloromethane,  dichloromethane,and

bromomethane occurs primarily by inhalation.

     Observed correlations among concentrations of trihalo-

methanes in finished water are  attributed to the presence

of common organic precursor materials in raw water  (Natl.
Acad. Sci., 1978).  Among the halomethanes considered in
this report, bromodichloromethane seems to predominate in
drinking waters.  Concentrations of bromodichloromethane
in raw and finished water samples are generally in  the area
of 6 iig/1 or less, and thus represent a reasonable  upper
limit for anticipated levels of any halomethane in  water
(excluding chloroform and carbon tetrachloride).
     Recent reports showing that chloromethane, bromomethane,
tribromomethane, dichloromethane, and bromodichloromethane
exhibit carcinogenic and/or mutagenic effects in certain
bioassay systems suggests the need for conservatism in the
development of water quality criteria for the protection
of human health.  Since the presently available carcinogen-
icity data base for these compounds is judged qualitatively
informative but quantitatively inadequate for risk  extrapol-
ation, an alternative approach is necessary for criteria
     At present levels in relatively unpolluted raw and
finished waters ( 10 jig/1) / the halomethanes pose little
threat for the production of non-carcinogenic toxic effects
in humans.  However, the possibility of carcinogenic effects
must be evaluated in light of current and past exposures
to halomethanes via water supplies.  Limited epidemiologic
studies have failed to show a clear association between
cancer mortality and bromine-containing trihalomethanes
at levels in water of about 5-10 ug/1.  Since the possible
association between human cancers and halomethanes cannot

presently be disproven,  it would be wise  to  limit their presence  in water

to no more than the median levels which are  currently encountered  (pendinq

better human risk data).  Thus,  a maximum level of 6 uq/J  in raw and  finished

waters could be considered as acceptable  for bromethane, chloromethane,

dichloromethane, tribromomethane, and bromodichloromethane.  From  the limited

animal bioassay data which are available  in  the strain A mouse lung tumor

system, a daily human  intake of  halomethanes at 12 ug/day  (6 ug/1  x 2 I/day)

represents a dose which  is about 100,000-fold less than the minimun daily

dose of tribromomethane  which caused a significant increase in tumor  formation

in mice if dose comparisons for  the two species are made on a per  kilogram

body weight basis.  Since there  exists considerable uncertainty over  the

human carcinogenic risks of halomethanes, a  safety factor of 100,000 seems

prudent for the development of an interim standard for all halomethanes

pending the results of further research.

     The 6 ug/1 maximum  acceptable  concentration for brontomethane, chloro-

methane, tribromomethane, dichloromethane, and bromodichloromethane does not

take into consideration  the contribution  to  total exposure from air and food.

Exposure via these media cannot  be  accurately predicted, although  it  is likely

that it is sufficient  large for  chloromethane, dichloromethane, and broroome-

thane to warrant the recommendation of a  water quality criterion below 6 ug/1.

Present levels of these  three compounds are  generally much less than  6 ua/1

and it is not likely that current anthropogenic sources would significantly

increase their level in water.

     For criteria-setting purposes it is recommended that
a criterion of 2 ug/1 be adopted for branomethane, chloro-
metbane, dichloromethane, tribromomethane, and bromodichloro-
methane, based upon analogy to the structure and biological
activity of chloroform.  Despite the presently inadequate
data base for most of these compounds, it can nevertheless
be predicted that similar biological effects, including
neoplastic transformation, may be encountered.  Since the
recommended criterion for chloroform was derived from reli -
able experimental data, it represents the most applicable
value for all of the halomethanes which are suspected carcino-
     Evidence for mutagenicity of dichlorodifluoromethane
is equivocal and there is no evidence as yet for carcino-
genicity as a result of direct exposure.  Chronic toxicity
data for dichlorodifluoromethane is quite limited.  In the
only long-term (two years) feeding study reported (U.S.
EPA, 1976, citing Sherman, 1974) the maximum dose level
producing no observed adverse effect (in dogs) was 80 mg/kg/day,
Applying an uncertainty factor of 1000 (Natl. Acad.  Sci.,
1977) to this data yields a presumptive "acceptable daily
intake" of 0.08 mg/kg/day.  For a man weighing 70 kg, consuming
two liters of water per day and absorbing at 100 percent
efficiency, and assuming that the water is the sole source
of exposure, this acceptable intake level translates into
a criterion level as follows:  (0.08) (70)/2 = 2.8 mg/1.

     There is no evidence  for mutagenicity of trichlorofluoro-

methane, and no evidence as yet for carcinogenic!ty as a

result of direct exposure.  The only data on toxicity testing

using prolonged exposure at relatively low test concentra-

tions is from a report  (Jenkins, et al.  1970) which showed

no observed adverse effects in rats and guinea pigs exposed

continuously by inhalation for 90 days at 5,610 mg/m .

If the reference man weighing 70 kg breathed this atmosphere

and absorbed the compound at 50 percent efficiency, h:s

estimated exposure dose would be 5,610 x 23 x 0.5 = 64,515

ing/day or 922 mg/kg/day.  Applying an uncertainty factor

of 1,000 (Natl. Acad. Sci., 1977) to this data yields a

presumptive "acceptable daily intake" of 0.922 mg/kg/day

for trichlorofluoromethane.  Assuming man's weight to be

70 kg and his absorption of ingested compound to be 100

percent efficient, and that his sole source of exposure

is water consumed at two  liters/day, the acceptable intake

is translated into a criterion level as follows:  (0.922)

(70)/2 = 32.3 mg/1.

     Criterion levels intended to protect the public against

unacceptable risk of toxicity, mutagenicity, or carcinogeni-

city from exposure to selected halomethanes in water for

consumption, derived as described in the foregoing text,

are summarized as follows  (rounded off):

           Compound                           (mg/1)
     Bromodichloromethane                     2 x 10
     Tribromomethane                          2 x 10
     Dichloromethane                  _        2 x _10~_
     Bromomethane                             2 x 10
     Chloromethane                            2 x 10~
     Dichlorodifluoromethane                  3
     Trichlorofluoromethane                   32
     Adoption of the presently recommended criterion ror
chloroform (2 fig/1) as the recommended level  for other pos
sibly carcinogenic halomethanes should provide an adequate
margin of safety in the absence of sufficient data foi quanti-
tative risk assessment.  This criterion is intended to reduce
carcinogenic risks to the public, and takes into account
the fact that exposure to halomethanes also occurs through
foods and via inhalation.  Although the potential carcinogen-
icity of bromodichloromethane, tribromomethane, dichloro-
methane, bromomethane, and chloromethane cannot be adequately
assessed at present, the adoption of an interim water quality
standard in excess of 2 /jg/1 may be interpreted as approval
to discharge larger quantities of these substances than
of chloroform.  Such a practice is clearly unwarranted until
such time that concerns over possible carcinogenic activity
have been resolved.

                          APPENDIX I

              Summary and Conclusions Regarding

             the Carcinogenicity of Halomethanes*

     The halomethanes addressed  in  this report afe-b~romomethane,

chloromethane, dichloromethane,  tribromomethane, bromodich]oro-

methane, dichlorodifluoromethane, and trichlorofluoromethare.

Chloroform, which is also a trihalomethane, is discussed

in another document.

     Positive associations between  cancer mortality rctes

in humans and trihalomethanes in drinking water  have teen

reported.  In addition to chloroform, these trihalomethanes

consisted primarily of bromodichloromethane, chlorodibromo-

methane, and also barely measurable levels of tribromomethane.

There have been positive results for tribromomethane using

strain A/St. male mice in the pulmonary adenoma  bioassay.

Bromomethane, chloromethane, dichloromethane, bromodichloro-

methane, and tribromomethane have been reported  as mutagenic

in the Ames1 test without metabolic activation.  Dichloroci-

fluoromethane caused a significant  increase in mutant frequency

in Neurospora crassa (mold), but was negative in the Ames'

test.  No data implicating trichlorofluoromethane as a possible

carcinogen have been published.

     Because positive results for the mutagenic  endpoint

correlate with positive results  in  ir\ vivo bioassay for

oncogenicity, mutagenic data for the halomethanes suggests

that several of the compounds might be carcinogenic.  Carcino-

genicity data currently available for the halomethanes are

not adequate for the development of water criteria levels.

We suggest that the criteria level be the same as that: for

chloroform (2 ug/1).
*This summary has been prepared and approved by the Carcinogens

 Assessment Group, EPA, June, 1979.


Ahmed, A.E., et al.  1977.  Metabolism of haloforms to carbon

monoxide, I. In vitro studies.  Drug Metab. Dispos.  5: 198.


Allen and Hanbury.  1971.  An investigation of possible

cardiotoxic 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 sub-

stances in workroom air.  Cincinnati, Ohio.

American National Standards Institute.  1970.  American

national standard for acceptable concentrations of methyl

bromide (monobromomethane).  ANSI Z37.24.

Andrews, A.W., et al.  1976.  A comparison of the mutagenic

properties 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.

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 propellants on
the respiratory 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 respiratory and circulatory systems.  X. Proposed classi-
fication.  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.  (Russian)
5: 92.   (Abstract.)

Azar, A., et al.  1972.  Experimental human exposures to
fluorocarbon 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

Baird, T.T.  1954.  Methyl chloride poisoning.  Br. Med.
Jour. 2: 1353.

Balander, P.A., and M.G. Polyak.  1962.  Toxicological charac-
terization of methyl bromide.  Gigiena i Toksikol. Novykh.
Pestitsidov i Klinika Otravlenii, Dokl. 2-oi  (Vtoroi) Vses.
Konf. 412.

Ballantyne, B., et al.  1976.  The ophthalmic toxicology
of dichloromethane.  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 lodomethane. Biochem.
J. 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.

Blake, D.A., and G.W. Mergner.  1974.  Inhalation studies

on the biotransformation and elimination of  {  C)-trichloro-

f luoromethane and (O-dichlorodifluarometh'ane'in-beagles.

Toxicol.  Appl. Pharmacol.  30: 396.

Boyland, E., et al.  1961.  Metabolism of polycyclic compounds.

18. The secretion of naphthalene l:2-dihydronaphthlene and

1:2 epoxy-1,2,3,4-tetrahydronapthalene in rat bile.  Biochem.

Jour. 78:376.

Bowman, F.G., et al.  1978.  The toxicity of some halometh-

anes in mice.  Toxicol. Appl. Pharmacol.  44: 213.

Bridbord, K., et al.  1974.  Exposure to halogenated hydro-

carbons in the indoor environment.  Presented at Conf.

Publ. Health Implications of Plastic Manufacturing, Pinehurst,


Browning, E.  1965.   Toxicity and metabolism of industrial

solvents.  Elsevier  Publishing Co., Amsterdam.

Bruhin, J.  1943.  Deutsches Gesund Gerichtles Medicine

37, A253.  Thesis.  Zurich, Switzerland.  (See von Oettingan,


Campbell, K.  1978.   Unpubl. data.


Cantor, K.P., and L.J. McCabe.  1977.  The epidemiologic

approach to the evaluation of organics in drinking water.

Proc. Conf. Water Chlorination: Environ. Impact and Health

Effects.  Gatlinburg, Tenn.  Oct. 31 - Nov. 4.

Cantor, K.P., et al.  1978.  Associations of halomethanes

in drinking water with cancer mortality.  Jour. Natl. Cancer

Inst.  (In press.)

Carlsson, A., and M. Hultengren.  1975.  Exposure to methy-

lene 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.  U.S. Natl.

Tech. Inf. Serv.

Carter, V.L. , et al.  1970b.  Effect of bromotnfluoromethane

on operant behavior in monkeys.  Toxicol. Appl. Pharmacol.

17: 307.

Chiou, W.L., and S. Niazi.  1973.  A simple and ultra-sensi-

tive 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.

Clark, D.G., and D.J. Tinston. 19|2a.  The influence of
fluorocarbon propellants on the alrrythmogenic activities
of adrenaline and isoprenaline.
Toxicity. 13: 212.
Proc. Eur. Soc. Study Drug
Clark, D.G., and D.J. Tinston. l
Cox, P.J., et al.  1972.  A comparison of the interactions

of tnchlorofluoromethane and carbon tetrachloride with

hepatic cytochrome P-450.  Biochem. Jour.  130: 87.

Cox, R.A., et al.  1976.  Photochemical oxidation of halocar-

bons in the troposphere.  Atmos. Envir-on. _ 1-01 305. 

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. Environ. Prot.

Agency, Research Triangle Park, N.C.

Davis, L.N., et al.  1977.  Investigation of selected poten-

tial environmental 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. Environ. Prot.

Agency, Washington, D.C.

Dennis, N.M., et al.  1972.  Formation of methyl chloride

during methyl bromide fumigations.  Jour. Econ. Entomol.

65: 1753.

Department of Health, Education, and Welfare.  1975.  Regis-

try of toxic effects of chemical substances.  Washington,


DiVincenzo, G.D., and M.L. Hamilton.  1975.  Fate and disposi-

tion of (  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 chemical warfare agents.  Nature  58: -43-2*-  ------

Doherty, R.E., and D.M. Aviado.  1975.  Toxicity of aerosol

propellants on the respiratory and circulatory  systems.

VI. Influence of cardiac and pulmonary vascular lesions

in the rat.  Toxicology  3: 213.

Donahue, E.V., et al. 1978. Detection of mutagenic impurit:es

in carcinogens and noncarcinogens by high-pressure liquid

chromatography and the Salmonella/Microsome test. Cancer

Res. 38: 431.

Drawneek, W. , et al.'1964. Industrial methylbromide poisoning

in fumagators. Lancet 2: 855.

Dunavskii, G.A.  1972.  Functional condition of circulatory

organs in workers employed in the production of organochlo-

rine compounds.  Gig. Tr. Prof. Zabol. (Russian)  16: 48.


DuPont de Nemours and Co.  1968.  Human skin absorption

studies with trichlorotrifluoroethane, F-113.  Med.  Res.

Proj.  Rep. No.  84-68.

DuPont de Nemours and Co.  1973.  Interstate Commerce Commis-
sion regulations and containers for freon fluorocarbons.
Bull.  D-75.

Dykan, V.A.  1962.  Changes in liver and kidney functions
due to methylene bromide and bromoform.  Nauchn;"Trtfdy U-kr
Nauchn.-Issled. Inst.  Gigieny Truda i Profzabolevanit 29: 82.

Eddy, C.W., and F.D. Griffith.  1961.  Metabolism of  -4C-
dichlorodifluoromethane by rats.  Presented at Am. Ind.
Hyg.  Assoc. Conf. Toronto, Can. May, 1971.

Evtushenko, G.Y.  1966.  Methyl chloride toxicology.  Gig.
Tr. Prof. Zabol.  10: 20.

Fassett.  1978.  In forum discussion, Session II, Toxicity
of halogenated solvents, aerosol propellants, and fire-extm-
guishants.  Proc. 3rd 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)  (German)   162: 34.

 Getzendaner, M.E.,  et  al.   1968.   Bromide  residues from
 methyl  bromide  fumigation  of  food  commodities.   Jour.
 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 neuroi^ndo-
 crine regulation and oxidation-reduction by certain commer -
 cial  poisons.   Plenuma Patofiziol  Sibiri i Dal'n.  Vos'..
 Sb. 88.

 Greenberg, J.O.  1971.  The  neurological  effects  of  methyl
 bromide poisoning.  Ind. Med.  and Surg.  40:  27.

 Grimsrud, E.P.,  and R.A. Rasmussen.   1975.   Survey and  analy-
 sis of  halocarbons  in  the  atmosphere  by gas chromatography-
 mass  spectrometry.   Atmos.  Environ.   9: 1014.

 Hansen, H.,  et  al.   1953.   Methyl  chloride intoxifica :ion:
 Report  of 15 cases.  AMA Arch.  Ind. Hyg. Occup.  Med.  8:

 Harsch, D.   1977.   Study of halocarbon  concentrations in
'indoor  environments.   Final rep. EPA  Contract No.  WA 5-99-
 2922-J.   U.S. Environ.  Prot.  Agency,  Washington, D.C.

Harsch, D., and R.A. Rasmussen.  1977.  Identification of
methyl bromide in urban  air.  EPA Contract No. WA 6-99-2922-
J.  Off. Res. Dev., U.S. Environ. Prot. Agency, Washing-
ton, D.C.  (unpubl. rep.)

Haun, C.,  et al.  1972.  Continuous animal exposure _to low
levels of  dichloromethane. Proc. 3rd Annu.  Conf. Environ.
Toxicol.   AMRL-TR-130: 12.  Aerospace Med.  Res. Lab., Wrijht
Patterson  Air Force Base, Ohio.

Health and Welfare Canada. 1977. Environmental Health Direct-
orate national survey of halomethane in drinking watec.

Heppel, L.A., and P.A. Neal.  1944.  Toxicology of dichloro-
methane (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
basin.  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. Environ. Prot. Agency,
Washington, D.C.

Hughes, J.P.  1954.  Hazardous exposure to some so-called

safe solvents.  Jour. Am. Med. Assoc.  156: 234.

International Agency for Research on Cancer.  1978.  Informa-

tion bulletin on the survey of chemicals being tested for

carcinogenicity, No. 7.  World Health Organ., Lyon, France

Irish, D.D. , et al.  1940.  The response attending exjosuri*

of laboratory animals to vapors of methyl bromide.  Jour.

Ind. Hyg. Toxicol.  22: 218.

Irish, D.D,, et al.  1941.  Chemical changes of methyl bro-

mide 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 expo-

sure of laboratory animals to trichlorofluoromethane.  Tox .-

col.  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 dichloro-

methane on Salmonella typhimurmm. 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.)

Kehoe, R.A.   1943.  Unpublished report.  (Cited in Azar,

et al. 1972.)

Killen, S.M., and W.S. Harris.  1972.  Direct depression

of myocardial contracility by the aerosol propellant qas,

dichlorodifluoromethane.  Jour. Pharm. Exp. Ther.   183:  245.

Kleopfer, R.D. 1976. Analysis of drinking water for organic

compounds. Identification and analysis of organic  pollutan-s

in water. Ann Arbor Science, Ann Arbor, Mich.

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 CC13F 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 estima-

ting 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.        "    ---------

Lehmann, K.B., and I. Schmidt-Kehl.  1936.  The thirteen

most important chlorinated aliphatic hydrocarbons from the

standpoint of industrial hygiene.  Arch. Hyg.  116: 121.

Lewis, S.E.  1948.  Inhibition of SH enzymes by methyl bro-

mide.  Nature  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

compounds.  Environ. Sci. Technol.  9: 1042.

Longley, E.O., and A.T.  Jones.  1965.  Methyl bromide poison-

ing 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 CC13E com en

trations in rural southern England and southern Ireland.

Atmos.  Environ.  6: 91"7.

Lovelock, J.E.  1974.  Atmospheric halocarbons and strato-

spheric ozone.  Nature  252: 292.     _    _._.__._

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.

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 follow-

ing exposures 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 environment.  Endeavour 34: 13.

Mellerio, F., et al. 1973.  Electroencephalography and accte

methyl bromide poisoning. Electroencephalogr.  Clin.  Neurcphy-

siol. 34: 732.

Mellerio, F.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 pesti-

cides in a model ecosystem.  Univ.  Illinois Water Resour.

Center, UILU-WRC-0069.   PB 225479,  Natl. Tech. Inf. Serv.,

Springfield, Va.

Miller, D.P., and H.W.  Haggard.   1943.  Intracellular penetra-

tion of bromide as feature in toxicity of alkyl bromides.

Jour.  Ind. Hyg. Toxicol.  25: 423.                 i

Miller, E.G.  1978.  Some current perspectives on chemical

carcinogenesis in humans and experimental animals: presiden-

tial address.  Cancer Res.  38:  1479.

Miller, J.W.  1943.  Fatal methyl bromide poisoning.   Arch.

Pathol.  36: 505.

Mizyokova, I.G., and G.N. Bakhishev.  1971. Specific treatment

of acute methylbromide  poisoning. Vrach. Delo.  7: 128.

Monro, H.A.U., et al. 1955.  Methyl bromide concentrations
in ship and railway car fumigation of peanuts.  Entomol.
Soc. Ontario, Annu. Rep. 86: 65.

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 in-
haled fluorinated hydrocarbon vapors.  Int. Jour. Appl.
Radiat.  Isotop.  23: 285.

Morgan, A.J.  1942.  Methyl chloride intoxication.  0. Jour.
Med.  41: 29.

Morris, J.C., and G. McKay.  1975.  Formation of halogenated
organics by chlorination of water supplies.  EPA 600/l-"5-
002. PB 241-511.  Natl. Tech. Inf. Serv., Springfield, Va.

Moskowitz, S. , and H. Shapiro.   1952.  Fatal exposure t~>
methylene chloride vapor.  Arch. Ind. Hyg. Occup.  Med.
6: 116.

Munson, A.E., et al. .1977.  Functional activity of the
reticuloendothelial system in mice exposed to haloalkanes
for ninety days.  Abstract.  14th Natl.  ReticuloendotheLi~l
Soc. Meet. Tucson, Ariz.  Dec.  6-9.
                              /_ ;

Munson, A.E., et al.  1978.  Reticuloendothelial system

function in mice exposed to four haloalkanes: Drinking water

contaminants.  Submitted: Soc. Toxicol.  (Abstract.)

National Academy of Sciences.  1977.  .Drinking water_and

health.  Washington, D.C.

National Academy of Sciences.  1978.  Nonfluormated halo-

methanes in the environment.  Washington, D.C.

National Cancer Institute.  1977.  Chemicals being tested

for carcinogenicity by the bioassay program.  Rep. Tech.

Inf. Resour. Branch, Natl. Cancer Inst., U.S. Dep. Health,

Edu. and Welfare, Bethesda, Md.

National Cancer Institute. 1978. Personal communication.

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,


National Library of Medicine.  1978b.  Toxicity of halometh-
anes.  Off-line bibliographic citation list generated by
Medlars II, Toxline before 1975 and 1975-1978.

Occupational Safety and Health Administration.  1976.  Gen-
eral industry standards. OSHA 2206, revised .January,- 1976.
U.S. Dep. Labor, Washington, B.C.

Ohta, T., et al.  1976.  Local distribution of chlorinated
hydrocarbons 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 chlo-
rine.  Nature  263: 44.

Patty, F.A. 1958. Industrial hygiene and toxicology.  2nd
ed. Vol. I. Toxicology. Interscience Publishers, John Wiley
and Sons, Inc., New York. (Cited in Natl. Acad. Sci., 1978).

Patty, F.A.  1963.  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  metabo-
lism 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. Aeronautical Space

Admin., Washington, D.C.

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

nucleoxide base analogs by pulmonary tumor response in Strain

A mice. Cancer Res. 35: 1411.

Prendergast, J.A., et al.  1967.  Effects on expenmeatal

animals of long-term inhalation of trichloroethylene, carbon

tetrachloride, 1,1,1-trichloroethane, dichlorodifluoromethane,

and 1,1-dichloroethylene.  Toxicol. Appl. Pharmacol.   10: 27C.

Price, P.J., et al. 1978. Transforming activities of  tnchlor-

oethylene and proposed Ind. alternatives. In Vitro 14: 290.

Quevauviller, A.  1965.  Hygiene et securite des pulseurs

pour aerosols medicamenteaux.  Prod, Probl. Pharm.  20: 14.

Quevauviller, A., et al.  1964.  Local tolerance in animals

to chlorofluorinated hydrocarbons.  Therapie  19: 247.

Rathus, E.M., and P.J. Landy.  1961.  Methyl bromide poison-

ing.  Br. Jour. Ind. Med.  18: 53.

Redford-Ellis, Mo, and A.H. Gowenlock. 1971a.  Reaction

of chloromethane with human blood.  Acta Pharmacol. ToxicoL.

30: 36.

Redford-Ellis, M., and A.H. Gowenlock. 1971b.  Reaction

of chloromethane 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.  Jour. Dairy Sci.  26: 205.

Rosenblum, I., et al.  I960.  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.  U.S. EPA
Contract No. PO-5-03-4528-J.  Ph.D. thesis. University of
North Carolina.

Sanders, V.M.,  et al.  1977.  Functional activity of the-  -
reticuloendothelial system  (RES) in mice exposed to the
halomethanes, drinking water contaminants.  Submitted: Va.
Jour. Sci.   (Abstract.)

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 mater-
ials.  3rd ed.   Reinhold Book Corp., New York.

Sayer, R.R., et al. 1930.  Toxicity of dichlorodiflourometh-
ane.  U.S. Bur. Mines Rep. R.I. 3013.

Schuller, G.B., et al.  1978.  Effect of four haloalkanes
on humoral and cell mediated immunity in mice.  Presented
Soc. Toxicol. Meet.

Schwetz, B.A.,  et al.  1975.  The effect of maternally in-
haled trichloroethylene, perchloroethylene, methyl chloroform,
and methylene chloride on embryonal and fetal development
in mice and rats.  Toxicol. Appl. Pharmacol.  32: 84.

Scott, R.  1976.  Household product safety.  The Washington

Scudamore, K.A., and S.G. Heuser.  1970.  Residual free
methyl bromide 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.

Shackelford, W.M., and L.H. Keith. 1976. Frequency of organic
compounds identified in water. EPA-600/4-76-062. Environ.
Res. Lab.  U.S. Environ. Prot. Agency, Athens, Ga.

Shargel, L., and R. Koss.  1972.  Determination of fluori-
nated hydrocarbon propellants in blood of dogs after aerosol
administration.  Jour. Pharmacol. Sci.  61: 1445.

Sherman, H.  1974.  Long-term feeding studies in rats and
dogs with dichlorodifluoromethane (Freon 12 Food Freezant).
Unpubl. rep. Haskell Lab.

Shimkin, M.B., and G.D. Stoner.  1975.  Lung tumors in mice:
application to carcinogenesis bioassay.  Adv. Cancer Res.
21: 1.

Sidwell, V.D., et al. 1974.  Composition of the edible portion

of raw  (fresh or frozen) crustaceans, finfish, and mollusks.

I.  Protein, fat, moisture, ash, carbohydrate, energy value,

and cholesterol.  Mar. Fisheries Revies 36: 21.

Simmon, V.F. et al. 1977.  Mutagenic activity of chemicals

identified in drinking water.  S. Scott, et al. , eds. ^n_

Progress in genetic toxicology.

Simmonds, P.G., et al.  1974.  Distribution of atmospheric

halocarbons in the air over the Los Angeles basin.  Atmos.

Environ.  8: 209.

Singh, H.B., et al.  1977.  Urban-non-urban relationships

of halocarbons, SFg, N20 and other atmospheric constituents.

Atmos. Environ.  11: 819.

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. 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. 1947c.  The acute and

chronic toxicity of methyl chloride. II. Symptomatology

of animals poisoned by methyl chloride, Jour. Ind. Hyg.

Toxicol.  29: 123.

Sokolova, I.P.  1972.  Hygienic standardization of some

funugants in the air of ship chambers after gas treatment.

Tr. Nauch. Konf., Nauch.-Issled. Inst.  Gig. Vod. Transp.

2: 160.

Speizer, F.E., et al.  1975.  Palpitation rates associated

with fluorocarbon exposure in a hospital setting.  New Eng-

land Jour. Med.  292: 624.

Spevac, L., et al.  1976.  Methyl chloride poisoning in

four members of a family.  Br. Jour. Ind. Med.  33:  272.

Stecher, P.G., et al.  1968.  The Merck Index.  8th ed.

Merck and Co., Inc., Rahway, N.J.

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 methylene 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 drinking 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.

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 atmosphere.  Nature  245: 27.

Su, C., and E. Goldberg.  1976.  Environmental concentrations

and fluxes of some halocarbons.  Iin H.L. Windom and R.A.

Duce, eds.  Marine pollutant transfer.  Lexington Books,

D.C. Heath and Co., Lexington, Mass.

Symons, J.M., et al.  1975.  National organics reconnaissance

survey for halogenated organics.  Jour. Am. Water Works

Assoc.  67:  634.

Taylor, G.J., and R.T. Drew.  1975.  Cardiomyopathy predis-

poses hamsters 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., Texas.

Theiss, J.C., et al.  1977.  Test for carcinogenicity of

organic contaminants of United States drinking waters by

pulmonary tumor response in strain A mice.  Cancer Res.

37: 2717.

Tourangeau,  F.J., and S.R. Plamondon.  1945.  Cases of expo-

sure to methyl bromide vapours.  Can. Jour. Publ. Health

36: 362.

Uehleke, H., and T. Warner.  1975.  A comparative study

of the irreversible binding of labeled halothane, trichloro-

fluoromethane, chloroform, and carbon tetrachloride to hep-

atic protein and lipids ^n vitro and in vivo.   Arch. Toxicol.

34: 289.

Uehleke, H., et al.  1977.  Metabolic activation of haloal-

kanes and tests in vitro for mutagenicity.  Xenobiotica

7: 393.

Underwriters Laboratories.  1971.  Comparative hazards of

modern refrigerants.  Data card No. UL5 and UL5-A."

U.S. EPA. 1975.  Preliminary assessment of suspected carcino-

gens in drinking water, and appendices.  A report to Congress,

Washington, D.C.

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 environ-

mental assessment.  Ifreragency energy-environment research

and development program report.  EPA 600/7-77-136a,b.  Environ.

Res. Lab., Research Triangle Park, N.C.

U.S. EPA. 1978a.  Statement of basis and purp'ose for an

amendment to the national interim primary drinking water

regulations on trihalomethanes, January, 1978.  Off. Water

Supply, Washington, D.C.

U.S. EPA. 1978b.  The National Organic Monitoring Survey.

Rep. (unpubl.). Tech. Support Div., Off. Water Supply, Wash-

ington, D.C.


Van Stee, E.W., and K.C. Back.  1971.  Brain and heart accumu-

lation of bromotrifluoronethane.  Rep. AD 721211.  Natl.

Tech.  Inf. Serv., Springfield, Va.

Veith, G.D., et al. An evaluation of using partition coefficients

and water solubility to estimate bioconcentration factors

for organic chemicals in fish.  (Manuscript)..

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. Pestits. Klin. Otravlenii  8: 386.

von Oettingen, W.F.  1955.  The halogenated hydrocarbons:

Toxicity and potential dangers.  No. 414.  U.S. Publ. Health

Serv., Washington, D.C.

von Oettingen, W.F.  1964.  The halogenated hydrocarbons

of industrial and toxicological importance.  Elsevier Publ.

Co., Amsterdam.

von Oettingen, W.F., et al.  1949.  Relation between the

toxic action 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 toxicity and pharmacodynamic action of chlorinated

methanes with special reference to their physical and chemi-

cal characteristics.  Arch. Int. Pharmacodyn. Ther.   81: 17.

                              c_j oa

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.  (Russian) 56.  (Abstract.)

Waritz, R.S.  1971.  Toxicology of some commercial"fluoro-

carbons.  Rep. AD 751429.  Natl. Tech. Inf. Serv.  Spring-

field, Va.

Watanabe, T., and D.M. Aviado.  1975.  Toxicity of aerosol
propellants 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.

Wilkness, P.E., et al.  1975.  Trichlorofluoromethane in

the troposphere, 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 catechol-

amine-induced arrhythmia.  Proc. 3rd Ann. Conf. Environ.

Toxicol.  AD Rep. No. 773766.  U.S. Natl. Tech. Inf. Serv.

Winneke, G.  1974.  Behavioral effects of methylene chloride

and carbon monoxide as assessed by sensory and psychomotor

performance.  Ln Behavioral toxicology - Early detection

of occupational hazards.  Publ. No. (NIOSH) 74-126.  U.S.

Dep. Health Edu. Welfare.

Wolburg, I.  1973.  The use of electroencephalography in

industrial toxicology.  Activ. Nerv. Super. (German)  15: 226,


Wyers, H.  1945.  Methyl bromide intoxication.  Br. Jour.

Ind. Med.  2: 24.
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